BY THANUJA BACHALA M.PHARMACY Sree Vidyanikethan College Of Pharmacy. There are many diseases, which haunt human beings with severe morbidity and mortality in spite of advancement of medicine and therapeutics. Few diseases were controlled with the discovery of newer drugs and few are still uncontrollable. Alzheimer's disease, which cripples the elderly people with dementia and increases the burden of the family and the government is one of them. Alzheimer's disease (AD) is the most common form of dementia, a neurologic disease characterized by loss of mental ability severe enough to interfere with normal activities of daily living, lasting at least six months, and not present from birth. AD usually occurs in old age, and is marked by a decline in cognitive functions such as remembering, reasoning, and planning. Initially, dementia is manifested by barely noticeable memory deficits. Eventually, the memory loss becomes more severe until it is incapacitating. Other symptoms such as confusion, the inability to articulate words correctly, and hallucinations occur with varying degrees. Affected individuals are also likely to develop seizures, hypertonicity (increased muscle movements), and incontinence. Etiology Between two and four million Americans have AD; that number is expected to grow to as many as 14 million by the middle of the 21st century as the population as a whole ages. Estimated 4 million cases in US (2000) (2000 - 46 million individuals over 60 y/o) Estimated 500,000 new cases per year Increase with age (prevalence) › 1% of 60 - 65 (10.7m) = 107,000 › 2% of 65 - 70 ( 9.4m) = 188,000 › 4% of 70 - 75 ( 8.7m) = 350,000 › 8% of 75 - 80 ( 7.4m) = 595,000 › 16% of 80 - 85 ( 5.0m) = 800,000 U.S. mortality rate by age 1999 CDC / 2000 census Males Females 1.0000 Alzheimer incidence 0.1000 probability 0.0100 0.0010 0.0001 0 10 20 30 40 50 60 70 80 90 100 Age The condition was first described in 1906 by Alois Alzheimer, a German physician. Alzheimer characterized two abnormal structures in the brain amyloid plaques and neurofibrillary tangles. Although there are several known causes of Alzheimer disease, about 75% of cases are sporadic and occur without a clear cause. Scientists assume that these cases are due to a combination of unknown genetic predisposing factors and environmental exposures. Need to get elderly, clinicians interested in screening for dementia Need test to screen patients for Alzheimer’s disease Test needs to be on multiple platforms: Doctor’s offices Best if computerized for rapid, objective assessment World-Wide Web – based testing, Test needs to be very brief (about 1-minute) Multiple test forms needed so it can be repeated often (quarterly) Screening should be done yearly after age 50, and repeated every 3 months for individuals over 65 years of age or with concerns Any change over time needs to be detected The test should be free Need program to handle positive screens sensitively and efficiently. New test to screen patients for AD: World-Wide Web – based testing, CD-distribution KIOSK administration Determine level of ability / impairment Test takes about 1-minute Test can be repeated often (e.g., quarterly) Any change over time can be detected Free test is at: www.medafile.com FUNCTIONAL BRAIN IMAGING (SPECT, PET – Medicare will pay special cases) EEG, Evoked Potentials (P300) REACTION TIMES (slowed in the elderly, especially when complex response is required. CSF ANALYSIS - ROUTINE STUDIES ELEVATED TAU (future possible) DECREASED AMYLOID (future possible) HEAVY METAL SCREEN (24 hr urine) GENOTYPING APO-LIPOPROTEIN-E (for supporting dx) AUTOSOMAL DOMINANT (young onset) I) Neurotransmitters Acetylcholine (Ach) is responsible for learning and memory Ach is found abundantly in Hippocampus (memory store) and cerebral cortex It was thought at that time that Alzheimer's disease might disrupt the synthesis of Ach. Alzheimer's disease might triggers the over- production of the enzyme that destroys Ach - Acetyl cholinesterase enzyme . Apart from Ach, other neurotransmitters implicated are serotonin, noradrenaline, and dopamine. Noradrenaline, dopamine deficits are responsible for sensory disturbances, aggressive behavior. II) Cholinergic hypothesis Degeneration of Cholinergic neurons of Hippocampus and cerebral cortex in Alzheimer's disease leads to deficiency in Ach, which is responsible for loss of cognition, behavioral changes, mood disturbances. III) Amyloid precursor protein (APP) APP - normal protein produced by healthy neurons Responsible for growth and maintenance of neurons Enzymes like a, b, g secretases cut APP to form A-beta protein ( which is insoluble , shorter and sticker) A-beta protein (insoluble, sticker) A-beta folds Fibrils (insoluble) Cluster and expand to form plaques. IV) Plaques Displaces or kills brain cells Damages cell's interiors Triggers an inflammatory response. To fight this inflammatory response, brain generates toxic free radicals . V) Neurofibrillary tangles Neurons branch off at te ends forming neuritis. Neuritis made up of skeletal structures called Microtubules. Microtubule gives shape to neuron, transport nutrients, chemical messengers. Microtubules are glued together by Tau Proteins . In healthy brain, Tau is firmly glued to the microtubules. In Alzheimer's disease, Tau proteins are destroyed by enzymes, leading to formation of Neurofibillary tangles. Without Tau proteins, neuronal cells shrinks, disintegrates and die. VII) Genes: Evidence has boiled down to chromosomes 14, 19, 21 APOLIPO for Alzheimer's disease Protein E4 (Apo E4) gene. Apo E4 leads to the insolubility of A- beta protein, forming Plaques. Familial AD (onset < 60 y/o) (<5%) all known autosomal dominant genes relate to b-amyloid Presenilin I, II (ch 14, 1) APP (ch 21) Non-familial (late onset) APOE Clinical studies suggest 40 – 50% due to e4 If e2 is considered, may be 95% of causation Population studies suggest 10 – 20% cause Evolution over last 300,000 to 200,000 years At least 20 other genes suspected of relating to AD Of all persons with Alzheimer disease, up to 25% of cases are thought to be part of a familial-based inheritance pattern. In general, these forms of Alzheimer disease are inherited as an autosomal dominant disorder, meaning that affected individuals have a 50% chance of passing on the mutated gene to their offspring. There is a late-onset familial form (AD2), three early-onset familial forms (AD1, AD3, AD4), and a form of Alzheimer disease associated with Down syndrome. AD1 ---10–15% of earlyonset Alzheimer disease and involves a protein called presenilin 1 that has a mutation in the gene that encodes it called PSEN1, which is found on chromosome 14. AD3 ---- 20–70% of the early-onset familial form and is caused by mutations in APP found on chromosome 21, which encodes a protein called amyloid beta A4. AD4 is extremely rare and is caused by mutations in PSEN2, localized to chromosome 1, and encodes a protein called presenilin 2. GenT %pop %AD #pop #AD risk If all US E2/2 1% 0.1% 0.5M .004M 0.8% .4 M E2/3 12 % 4% 5.5M .18M 3.2% 1.5 M E3/3 60% 35% 27.6M 1.4M 5.1% 2.3 M E3/4 21% 42% 9.6M 1.7M 18% 8.2 M E4/4 2% 16% .9M .6M 67% 30.7M JW Ashford, MD PhD, 2003 Less than 1% of all cases of Alzheimer disease-- chromosomal defect called trisomy 21 (also known as Down syndrome). This occurs when there are three copies of genes found on chromosome 21.These individuals usually develop Alzheimer disease after the age of 40. The APP gene, which encodes the amyloid precursor protein and is implicated in the pathogenesis of Alzheimer disease, is localized to chromosome 21; it is felt that people with Down syndrome overproduce this protein, resulting in its accumulation in the brain. The excess protein is thought to cause the disease. People with AD are also often depressed or anxious, and may suffer from sleeplessness, poor nutrition, and general poor health. It is important for the person with AD to eat well and continue to exercise. Diet and Supplements VITAMIN E. Studies have shown that AD patients have lower blood levels of vitamin E THIAMINE (VITAMIN B1). COBALAMIN (VITAMIN B12). ACETYL-L-CARNITINE. MELATONIN. Melatonin is a hormone that helps to regulate mood and sleep cycles. GINKGO. Ginkgo, the extract from the Ginkgo biloba tree is the most commonly used herbal treatment for AD. PHYTOESTROGENS. CLUBMOSS. Huperzine A is a compound isolated from clubmoss (Huperzia serrata). The two drugs approved for AD are tacrine hydrochloride (Cognex) and donepezil hydrochloride (Aricept), increase the brain levels of the neurotransmitter acetylcholine, thereby increasing the communication ability of the remaining neurons. Preliminary studies have also suggested a reduced risk for developing AD in older people who regularly use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen (Advil), and naproxen (Aleve), although not acetaminophen. Selegiline, a drug used in the treatment of Parkinson's disease, appears to slow the development of AD. AChEIs may improve, maintain, or slow the decline of cognitive, behavioral, and functional performance in patients with mild-to-moderate AD Delay of treatment leads to loss of potential benefit AChEIs may delay nursing home placement over 20 months, and potentially much more when started early. AChEIs have demonstrated consistent efficacy and safety in maintaining cognitive function, as measured by ADAS-cog in patients with mild-to-moderate AD for up to 1 year – relative to placebo!! Donepezil1 38 weeks Rivastigmine2 38–42 weeks Galantamine3 52 weeks (25-30% better) Increases amount of acetylcholine available in synaptic cleft by inhibiting breakdown of acetylcholine By modulating activity at nicotinic receptors, it may increase release of acetylcholine from surviving presynaptic nerve terminals Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit. May provide greatest delay of illness progression May require increase of dose after patient declines below initial baseline, to maintain benefit for longer term. Linear pharmacokinetics Bioavailability: 90% Half-life: 7 hours Low (18%) plasma protein binding Hepatic metabolism via multiple pathways, primarily CYP2D6 and CYP3A4 Renal excretion Simple, one-step dose escalation 8 mg/day starting dose for 4 weeks (4 mg bid) 16 mg/day maintenance dose for at least 4 weeks (8 mg bid) The flexibility to increase to 24 mg/day (12 mg bid) – should try after 12 weeks if further benefit sought Taken preferably with morning and evening meals Later, better with morning meal, mid-afternoon snack. (Avoid nocturnal cholinergic activation!!) Available in 4-mg, 8-mg, and 12-mg tablets and oral solution (4 mg/mL) Inspite of medicines the disease is incurable completely, The field of pharmaceutical Biotechnology called as Gene Therapy gives promising results for alzheimers. Gene therapy is a technique for correcting defective genes for disease development. Now the field of biotechnology started focusing disease on its genetic level and was very much stressed towards a particular gene that is responsible for the disease development. Gene therapy is a technique for introducing the genetic material of a gene in a patient that lacks that gene because of a mutation. But actually gene therapy works in the following ways 1. A "normal" gene is inserted into the genome to replace an "abnormal," disease- causing gene. 2. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. 3. The most common vector is a virus that has been genetically altered to carry normal human DNA University Hospitals Case Medical Center is one of 12 sites conducting the first Phase 2 clinical trial of a gene therapy for Alzheimer's disease (AD). The study uses a viral-based gene transfer system called CERE- 110. University Hospitals (UH) is the only site in the Midwest for the study. During the study, CERE-110 will be injected by a neurosurgeon into the nucleus basalis of Meynert, an area of the brain where nerve cells die in patients with AD. The first gene therapy for alzheimers among 12 centers was conducted at Georgetown's Georgetown University Medical Center in Memory Disorders Program. The phase II study examined the safety and possible benefits of CERE-110. CERE-110 contains a gene and is injected during surgery into a part of the brain affected by Alzheimer's disease. The gene will instruct brain cells to produce more of a protein, called Nerve Growth Factor or NGF, which helps nerve cells survive and function properly. The transfer of this gene into the brain is a medical technique called gene therapy. Neurosurgeons at the University of California in San Diego (UCSD) injected 2.5 million genetically modified cells into a 60-year-old woman's brain through a small hole drilled in her skull. The procedure took 11 hours. Scientists began by harvesting skin cells from the woman. Then they inserted into these skin cells the gene that directs the production of a protein called nerve growth factor (NGF). NGF is a naturally occurring protein in normal brains. One of its jobs is to keep brain cells alive by promoting growth and survival (much like food helps us grow and thrive). NGF helps the cholinergic system function properly. This system includes nerve cells that produce the neurotransmitter acetylcholine, a chemical signal the brain needs to process information and to function normally. In the brain of an Alzheimer's patient, the cholinergic cells stop making acetylcholine. Low acetylcholine levels can cause problems with memory, emotions, and language. The procedure carried out by insertion of the modified skin cells into the nucleus basalis, a group of cells about the size of your thumbnail at the base of the frontal lobe. This area contains many cholinergic nerve cells. The cells were injected only into the right side of the brain. The available NGF synthesis stimulators are as follows: a. Idebenone and b. Propentofylline CONCLUSION: In WASHINGTON scientists reported that The first attempt at gene therapy for Alzheimer’s patients appeared to significantly delay worsening of the disease in a few people who have tested it so far. Far more research is needed to see if the experimental treatment, which requires a form of brain surgery, really helps. But if the approach pans out, researchers say delivering protective substances, called growth factors, into a diseased brain holds the potential to rescue some dying brain cells Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203. Farlow M et al. Eur Neurol. 2000;44:236-241. Raskind MA et al. Neurology. 2000;54:2261-2268. Diagnosis and Management of Alzheimer's Disease. 2nd edition, edited by Serge Gauthier. London: Martin Dunitz, 1999. Luskin, Frederic M., Ellen M. DiNucci, Kathryn A. Newell, and William L. Haskell. "Complementary/Alternative Therapies in Select Populations: Elderly Persons." In Complementary/Alternative Medicine: An Evidence Based Approach. Edited by John W. Spencer and Joseph J. Jacobs. St. Louis: Mosby, 1999. Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. The John Hopkins University Press, 1995.