ALGHEIMER'S DISEASE

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ALZHEIMER’S DISEASE Presented By Sachchidanand Pathak Sunder Deep pharmacy College

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INDEX Introduction Stages of A lzheimer’s Disease Sign & Symptoms Pathogenesis of A lzheimer’s Disease Pathophysiology of Alzheimer’s Disease Diagnosis Treatment 11/23/2011 2

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NEURODEGENERATIVE DISORDER e.g.- Alzheimer’s disease (cause of dementia) Ischaemic brain damage (stroke) Parkinson’s disease 11/23/2011 3

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Mechanism of Neuronal Death:- Excitotoxicity Apoptosis Oxidative stress 11/23/2011 4

EXITOTOXICITY: 

EXITOTOXICITY 11/23/2011 5 open

APOPTOSIS: 

APOPTOSIS 11/23/2011 6

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ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. Although the risk of developing AD increases with age, in most people with AD symptoms first appear after age 60. For every 5-year age group beyond 65, the percentage of people with AD doubles. 7

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Neurons The brain has billions of neurons, each with an axon and many dendrites. To stay healthy, neurons must communicate with each other, carry out metabolism, and repair themselves. AD disrupts all three of these essential jobs.

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Stages of A lzheimer’s D isease Stage 1 (Mild ) - This stage can last from 2 to 4 years. Minor memory loss and mood swings. Become angry and frustrated . Stage 2 (Moderate ) - It is longest stage (2 to 10 years). Increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering. Stage 3 (Severe ) - This stage may last 1 to 3 years. Extreme shrinkage occurs in the brain. Patients are completely dependent on others for care. Weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control. 11/23/2011 9

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SYMPTOMS- Confusion Disturbances in short-term memory Problems with attention Language difficulties Unexplained mood swings Poor judgment Aphasia (inability to speak) Apraxia (mind-blindness) Agnosia (inability to understand) 11/23/2011 10

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Recent memory loss affecting job. Difficulty performing familiar tasks. Problems with language. Disorientation to time or place. Poor or decreased judgment. Problems with abstract thinking. Misplacing things. Changes in mood or behavior. Changes in personality. Loss of initiative. Alzheimer Warning Signs (Top Ten)

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PATHOGENESIS OF ALZHEIMER’S DISEASE Amyloid precursors protein (APP) ß amyloid protein (containing two residue) Aß40 Aß42 Aggregation Amyloid plaques Neuronal death APP cleavage involves three proteases: secretases α, β and γ. α-Secretase produces soluble APP, whereas β- and γ-secretases generate Aβ amyloid protein. 11/23/2011 12 Proteolytic cleavage

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PATHOPHYSIOLOGY AD characterized by atrophy of cerebral cortex and loss of cortical & subcortical neurons. The pathological hallmarks of AD are- Neurofibrillary tangles Amyloid plaque Neurofibrillary tangles- Microtubules provide structural support to neurons and tau provide to the microtubules. A protein called tau helps stabilize microtubules. When tau filaments undergo abnormal phosphorylation at a specific site, they cannot bind effectively to microtubules, and the microtubules collapse together to form neurofibrillary tangles. 11/23/2011 13

Neurofibrillary tangles: 

Neurofibrillary tangles 11/23/2011 14

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11/23/2011 Beta-amyloid Plaques Amyloid precursor protein (APP) is the precursor to amyloid plaque. APP sticks through the neuron membrane . Enzymes cut the APP into fragments of protein, including beta-amyloid. Beta-amyloid fragments come together in clumps to form plaques. 1. 2. 3. In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex.

PREVALENCE of AD : 

PREVALENCE of AD Estimated 4 million cases in US (2000). Increase with age (prevalence ) 1% of 60 - 65= 107,000 2% of 65 - 70= 188,000 4% of 70 - 75= 350,000 8% of 75 - 80= 595,000 16% of 80 - 85= 800,000 Estimated 500,000 new cases per year. 11/23/2011 16

AD Can Be Readily Diagnosed: 

AD Can Be Readily Diagnosed Diagnosis is a 2-step process : Detection through screening Laboratory and other Laboratory Tests Rule out vitamin B12 and folate deficiency. Rule out hypothyroidism with thyroid function tests. Blood cell counts, serum electrolytes, liver function tests. Other Diagnostic Tests CT or MRI scans may aid diagnosis.

Cholinergic Changes in AD: 

Cholinergic Changes in AD The most prominent neurotransmitter abnormalities are cholinergic. Reduced activity of choline acetyltransferase (synthesis of acetylcholine). Reduced number of cholinergic neurons in late AD (particularly in basal forebrain). Selective loss of nicotinic receptor subtypes in hippocampus and cortex.

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TREATMENT Acetylcholine esterase inhibitors - Physostigmine Neostigmine Four AChEI currently approved by the FDA for treatment of AD. Tacrine Denepezil Rivastigmine Galantamine Note -Tacrine are not wide clinically used due to their cause of hepatotoxicity while other depart from it. 11/23/2011 19

FIRST SUCCESSFUL TREATMENT: 

FIRST SUCCESSFUL TREATMENT CHOLINESTERASE INHIBITION (1st double blind study - Ashford et al., 1981 ) Presumably increases acetylcholine at synapses. Improvement in cognition (6-12 months better ). Improvement in function . Improvement in behavior (basal ganglia ). Slowing of disease course.

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NMDA receptor antagonist- e.g. Memantine(Namenda)-inhibiting glutamate-induced excitotoxicity Amyloid-ß degrading enzyme - Acyl peptide hydrolase Serine protease Researchers also are looking at other treatments, including : cholesterol-lowering drugs called statins. anti-oxidants and folic acid. anti-inflammatory drugs. substances that prevent formation of beta-amyloid plaques. nerve growth factor to keep neurons healthy. 11/23/2011 22

Medications Used for Noncognitive Symptoms of Dementia: 

Medications Used for Noncognitive Symptoms of Dementia 11/23/2011 23

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Ginkgo Biloba - flavone glycosides and bioflavonoids. Mechanisms of action is- Increasing blood flow. Decreasing the viscosity of blood. Antagonizing platelet activating factor receptors. Increasing tolerance to anoxia. Antiinfective properties. Preventing the damage of membranes caused by free radicals. Huperzine A – Huperzine A is an alkaloid isolated from the Chinese club moss, Huperzia serrata. It reversibly inhibits acetylcholinesterase. 11/23/2011 24

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REFERENCE Goodman Louis S. & Gilman Alfred , “The pharmacological basis of Therapeutics”, eleventh edition, 538 & 539. Rang H.P. & Dale M.M . , “Pharmacology”, sixth edition, 508-517. Tripathi KD , “Essential of medical pharmacology”, sixth edition, 2008, 471-73. Joseph T. DiPiro, and et.al ., “ Pharmacotherapy A Pathophysiologic Approach”, Seventh Edition, McGraw-Hill Companies, 1051-1058. 11/23/2011 25

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THANKS FOR YOUR ATTENTION 11/23/2011 26