Neurological Disorders by vRaGRt

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									                                                             daguerreotype
  Brain Damage

The Boston Post for September 21, 1848




                                                                  Phineas P. Gage
                                                          (July , 1823 – May 21, 1860)
   1st case widely cited in medicine to infer that brain function can alter personality
                                        ~1850
Pattern of injury is very localized
         -blood vessels spared

         - only frontal cortex damaged

         - loss of 1 eye




   Consciousness regained in days

   - personality/behavior dramatically altered

             - child-like, profane, disinhibited, inappropriate, inability to control anger and
               emotions.


   Referred to today as classic “hypofrontality”

             -common with traumatic injury to the frontal lobes

“Social Recovery”          Until 2008, commonly thought that he demonstrated these
                           symptoms until his death, 12 years later. But this was not true…
Brain Damage


  1.    Traumatic brain injury
  2.    Strokes
  3.    Alzheimer’s Disease
  4.    Parkinson’s Disease


  Other neurological disorders discussed in the book will
            NOT be subject to test questions
Traumatic Brain Injury
FACTS:

1.4 million who sustain a TBI each year in the United States (0.5% of people in U.S.)

50,000 die;
235,000 are hospitalized; and
1.1 million are treated and released from an emergency department.

What causes TBI?

Falls (28%)
Motor vehicle-traffic crashes (20%)
Struck by/against (19%)
Assaults (11%)

Who is at highest risk for TBI?

Males are about 1.5 times as likely as females to sustain a TBI.1
The two age groups at highest risk for TBI are 0 to 4 year olds and 15 to 19 year olds
Certain military duties (e.g., paratrooper) increase the risk of sustaining a TBI
                                                                     Langlois JA (2006)
Types of Traumatic Brain Injury

“Closed Head Injury”

        Concussion. Concussions are the most common type of TBI. A concussion is
damage to nerves or blood vessels in the brain often caused by an impact to the head.

         Contusions. A contusion is a bruise or bleeding on the brain that can be caused
by an impact.

           Diffuse Axonal Injury. This is tearing of nerve tissue or blood vessels when the
brain is jostled in the skull. It can result from shaking (for instance, shaken baby syndrome)
or whiplash

         Coup-countrecoup Injury. impact not only injures the site of impact, but causes
the brain to impact with the skull, causing injury to the opposite side of the brain.

   Symptoms:
          acute: confusion, visual disturbance, unconsciousness if severe
          long-term: memory problems, sensory problems .
                   - “dementia pugalistica”
  How does traumatic brain injury develop ?
      -direct, mechanical injury to neurons (axons, dendrites or soma)

      - damage to blood supply deprives neurons and glia of nutrients

      -Overactivity of glutamate receptors
                            -Activation of NMDA-type glutamate receptors

                                     -Inflow of too much Ca2+ into neurons

                                     - activates death enzymes that break down
                                     neuron

                                     -Impairs neuron ability to meet energy
                                     requirements
                                              -Triggers cell death

A little bit of Ca2+ inflow is good at the right time, too much is toxic
Strokes
     disruption of blood flow in brain
     3rd leading cause of death in adults
  1. Hemorrhage: bleeding in brain, blood vessel ruptures

             - can be from traumatic injury to blood vessel
             - can be from “aneurysm”

                  weakening of blood vessel wall, balloonlike
          dialation forms and can burst




            caused by some infections, toxins like cigarette
          Smoke. Can also be develomental abnormality.
2. Ischemia: blood flow to a brain region is blocked

               - a blockage that comes from another part
of the body is an “embolism” (vs. thrombosis)

      for example, a blood clot in leg, can travel to brain
and cause ischemia is gets stuck in a smaller artery.

“arteriosclerosis”: fat deposits in brain blood vessels grow
over time and block blood flow. (can become embolism)

How does a loss of blood supply kill neurons ?
      -deprived neurons become overexcited, release glutamate
      -glutamate activates NMDA receptors
      - and because no blood supply=no energy, no reuptake of glutamate
Dementias       deterioration of intellectual abilities due to disease
                                   *memory, judgment, concentration
                                   *usually w/ personality changes, emotional
                                   instability
    What causes dementia ??
    12-15% stroke
    12-15% Huntingtons, Parkinson’s Diseases (motor diseases)
             * other similar disease that are rare

    >5% Korsakoff’s syndrome

       severe anterograde amnesia


     Alzheimer’s Disease (leading cause of severe dementia in U.S.)
            - +1% of population, most over 65 yrs old
The severity and type of symptoms observed is directly related to death of
                        neurons in several brain regions.
    Causes ?

    We do NOT know what causes Alzheimer’s Disease !

But, we know that…:
  1. Risk of developing it is heritable
               there is a “genetic” factor involved
   2. Some AD patients have a specific genetic problem
   That can cause early-onset and severe form (~45 yrs old)


  3. But, many other AD patients don’t have family members
     with AD and don’t have an identified genetic problem




            Alzheimer’s Disease is probably just 1 term used to describe
               the symptoms of lots of different diseases that cause
                      brain damage and similar symptoms.
    I. Plaques: most AD patients have plaques in
            parts of the brain that show cell loss

                                in early AD: medial temporal lobe areas
                                    (hippocampus) and cortex
                                          (all areas that produce or receive acetylcholine)

                                in late AD: lots of areas

Key to understanding plaques:

1. Plaques are made of a protein called beta-amyloid

2. Beta amyloid come from a normal protein that neurons need to function normally,
called Amyloid Precursor Protein (APP)

3. but, APP is cut by enzymes into abnormal amounts of beta amyloid.

                   -neurons can get rid of a small amount of beta amyloid, but
if there is too much, beta amyloid clumps together to form plaques inside of neurons.
Neurons don’t function normally and die-off
II. Tangles: Many AD patients also have “tangles” in
neurons

Microtubules are long string-like structures that transport
things from the cell body to the end of the axon and dendrites


                                Tau proteins (like rungs of a ladder)




             In AD, these microtubules break apart and
             collapse into a tangles mess and neurons don’t function normally,
             so they die-off.
              Normal Human




                                 Gross Pathology:

                                 Ventricles larger

                                 gray matter loss
Human with Alzheimer’s Disease

                                 white matter loss
Drug Treatment of Dementias
      Drugs approved by the U.S. Food and Drug Administration

               Cognex®
               Aricept®
               Reminyl®                YOU DON’T NEED TO KNOW THESE
               Exelon®
               Namenda®
All are inhibitors of acetylcholinesterase, except Namenda


      1. Acetylcholine is release from “presynaptic” neuron, and then re-absorbed

               lots of it in hippocampus and cortex

      2. Acetylcholinesterase is an enzyme that breaks down acetylcholine

      3. That means that more acetylcholine is present in synaptic cleft to stimulate
      receptors on neurons in learning/memory areas
Key facts about acetylcholinesterase inhibitors:

         some improvement in daily living skills
         some delay in progression of disease

BUT, typically a small effect and occurs in a small % of patients

Can be very toxic to the liver


Namenda® FDA approved to treat late-stage Alzheimer’s

                    the newest approved drug (2004)


Namenda® - blocks the NMDA receptor for a very short period of time

-Based on theory that over activity of NMDA receptors contribute
 to neuron death in Alzheimer’s disease

Does it work ?: small effects in a small # of patients


      But, these small effects have a dramatic effect on quality of life
Parkinson’s Disease


   mentioned in the Ayurveda, the system of
   medicine practiced in India as early 7,000 years
   ago , and in the first Chinese medical text, Nei
   Jing, which appeared 2500 years ago


   "An Essay on the Shaking Palsy," published in
   1817 by a London physician named James
   Parkinson,
Symptoms
  Difficulty initiating movement
  Shuffling gait
  “Cogwheel” rigidity
  Tremor at rest
  Advanced stages may include psychiatric complications
     depression
     hallucinations    http://www.youtube.com/watch?v=13ftfmYwfaw
     Paranoia
     Cognitive decline
Incidence
  Onset usually appears after age of 40 years
    but can begin at any time including childhood when
     it is termed juvenile parkinsonism

  affects 1% aged 50 years and over


  10% aged 60 years and over may have undiagnosed,
  early stages of the disease

  about 1½ times more common in men than in
  women
Subtypes
  Primary (idiopathic- most common)
     unknown origin but not induced by obvious stimulus


  Secondary (parkinsonism)
     related to drugs, stroke, or trauma, other stimuli


  Familial
     genetically linked
     accounts for < 20% of the diagnosed cases
Progression: identified too late ?
 Considerable dopamine loss must occur before the
 disease is apparent

   clinical diagnosis is usually made after  80% loss in
    basal ganglia dopamine content

   symptoms may emerge after a 60% reduction in basal
    ganglia dopamine content



 The disease is probably present > 20 years before
 diagnosis
            Meso-Striatal Dopamine system
COMPONENTS OF THIS SYSTEM


1. Substantia Nigra- in midbrain
  - send fibers to Basal Ganglia
  - releases dopamine = movement

2. Basal Ganglia (part of striatum)-
  -sends fibers to motor cortex
   -receives fibers from sensory
    cortex and substantia Nigra
      In Parkinson’s Disease
      Substantia Nigra neurons die
      = reduced excitatory input
      into basal ganglia

      The two parts of the basal
      ganglia (Caudate and
      Putamen) also die
Postmortem Analysis




                             brain photographs courtesy of the
                             University of Utah Medical School
 Shrunken Substantia Nigra
                             Roberta J. Seidman, M.D., SUNY
PET Scan




    Loss of cellular activity in the Basal Ganglia
  Pathology in Parkinson’s Disease


Lewy body pathology: these bodies are circular structures
found in cytoplasm.




      -Dense core of protein called α-synuclein

          - normally aids in synaptic vesicle function

      Abnormality in gene that makes this protein is a
      significant risk for Parkinson’s disease

      Many environmental toxins lead to clumping of
      α-synuclein too (pesticides, drugs of abuse ?)
Parkin abnormalities ? (familial PD)
  gene mutation that is a risk factor for Parkinson’s Disease



 Parkin: a protein found in neurons that transport abnormal proteins
         to a “proteosome” and tag these proteins with a “death flag”
          called “ubiquitin”.

 “Ubiquitination” of a protein signals the proteosome to degrade the
  protein into its amino acid subparts.

 Overactivity of Parkin in brain regions controlling motor function can
 cause over-activation of the proteosome

                  neuronal death
Treatment

 Levodopa (L-dopa) therapy (L-dopa is a dopamine precursor)
    generally very effective for the first 2 to 5 years of
     treatment after which the on-off effect develops

 Direct-acting dopamine receptor agonists


 Experimental brain surgery
    lesions of nuclei that inhibit basal ganglia
        - remove inhibition of dying neurons, they may be more active = motor
         control
    neural tissue implants (e.g., fetal dopamine cells)
           Substantia nigra cells were surgically implanted into the right putamen. Note
           the continued degeneration seen on the contralateral (left) side revealed by the
           PET.

                                                       PET images courtesy of the UCLA School
                                                       of Medicine, Division of Brain Mapping

Recently, Deep Brain stimulation - indwelling electrodes
implanted in some of the dying neurons. Patients can stimulate
electrodes , provides a brief pulse to these neurons, which
rapidly restores some control of motor activity.

								
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