Parkinson's Disease: Challenges, Progress, and Promise by amazmazin

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									Parkinson’s Disease:




  Challenges, Progress,
     and Promise


                          NOVEMBER 2004

                          National Institute of
                          Neurological Disorders
                          and Stroke

                          National Institutes of Health
Contents
                                                                                                                                            Margaret,                                          Joel,
                                                                                                                                                   a woman in her thirties,...                       a retired university professor,...
                                                                                                                                            ...began to experience tremors and stiffness       ...went for regular walks with his wife. Ten years
                                                                                                                                            of her left arm while she walked. When these       ago, his wife began to notice that he was
       Introduction __________________________________________________________________________________________________________ 2            symptoms continued, she saw several                shuffling his feet and was not swinging his arms
                                                                                                                                            neurologists to determine what was going on.       as most people do while walking. She also
                                                                                                                                            Because she was young, the doctors initially       noticed some changes in his posture and
                                                                                                                                            thought she might have a brain tumor or            unusual movements of his left arm. Joel’s
   1
       Brain and Movement: The Basics____________________________________________________________________ 5                                 multiple sclerosis. However, after a brain         primary doctor referred him to a neurologist,
                                                                                                                                            scan and neurological examinations, she was        who told him he had Parkinson’s disease and
                                                                                                                                            diagnosed with Parkinson’s disease.                prescribed a combination of drugs to treat the
                                                                                                                                                                                               symptoms. He later saw a movement disorder
   2                                                                                                                                        Margaret did not take any medications for the
       What Goes Wrong In Parkinson’s Disease?___________________________________________________ 6                                         disease until several years after her diagnosis.
                                                                                                                                                                                               specialist as well.

                                                                                                                                            She then began medication that reduced her         Joel’s symptoms have gradually grown worse
                                                                                                                                            symptoms but did not stop the disease from         with time. He now has tremors and rigidity
   3                                                                                                                                        getting worse. She eventually developed            of movements on both sides of his body, and
       How Can We Treat Parkinson’s Disease? _______________________________________________________ 8                                      involuntary movements called dyskinesias,          balance problems when his medication wears off.
                                                                                                                                            which are a common side effect of levodopa,        The disease also makes it difficult to project his
       Drug Treatments ___________________________________________________________________________________________________________ 8
                                                                                                                                            the most common Parkinson’s drug. Because          voice. He takes a combination of drugs that
                                                                                                                                            of this, she decided to undergo a new therapy      help him to walk and to perform daily tasks.
       Surgical Treatments________________________________________________________________________________________________________ 8
                                                                                                                                            called deep brain stimulation (DBS), which         However, he can no longer work in the
       Complementary and Supportive Therapies________________________________________________________________________ 10                    provides electrical stimulation to the brain       woodworking shop he had developed as a
                                                                                                                                            through surgically implanted wires. The DBS        retirement hobby. His loss of mobility and
                                                                                                                                            immediately reduced the amount of levodopa         speech impairment limit his social interactions.
                                                                                                                                            Margaret needed to take, which stopped the         He and his wife also have had to give up many
   4                                                                                                                                        dyskinesias. The stimulation has since been        of their retirement travel plans.
       Research Findings and New Directions ________________________________________________________ 11
                                                                                                                                            adjusted externally many times in order
       Genetics ______________________________________________________________________________________________________________________ 11   to improve control of her symptoms. While
                                                                                                                                            Margaret still takes medication, she needs
       Environmental Factors ___________________________________________________________________________________________________ 18         fewer pills than before the DBS.

                                                                                                                                            Now, almost 25 years after her diagnosis,
       Pathways to Parkinson’s Disease ______________________________________________________________________________________ 20                                                               Joel and Margaret are two of the many people in the
                                                                                                                                            Margaret is able to function very well in the
                                                                                                                                                                                               United States who are living with Parkinson’s disease
                                                                                                                                            morning and early afternoon. Late in the day,
       Models for Parkinson’s Disease ________________________________________________________________________________________ 26                                                              (PD), a complex disorder of the central nervous system.
                                                                                                                                            however, problems with balance, speech, and
                                                                                                                                                                                               PD is the second most common neurodegenerative
                                                                                                                                            fatigue return. She manages by planning her
       Therapeutic Approaches ________________________________________________________________________________________________ 29                                                              disease in the United States, after Alzheimer’s disease.
                                                                                                                                            activities carefully, avoiding many commitments
                                                                                                                                                                                               The defining characteristics of PD include tremor,
                                                                                                                                            during the late afternoon and evening, and
       Other Clinical Research __________________________________________________________________________________________________ 36                                                           slowness of movement (bradykinesia), rigidity, and
                                                                                                                                            increasing her medication when necessary.
                                                                                                                                                                                               impaired balance and coordination. As these symptoms
                                                                                                                                                                                               become more pronounced, patients may have difficulty
                                                                                                                                                                                               walking, talking, or completing simple tasks. They
       Conclusion____________________________________________________________________________________________________________ 39                                                               also may experience depression, difficulty sleeping,
                                                                                                                                                                                               and other problems.




                                                                                                                                                                                                              Parkinson’s Disease: Challenges, Progress, and Promise   1
                                                                                                                           made substantial progress in understanding PD.
                                                                                                                           Some highlights of this research include the


            Introduction                                                                                                   discovery and characterization of several genes
                                                                                                                           linked to familial PD; the expansion of research
                                                                                                                           on potential environmental factors that may
                                                                                                                           underlie PD; and studies of potential new
                                                                                                                           therapies, including growth factor
                                                                                                                           administration, drug therapy, and deep
                                                                                                                           brain stimulation.

                                                                                                                           As part of its mission to reduce the burden of
                                                                                                                           neurological disease, NINDS is committed to
                                                                                                                           expanding translational research – studies that
                                                                                                                           translate or develop promising findings in basic
                                                                                                                           research into effective treatments in the clinic.     As part of the implementation process for the
                                                                                                                           PD research is considered prime territory for         PD research agenda, NIH convened a summit
                                                                                                                           translation because exciting new discoveries in       with several outstanding scientists in July 2002
                                                                                                                           basic science have accelerated our understanding      to gain a better sense of where the field of PD
                                                                                                                           of the disease over the past few years. The           research stands internationally and to collect
                                                                 major neurodegenerative disorder, and defeating
            E    ver since PD was first described in 1817,
                 scientists have pursued the causes and
            treatment of the disease. In the early 1960s,
                                                                 PD remains a significant challenge.
                                                                                                                           Institute is supporting three coordinated
                                                                                                                           programs to encourage translational research
                                                                                                                           projects that focus on PD and other neurological
                                                                                                                                                                                 information on "roadblocks" that impede
                                                                                                                                                                                 progress. This meeting led to a set of
                                                                 The National Institute of Neurological Disorders                                                                recommendations that were compiled into a
            scientists identified the primary problem                                                                      disorders. These programs provide tools and           matrix (see p. 4) of short-to-long range and low-
                                                                 and Stroke (NINDS), part of the National
            underlying the disease: the loss of brain cells                                                                resources for therapy development, support work       to-high risk action items in order to address
                                                                 Institutes of Health (NIH), has a long history of
            that produce a chemical called dopamine, which                                                                 necessary to begin clinical testing, and offer        some of these roadblocks. The matrix identifies
                                                                 support for PD research. In 1997, recognizing
            helps to coordinate and control muscle activity.                                                               career development and training experience for        goals that can help to advance PD research and
                                                                 the need to accelerate the pace of PD research,
            This discovery led to the first successful                                                                     investigators interested in translational research.   places them within a general time frame of when
                                                                 Congress signed the Morris K. Udall Parkinson’s
            treatment for PD and suggested ways of devising                                                                                                                      progress might reasonably be expected. This
                                                                 Disease Research Act into law. The Udall Act              The NIH conducts a vigorous and expanding
            new and even more effective therapies.
                                                                 directed the NIH to expand and coordinate                 program of research focused on PD. In 2000, the       matrix helps to guide research planning at NIH,
            Parkinson’s research continues to be a very active
                                                                 Parkinson’s research with the purpose of finding          agency convened a workshop to create an               but is also designed as a tool for the entire PD
            field, with new and intriguing findings reported
                                                                 a cure or treatment for this disease, and to award        agenda for PD research. The attendees included        community. It includes important responsibilities
            every day.
                                                                 Core Center Grants — designated as Morris K.              intramural, extramural, and industry scientists;      for voluntary and private funding organizations,
            Research suggests that PD affects at least 500,000   Udall Centers of Excellence for Parkinson's               representatives from several Parkinson's advocacy     and will lead to opportunities for collaboration
            people in the United States, and some estimates      Disease (PD) Research — to encourage                      groups; and ethicists. They developed an agenda       with other government agencies and the
            are much higher. Society pays an enormous price      complementary research and to provide training            that comprises four major areas: understanding        international community as well. This matrix is
            for PD. The total cost to the nation is estimated    for scientists undertaking PD research.                   PD, developing new treatments, creating new           intended to be a living document that can be
            to exceed $6 billion annually. The financial and                                                               research capabilities, and enhancing the              revised and expanded as current goals are
                                                                 The Udall Centers of Excellence have embarked
            public health impact of this disease is expected                                                               research process.                                     achieved and new goals are identified.
                                                                 on diverse research avenues, but they all share a
            to increase as the population ages.
                                                                 common goal: scientific research to improve the           The PD research agenda is also relevant for           Twelve different NIH Institutes and Centers fund
            In recent years, Parkinson’s research has            diagnosis and treatment of patients with PD and           other diseases. PD research can lead the way in       research on PD, including the National Institute
            advanced to the point that halting the               related neurodegenerative disorders and to gain           the fight against all forms of neurodegeneration,     of Neurological Disorders and Stroke, National
            progression of PD, restoring lost function, and      a better understanding of the fundamental                 and research on other types of neuro-                 Institute on Aging, National Institute of Mental
            even preventing the disease are all considered       cause(s) of the disease. These centers, along             degeneration also can provide vital clues about       Health, National Institute of Environmental
            realistic goals. However, we cannot yet cure any     with many other labs funded by the NIH, have              how PD may be cured.                                  Health Sciences, National Human Genome


2   Parkinson’s Disease: Challenges, Progress, and Promise                                                            “AUGUSTUS DIVINUS CONUBIUM NOKSH                             Parkinson’s Disease: Challenges, Progress, and Promise   3
            Research Institute, National Institute on                           multifaceted disease, and each of these Institutes
            Deafness and Other Communication Disorders,                         brings a valuable perspective to confronting the
            National Institute of Nursing Research, National
            Institute on Drug Abuse, National Institute of
            Biomedical Imaging and Bioengineering,
                                                                                biological complexities of the disorder, to
                                                                                pursuing the diverse therapeutic strategies
                                                                                showing promise, and to providing the resources
                                                                                                                                        1. Brain and
            National Institute of Child Health and Human
            Development, National Center for
                                                                                necessary to carry out a research agenda of this
                                                                                breadth.
                                                                                                                                           Movement:
            Complementary and Alternative Medicine, and
            National Center for Research Resources.
            Representatives from each of these Institutes, as
                                                                                The NINDS also tracks PD research conducted
                                                                                in other countries. This worldwide tracking
                                                                                activity helps researchers identify potential areas
                                                                                                                                           The Basics
            well as from the Department of Defense and the                      for international collaboration and reduces the
            Department of Veterans Affairs, meet twice a                        chance of duplicated activities.
            year under the leadership of NINDS to discuss                       This report serves to highlight and update the
            research and initiatives for PD, to plan meetings                   substantial progress made in PD research during
            and workshops, and to coordinate research                           the past 5 years. While the report highlights the
            efforts across federal agencies. This committee                     work of the Udall Centers, many contributions
            is called the Parkinson’s Disease Coordinating                      have been made by other NINDS grantees and
            Committee (PDCC). Parkinson’s is a                                  researchers around the world.

                                                                                                                                                                                               cell is also a neuron, it will carry the signal on
               Parkinson’s Disease Research Community Goals Matrix                                                                      W       hen a person initiates a movement,
                                                                                                                                                information from the senses, from parts
                                                                                                                                        of the brain that control planning, and from
                                                                                                                                                                                               to the next cell. If the receiving cell is a muscle
                                                                                                                                                                                               fiber, it will react to the stimulation by
                                              Short Term                          Medium Term                   Long Term
                                                (0-3 years)                          (4-6 years)                 (7-10 years)           other brain regions travels to a region called the     contracting, which creates movement.
                                                                                                                                        striatum. The striatum then interacts with other
              High        • Understanding Gene/Environment Interactions       • General Roadblocks to    • Translational Research/
              Risk                                                              Advancing PD Research      Therapeutics                 areas of the brain — the substantia nigra, globus
                          • Biomarker Development
                                                                                                           Development                  pallidus, and thalamus — to send out signals that
                                                                                                                                        control balance and coordination. These signals
                          • Core Facilities and Resources                                                                               travel to the cerebellum, which controls muscle
                          • Integration of PD Research Centers
             Medium                                                                                                                     coordination, and then finally down the spinal
                          • Public-Private Partnerships
             Risk                                                                                                                       cord to peripheral nerves in the limbs, head,
                          • Gene Discovery
                          • Translational Research/Therapeutics Development                                                             and torso, where they control the muscles.

                                                                                                                                        The molecules that carry information through
                          • Core Facilities and Resources                     • Core Facilities and
                                                                                Resources                                               the brain and spinal cord are called
                          • General Resources
                                                                              • Brain Banks                                             neurotransmitters. Neurotransmitters are special
                                 – Gene Therapy Resources
                                 – Animal Models                              • Clinical Trials of                                      chemicals produced by neurons that accumulate
                                 – Brain Banks                                  Non-motor Symptoms                                      in tiny sacs at the end of nerve fibers. When
              Low
              Risk        • Integration of PD Research Centers                                                                          stimulated, these sacs release neurotransmitters
                          • Public-Private Partnerships                                                                                 into the gap between neurons, called a synapse.
                          • Basic Cell Biology Research                                                                                 The neurotransmitters cross the synapse and
                          • General Roadblocks to Advancing PD Research                                                                                                                      Neurons transmit signals across tiny spaces called synapses. Signaling
                                                                                                                                        attach to proteins called receptors on the           chemicals called neurotransmitters are gathered into sacs called synaptic
                          • Understanding Gene/Environment Interactions                                                                                                                      vesicles. When the nerve receives a signal, these sacs release their
                                                                                                                                        neighboring cell. These signals change the           neurotransmitters into the synapse. Proteins called receptors, found on
                                                                                                                                        properties of the receiving cell. If the receiving   the receiving neuron, bind to the neurotransmitters and trigger a new
                                                                                                                                                                                             nerve impulse.




4   Parkinson’s Disease: Challenges, Progress, and Promise                                                                            “AUGUSTUS DIVINUS CONUBIUM NOKSH                                    Parkinson’s Disease: Challenges, Progress, and Promise         5
                                                                 Another cellular characteristic of PD is the                                      Another commonly used scale is the Unified
                                                                 presence of Lewy neurites – swollen nerve fibers                                  Parkinson’s Disease Rating Scale (UPDRS). This
                                                                                                                                                                                                                                                                      Brain

            2. What Goes                                         containing alpha-synuclein and other proteins.
                                                                 The accumulation of alpha-synuclein in these
                                                                 nerve fibers may interfere with transmission
                                                                                                                                                   much more complicated scale has multiple ratings
                                                                                                                                                   that measure mental functioning, behavior, and
                                                                                                                                                   mood; activities of daily living; and motor function.
                                                                                                                                                                                                                                                                                   Motor Cortex


               Wrong In                                          of nerve signals or other important neuronal
                                                                 functions.
                                                                                                                                                   Both the Hoehn and Yahr scale and the UPDRS are
                                                                                                                                                   used to measure how individuals are faring and


               Parkinson’s                                       PD is a devastating and complex disease that
                                                                 interferes with movement more and more as
                                                                                                                                                   how much treatments are helping them.

                                                                                                                                                   Diagnosing PD is dependent on clinical
                                                                                                                                                                                                                                                                                       Cerebellum



               Disease?
                                                                 time goes on. It also produces a wide range of                                    observations. There are currently no blood or
                                                                 other problems for patients. Symptoms of the                                      laboratory tests that have been proven to help in
                                                                 disease vary somewhat, but they may include                                       diagnosing this disease.
                                                                 problems with swallowing and chewing, speech                                                                                                                                                                           Globus
                                                                 impairments, urinary problems or constipation,                                                                                                                                      Thalamus                           Pallidus
                                                                 excessive sweating and other skin problems,                                                                                                              Dopamine Pathways
                                                                 depression and other emotional changes, and                                                                                                                   Substantia Nigra
                                                                                                                                                                                                                                                                                           Striatum
                                                                 difficulties with sleep. No one can predict which
                                                                                                                                                                                                       The dopamine pathway in the brain. Dopamine signals
                                                                 of these symptoms will affect a particular patient,                                                                                   travel from the substantia nigra to brain regions including
                                                                                                                                                                                                       the striatum, the globus pallidus, and the thalamus in order


            T    he primary area of the brain that is affected
                 by PD is the substantia nigra. It contains
            a specialized set of neurons that send signals in
                                                                 and the intensity of the symptoms varies from
                                                                 person to person. None of these secondary
                                                                 symptoms is fatal, although swallowing problems
                                                                                                                                                                                                       to control movement and balance. In PD, most of the
                                                                                                                                                                                                       dopamine signals from the substantia nigra are lost.



            the form of a neurotransmitter called dopamine.      can cause choking.                                                                  Hoehn and Yahr Staging of Parkinson's Disease
            The signals travel to the striatum via long fibers
                                                                 The progression of symptoms in PD may take 20
            called axons. The activity of this pathway                                                                                                          • Signs and symptoms on one side only                                   • Usually presents with tremor of one limb
                                                                 years or more. In some people, however, the                                         Stage
            controls normal movements of the body.                                                                                                              • Symptoms mild                                                         • Friends have noticed changes in posture,
                                                                 disease progresses much more quickly. To the                                        one
                                                                                                                                                                • Symptoms inconvenient but not disabling                                 locomotion and facial expression
            When neurons in the substantia nigra                 right is one commonly used system for
            degenerate, the resulting loss of dopamine           describing how the symptoms of PD progress.
                                                                                                                                                                • Symptoms are bilateral
            causes the nerve cells of the striatum to fire                                                                                           Stage
                                                                                                                                                     two        • Minimal disability
            excessively. This makes it impossible for people
                                                                                                                                                                • Posture and gait affected
            to control their movements, leading to the
            primary motor symptoms of PD. Many
                                                                                                                                                                • Significant slowing of body movements                                 • Generalized dysfunction that is moderately
            Parkinson's patients eventually lose 80 percent                                                                                          Stage      • Early impairment of equilibrium on walking or                           severe
                                                                                                                                                     three        standing
            or more of their dopamine-producing cells.

            While the neurons’ underlying cause of death
            remains uncertain, researchers have identified                                                                                                      • Severe symptoms                                                       • No longer able to live alone
                                                                                                                                                     Stage      • Can still walk to a limited extent                                    • Tremor may be less than earlier stages
            several cellular characteristics that are common                                                                                         four
                                                                                                                                                                • Rigidity and bradykinesia
            in this disease and which appear to play a role in
            the neuronal degeneration. Chief among these
                                                                 PET images from a normal volunteer (left) and a PD patient (right). The
            characteristics is the presence of Lewy bodies in    increased uptake of glucose in the striatum (arrows) of the PD subject,                        • Cachectic stage                                                       • Requires constant nursing care
                                                                 compared to the normal subject, is evident. Cortical glucose uptake is              Stage
            neurons of the substantia nigra, the brainstem,                                                                                          five       • Invalidism complete
                                                                 otherwise similar in the two subjects. The color scale on the right shows
                                                                 the cerebral glucose metabolic rate, which reflects the amount of brain                        • Cannot stand or walk
            and other parts of the brain. Lewy bodies are        activity. [Credit: David Eidelberg, M.D., The Institute for Medical Research,
            dense clumps, or aggregates, of proteins.            North Shore-Long Island Jewish Health System, Manhasset, NY]




6   Parkinson’s Disease: Challenges, Progress, and Promise                                                                                       “AUGUSTUS DIVINUS CONUBIUM NOKSH                                                                   Parkinson’s Disease: Challenges, Progress, and Promise   7
                                                                                                                                                                                                 Deep Brain
                                                                                                                                                                                                 Stimulation
                                                                                                                                                                                                 For many years, the only surgical treatments for PD
                                                                                                                                                                                                 were pallidotomy and thalamotomy – procedures in
                                                                                                                                                                                                 which surgeons selectively destroy small portions of

            3. How Can                                                                                                                                                                           the brain in order to relieve tremor and rigidity. The
                                                                                                                                                                                                 tissue destruction is irreversible. Because these


               We Treat
                                                                                                                                                                                                 procedures often led to troubling side effects,
                                                                                                                                                                                                 surgery was largely replaced with drug therapy once
                                                                                                                                                                                                 levodopa became available for PD in the 1960s.


               Parkinson’s                                                                                                                                                                       In the 1980s, researchers in France discovered that
                                                                                                                                                                                                 chronic stimulation (now termed deep brain


               Disease?                                                                                                                                                                          stimulation or DBS) of a brain region called the
                                                                                                                                                                                                 thalamus could block tremors in patients with
                                                                                                                                                                                                 essential tremor. Studies in a monkey model for PD
                                                                                                                                                                                                 also revealed the brain circuits that are altered in
                                                                                                                       One surgical treatment for PD is called deep brain stimulation (DBS).     this disease and pointed to a brain region called the
                                                                                                                       DBS can be performed on either one side (unilateral) or both sides of     subthalamic nucleus as a key target. This discovery
                                                                                                                       the body (bilateral). In bilateral DBS, electrodes are implanted in the
                                                                                                                       subthalamic nucleus or the globus pallidus of the brain. Insulated        opened the door to a new era of surgical
                                                                                                                       wires are then passed under the skin of the head, neck, and shoulder
                                                                                                                       to connect the electrodes to battery-operated neurostimulators that
                                                                                                                                                                                                 treatments. Investigators then examined the effects
                                                                                                                       are implanted under the skin, usually near the collarbones. Impulses      of stimulating the subthalamic nucleus in patients
                                                                                                                       from the neurostimulators interfere with and block the brain signals
                                                                                                                       that cause PD symptoms.                                                   with PD and found that the stimulation had
                                                                                                                                                                                                 profound effects on patients’ tremor, slowness, and
                                                                example, anticholinergic drugs decrease the            Brain surgery was one of the first treatments for                         stiffness. In DBS, electrodes are implanted into the

            T    here are currently two main types of
                 treatment for PD: drug treatments and
            surgery.
                                                                activity of the neurotransmitter acetylcholine.
                                                                These drugs help to reduce tremors and muscle
                                                                                                                       PD. Surgeons discovered that, by removing or
                                                                                                                       destroying parts of the brain that were
                                                                                                                                                                                                 brain and connected to a small electrical device
                                                                                                                                                                                                 called a pulse generator that can be externally
                                                                                                                                                                                                 programmed. DBS reduces the need for levodopa
                                                                stiffness, which can result from having more           “misfiring,” some of the symptoms of PD could                             and related drugs, which in turn decreases the
            Drug Treatments                                     acetylcholine than dopamine.                           be alleviated. The most common early brain                                involuntary movements called dyskinesias that are a
                                                                                                                       operations for PD were pallidotomy, which                                 common side effect of levodopa. It also helps to
            Medications for PD fall into three categories.      The third category of drugs prescribed for PD
                                                                                                                       destroyed part of the globus pallidus, and                                alleviate fluctuations of symptoms and to reduce
            The first category includes drugs that work         includes medications that help control the non-
                                                                                                                       thalamotomy, which destroyed part of the                                  tremors, slowness of movements, and gait problems.
            directly or indirectly to increase the level of     motor symptoms of the disease. For example,                                                                                      Unlike pallidotomy and thalamotomy, DBS is
                                                                                                                       thalamus. These procedures were irreversible
            dopamine in the brain. People cannot simply         people with PD-related depression may be                                                                                         reversible. However, it requires careful programming
                                                                                                                       and often led to complications. Clinicians have
            take dopamine pills because dopamine does not       prescribed antidepressants.                                                                                                      of the stimulator device in order to work correctly.
                                                                                                                       improved these techniques a great deal, but
            easily pass through blood vessels into the brain.                                                          while they are much safer now, they are still                             DBS has now been approved by the U.S. Food and
                                                                ———————————————————————————————————————
            The most common drugs for PD are dopamine                                                                  irreversible.                                                             Drug Administration, and it is widely used as a
            precursors – substances such as levodopa that                                                                                                                                        treatment for PD. It also is used to treat dystonia
            cross the blood-brain barrier and are then          Surgical Treatments                                    In recent years, scientists have found that they                          and essential tremor, and it is being tested for
                                                                                                                       can mimic the effects of pallidotomy and                                  disorders such as Tourette syndrome, epilepsy, and
            changed into dopamine. Other drugs mimic
                                                                At present, there are two commonly used                thalamotomy by deep brain stimulation (DBS).                              depression. Researchers are continuing to study DBS
            dopamine, prevent or slow its breakdown, or
                                                                surgical treatments for PD: pallidotomy and            With DBS, an electrode is implanted in the brain                          and to develop ways of improving it. They are
            increase the amount of it that is released.                                                                                                                                          conducting clinical studies to determine the best
                                                                deep brain stimulation. Because these                  in a way that calms the abnormal neuronal
            The second category of PD drugs affects other       procedures are invasive, they are usually reserved                                                                               part of the brain to receive stimulation and to
                                                                                                                       firing. This procedure is much safer than
                                                                                                                                                                                                 determine the long-term effects of this therapy.
            neurotransmitters in the body in order to ease      for severely afflicted Parkinson's patients who do     pallidotomy or thalamotomy because the
                                                                                                                                                                                                 They also are working to improve the technology
            some of the symptoms of the disease. For            not get adequate relief from medications.              electrodes can be turned off if the patient                               available for DBS.




8   Parkinson’s Disease: Challenges, Progress, and Promise                                                           “AUGUSTUS DIVINUS CONUBIUM                                    NOKSH                 Parkinson’s Disease: Challenges, Progress, and Promise   9
                                                                                    and put underused and rigid muscles through a
                                                                                    full range of motion. Exercise cannot stop
                                                                                    disease progression, but it may improve body
                                                                                    strength so that the person can better cope with
                                                                                    his or her disability. Researchers are studying           4. Research
                                                                                                                                                 Findings
                                                                                    whether exercise also may improve the response
                                                                                    to levodopa and/or increase levels of beneficial
                                                                                    compounds called neurotrophic factors in the
                                                                                    brain. Targeted exercises also may improve
                                                                                    balance, help people overcome gait problems,                 and New
            PET brain scan images from a normal control subject and three
            patients at different stages of PD. The images exhibit a progressive
            decline of dopamine uptake in the brain's striatum with increasing
            disease severity. H&Y is the Hoehn and Yahr scale reflecting the
                                                                                    and strengthen certain muscles so that people
                                                                                    can speak and swallow better. Although
                                                                                    structured exercise programs help many patients,
                                                                                                                                                 Directions
            clinical severity of the disease. [Credit: David Eidelberg, M.D., The
            Institute for Medical Research, North Shore-Long Island Jewish Health   more general physical activity, such as walking,
            System, Manhasset, NY]
                                                                                    gardening, swimming, and using exercise
                                                                                    machines, is also beneficial.
             experiences problems. The stimulation also can
                                                                                    Some early reports suggested that dietary
             be adjusted to match the patient’s needs.
                                                                                    supplements may be protective in PD. In
             Because of this, DBS is now the primary surgical
                                                                                    addition, a phase II clinical trial of a supplement
             intervention for PD. In 1997, the U.S. Food and                                                                                                                                   inherited and sporadic (non-hereditary) cases of
             Drug Administration (FDA) approved DBS for
             the treatment of essential tremor using a single
                                                                                    called coenzyme Q10 suggested that large doses
                                                                                    of this substance can slow disease progression in
                                                                                                                                            D     uring the past five years, researchers
                                                                                                                                                  have made substantial advances in our
                                                                                                                                            understanding of the biological factors involved
                                                                                                                                                                                               the disease. The same genes and proteins that
                                                                                                                                                                                               are altered or missing in inherited cases may also
             implanted electrode on one side of the brain. In                       patients with early-stage PD. The NINDS and the
                                                                                                                                            in PD. They are beginning to decipher the roles    be altered in sporadic cases by environmental
             January 2002, the FDA approved DBS for PD                              National Center for Complementary and
                                                                                                                                            of individual genes and environmental factors in   toxins or other factors.
             using two implanted electrodes — one on each                           Alternative Medicine (NCCAM) are funding
                                                                                                                                            PD and to learn how the interplay of these
                                                                                    research to determine if folate, coffee, dietary                                                           Identifying gene defects can also help
             side of the brain. Recently, the FDA also                                                                                      factors can lead to the disease. Each abnormal
                                                                                    antioxidants, fat, alcohol, and/or dairy products                                                          researchers understand how PD occurs, develop
             approved a technologically advanced electrode                                                                                  gene or environmental factor that is identified
                                                                                    are beneficial. While there is currently no                                                                animal models that accurately mimic the
             apparatus that can be controlled by the patient                                                                                provides another clue to help solve the mystery
                                                                                    evidence that any specific dietary factor is                                                               neuronal death in human PD, identify new drug
             through use of a remote control device.                                                                                        of PD.
                                                                                    beneficial in PD, a normal, healthy diet can                                                               targets, and improve diagnosis. The genetic
             ———————————————————————————————————————
                                                                                    promote overall well-being for PD patients just as      ———————————————————————————————————————
                                                                                                                                                                                               approach has been very successful, with new
                                                                                    it would for anyone else.                                                                                  discoveries occurring at an unprecedented pace.
             Complementary and                                                                                                              Genetics                                           The following summary highlights current
                                                                                    Other complementary therapies that are used by
             Supportive Therapies                                                   some individuals with PD include massage                Until the last decade, many researchers believed
                                                                                                                                                                                               knowledge about the genes known to be involved
                                                                                                                                                                                               in PD, and the functions of the proteins these
             A wide variety of complementary and supportive                         therapy, yoga, tai chi, acupuncture, ginkgo             that PD was caused solely by environmental         genes produce.
             therapies may be used for PD. Among these                              biloba (for concentration problems), and the            factors. However, the discovery of gene
             therapies are standard rehabilitation techniques,                      Alexander technique, which optimizes posture            mutations in familial, or inherited, forms of PD
                                                                                                                                                                                               ■   alpha-synuclein
             which can help with problems such as gait and                          and muscle activity. There have been limited            has led to an explosion of research on PD genes
             voice disorders, tremors and rigidity, and                                                                                     and the function of the proteins that are              The first PD-related gene to be identified was
                                                                                    studies suggesting mild benefits with many of
             cognitive decline. Exercise may help people                                                                                    encoded by these genes.                                alpha-synuclein. Researchers at NIH and
                                                                                    these therapies, but they do not slow PD and
             improve their mobility. Physical therapy or                                                                                                                                           other institutions studied the genetic profiles
                                                                                    there is no convincing evidence that they are           Although most people do not inherit PD,
             muscle-strengthening exercises may tone muscles                                                                                                                                       of a large Italian family and three Greek
                                                                                    beneficial.                                             studying the genes responsible for the inherited       families with familial PD and found that their
                                                                                                                                            cases can help researchers understand both             disease was related to a mutation in this gene.



10   Parkinson’s Disease: Challenges, Progress, and Promise                                                                               “AUGUSTUS DIVINUS CONUBIUM                NOKSH              Parkinson’s Disease: Challenges, Progress, and Promise   11
               They found a second alpha-synuclein mutation                                                              at the Columbia University Udall Center,
               in a German family with PD. These findings                                                                along with colleagues at Brigham and
                                                                                                                                                                                                                                              Parkinson's
               prompted studies of the role of alpha-                                                                    Women’s Hospital and the Albert Einstein                                                                             Gene Location

               synuclein in PD, which led to the discovery                                                               College of Medicine, have found that normal
               that Lewy bodies from people with the                                                                     alpha-synuclein is broken down by lysosomes,
               sporadic form of PD contained clumps of                                                                   which act as the cell’s garbage disposal system.
               alpha-synuclein proteins. This discovery                                                                  Mutant alpha-synuclein, however, blocks the
               revealed a potential link between hereditary                                                              pathway into the lysosomes. This inhibits the
               and sporadic forms of the disease and sparked                                                             breakdown of alpha-synuclein as well as other
               investigations into the normal function of                                                                proteins. This may trigger a toxic buildup of
               alpha-synuclein as well as the possible effects                                                           protein “garbage” inside the cell.
               of alpha-synuclein mutations on normal                                                                                                                            Researchers studying a family with a hereditary form of PD discovered
                                                                                                                         Researchers are continuing to study the alpha-          that members of this family had a triplication of the normal alpha-
               cellular activity.                                                                                                                                                synuclein gene on one chromosome. This image shows the three
                                                                                                                         synuclein gene to clarify how it affects PD.
                                                                                                                                                                                 alpha-synuclein genes (pink) on one copy of chromosome 4.
               One theory about how alpha-synuclein is                                                                   For example, Mayo Clinic Udall Center
               associated with PD holds that the mutated                                                                 researchers are assessing the alpha-synuclein
               protein interferes with cell membranes.                                                                   gene in a large group of people with PD, and        ■   Parkin
               Within the cell body, individual molecules of      protein disposal system and cause neurons to           in a control group of healthy people who                Genetic studies on a rare, juvenile-onset form
               alpha-synuclein join together to form tiny         die. A group of researchers at NIH and other           match the PD patients in age, gender, and               of PD led to the discovery of the parkin gene.
               protein threads called fibrils; this process is    institutions investigated a rare familial form of      demographics, in order to look for variations           Originally, this form of PD was not linked to
               called fibrillization. Investigators at the        early-onset PD and discovered that a                   in the gene that may affect susceptibility to the       Lewy bodies. However, Mayo Clinic Udall
               Brigham and Women’s Hospital Udall Center          multiplication of the normal alpha-synuclein           disease. Investigators at the Johns Hopkins             Center scientists have found parkin mutations
               and elsewhere have shown that mutations in         gene, and a corresponding increase in alpha-           University Udall Center have developed mice             that are accompanied by Lewy body pathology.
               the alpha-synuclein gene disrupt the               synuclein protein, can cause the disease. The          with alpha-synuclein gene mutations and                 Further studies have shown that parkin is a
               fibrillization process and lead to the             researchers analyzed blood samples from a              found that the mice accumulate alpha-                   part of the so-called ubiquitin-proteasome
               accumulation of protofibrils, an intermediate      family, the "Iowa kindred," in which many              synuclein in the midbrain, cerebellum,                  system, which breaks down proteins in the cell.
               step in alpha-synuclein fibrillization. They       relatives developed PD or related neurological         brainstem, and spinal cord and develop an               This suggests that parkin mutations may lead
               found that alpha-synuclein protofibrils have       diseases. In the relatives with PD, the                adult-onset neurodegenerative disease with              to accumulation of toxic proteins within
               protein structures which resemble bacterial        researchers found four copies of the alpha-            symptoms resembling human PD, including                 neurons. Researchers also have shown that
               and insect toxins that make membranes leaky.       synuclein gene — an abnormal triplication of           motor dysfunction, bradykinesia, and dystonia.          parkin interacts with synphilin-1 and alpha-
               This could trigger cell death and may explain      three alpha-synuclein genes on one copy of                                                                     synuclein and mediates an important step in
                                                                                                                         The discovery of alpha-synuclein has paved the
               the toxicity of Lewy body proteins. This idea is   chromosome 4 and one gene on the other                                                                         protein handling. When alpha-synuclein,
                                                                                                                         way for other genetic linkage studies in
               supported by studies from the Massachusetts        chromosome 4 — instead of the usual two                                                                        another protein called synphilin-1, and parkin
                                                                                                                         families with PD (see Gene Discoveries, p. 15).
               General Hospital and Massachusetts Institute       copies of the alpha-synuclein gene. This                                                                       are injected together into cells in culture, they
                                                                                                                         Within the past 5 years, many regions of the
               of Technology Udall Center showing that            multiplication resulted in an abnormally large                                                                 form inclusions in the cell that are similar to
                                                                                                                         genome have been linked to PD and four
               alpha-synuclein is located near cell               amount of alpha-synuclein in the cells.                                                                        Lewy bodies. This suggests that parkin may be
                                                                                                                         additional PD genes have been identified,
               membranes in postmortem brain tissue from                                                                                                                         important in both inherited and sporadic
                                                                  A third theory proposes that mutant alpha-             including parkin, DJ-1, PINK1, and DRDN.
               people with diffuse Lewy body disease.                                                                                                                            forms of the disease. Several studies have
                                                                  synuclein interferes with the normal
               Another study suggests that a buildup of                                                                                                                          suggested that normal parkin protects neurons
                                                                  housekeeping functions of cells and lets
               normal alpha-synuclein may clog up the cell’s                                                                                                                     from diverse threats, including alpha-synuclein
                                                                  proteins build up to toxic levels. Researchers
                                                                                                                                                                                 toxicity, proteasomal dysfunction, and
                                                                                                                                                                                 excitotoxicity. Other evidence indicates that




12   Parkinson’s Disease: Challenges, Progress, and Promise                                                           “AUGUSTUS DIVINUS CONUBIUM                 NOKSH                 Parkinson’s Disease: Challenges, Progress, and Promise                 13
                                                                                                                                                                                    Gene Discoveries
                                                                                                                                                                                    One of the most dramatic changes in PD research in
                 parkin degrades alpha-synuclein and that it            Scientists at the Johns Hopkins University             ■   DRDN                                             the past decade has been the emergence of genetics
                 accumulates on Lewy bodies in neurons within           School of Medicine Udall Center have                                                                        as a major tool for understanding the disease. Until
                                                                                                                                   Researchers at NIH and colleagues from
                 the substantia nigra, brainstem, and cortex of         examined mutant DJ-1 genes in cultured                                                                      the mid-1990s, most researchers believed that PD
                                                                                                                                   several European institutions recently
                 people with PD.                                        human cells and found that the mutation                                                                     was caused solely by environmental factors.
                                                                                                                                   identified mutations in a gene called DRDN
                                                                        reduces stability of the DJ-1 protein. These                                                                However, researchers at the UMDNJ-Robert Wood
                 Findings from a different group of studies                                                                        that appear to cause a late-onset form of PD.    Johnson Medical School in New Jersey had identified
                                                                        mutant proteins are degraded by proteasomes
                 suggest that parkin may help to regulate the                                                                      This gene, found in several English and          an Italian family with what appeared to be an
                                                                        more quickly than usual and cannot form
                 release of dopamine from substantia nigra                                                                         Basque families, is located in a chromosomal     inherited form of PD. In 1995, they began to
                                                                        chains as the normal proteins do. Thus, the
                 neurons. In a mouse model for PD that is                                                                          region formerly called PARK8. DRDN codes         collaborate with researchers at the National Human
                                                                        abnormal form of DJ-1 may not be able to
                 genetically engineered to lack the parkin                                                                         for a protein called dardarin – a name derived   Genome Research Institute (NHGRI), who analyzed
                                                                        perform its normal functions within the cell.                                                               DNA from these patients. Within a few years, the
                 gene, researchers found higher-than-normal                                                                        from the Basque word for tremor. The
                 levels of dopamine in the striatum. However,                                                                      function of this protein is still unknown.       NHGRI researchers had traced the disease in this
                 the neurons normally activated by dopamine         ■   PINK1                                                                                                       family to a mutation in the alpha-synuclein gene.
                                                                                                                                                                                    Investigators soon identified alpha-synuclein
                 required more stimulation to produce a                 Mutations in a gene called PTEN-induced
                 response. The mice without parkin also had
                                                                                                                               ■   Other Genes That May Play a Role                 mutations in several other families as well.
                                                                        kinase 1 (PINK1), also known as PARK6, have
                 impairments in tests that require muscle               been identified in several families with PD.               in Parkinson’s Disease                           These findings touched off an explosion of work on
                 coordination. These studies indicate that              Kinases help to regulate protein function in               UCH-L1 – Scientists at NIH and elsewhere         the function of alpha-synuclein as well as intensive
                 parkin may help to regulate the release of                                                                                                                         searches for other PD genes. Researchers soon
                                                                        both normal and disease states. The PINK1                  have identified a mutation in the Ubiquitin
                                                                                                                                                                                    discovered that alpha-synuclein is a major
                 dopamine from nigral neurons.                          gene codes for a protein active in                         Carboxyl-Terminal Hydrolase L1 (UCH-L1)
                                                                                                                                                                                    component of Lewy bodies, suggesting that it might
                                                                        mitochondria, which convert food into energy               gene in a German family with PD. In addition,
                 Researchers at the Duke University Udall                                                                                                                           play a role in sporadic forms of the disease as well as
                                                                        inside the cell. Cell culture studies suggest that         researchers at the Mayo Clinic Udall Center
                 Center have shown that people with a parkin                                                                                                                        inherited ones. They also located four more PD
                                                                        PINK1 may help to protect the cell and that                have identified a variation of the gene, also    genes – parkin, DJ-1, DRDN, and PINK1 – and several
                 mutation in just one copy of the gene have a
                                                                        mutations in this gene may increase                        called PARK5, that is associated with an         other genes that appear to influence the disease,
                 higher risk of getting PD as they get older
                                                                        susceptibility to cellular stress. The discovery           increased risk of PD in some families. UCH-      although their role is not yet clear. In 2003,
                 than people without these mutations.
                                                                        of this gene provides a direct molecular link              L1 is an important member of the ubiquitin-      investigators at the National Institutes of Health and
                 Understanding why this happens could lead to
                                                                        between mitochondrial dysfunction and the                  proteasome system that performs                  elsewhere discovered that, in one large family, a
                 strategies for preventing PD in people who are
                                                                        development of PD.                                         “ubiquitination,” a process that tags proteins   triplication of the normal alpha-synuclein gene
                 genetically predisposed to the disease.
                                                                                                                                   for breakdown. Ubiquitination is critical for    caused the disease. The extra genes cause
                                                                                                                                   the proper handling of misfolded proteins.       overproduction of alpha-synuclein, which can
             ■   DJ-1                                                                                                                                                               accumulate inside brain cells.
                                                                                                                                   synphilin-1 – Researchers at the Johns Hopkins
                 The DJ-1 (PARK7) gene has been linked to
                 another early-onset form of PD. This protein
                                                                        Scientists at the                                          University School of Medicine Udall Center
                                                                                                                                                                                    Together, these studies have dramatically changed
                                                                                                                                                                                    researchers’ understanding of how PD develops.
                 is involved in regulating gene activity and in             Duke University                                        have found that a protein called synphilin-1
                                                                                                                                   interacts with alpha-synuclein and promotes
                                                                                                                                                                                    Hundreds of investigators are now looking for
                 protecting cells from a damaging process                                                                                                                           additional PD genes and studying how the proteins
                 called oxidative stress. Mayo Clinic Udall               Udall Center                                             the formation of cellular inclusions             produced by these genes affect cells. Others are
                                                                                                                                   resembling Lewy bodies. Studies are now          examining how genes and environmental factors
                 Center researchers are screening patient                 have shown that specific genetic                         underway to define the normal location and
                 samples for mutations in DJ-1, as well as other                                                                                                                    may interact to produce the disease. These studies

                 genes, to find out if these mutations are
                                                                        variations in mitochondrial DNA,                           function of synphilin-1.                         may lead to vastly improved treatments for the
                                                                                                                                                                                    disease, or possibly even ways of preventing it.
                 common among people with PD or restricted              known as genetic polymorphisms,
                 to just a few families. They also have evaluated
                                                                               increase the risk of PD.
                 DJ-1 in early-onset PD cases and identified a
                 DJ-1 gene variation called R98Q.




14   Parkinson’s Disease: Challenges, Progress, and Promise                                                                  “AUGUSTUS DIVINUS CONUBIUM                  NOKSH             Parkinson’s Disease: Challenges, Progress, and Promise   15
             PACRG – This gene, called parkin co-regulated                                                             may be linked to PD. They have finished               analysis). Genes identified by the genomic
             gene, was identified by researchers at the Mayo                                                           intensive sequencing of seven mitochondrial           convergence technique are relatively likely to
             Clinic Udall Center. PACRG appears to interact                                                            genes in frontal cortex samples from a small          play a role in PD. This combination of two
             with parkin and to be part of the protein                                                                 group of people with the disease and an equal         powerful techniques saves investigators time and
             degradation system. This protein also appears                                                             number of controls. They found potentially            effort compared to studying the results of gene
             to be a component of Lewy bodies.                                                                         important mutations in genes called ND2, ND4L,        expression or linkage analysis alone. This
                                                                                                                       and ND5. These findings counter the hypothesis        approach has been used successfully to identify
             GSTO-1 and -2 – A gene called glutathione S-
                                                                                                                       that PD is caused simply by an increase in age-       the GSTO-1 gene.
             transferase omega-1 (GSTO-1) appears to affect
                                                                                                                       related mtDNA mutations. The University of
             the age of onset for PD and Alzheimer’s disease.
                                                                                                                       Virginia researchers also have developed
             GSTO-1 is one of a family of genes that break
                                                                                                                       methods to remove and replace the human
             down and recycle many compounds in cells,
                                                                                                                       mitochondrial genome. These technologies may
             including drugs, carcinogens, and the products
                                                                                                                       lead to mitochondrial gene replacement as a
             of oxidative stress. Studies suggest that GSTO-1
                                                                                                                       method of treating PD and other sporadic
             may modify an inflammatory compound called
                                                                                                                       neurodegenerative diseases. They could also be
             interleukin-1 beta and protect against the
                                                                 apolipoprotein E – Duke University researchers        used to show whether these mitochondrial gene
             inflammation commonly found in brains from
                                                                 conducting a genomic screen to identify genes         mutations cause PD and related diseases.
             people with PD. Scientists also have identified a
                                                                 influencing age of onset for PD and Alzheimer’s
             related gene, glutathione S-transferase omega-2                                                           Duke University researchers also are investigating
                                                                 disease have found that normal genetic
             (GSTO-2).                                                                                                 the role of the mitochondrial genome in PD.
                                                                 variations in the apolipoprotein E protein affect
                                                                                                                       They have discovered that specific DNA regions
             tau – The tau protein is an important               the age of onset for PD, just as they do for
                                                                                                                       and variations are associated with an increased
             component of microtubules, which are part of        Alzheimer’s.
                                                                                                                       risk of PD. This work has led to a collaborative
             the cell's structural support system and help to
                                                                 PARK3, PARK9, PARK10, and PARK11 – These              study with the University of Virginia investigators
             deliver substances throughout the cell. Recent
                                                                 are chromosomal regions that have been                to look more closely at how these mitochondrial
             studies have linked an abnormal tau protein to a
                                                                 implicated in families with PD. The                   DNA variations affect cellular functions.             Researchers at the Duke University Udall Center
             parkinsonian disorder, frontotemporal dementia
                                                                 chromosomal regions have not been narrowed                                                                  have performed the first large expression studies
             with parkinsonism linked to chromosome 17                                                                 Researchers are developing a variety of new
                                                                 down to specific genes, but researchers are                                                                 to identify genes that are abnormally active or
             (FTDP-17). Additional studies have suggested                                                              approaches to speed research on genes and on
                                                                 working to identify the genes and to determine                                                              inactive in areas of the brain affected most by
             that aberrations in the tau protein contribute to                                                         the functions of the proteins they produce. For
                                                                 their function. People with PARK3 have a                                                                    PD. They also have compared gene activity in
             the pathology of sporadic PD. Mayo Clinic Udall                                                           example, scientists at the Duke University Udall
                                                                 relatively late age of onset, much like sporadic                                                            PD with that in similar diseases such as
             Center researchers are sequencing the tau gene                                                            Center have developed a new approach called
                                                                 PD. PARK9 has been identified in one Jordanian                                                              progressive supranuclear palsy and FTDP-17. In
             in samples from their patients with familial                                                              “genomic convergence” to study PD and other
                                                                 family. PARK10 is linked to age of onset of PD in                                                           addition, they have helped develop new gene
             parkinsonism to determine if it plays a role in                                                           common diseases. This approach identifies and
                                                                 Icelandic families. PARK11 was identified in                                                                analysis techniques that can determine if specific
             these forms of PD.                                                                                        prioritizes candidate susceptibility genes for PD
                                                                 pairs of siblings and appears to affect                                                                     genetic variants make an individual more
                                                                                                                       by taking data from gene expression studies and
             fibroblast growth factor 2 – This growth factor     susceptibility to the disease.                                                                              susceptible to PD. These tests, called the
                                                                                                                       merging it with data from studies that detect
             helps to maintain neurons. Studies by Duke                                                                                                                      Pedigree Disequilibrium Test (PDT) and Geno-
                                                                 The search for additional PD-related genes            chromosomal regions linked to PD (linkage
             University researchers suggest that mutations                                                                                                                   PDT, have improved on previously available
                                                                 continues on many fronts. University of Virginia
             in the FGF2 gene may be a risk factor for PD.                                                                                                                   techniques.
                                                                 Udall Center researchers are working to define
                                                                 mitochondrial DNA (mtDNA) mutations that




16   Parkinson’s Disease: Challenges, Progress, and Promise                                                          “AUGUSTUS DIVINUS CONUBIUM                  NOKSH              Parkinson’s Disease: Challenges, Progress, and Promise   17
                                                                  study has shown that mutations in the parkin                                                                                 A study of people in the World War II Veteran
                                                                  gene may be a risk factor for late-onset PD as                                                                               Twins Registry has suggested that genetic factors
                                                                  well as the juvenile-onset disease.                                                                                          do not play a major role in causing sporadic PD
                                                                                                                                                                                               that begins after age 50. However, genetic
                                                                  NINDS also is sponsoring a DNA and cell line
                                                                                                                                                                                               factors do appear to play a role when the disease
                                                                  repository to enhance gene discovery by
                                                                                                                                                                                               begins at or before age 50. A number of other
                                                                  supplying DNA samples, cell lines, and clinical
                                                                                                                                                                                               twin studies have found similar results. The
                                                                  and pedigree data to the neuroscience
                                                                                                                                                                                               chance that two siblings will both have PD is
                                                                  community.
                                                                                                                                                                                               similar for fraternal and identical twins,
                                                                  Research on the genetics of PD also receives                                                                                 suggesting that environmental exposures are
                                                                  funding from other NIH institutes. The National                                                                              more important than genetics in determining
                                                                  Human Genome Research Institute is sponsoring                                                                                who will get the disease. Other studies have
                                                                  a clinical study to identify people with inherited                                                                           found that fraternal and identical twins of
                                                                  PD and to look for gene mutations in these                                                                                   people with PD often have significant loss of
                                                                  individuals, and the National Institute of                                                                                   dopamine neurons even when they don’t
             Mayo Clinic Udall Center researchers have            Environmental Health Sciences is sponsoring a                                                                                experience any symptoms.
             gathered information and DNA samples from            study to look at nine candidate genes in a sample
                                                                                                                                                                                               In another line of research, investigators are
             more than 200 PD families. They also are             of 800 people with PD and their siblings to
                                                                                                                                                                                               studying a disorder with a unique combination
             collaborating with investigators from other          clarify what role these genes might play in the
                                                                                                                                                                                               of parkinsonian symptoms, dementia, and motor
             countries. They have worked with researchers at      development of this disease.                           A cycad plant and cycad seed. Researchers suspect that a disorder
                                                                                                                         with a unique combination of parkinsonian symptoms, dementia, and
                                                                                                                                                                                               neuron disease found in some people from the
             the University of British Columbia to study                                                                 motor neuron disease, found in some people from the island of Guam,   island of Guam to see if it might be due to an
             affected and unaffected PD family members with       Environmental Factors                                  results from consumption of animals that eat neurotoxic cycad seeds
                                                                                                                         found on that island.                                                 environmental factor or factors. A similar
             positron emission tomography (PET) scans. In
                                                                  Although the importance of genetics in PD is                                                                                 syndrome has been identified in people from the
             addition, they have screened familial PD cases
                                                                  increasingly recognized, many researchers still                                                                              Kii peninsula in Japan. Researchers have long
             for DNA expansion mutations and identified 12                                                               factors present in industrial and agricultural
                                                                  believe that environmental exposures also                                                                                    speculated that the disorder on Guam might be
             families who have mutations for spinocerebellar                                                             areas might increase the risk of PD.
                                                                  increase a person’s risk of developing the                                                                                   related to the consumption of animals that eat
             ataxia type 2. They also have worked with the
                                                                  disease. Even when genes are a factor in the           Another piece of evidence comes from                                  toxic cycad seeds found on that island. A 2002
             European Consortium on Parkinson’s Disease to
                                                                  disease, as with many familial cases, exposure         observations of people who have been                                  study found neurotoxins in flour from cycad
             complete a preliminary genetic analysis of 350
                                                                  to toxins or other environmental factors may           accidentally poisoned with the toxin MPTP                             plants and showed that mice fed the cycad flour
             pairs of siblings. This effort has identified five
                                                                  influence when symptoms of the disease appear          (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine),                       developed behavioral changes and neuron loss
             regions of the genome that appear especially
                                                                  and/or how the disease progresses.                     which sometimes contaminates street drugs.                            much like those seen in PD.
             significant and are being studied for potential
                                                                                                                         MPTP is structurally similar to some pesticides.                      Viruses are another possible environmental
             PD genes.                                            One of the primary pieces of evidence that
                                                                                                                         A breakdown product of MPTP, called MPP+,                             trigger for PD. People who developed
                                                                  environmental factors play a role in the
             Several additional large-scale efforts to identify                                                          is toxic to substantia nigra neurons — the
                                                                  development of PD is that the relative risk of the                                                                           encephalopathy after a 1918 influenza epidemic
             genes that play a role in PD are underway.                                                                  neurons that are affected in PD. MPTP
                                                                  disease is higher in industrialized countries than                                                                           were later stricken with severe, progressive
             NINDS is helping to sponsor PROGENI                                                                         produces a severe, permanent parkinsonian
                                                                  in less industrialized ones. In addition, studies                                                                            Parkinson’s-like symptoms. A group of
             (Parkinson’s Research: the Organized Genetics                                                               syndrome in affected people, and is now used to
                                                                  have found that farmers and other agricultural                                                                               Taiwanese women developed similar symptoms
             Initiative), which is looking at genes and other                                                            create animal models of PD. This discovery
                                                                  workers have an increased risk of developing PD.                                                                             after herpesvirus infections. In the latter case,
             potential PD risk factors in 900 pairs of siblings                                                          demonstrated that a toxic substance can damage
                                                                  Taken together, these studies suggest that toxic                                                                             the symptoms were linked to a temporary
             in North America. Among other discoveries, this                                                             the brain and produce parkinsonian symptoms.
                                                                  chemicals or exposure to other environmental                                                                                 inflammation of the substantia nigra, and later




18   Parkinson’s Disease: Challenges, Progress, and Promise                                                            “AUGUSTUS DIVINUS CONUBIUM                               NOKSH                 Parkinson’s Disease: Challenges, Progress, and Promise   19
             disappeared. However, these cases showed that                                                                           ■   Mitochondria, Oxidative Stress, and                 causes oxidative protein and DNA damage and
             viruses can sometimes affect the region of the                                                                              Programmed Cell Death                               increases susceptibility to free radical-induced
             brain damaged in PD. Other studies have found                                                                                                                                   cell death. It also leads to the same
                                                                                                                                         For years, mitochondria, the “energy plants” of
             evidence of activated immune cells and the                                                                                                                                      pathological, biochemical, and behavioral
                                                                                                                                         the cell, have been implicated in the
             accumulation of inflammation-associated                                                                                                                                         features seen in PD. Despite the fact that it
                                                                                                                                         development of PD. Mitochondria are unique
             proteins in PD. These changes might be                                                                                                                                          inhibits complex I throughout the brain,
                                                                                                                                         parts of the cell that have their own DNA
             triggered by viruses in some cases.                                                                                                                                             rotenone causes degeneration only in
                                                                                                                                         (mtDNA). This DNA is separate from the
                                                                                                                                                                                             dopamine neurons. Studies suggest that these
             Scientists are continuing to study environmental                                                                            genes found in the nucleus of every cell. Most
                                                                                                                                                                                             neurons are selectively vulnerable to complex I
             toxins such as pesticides and herbicides that can                                                                           research on the role of mitochondria in PD          impairment.
             cause PD symptoms in animals. Researchers                                                                                   points to abnormalities in the largest
                                                                                                                                         component of the mitochondrial energy               Scientists at the Duke University Udall Center
             supported by the NINDS and the National
                                                                                                                                         processing machinery — a group of proteins          have found evidence that specific genetic
             Institute on Aging have shown that exposing
                                                                                                                                         known as complex I.                                 variations in mtDNA, known as genetic
             rodents to the pesticide rotenone can cause
                                                                                                                                                                                             polymorphisms, can increase the risk of
             cellular and behavioral changes that mimic those                                                                            Several lines of research suggest a
                                                                  Problems with mitochondria, the structures that produce energy                                                             getting PD, while other mtDNA variations are
             seen in PD. Work supported by the National           for all cells, have been linked to the development of PD.
                                                                                                                                         mitochondrial role in protein aggregation,
             Institute of Environmental Health Sciences has                                                                              Lewy body formation, and neuronal death.
             shown that other agricultural compounds also                                                                                Mitochondria are major sources of free
                                                                  Along with genetic studies, these environmental
             can produce abnormalities in cells that are                                                                                 radicals — highly unstable molecules that
                                                                  studies lay the groundwork for a comprehensive
             similar to those seen in PD. This research is                                                                               damage components of the cell, such as
                                                                  understanding of how PD develops and how it
             supported through a program called the                                                                                      membranes, proteins, and DNA. This process
                                                                  might be prevented.
             Collaborative Centers for Parkinson’s Disease                                                                               is often referred to as oxidative stress.
             Environmental Research (CCPDER)                      ———————————————————————————————————————
                                                                                                                                         Oxidative stress-related changes, including
             Consortium. This program sponsors a variety of                                                                              free radical damage to DNA, proteins, and
             projects to examine how occupational exposure        Pathways to Parkinson’s                                                fats, have been detected in brains of PD
             to toxins and use of caffeine and other              Disease                                                                patients.
             substances may affect risk, and whether inherited
                                                                  Many researchers are working to understand the                         Research has shown that an array of toxins,
             genetic mutations may predispose certain people
                                                                  complex cellular activities and protein                                including MPTP and a pesticide and herbicide
             to developing PD after exposure to certain
                                                                  interactions that may lead to PD. Cellular factors                     called rotenone, can affect mitochondrial
             chemicals.
                                                                  that have been implicated in PD include                                complex I and increase the number of free
             Researchers at Rush-Presbyterian-St. Luke’s          mitochondrial interactions, oxidative stress,                          radicals it produces. Researchers at the
             Medical Center have examined whether prenatal        programmed cell death (a biochemical chain of                          Columbia University Udall Center have found         A dopamine-producing neuron that is undergoing programmed cell
             exposure to toxins may increase the risk of PD.      events by which cells self-destruct), excitotoxicity,                  that these free radicals can modify alpha-          death after exposure to the toxin 6-hydroxydopamine. The red
                                                                                                                                                                                             staining demonstrates that this is a dopamine neuron. The green
             They found that exposure to a bacterial toxin        protein aggregation, immune factors, and the                           synuclein in a way that causes it to aggregate      shows cleavage of a cellular protein called actin due to activity of
                                                                                                                                                                                             cell death proteins called caspases. The blue shows clumping of
             called lipopolysaccharide during development in      ubiquitin-proteasome protein degradation                               or clump together into minute fibers, called        the neuron's nuclear DNA, due to programmed cell death.
                                                                  system. While these factors represent many                                                                                 [Credit: Robert E. Burke, M.D., Columbia University, New York, NY.
             rats leads to the birth of animals with fewer than                                                                          fibrils.                                            Reprinted from Experimental Neurology, 2002, vol. 175, with
             the normal number of dopamine neurons. This          different lines of research, scientists are                                                                                permission from Elsevier.]

                                                                  beginning to understand how they may fit                               Investigators at Emory University have
             dopamine neuron loss persists into the animals’
                                                                  together to form a full picture of how PD                              modeled the process by which mitochondrial
             adulthood and increases with age, which mimics
                                                                  develops.                                                              defects produce oxidative stress by using
             the course of human PD.
                                                                                                                                         rotenone. In rats, chronic rotenone exposure




20   Parkinson’s Disease: Challenges, Progress, and Promise                                                                        “AUGUSTUS DIVINUS CONUBIUM                        NOKSH          Parkinson’s Disease: Challenges, Progress, and Promise          21
               associated with a lowered risk of the disorder.                                                             complex I activity make the most Lewy bodies.            Studies have suggested that UCH-L1 is
               They also have found that PD patients have                                                                  These findings show that PD mitochondrial                involved in the production of ubiquitin.
               more mtDNA variations than patients with                                                                    gene expression in a cybrid model is sufficient          Mutations in the parkin gene also interfere
               other movement disorders or Alzheimer’s                                                                     to spontaneously cause development of Lewy               with normal proteasomal function. Scientists
               disease. Researchers still need to define how                                                               bodies, providing strong support for the idea            at the Johns Hopkins University Udall Center
               these mtDNA variations may lead to PD.                                                                      that mitochondrial defects are key to the                have shown that treatment with a toxin that
                                                                                                                           development of sporadic PD.                              inhibits the ubiquitin-proteasome system
               Mitochondria also are thought to initiate
                                                                                                                                                                                    causes cells with mutant alpha-synuclein to be
               a process called programmed cell death.                                                                     Collectively, these results demonstrate that             susceptible to programmed cell death. This
               Programmed cell death, or apoptosis, is                                                                     mitochondrial-induced programmed cell                    cell death is accompanied by activation of
               necessary for normal embryonic development.                                                                 death contributes to the neuronal loss in PD.            caspases and by injury to the mitochondria.
               Scientists believe programmed cell death                                                                    This suggests that a possible treatment strategy         These changes could be blocked by
               allows cells to die without disturbing their                                                                for PD is to inhibit the cascade of events               cyclosporin A, which prevents the release of
               surrounding environment. However,
                                                                                                                           associated with programmed cell death.                   factors that activate caspases.
               programmed cell death also has been               suggest that programmed cell death plays a                Accordingly, scientists have discovered that
               implicated in many neurodegenerative              role in animal models for PD and that it also                                                                      Proteasome inhibition results in accumulation
                                                                                                                           inhibiting the release of cytochrome c and
               diseases and conditions, including PD.            may be involved in the human disease.                                                                              of molecules normally degraded by the
                                                                                                                           caspases from mitochondria with the drugs
               Several molecules are known to participate                                                                                                                           ubiquitin-proteasome pathway, such as p53,
                                                                 Scientists at the University of Virginia Udall            minocycline, pramipexole, and bongkreckic
               in the programmed cell death pathway; some                                                                                                                           NFKB, and Bax. These molecules help to
                                                                 Center have found that treatment with MPP+,               acid can protect cells from degeneration.
               promote cell survival while others promote                                                                                                                           promote programmed cell death.
                                                                 a toxic derivative of MPTP that inhibits                  These drugs may be clinically useful as
               cell death. An important topic in
                                                                 mitochondrial complex I, influences several               neuroprotectants to prevent PD.
               neuroscience research is the relationship
                                                                 molecules known to play a role in                                                                              ■   Protein Aggregation
               between these pro-death and pro-survival
               molecules.
                                                                 programmed cell death. Interestingly, some of         ■   Protein Degradation (Ubiquitin-
                                                                 these changes required activation of nitric                                                                        PD is characterized by fibrillar inclusions
                                                                                                                           Proteasome System)
               Mitochondria trigger programmed cell death        oxide, a free radical that is often expressed in                                                                   inside the cell called Lewy bodies. Lewy bodies
                                                                                                                           Another major area of PD research involves               include clumps (aggregates) of alpha-
               by releasing a substance called cytochrome c      injured or damaged cells. The role of nitric
                                                                                                                           the cell’s protein disposal system, called the           synuclein fibrils and other proteins. There is
               that activates proteins called caspases and       oxide in programmed cell death was
                                                                                                                           ubiquitin-proteasome system. Researchers                 strong evidence that this protein aggregation
               other cell death factors. Researchers believe     confirmed in an experiment in which cells
                                                                                                                           believe that if this disposal system fails to work       initiates a cascade of events that culminates in
               this may occur in response to oxidative stress    were treated with nitric oxide instead of
                                                                                                                           correctly, toxins and other substances may               neurodegeneration. If so, then inhibiting
               and mitochondrial toxins.                         MPP+. This treatment produced the same
                                                                                                                           build up to harmful levels, leading to cell              aggregation may be a way of treating PD.
                                                                 programmed cell death-related changes as
               The idea that programmed cell death plays a                                                                 death.
                                                                 MPP+. Other experiments have shown that                                                                            Many researchers are trying to learn the
               role in PD has been strengthened by studies
                                                                 mice lacking Bax and nitric oxide are                     In the ubiquitin-proteasome system, a                    function of Lewy bodies. Some studies argue
               performed at the Udall Centers. For example,
                                                                 protected against MPTP toxicity.                          chemical called ubiquitin acts as a “tag” that           that Lewy bodies are a byproduct of
               Columbia University scientists have discovered
               that, in an MPTP mouse model for PD, a pro-       Investigators at the University of Virginia Udall         marks certain proteins in the cell for                   degenerative processes within neurons, while
               cell death molecule known as Bax is abundant      Center also have developed hybrid cells, called           degradation by the proteasomes. The                      others suggest that Lewy bodies are a
               in dopamine-producing neurons of the              cybrids, in which mitochondrial DNA from PD               ubiquitin-proteasome system involves                     protective mechanism by which neurons lock
               substantia nigra. They also showed that mice      patients is placed in neuroblastoma (cancer)              interactions between several proteins,                   away abnormal molecules that might otherwise
               lacking the Bax gene were protected from          cells. These cybrids develop Lewy bodies just             including parkin and UCH-L1. This suggests               be harmful. In addition, some research
               brain damage caused by MPTP. These results        like those in the dopamine neurons of PD                  that disruption of the ubiquitin-proteasome              suggests that protofibrils – an intermediate
                                                                 patients. The cybrid cell lines with the lowest           pathway is part of the mechanism by which                step in the development of alpha-synuclein
                                                                                                                           mutations in these genes cause PD.                       fibrils – may be damaging to the cell.




22   Parkinson’s Disease: Challenges, Progress, and Promise                                                          “AUGUSTUS DIVINUS CONUBIUM                     NOKSH               Parkinson’s Disease: Challenges, Progress, and Promise   23
                                                                                       Researchers at the Massachusetts General                                                                    dying from excitotoxicity, and causes its
                                                                                       Hospital and Massachusetts Institute of
                                                                                       Technology Udall Center have found that
                                                                                                                                            There is strong                                        degradation. However, mutated parkin cannot
                                                                                                                                                                                                   trigger degradation of cyclin E. When the
                                                                                       alpha-synuclein aggregates lead to altered                evidence that                                     researchers increased the amount of parkin
                                                                                                                                                                                                   in dopamine neurons that were overstimulated
                                                                                       gene expression. By studying brain tumor
                                                                                       cells, they have found that overexpression of
                                                                                                                                            protein aggregation                                    with a drug called kainate, they found that the
                                                                                       several chaperone proteins – proteins that                  initiates a cascade of                          parkin reduced cyclin E and prevented the
                                                                                       help other proteins fold correctly – suppresses                                                             cells from dying. Reducing parkin in these
                                                                                                                                            events that culminates in
                                                                                       aggregation of alpha-synuclein. However, a                                                                  neurons increased the amount of cell death
                                                                                       mutant form of one of these proteins does not                neurodegeneration. If so,                      due to overstimulation. Interestingly, the
                                                                                                                                                                                                   researchers found excess cyclin E in the
                                                                                       decrease alpha-synuclein aggregation. Taken            then inhibiting aggregation may
                                                                                       together, these data suggest that molecular                                                                 dopamine neurons of some patients with
                                                                                       chaperones aid the handling of misfolded or
                                                                                                                                                  be a way of treating PD.                         sporadic PD as well as in patients with the
                                                                                       aggregated alpha-synuclein.                                                                                 inherited form of the disease that is linked
                                                                                                                                                                                                   to parkin.
                                                                                       Aberrations in the tau protein also may
               This drawing shows a Lewy body, a hallmark of PD, inside the cell       contribute to the protein aggregation seen in
               body of a neuron. Lewy bodies are clumps of alpha-synuclein and
                                                                                                                                                                                               ■   Inflammation
                                                                                       PD. Mayo Clinic Udall Center researchers             dysfunction of mitochondrial complex I, due
               other proteins.
                                                                                       have studied a line of mice, called hTau mice,                                                              Another interesting line of research on cell
                                                                                                                                            to gene mutations or exposure to toxins,
                                                                                       that overexpress the tau protein. These mice                                                                death in PD is focusing on the role of
               Researchers at the Brigham and Women’s                                                                                       causes a decrease in the cell’s energy supply.
                                                                                                                                                                                                   inflammation. Inflammatory responses occur
                                                                                       have neurofibrillary tangles containing both         This can make dopamine-producing neurons
               Hospital Udall Center have found that free                                                                                                                                          in the brain during disease and after many
                                                                                       synuclein and tau, and they exhibit premature        vulnerable to glutamate and to an increased
               radicals induce formation of alpha-synuclein-                                                                                                                                       types of injury. Studies in the last decade have
                                                                                       cell death early in life. Experiments show that      production of nitric oxide and other free
               dopamine compounds that stabilize                                                                                                                                                   shown that inflammation is common to a
                                                                                       synuclein and tau may interact to promote the        radicals. These changes cause oxidative stress,
               protofibrils. They also showed that the alpha-                                                                                                                                      variety of neurodegenerative diseases,
               synuclein in protofibrils binds to vesicles                             fibrillization of both proteins.                     cell death, and alpha-synuclein aggregation.
                                                                                                                                                                                                   including PD, Alzheimer's disease, HIV-1
               inside the cell, which could trigger cell death                                                                              Other evidence that excitotoxicity plays a role        associated dementia, and amyotrophic lateral
               and may explain the toxicity of alpha-                              ■   Excitotoxicity                                       in PD comes from a unique disease found in             sclerosis. The inflammation in these diseases
               synuclein and other fibril-forming proteins.                            Another common topic of PD research is               people from Guam. This disease features a              involves activation of microglia — specialized
               They are now studying purified proteins under                           excitotoxicity – overstimulation of nerve cells      combination of motor neuron disease,                   support cells in the brain that produce
               carefully controlled conditions in culture to                           that leads to cell damage or death.                  parkinsonian symptoms, and dementia, and               immune system signaling chemicals called
               determine what factors make the proteins                                In excitotoxicity, the brain becomes                 researchers believe it results from a toxin that       cytokines. Several studies by Columbia
               clump together and what structure the                                   oversensitized to the neurotransmitter               comes from cycad seeds and acts on glutamate           University scientists have implicated pro-
               aggregated proteins form. They are                                      glutamate, which increases activity in the           receptors. This suggests that excitotoxicity is        inflammatory molecules in cell death
               collaborating with other researchers to                                 brain.                                               central to the development of the                      following MPTP treatment. Inhibiting the
               develop agents that can help to image protein                                                                                parkinsonian disorder in Guam.                         inflammatory response with drugs or by
               aggregates using single photon emission                                 The dopamine deficiency in PD causes
                                                                                                                                                                                                   genetic engineering prevented some of the
               computed tomography (SPECT), and they are                               overactivity of neurons in the subthalamic           Studies at Columbia University have shown
                                                                                                                                                                                                   neuronal degeneration that normally occurs
               investigating whether PD may result from a                              nucleus, which may lead to excitotoxic               that the normal form of parkin may play a role
                                                                                                                                                                                                   with MPTP treatment.
               loss of normal alpha-synuclein function, rather                         damage there and in other parts of the brain.        in preventing excitotoxicity in PD. Scientists
               than from the accumulation of aggregates.                               In addition, researchers have found that             found that parkin tags a protein called cyclin
                                                                                                                                            E, which accumulates in neurons that are




24   Parkinson’s Disease: Challenges, Progress, and Promise                                                                              “AUGUSTUS DIVINUS CONUBIUM                NOKSH               Parkinson’s Disease: Challenges, Progress, and Promise   25
               Although inflammation can be damaging,
               studies have shown that activating immune
                                                                 Models for Parkinson’s                                categories: toxin-induced models that show how
                                                                                                                       environmental factors trigger parkinsonian
                                                                                                                                                                                6-Hydroxydopamine is another toxin that kills
                                                                                                                                                                                dopamine neurons, producing neuron death
               cells in specific ways also can protect nerve     Disease                                               symptoms, genetic models that show how gene              and parkinsonian symptoms in rats and mice.
               cells in animal models of spinal cord and         Much of the research that is leading to advances      defects can affect the brain, and spontaneously          The 6-hydroxydopamine model has been used
               brain injury. Recently, researchers at the        in understanding and treating PD would not be         occurring models that mimic some of the                  to evaluate potential PD therapies such as cell
               University of Nebraska Medical Center and at      possible without research models – cell lines and     features of PD. The cellular and behavioral              transplantation and neurotrophic factors.
               the Columbia University Udall Center in New       animals with features that mimic those of human       changes in toxin-induced models often overlap
                                                                                                                                                                                In the late 1990s, researchers at the Emory
               York successfully reduced the amount of           PD. Scientists use these models to investigate        with those that have gene defects, providing
                                                                                                                                                                                University Udall Center developed a new
               neurodegeneration in a mouse model for PD         questions such as what goes wrong in PD, how          further evidence that PD results from both
                                                                                                                                                                                model using a pesticide and herbicide called
               by using an experimental vaccine to modify        does cellular damage lead to behavioral               environmental and genetic factors.
                                                                                                                                                                                rotenone. Rotenone interferes with the
               the behavior of microglia in the brain.           symptoms, and how might potential new                                                                          activity of mitochondrial complex I. The
               Research at the Columbia University Udall         treatments affect the disease process. For            ■   Toxin-Induced Models                                 rotenone model is the first one that produces
               Center has shown that dopamine neurons in         example, levodopa, the drug most commonly                 The two best-known and widely used animal            selective neuron degeneration, Lewy bodies,
               brains from patients with PD have higher          used to treat PD, was shown to counteract PD              models in PD research are the MPTP model             and behavioral changes similar to those seen
               levels of an inflammatory enzyme called COX-      symptoms in an animal model before it was                 and the 6-hydroxydopamine model. MPTP is             in humans with PD. Rats exposed to rotenone
               2 than those of people without PD. COX-2          tested in humans.                                         a toxin that kills neurons in the substantia         develop large inclusions in substantia nigra
               triggers inflammation in damaged tissues. The                                                               nigra, causing symptoms that closely resemble        neurons that resemble Lewy bodies and
               scientists also found elevated levels of COX-2                                                              PD. Investigators discovered this reaction in        contain alpha-synuclein and ubiquitin.
               in a mouse model for PD. When they gave                                                                     the 1980s when heroin addicts in California          Rotenone-treated animals also develop
               these mice a drug called rofecoxib that                                                                     who had taken a street drug contaminated             bradykinesia, rigidity, and gait problems.
               inhibits COX-2, it doubled the number of                                                                    with MPTP developed severe parkinsonism.
                                                                                                                                                                                A common theme among the toxin-induced
               neurons that survived. Surprisingly, however,                                                               This discovery allowed researchers to simulate
                                                                                                                                                                                Parkinson models is that the toxins interfere
               the researchers did not find reduced                                                                        PD in animals for the first time.
                                                                                                                                                                                with activities of mitochondria. This
               inflammation with this drug. Instead, they
                                                                                                                                                                                knowledge has helped researchers develop
               found that the COX-2 inhibitor may protect
                                                                                                                                                                                additional models using different agents that
               neurons by preventing oxidative stress.
                                                                                                                                                                                act on mitochondria. For example, scientists
               Other studies suggest that the protein GSTO-                                                                                                                     have developed new rodent models by
               1, which has been linked to the age of onset of
                                                                                                                         Research at the                                        administering the pesticides paraquat and
               PD, may modify the inflammatory cytokine                                                                Columbia University                                      maneb, and by using a combination of MPTP
               interleukin-1 beta and therefore may reduce                                                                                                                      and the drug probenecid.
               the inflammation found in brains from people                                                               Udall Center
               with PD. It also may protect against                                                                    has shown that dopamine neurons                      ■   Genetic Models
               programmed cell death.
                                                                 Researchers at the Udall Centers and other                in brains from patients with PD                      The discoveries of genetic mutations in some
             ———————————————————————————————————————             institutions are continually refining existing                                                                 hereditary cases of PD have prompted the
                                                                                                                          have higher levels of an                              development of mouse models genetically
                                                                 research models and developing new ones.
                                                                 Current models range from specialized, hybrid         inflammatory enzyme called COX-2                         engineered to have mutations or deletions of
                                                                                                                                                                                PD genes. These so-called transgenic mice
                                                                 cells in culture dishes to rats and other animals       than those of people without PD.
                                                                 with the same genetic defects identified in                                                                    have become excellent models to study how
                                                                 humans with PD. These models fall into three                                                                   PD develops. Genetic engineering has also




26   Parkinson’s Disease: Challenges, Progress, and Promise                                                          “AUGUSTUS DIVINUS CONUBIUM                  NOKSH              Parkinson’s Disease: Challenges, Progress, and Promise   27
             Neuroprotection
             A major goal of PD research is the development of
             new therapies. Currently available treatments for              been used to develop cell lines that model               gait. The second spontaneous mouse model
             PD can effectively control motor symptoms of the               some of the processes that go awry in PD.                for PD is called the quaking mouse because it
             disease in the early stages, but they don’t slow or
                                                                                                                                     develops tremors soon after birth. Due to a
             halt the relentless progression of the disease. An             One example of a genetic model — human
                                                                                                                                     chromosomal deletion, these mice lack both
             explosion of discoveries during the past decade is             neuronal cells that contain mutant alpha-
                                                                                                                                     the parkin gene and the PACRG gene. Unlike
             now providing renewed hope of a therapy that will              synuclein — was developed by researchers at
                                                                                                                                     humans with parkin deletions, this mouse does
             prevent the underlying nerve damage in this disease            the Mayo Clinic Udall Center. These cells
             – a strategy known as neuroprotection.
                                                                                                                                     not have a loss of dopamine-producing
                                                                            develop levels of alpha-synuclein 25- to 50-fold
                                                                                                                                     neurons or a buildup of alpha-synuclein.
             The idea of neuroprotection for PD is not new. A               higher than in controls. When these cells are
                                                                                                                                     However, it may help investigators understand
             number of clinical studies have tested different               exposed to rotenone, unusual forms of
                                                                                                                                     the function of the parkin protein.
             compounds to see if they might stop the disease                synuclein begin to appear.                                                                                  therapies for many neurological diseases.
             progression. Some studies initially showed small
                                                                                                                                                                                        Researchers are investigating whether
             positive effects, but most of these studies included a
                                                                            Researchers at the University of Virginia Udall
                                                                            Center have developed hybrid cells, called
                                                                                                                                 Therapeutic Approaches                                 neurotrophic factors can halt dopamine cell
             limited number of patients and did not examine the
                                                                            cybrids, that have mitochondrial DNA from            While levodopa and other drugs can provide             degeneration and help to repair brain cells in
             effects of these therapies over a long period of time.
                                                                            PD patients inserted into tumor cells. These         initial relief from parkinsonian symptoms, none        PD. One such drug, glial cell line-derived
             In addition, researchers have no good way of
             measuring whether these or other compounds truly               cybrids develop Lewy bodies just like those in       of these treatments halts the loss of dopamine         neurotrophic factor (GDNF), has been shown
             prevent neuronal damage. Consequently,                         the dopamine neurons of PD patients. Before          neurons and nerve fibers. Thus, new treatments         to protect dopamine neurons and to promote
             researchers cannot be sure that the positive effects           this model was developed, researchers needed         that slow the underlying disease are desperately       their survival in models of PD. Researchers at
             seen in these studies are due to neuroprotection or            brain samples from PD patients in order to           needed. As knowledge about this disorder grows,        the University of Kentucky Udall Center have
             if they represent short-term effects on symptoms.              study Lewy bodies.                                   potential new ways of preventing and treating          helped to develop a technique for delivering
             Recently, a wealth of new information about how                                                                     the disease are being revealed. Promising              these molecules directly into the brain. When
                                                                            Researchers also have developed strains of
             neurons may be damaged in PD has allowed                                                                            treatments in development include new drug             GDNF was given for a period of 3 to 6 months,
                                                                            mice with mutations in the alpha-synuclein
             investigators to identify many potential new ways of                                                                therapies (including neurotrophins,                    it prompted repair of dopamine neurons and
                                                                            and parkin genes. Mice with alpha-synuclein
             treating this disease, including nerve growth factors,                                                              neuroprotectants, and immunotherapy), surgical         improvement in their function. It also seemed
                                                                            mutations develop an adult-onset
             anti-inflammatory drugs, and antioxidants. To                                                                       therapies, cell transplantation, gene therapy, and     to protect damaged dopamine cells from
                                                                            neurodegenerative disease characterized by
             overcome some of the problems that have plagued                                                                     transcranial magnetic stimulation.                     further degeneration. The researchers are
             previous studies, in 2002 an NINDS-sponsored                   movement dysfunction and pathological
                                                                                                                                                                                        now conducting an FDA-approved Phase I
             committee conducted a systematic review of data on             aggregation of alpha-synuclein. Mice without
             59 potential neuroprotective agents for PD. This               the parkin gene show abnormal regulation of
                                                                                                                                 ■   Drug Therapy
             committee ultimately selected four of the most                 dopamine in the striatum and impairments in              Current treatment for PD relies primarily on
             promising drugs for study in a series of clinical trials
             known as Neuroprotection Exploratory Trials in
                                                                            behavioral tests that require muscle
                                                                            coordination. Researchers are now working to
                                                                                                                                     drugs to control the symptoms. While these
                                                                                                                                     drugs work well early in PD, they progressively
                                                                                                                                                                                          In recent years,
             Parkinson’s Disease (NET-PD). These drugs —                    develop animal models without normal DJ-1                fail as more nerve cells die. Drug-induced        Parkinson’s research
             coenzyme Q10, GPI-1485, creatine, and minocycline
             — are now being tested at more than 40 centers in
                                                                            function.                                                dyskinesias and fluctuations of motor
                                                                                                                                     symptoms also limit drug benefits in many
                                                                                                                                                                                              has advanced to
             the United States and Canada. Researchers hope
             that this new approach to selecting and testing
                                                                        ■   Spontaneously Occurring Models                           cases.                                               the point
             compounds will lead to the first proven                        Scientists have identified two spontaneously             Neurotrophic factors – molecules that support        that halting the progression
             neuroprotective therapy or therapies for PD and                occurring strains of mice that may be useful as          survival, growth, and development of brain
                                                                                                                                     cells – are one focus of new drug research.
                                                                                                                                                                                            of PD, restoring lost function,
             revolutionize treatment of this disease.                       models for PD. The first strain is known as
                                                                            reeler mice. These mice have reduced                     These chemicals are being studied as potential    and even preventing the disease
                                                                            dopamine activity in the striatum and several                                                                are all considered realistic goals.
                                                                            other brain areas, which results in an impaired




28   Parkinson’s Disease: Challenges, Progress, and Promise                                                                    “AUGUSTUS DIVINUS CONUBIUM                   NOKSH           Parkinson’s Disease: Challenges, Progress, and Promise   29
                                                                  for PD. FGF-2 is essential for the long-term        Investigators at the Harvard University Medical        Parkinson's Disease Neuroprotection Clinical
                                                                  survival of dopamine neurons, and impaired          School and McLean Hospital Udall Center,               Centers to study these and other potential
                                                                  FGF-2 function may be a common underlying           along with other researchers, have identified          neuroprotectant drugs.
                                                                  cause of the neuronal degeneration in PD.           genes that are neuroprotective in a variety of
                                                                                                                                                                             A variety of other compounds have been
                                                                  FGF-2 also stimulates the survival of dopamine      systems, from cell culture to primate models of
                                                                                                                                                                             tested as potential therapies for PD. Some
                                                                  neurons when they are transplanted into the         PD. Increasing the expression of these genes,
                                                                                                                                                                             studies have found that proteins called alpha-2
                                                                  brain.                                              or mimicking their function with drugs, may
                                                                                                                                                                             adrenergic receptors play a role in the
                                                                                                                      be a new way to prevent brain damage in PD.
                                                                  Another developing area of PD drug research                                                                dyskinesias that commonly develop in PD
                                                                  is neuroprotection – finding ways to prevent        Therapies that change how the immune                   patients treated with levodopa. Blocking these
                                                                  the ongoing degeneration of dopamine                system reacts also may protect nerve cells in          receptors has been successful in reducing
                                                                  neurons that is a hallmark of PD. In 2002, a        PD. For example, animal studies of the                 dyskinesia in animal models of PD. An alpha-
                                                                  multicenter clinical trial suggested that a         antibiotic minocycline, which has been used in         2 adrenergic receptor blocker called JP-1730 is
                                                                  compound called coenzyme Q10 (also known            humans for decades, have shown that it has             now being studied in an NINDS-sponsored
                                                                  as ubiquinone), which is believed to improve        anti-inflammatory effects in the brain and that        clinical trial to determine if it is safe and
               dose-escalation trial of chronic GDNF              mitochondrial function, can slow the rate of        it may prevent programmed cell death. In               effective against dyskinesia and/or other PD
               administration in ten patients with advanced       deterioration in PD. Another early clinical         another study, researchers at the University of        symptoms. Another drug, levetiracetam, is
               PD at the University of Kentucky Medical           trial tested a compound called GPI-1485,            Nebraska Medical Center and the Columbia               also being tested in a controlled clinical trial
               Center. The investigators also are studying the    which acts as a neurotrophin, and found that        University Udall Center in New York have               to see if it can reduce dyskinesias in
               mechanisms by which neurotrophic factors           it was well-tolerated and appeared to slow the      shown that an experimental vaccine using a             Parkinson’s patients without interfering with
               affect the function of dopamine neurons and        loss of dopamine nerve terminals. A third           drug called copolymer-1 can modify the                 other PD drugs. Levetiracetam, which is
               the long-term effects of these proteins on         drug, creatine, which affects mitochondrial         behavior of supporting (glial) cells in the            approved by the FDA to treat epilepsy, is not
               brain systems. Another clinical trial in the       function and acts as an antioxidant, prevents       brain so that their responses are beneficial to        an alpha-2 adrenergic receptor blocker.
               United Kingdom used tiny pumps implanted           MPTP-induced neuronal damage in rats.               the nervous system rather than harmful. The            Instead, researchers believe it may work by
               under the skin to deliver GDNF and has                                                                 vaccine reduced the amount of                          interfering with the neurotransmitter GABA
               shown promising initial results.                                                                       neurodegeneration in a mouse model for PD.             (gamma-amino butyric acid).
                                                                                                                      Another study by neurologists at the Columbia
               GDNF is one of a family of compounds called         While levodopa and                                 University Udall Center has shown that a drug
                                                                                                                                                                             Another clinical trial is studying GM1
                                                                                                                                                                             ganglioside, a chemical which contributes to
               neurotrophins or nerve growth factors. Many
               of these neurotrophins are potential therapies    other current drugs                                  called rofecoxib, which inhibits an
                                                                                                                      inflammatory enzyme called COX-2, prevents
                                                                                                                                                                             cell growth, development, and repair, to
               for PD. Examples include neurotrophin-4
               (NT-4), brain-derived neurotrophic factor
                                                                      can provide                                     about half of the dopamine neuron death in a
                                                                                                                                                                             determine if this drug can improve symptoms,
                                                                                                                                                                             delay disease progression, and/or partially
                                                                                                                      mouse model for PD.
               (BDNF), and fibroblast growth factor 2 (FGF-      initial relief from parkinsonian                                                                            restore damaged brain cells in PD patients.
               2). One study has shown that GDNF and NT-4                                                             NINDS is now supporting a series of pilot              Preliminary studies have shown beneficial
                                                                   symptoms, none of these
               can protect dopamine neurons in culture                                                                clinical trials to test the effects of four of these   effects of this drug on the dopamine system in
               from oxidative stress. Studies in mice have              treatments halts the loss of                  potential neuroprotectants — coenzyme Q10,             animal models.
               shown that BDNF can increase the number of           dopamine neurons and nerve                        GPI-1485, creatine, and minocycline — in
                                                                                                                                                                             Several chemicals are being tested as potential
               dopamine receptors produced by brain cells.                                                            people with early, untreated PD (see
               This may increase the brain’s responsiveness
                                                                 fiber. Thus, new treatments that                     Neuroprotection, p. 28). This series of clinical
                                                                                                                                                                             treatments for the mood disorders that
                                                                                                                                                                             sometimes occur in people with PD. One
               to dopamine. Other studies have shown that            slow the underlying disease                      trials is called Neuroprotection Exploratory
                                                                                                                                                                             clinical trial is investigating whether a drug
               BDNF protects dopamine neurons from                                                                    Trials in Parkinson's Disease (NET-PD).
                                                                              are desperately needed.                 NINDS is also supporting a network of
                                                                                                                                                                             called quetiapine can help to reduce psychosis
               damage in the 6-hydroxydopamine rat model
                                                                                                                                                                             and/or agitation in PD patients with




30   Parkinson’s Disease: Challenges, Progress, and Promise                                                        “AUGUSTUS DIVINUS CONUBIUM                   NOKSH            Parkinson’s Disease: Challenges, Progress, and Promise   31
                 dementia, and in dementia patients with                                                               However, very little is known about these           Yet another transplantation approach employs
                 parkinsonian symptoms. Another clinical                                                               different types of cells, and researchers need      retinal pigment epithelial cells, which produce
                 study is examining whether s-adenosyl-                                                                to better understand the fundamental biology        dopamine and can be cultivated in large
                 methionine (SAM-e), a food supplement that                                                            of stem cells and neural precursor cells before     numbers. These cells are attached to
                 improves dopamine transmission, can help to                                                           such technologies can be used to treat PD in        microscopic gelatin beads and implanted into
                 alleviate depression in patients with PD.                                                             a safe, effective, and predictable manner.          the brains of PD patients as part of a clinical
                                                                                                                                                                           trial to determine if they can enhance brain
                 A number of clinical studies have suggested                                                            In several early clinical studies, grafting of
                                                                                                                                                                           levels of dopamine and thus reduce the
                 that cholinesterase inhibitors, which are                                                             fetal-derived dopamine tissue led to an
                                                                                                                                                                           symptoms of PD.
                 commonly used for Alzheimer’s disease, can                                                            increase in dopamine production in the
                 also have a positive effect on cognition,                                                             brains of people with advanced PD.                  One of the key problems with stem cell
                 psychiatric symptoms, and global function in                                                          Unfortunately, these studies showed few long-       transplantation is to control and manage
                 patients with PD plus dementia. Additional                                                            term benefits and led to unanticipated side         how the cells become dopamine-producing
                 clinical studies are now underway.                                                                    effects such as dyskinesias. These problems         neurons. Recently, investigators found that
                                                                                                                       preclude widespread use of this particular          genetically engineering mouse embryonic
             ■   Surgical Therapies                                                                                    approach.

                 Surgical treatments for PD, especially
                                                                   Investigators at the                                 Investigators at the Harvard University
                 pallidotomy and deep brain stimulation               Harvard University                               Medical School and McLean Hospital Udall
                 (DBS), are important options for improving
                 the lives of people affected by this disease.
                                                                    Medical School and                                 Center have injected mouse embryonic stem
                                                                                                                       cells directly into the rat brain and found that
                 Investigators are continuing to evaluate these    McLean Hospital                                     these cells can develop into dopamine
                                                                                                                       neurons. They also have shown that they can
                 procedures in patients.
                                                                          Udall Center,                                generate dopamine neurons from rodent
                 NINDS is supporting a great deal of research
                 about DBS, including studies that aim to
                                                                        along with other researchers,                  embryonic stem cells. They are now testing
                                                                                                                       primate and human embryonic stem cells in
                 improve the technology for DBS and a large-       have identified genes that are
                                                                                                                       animal models of PD with a goal of moving
                 scale clinical trial done in collaboration with
                                                                   neuroprotective in a variety of                     this therapy into human clinical trials.
                 the Department of Veterans Affairs that
                 compares DBS to the best medical                  systems, from cell culture to                        Some researchers have found that muscle
                 management with drugs. Investigators are                primate models of PD.                         progenitor cells isolated from the muscle of
                 studying normal brain circuits in order to find                                                       adult rats can be induced to form cells with
                 the best placement for the electrodes in the                                                          neuron-like properties. Although it is unclear      stem cells to produce a protein called Nurr1
                 brain and the best stimulation patterns for                                                           whether these cells can actually function like      led to a four- to five-fold increase in the
                 DBS. In addition, they are working to develop     researchers are working to develop cell             neurons, this finding raises the possibility that   number of dopamine neurons produced in
                 a screening tool to identify PD patients who      transplantation therapies. In addition to           muscle tissue may be a source of progenitor         culture. Nurr1 also enhanced the neurons’
                 will get the most benefit from DBS.               embryonic stem cells, which have the potential      cells to treat diseases of the nervous system. In   ability to produce and release dopamine.
                                                                   to become any kind of cell in the body,             another study, researchers transplanted             The identification of this important factor in
                                                                   researchers are experimenting with adult            dopamine-producing brain cells from pigs            dopamine neuron development paves the way
             ■   Cell Transplants
                                                                   neural stem cells, neural precursor cells, and      into the brains of PD patients and found some       for new therapies that require management of
                 Cell replacement through transplantation is
                                                                   fetal-derived dopamine-producing neurons.           evidence of clinical improvements. The              stem cell differentiation.
                 an emerging approach for repairing the
                                                                   Even cells derived from non-neuronal tissue         immune systems of these patients had to be
                 damage PD causes in the brain. Many
                                                                   are being considered for PD research.               suppressed so that the grafted pig cells would
                                                                                                                       not be rejected..




32   Parkinson’s Disease: Challenges, Progress, and Promise                                                         “AUGUSTUS DIVINUS CONUBIUM                 NOKSH           Parkinson’s Disease: Challenges, Progress, and Promise   33
                                                                       The NIH has established an NIH Stem Cell             The NINDS is supporting a consortium called
                                                                       Unit to help characterize stem cells for future      the Parkinson's Disease Gene Therapy Study
                                                                       clinical use and to learn how to control             Group, which is investigating dopaminergic
                                                                       differentiation in federally approved                enzyme gene therapy and neurotrophic gene
                                                                       stem cell lines.                                     therapy in animal models of PD. This
                                                                                                                            consortium includes many Parkinson's experts
                                                                   ■   Gene Therapy                                         from research centers across the country. The
                                                                                                                            investigators are comparing different genes
                                                                       Gene therapy offers great potential for PD and
                                                                                                                            and testing different gene delivery
                                                                       many other brain disorders. With this type of
                                                                                                                            approaches. As part of this project, researchers
                                                                       therapy, viruses are engineered to deliver
                                                                                                                            at Northwestern University in Illinois have
                                                                       genes that increase the supply of dopamine,
                                                                                                                            developed a viral gene vector with a special
                                                                       prevent cell death, or promote regeneration
                                                                                                                            modification that allows the introduced gene
                                                                       of neurons. Although this approach is
                                                                                                                            to be temporarily “turned off” when the
                                                                       promising, researchers need to develop
                                                                                                                            patient is given a small dose of a specific
                                                                       efficient and safe means to deliver genes to
                                                                                                                            antibiotic. The development of this vector
                                                                       brain cells in order for gene therapy to be
                                                                                                                            should permit researchers to better control
                                                                       used in humans. Many researchers are
                                                                                                                            the delivery of genes once the vector is in the
                                                                       working to develop better viral vectors –
                                                                                                                            host. The researchers are now conducting           The most common gene therapy strategy uses viruses to carry
                                                                       viruses that can carry genes into the targeted                                                          beneficial genes into targeted cells. Here a virus is shown attaching
                                                                                                                            safety and toxicity studies of this new vector     to a host cell. The viral DNA, which is contained in the capsule at
               Other studies have shown that embryonic stem            cells – and to find ways of improving the
                                                                                                                            with the hope that it will prove safe enough       the top of the virus, will be injected into the cell. Under normal
               cells also form dopamine cells if they are              transfer of these vectors to the brain. As                                                              circumstances, the viral DNA will then “hijack” the cell and force it to
                                                                                                                            for testing in humans.                             produce more viruses. In gene therapy, however, the virus’ disease-
               transplanted directly into the brain and that           researchers accumulate more information                                                                 causing genes are replaced with the beneficial gene, and the virus
                                                                                                                                                                               injects that gene into the cell.
               these cells can reduce motor dysfunction and            about the safety and efficacy of different           NINDS-funded investigators have found that
               normalize dopamine production in an animal              delivery systems, research on gene therapy for       using a genetically modified virus to deliver
               model of PD. A low cell concentration of                PD can move forward.                                 specific growth factors to primates with a
               embryonic stem cells increases the influence                                                                 parkinsonian condition leads to dramatic
               of the host brain, increasing the number of                                                                  improvements in symptoms. Another group            causing them to convert levodopa to
               dopamine cells produced and reducing the                                                                     of researchers has shown that engineering a        dopamine. This essentially mimics the
                                                                                                                            virus to deliver enzymes important for the
               likelihood that the stem cells will develop into
               tumors.
                                                                     Cell replacement                                       production of levodopa can have beneficial
                                                                                                                                                                               function of the dopamine neurons that are
                                                                                                                                                                               lost in PD and may reduce the need for drugs

               Researchers at NINDS are studying signals that
                                                                  through transplantation                                   effects in a rat model of PD.                      that increase the level of dopamine in the
                                                                                                                                                                               brain.
               control the proliferation and differentiation of    is an emerging approach                                  Investigators also are experimenting with the
                                                                                                                            gene for 1-amino acid decarboxylase (AADC),
               stem cells. Along with other researchers, they                                                                                                                  Researchers also are experimenting with gene
               have shown that stem cells can generate nerve
                                                                      for repairing the damage PD                           an enzyme that converts levodopa into              therapy to deliver the GDNF gene to the
               cells that are capable of establishing              causes in the brain. Many                                dopamine. Research in animal models has            brain. In a monkey model, GDNF prevented
               connections (synapses) with other neurons.                                                                   shown that neurons in the striatum can be          dopamine neurons from dying, and the
                                                                  researchers are working to                                given the AADC gene using a viral vector,          monkeys regained some of their lost motor
               They also have shown that mouse embryonic
               stem cells can be manipulated to generate              develop cell transplantation                                                                             skills.
               central nervous system stem cells.                           therapies.




34   Parkinson’s Disease: Challenges, Progress, and Promise                                                              “AUGUSTUS DIVINUS CONUBIUM                NOKSH             Parkinson’s Disease: Challenges, Progress, and Promise               35
                                                                    controls functions such as blood pressure
             ■   Transcranial Magnetic Stimulation
                                                                    and heart rate. Individuals with PD often
                 Transcranial magnetic stimulation (TMS) is a
                                                                    experience symptoms such as orthostatic
                 technique that uses an insulated wire coil
                                                                    hypotension, or a drop in blood pressure
                 placed on the scalp to create a magnetic pulse
                                                                    upon standing, and the loss of sympathetic
                 that stimulates the brain. Investigators at
                                                                    nerves observed in this study may help to
                 NINDS are conducting clinical studies of TMS
                                                                    explain why this occurs.
                 and a related technique called transcranial
                 electrical polarization to learn if they might     In another study, researchers at the Columbia
                 have beneficial effects for people with PD.        University Udall Center have developed a
                 Studies have suggested that these techniques       method to track the progression of PD in
                 might be able to alter brain circuits in           patients at early stages of the disease using
                 beneficial ways. Some studies of TMS have          PET imaging techniques. These techniques
                 shown small effects on bradykinesia. TMS also      allow the researchers to examine dopamine
                 may be able to produce beneficial effects on       transporter binding, a measure of dopamine
                 gait and freezing.                                 levels, in the brains of people with PD and in
                                                                    healthy individuals. They have found that the
                                                                    onset of motor symptoms in people with PD is
                 Other Clinical Research                            accompanied by a 70 percent loss of
                                                                    dopamine in the brain. They also studied how        Some investigators are using neuroimaging of      Another important area of research aims to
                 While many clinical studies are investigating
                                                                    DBS changes activity in the brain. PET              dopamine and other chemicals in the brain to      improve rehabilitation and assistive technology
                 potential new treatments, clinical research also
                                                                    imaging of PD patients shows hyperactivity in       assess how the brain functions during             for people with PD. This research includes
                 can help to reveal better ways of diagnosing
                                                                    some brain regions prior to treatment,              cognition, sleep, and activity, and how DBS       studies of ways to improve posture and
                 and tracking PD.
                                                                    probably resulting from the loss of dopamine.       changes these functions. Another NINDS-           movement in people after they have been
                 In a series of studies, intramural researchers     DBS suppresses this hyperactivity. The              sponsored clinical study is using single photon   treated with DBS, studies on the effects of
                 at NINDS have found evidence that PD causes        stimulation also was accompanied by                 emission computed tomography (SPECT) and          exercise, studies of voice training, and
                 widespread damage to the sympathetic               improvement in motor function. This study           magnetic resonance imaging (MRI) to               development of an assistive device for people
                 nervous system, in addition to the substantia      helped to reveal how DBS may improve                examine the brain’s nicotine receptors, which     with vocal impairment. Other studies are
                 nigra. The sympathetic nervous system              symptoms in PD.                                     respond to the neurotransmitter acetylcholine.    focusing on treatments for cognitive
                                                                                                                        Previous studies have shown changes in the        impairment, memory problems, urinary tract
                                                                                                                        acetylcholine system in PD patients. These        dysfunction, sleep disorders, and micrographia
                                                                                                                        changes tend to be more pronounced in             (abnormally small handwriting due to
                                                                                                                        patients with dementia. The current study         difficulty with fine motor control).

                 Researchers at the                                                                                     should clarify how acetylcholine interacts with
                                                                                                                        other neurotransmitters in people with PD,
                              Columbia University Udall Center                                                          and may lead to new ways of diagnosing or
                                                                                                                        treating the disease.
                                              have developed a method to track the progression of PD
                                                                                                                        Other researchers are assessing quality of life
                     in patients at early stages of the disease using PET imaging techniques.
                                                                                                                        in patients with PD and other neurological
                                                                                                                        conditions and working to develop a global
                                                                                                                        statistical test for diagnosing PD.




36   Parkinson’s Disease: Challenges, Progress, and Promise                                                          “AUGUSTUS DIVINUS CONUBIUM                 NOKSH         Parkinson’s Disease: Challenges, Progress, and Promise   37
                                                                                                          Conclusion




                                                                                                       Conclusion and Future Directions

                 Another important area of research
                                                                                                       W       hile Parkinson's is a complex disease, research has progressed a great deal in recent years.
                                                                                                               Halting the progression of PD, restoring lost function, and even preventing the disease
                                                                                                       are now considered realistic goals. Much of the recent progress has been funded by the NINDS
                              aims to improve rehabilitation                                           through the Udall Parkinson’s Disease Research Centers of Excellence and many other grants.
                             and assistive technology for people with PD. This research includes       Researchers have identified many susceptibility genes and potential environmental risk factors for
                 studies of ways to improve posture and movement in people after they                  PD, and these studies are contributing to a much-improved understanding of how PD develops.
                   have been treated with DBS, studies on the effects of exercise, studies of          A number of promising therapies have been developed as a result of this understanding and are
                                 voice training, and development of an assistive device for people     now being tested in humans and in animal models. Continuing studies to improve
                              with vocal impairment.                                                   understanding of the underlying biology of the disease will lead to better ways of relieving the
                                                                                                       symptoms of Parkinson's patients and ultimately preventing or halting the disease.




38   Parkinson’s Disease: Challenges, Progress, and Promise                                          “AUGUSTUS DIVINUS CONUBIUM          NOKSH                          Parkinson’s Disease: Challenges, Progress, and Promise   39
                      Morris K. Udall Centers of Excellence
                      for PD Research

                 Overview                                                 Recently, the NINDS has funded a Parkinson’s
                                                                          Disease Data Organizing Center (PD-DOC) to collect
                                                                                                                                  Future                                               Udall Centers Across the Country
                 As part of its efforts to defeat PD, the NINDS           information from all PD centers, thus allowing for      NINDS is committed to continuing and                 Brigham and Women's Hospital
                 supports a number of Centers of Excellence for           standardized data, resources, and reagents to be                                                             Boston, Massachusetts
                                                                                                                                  enhancing the tradition of scientific excellence
                 Parkinson’s Disease Research throughout the              shared widely within the PD community. The                                                                   Director: Peter Lansbury, Jr., Ph.D.
                                                                                                                                  that has been fostered by the Udall Centers over
                 country. The Centers’ multidisciplinary research         NINDS hopes that research at these Centers of           the past 5 years. To this end, NINDS and the         Columbia University
                 environment allows scientists to take advantage of       Excellence will lead to clinical trials of new          National Institute of Environmental Health           New York City, New York
                 new discoveries in the basic and technological           treatments in patients with PD.
                                                                                                                                  Sciences released a Program Announcement in          Director: Robert Burke, M.D.
                 sciences that can lead to clinical advances, and, in
                 addition, allows for collaborations across centers                                                               October 2002 to renew the Institute’s                Duke University
                 which can expedite the pace of research. Most of         History                                                 commitment to the program and to aid current         Durham, North Carolina
                                                                                                                                  and prospective Udall Center investigators in        Director: Jeffery M. Vance, M.D.
                 the Centers also provide state-of-the-art training for   On November 13, 1997, the President of the United
                 young scientists who are preparing for research          States signed into law The Morris K. Udall              developing competitive applications for funding.     Harvard University Medical School
                 careers investigating PD and related neurological        Parkinson’s Disease Research Act (P.L. 105-78). Prior   NINDS has also announced an increase in funds        and McLean Hospital
                 disorders. Some of the topics that the Centers           to the passage of this Act, the NINDS had already       that may be allotted to the Centers to fund the      Belmont, Massachusetts
                 address include:                                         recognized the need to establish Centers of                                                                  Director: Ole Isacson, M.D.
                                                                                                                                  types of clinical research needed to capitalize on
                                                                          Excellence in PD research, and as a result, released    the increasing number of findings in the basic       Johns Hopkins University School of Medicine
                 • Neuronal and mitochondrial genetic studies to
                                                                          an initial Request for Applications (RFA) to solicit                                                         Baltimore, Maryland
                   elucidate key proteins involved in                                                                             sciences. In addition, NINDS staff members are
                                                                          these centers. Of the applications that were received                                                        Director: Ted M. Dawson, M.D., Ph.D.
                   neurodegeneration and to determine genetic                                                                     working with the research community to develop
                                                                          in response to this RFA, NINDS selected three
                   differences between familial and sporadic PD                                                                   a standard, minimum amount of clinical               Massachusetts General Hospital
                                                                          centers for funding. Following the passage of the                                                            and Massachusetts Institute of Technology
                 • Studies of the structure and function of proteins
                                                                                                                                  information to be collected about each PD
                                                                          Udall Act, NINDS issued a second RFA for PD                                                                  Boston, Massachusetts
                   involved in cell death and degeneration                Centers of Excellence and funded eight additional       patient, allowing information from different
                                                                                                                                                                                       Director: Anne Young, M.D., Ph.D.
                                                                          grants. All of the Udall Centers focus on scientific    studies to be compared and combined. NINDS
                 • Studies of the anatomical structures and brain                                                                                                                      Mayo Clinic
                                                                          research designed to improve the diagnosis and          believes that all of these efforts will help to
                   chemicals involved in PD                                                                                                                                            Jacksonville, Florida
                                                                          treatment of patients with PD and related               strengthen the Udall program in the coming
                                                                                                                                                                                       Director: Dennis W. Dickson, M.D.
                 • Studies to improve animal models of PD                 neurodegenerative disorders and on research to          years.
                                                                          gain a better understanding of the fundamental                                                               Northwestern University
                 • Imaging studies involving PET
                                                                          cause(s) of the disease. The Centers have lived up to
                                                                                                                                                                                       Chicago, Illinois
                 • Studies of PD risk factors in people of different                                                                                                                   Director: D. James Surmeier, Ph.D.
                                                                          their expectation to foster an environment that
                   gender and ethnicity                                   enhances the research effectiveness of investigators                                                         University of California, Los Angeles
                                                                          in a multidisciplinary setting, utilizing specialized                                                        Los Angeles, California
                 • Animal studies testing possible PD treatments,
                                                                          methods relevant to the study of these disorders.                                                            Director: Marie-Francoise S. Chesselet, M.D.
                   such as neuroprotective therapies, implantation of
                   genetically engineered cells, DBS, and levodopa        The Centers of Excellence for Parkinson’s Disease                                                            University of Kentucky
                   drug therapy.                                          Research program was developed in honor of              NINDS is committed                                   Lexington, Kentucky
                                                                                                                                                                                       Director: Greg A. Gerhardt, Ph.D.
                 These Centers have contributed greatly to the PD
                 research field. Their many significant achievements
                                                                          former Congressman Morris K. Udall, who died in
                                                                          1998 after a long battle with PD. Mr. Udall was
                                                                                                                                        to continuing                                  University of Pittsburgh
                 include discovery of the UCH-L1, PACRG, and GSTO-        elected to the U.S. House of Representatives in 1961     and enhancing                                       Pittsburgh, Pennsylvania
                                                                          in a special election to replace his brother Stewart                                                         Director: Michael J. Zigmond, Ph.D.
                 1 genes, development of the rotenone rat model for                                                                 the tradition of scientific
                 PD, the discovery that PD mitochondrial gene             who left the position to become President John F.                                                            University of Virginia
                 expression is sufficient to spontaneously cause          Kennedy's Secretary of the Interior. Udall was            excellence that has been                           Charlottesville, Virginia
                 development of Lewy bodies in cells, and the first       diagnosed with PD in 1979, but he remained active                                                            Director: G. Fred Wooten, M.D.
                                                                          as a Member of Congress until May 1991.
                                                                                                                                  fostered by the Udall Centers
                 United States clinical trial of chronic GDNF                                                                                                                          Coordinating data and resources from all these centers:
                 administration in patients with advanced PD.                                                                          over the past 5 years.                          Parkinson’s Disease Organizing Center
                                                                                                                                                                                       University of Rochester
                                                                                                                                                                                       Rochester, New York
                                                                                                                                                                                       Director: Roger Kurlan, M.D.


40   Parkinson’s Disease: Challenges, Progress, and Promise                                                                                                                                          Parkinson’s Disease: Challenges, Progress, and Promise   41
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


NIH Publication No. 05-5595
November 2004

								
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