Alzheimer s Disease

1. Alzheimer’s Disease 18 Nov 2004 Dr.pitiporn rattanataweeboon

2. Alzheimer’s disease progressive and fatal neurodegenerative disorder Prevalence in 2000 in the United States was 4.5 million. the number of symptomatic cases in the United States is predicted to rise to 13.2 million by 2050.

3. clinical syndrome of AD memory defecit with difficulty learning and recalling new information progressive language disorder beginning with anomia and progressing to fluent aphasia disturbances of visuospatial skills environmental disorientation , difficulty copying figures in MMSE deficits in executive function (planning,insight, judgment) the patient is unaware of memory or cognitive compromise.

4. Neuropsychiatric symptoms : - Apathy : early - Diminished interest - Agitation becomes increasingly - Depressive symptoms :50% of patients - Delusions : 25% of patients

5. Motor systems abnormalities are absent in AD until the final few years of the disease Survival 7 to 10 years after onset of symptoms and typically die from bronchitis or pneumonia.

7. 15 % each year of patients with mild cognitive impairment progress to dementia, usually Alzheimer’s disease Mini-Mental State Examination :specificity 96% , sensitivity 63% (standard cutoff score = 24 ) substantial proportion of cases of early dementia undetected.

8. RISK FACTORS Age Family history apolipoprotein 4 (APOE 4) allele Others: head injury, low serum levels of folate and vitamin B12 , elevated plasma homocysteine

9. pathophysiology

11. Diagnosis Based on the criteria National Institute of Neurologic and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) excluding other common causes of dementia in the elderly. Screening for thyroid dysfunction and vitamin B12 deficiency syphilis in typical clinical circumstances Neuroimaging should be obtained (identify vascular dementia ,other intracranial pathology)

15. Treatment

16. Antiamyloid Therapies: No antiamyloid therapies are currently available. Immunization reduces pathological signs of Alzheimer's disease in transgenic mice that have the amyloid precursor protein mutation. - This clinical trial was interrupted when encephalitis developed in 6 % of the patients. Statins : metabolism of cholesterol involved in the generation of beta-amyloid peptide - preliminary evidence suggests that statins may be beneficial in reducing the accumulation of beta-amyloid peptide

17. Neuroprotective Agent Antioxidants: alpha-tocopherol (vitamin E ) A randomized, placebo-controlled trial compared the effect of vitamin E, selegiline, the two drugs together, and placebo results : significant delay in the primary outcomes ( time to death, placement in a nursing home, development of severe dementia, or a defined severity of impairment of Activities of daily living ) in the selegiline,vitamin E , and combination-therapy groups, as compared with the placebo group.

18. vitamin E :230 days selegiline :215 days 145 days for those receiving both agents. No differences in cognitive function in the four groups. No statistically significant differences in vital signs, weight change, laboratory values, adverse events On the basis of this study, many practitioners have added high-dose vitamin E supplements (2000 IU daily) to their standard treatment regimen for Alzheimer's disease.

19. Memantine an N-methyl-D-aspartate antagonist interfere glutamatergic excitotoxicity improvement on the function on hippocampal neurons A double-blind, placebo-controlled trial of memantine in patients with moderate-to-severe Alzheimer's disease showed the superiority of memantine over placebo as indicated by both the Activities of Daily Living Inventory and the Severe neuropsychological test for patients with severe dementia), but not on the Global Deterioration Scale

20. memantine with cholinesterase inhibitor in patients with moderate-to-severe Alzheimer's disease reduced decline in activities of daily living, and a reduced frequency of new behavioral symptoms as compared with those receiving placebo.

21. Antiinflammatory Agents brains of patients with Alzheimer's disease have microscopic evidence of inflammation evidence is insufficient to support treatment with antiinflammatory agents Primary-prevention trials have not yet explored the possible value

22. Hormone-Replacement Therapy randomized, placebo-controlled trials of estrogen-replacement therapy in such women showed no benefit

23. Cholinesterase Inhibitors Standard of care for patients with Alzheimer's disease Treatment of mild-to-moderate patients significant difference between patients receiving the drug and placebo in terms of the scores for cognitive function and global assessment scales

24. The ADAS-Cog shows a typical rate of increase of seven points annually in untreated populations. A four-point decrease in the ADAS-Cog in the course of a clinical trial is equivalent to reversing the symptoms of the disease by approximately six months, and a seven-point decrement is equivalent to reversing the symptoms by approximately one year.

26. Side effects

27. Others:weight loss, insomnia, abnormal dreams, muscle cramps, bradycardia, syncope, and fatigue. Adverse effects occur during the initiation of treatment; reduced with slower rates of drug titration introducing cholinesterase inhibitors at low doses, increasing the dose gradually, and administering the medication with meals may limit gastrointestinal side effects

28. The optimal duration of treatment with cholinesterase inhibitors is uncertain. The duration of most blinded trials :six months. Trials lasting one year have also shown a difference between patients receiving the active drug and patients receiving a placebo. Patients continue to derive benefit from therapy for two to three years

29. Specific strategies for switching agents :not tested in adequate numbers of patients Concurrent administration of more than one cholinesterase inhibitor has not been studied and is not advised. Cholinesterase inhibitors are commonly administered with vitamin E and memantine

30. Other Treatments for Cognitive Deterioration ginkgo biloba had small but statistically significant effects as compared with placebo in patients with Alzheimer's disease. A primary-prevention trial to determine whether ginkgo biloba reduces the rate of development of Alzheimer's disease is currently in progress. Huperzine A is a cholinesterase inhibitor, and preliminary clinical trials have shown it to be of benefit in Alzheimer's disease

31. Management of Neuropsychiatric Symptoms and Behavioral Disturbances Safety issues : - Driving - Cooking - Wandering - Falls

32. Treatment of behavioral symptoms wandering, hoarding or hiding objects, withdrawal, and socially inappropriate behavior are often more responsive to behavioral therapy Other problems, such as agitation, aggression, delusions, and hallucinations, may be more responsive to medications

34. Health Maintenance and General Medical Treatment Exercise Control hypertension and other medical conditions Annual immunization against influenza Dental hygiene Use of eyeglasses and hearing aids Nutrition, hydration, and skin care.

36. Reference Devid S. Geldmacher and Peter J. Whitehouse . Evaluation of Dementia. NEJM.Aug 1996 ;330-335 Jeffrey L Cummings .Alzheimer Disease .JAMA ,May 8 ,2002 ;2335-2338 Claudia H . Kawas. Early Alzheimer’s Disease . NEJM.Sep 11,2003 ;1056-1062 Jeffrey L Cummings ,Drug Therapy Alzheimer’s Disease . NEJM, July 1,2004;56-65