AGEING, MEMORY LOSS AND ALZHEIMER’S DISEASE?

1. AGEING, MEMORY LOSS AND ALZHEIMER’S DISEASE? Dr JANE HECKER Dept Internal Medicine, Royal Adelaide Hospital College Grove Hospital

3. MEMORY • Age • health (chronic pain, exercise, diet, alcohol,) • attitudes(anxiety, poor self-confidence) • lifestyle (participation in cognitive activities) • lifestyle (stress, workload, fatigue, relationship problems)

4. DIFFERENTIAL DIAGNOSISDEMENTIA • Depression • Delirium • Drugs • Decline in memory

5. DEMENTIA • Alzheimer’s disease 60% • Vascular dementia 20% • Dementia with Lewy bodies 10-15% • Fronto-temporal dementia 10% • Dementia associated with other neurological conditions e.g. Parkinson’s disease • Mixed dementia

6. Prevalence of Alzheimer’s disease 50% 30% 16% 8% 4% 2% 1% Kurz A. Eur J Neurol 1998; 5(Suppl 4): S1-8 Wimo A et al. Int J Geriatr Psychiatry 1997; 12: 841-56

7. Advantages of an early diagnosis of AD • Enables early treatment - cognitive enhancers • Future planning for patient and caregiver • Early provision of community support and healthcare resources can decrease stress • May provide cost savings and delay institutionalisation Ref: Doraiswamy et al, 1998.

8. HISTORICAL POINTERS • Forgetting recent events despite prompting • Failure to attend appointments • Frequent repetition of statements, stories or questions • Frequent lost or misplaced items • Losing track in conversation, word-finding difficulty • Difficulty understanding conversation or following the story in a book or on TV • Confusion with time eg. day, date, time of day • Becoming lost, unable to find the way

9. HISTORICAL POINTERS • Difficulty handling money or paying bills • Difficulty working gadgets, planning or preparing meals, performing handyman tasks • Neglect of personal care, home maintenance or nutrition • Withdrawal from previous community and social activities (poor work performance if employed) • Difficulty coping with new events or change to routine • Personality and behaviour change

10. Clinical features of AD • Loss of cognition • short-term memory • language • visuospatial functions • Loss of daily function • instrumental activities of daily living (ADL) • self-maintenance skills • Behaviour and personality change

12. AD: a progressive CNS disorderwith a characteristic pathology Brainatrophy Senileplaques Neurofibrillary tangles Katzman, 1986; Cummings and Khachaturian, 1996

13. Natural history of Alzheimer’s disease Severe Early diagnosis Mild-to-moderate 30 Symptoms 25 Diagnosis 20 Mini-Mental State Examination (MMSE) Loss of functional independence 15 Behavioural problems 10 Nursing home placement 5 Death 0 1 2 3 4 5 6 7 8 9 Time (years) Feldman and Gracon. The Natural History of Alzheimer’s Disease. London: Martin Dunitz, 1996

14. N. basalis Meynert Cortex Hippocampus Cholinergic Deficit underlies clinical symptoms Cholinergic deficit • progressive loss of cholinergic neurones • progressive decrease in available ACh • impairment in ADL, behaviour and cognition Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978

15. Treating Alzheimer’s Disease

16. ChAT ACh Cholinesterase Inhibitors M2 Choline + Acetate (-) ACh AChE X (+) Muscarinic 1 receptor Central Cholinergic Synapse Acetyl CoA + Choline Post synaptic

17. OH H H NH2 O O O N O N N O Galantamine Tacrine Donepezil Mechanism: AChE/BuChE-I Inhibition: reversible Mechanism: AChE-I Inhibition: reversible Mechanism: AChE-I Inhibition: reversible O O O O N OH O O P H P N O O Cl Cl N O O Cl N O Cl N Cl Physostigmine Metrifonate Rivastigmine Mechanism: AChE/BuChE-I Inhibition: pseudo-irreversible Mechanism: AChE/BuChE-I Inhibition: irreversible Mechanism: AChE/BuChE-I Inhibition: pseudo-irreversible Cholinesterase inhibitors: a rational therapeutic approach in AD Weinstock, 1999

18. CHOLINESTERASE INHIBITORS-Second Generation • Donepezil (Aricept) • Rivastigmine (Exelon) • Galantamine (Reminyl)

19. A.D. CLINICAL TRIALS 9204 patients in 21 clinical trials  modest benefit in mild-mod AD • Donepezil :- 8 trials, 2664 patients • Rivastigmine :- 7 trials, 3370 patients • Galantamine :- 6 trials, 3170 patients

20. ABC: the key symptom domainsaffected in AD Activities of daily living Behaviour Cognition

21. AAN Guidelines CONCLUSIONS • ‘Significant treatment effects have been demonstrated with several different cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) indicating that the class of agents is consistently better than placebo. The disease eventually continues to progress despite treatment and the average “effect size” is modest. Global changes in cognition, behaviour, and functioning have been detected by both physicians and caregivers, indicating that even small measurable differences may be clinically significant.’

22. Mean change in daily time spent by caregiver assisting with ADL at 6 months: GAL-INT-1 * Galantamine 24 mg/day Change from baseline in daily time spent assisting with ADL (min) Placebo * p < 0.05 vs baseline

23. NICE RECOMMENDATIONS:COST EFFECTIVENESS • cost savings on institutional care not well established • quality of life (QALY) not easily measured • Oscar Wilde “knowing the price of everything and the value of nothing”

24. Therapeutic Dilemmas: Alzheimer’s Disease • Which drug? • Who to treat? • When to start treatment? • How long to treat? • By whom? • Whether to treat?

25. Memantine (Ebixa) • NMDA receptor antagonist • trialled predominantly in moderately severe to severe dementia • modest benefit in cognition, function, behaviour • expensive ~ $180 per month, no PBS subsidy

26. PREVENTION? AN OUNCE OF PREVENTION IS WORTH A POUND OF CURE Benjamin Franklin

29. Protective Factors? • NSAID’s (anti-inflammatories) • statins (cholesterol lowering) • moderate alcohol consumption • higher education • ongoing intellectual stimulation • physical and leisure / social activities • diet - fruit and vegetables, low in saturated fat

30. The pathological cascade of AD Clinical symptoms Cholinergic dysfunction Neurodegeneration Neurofibrillary tangles Genetic risk factors TAU hypophosphorylation -amyloid Apo-E PS1,2 Environmental risk factors Pathogenetic mutations APP

31. Post and Whitehouse - “Guidelines on Ethics of Care of People with Alzheimer’s Disease” “As the 20th century draws to a close, it is the decline of the mind contained in a still viable body that raises some of the most urgent concerns for medical ethics and society. The emphasis on technical reason and productivity that characterizes our modern industrial cultures may create a bias against people with dementia. It is important to realize that emotional and relational well-being can be enhanced despite dementia and to insist that human dignity can still be respected. In severe dementia, the finest expression of this respect may be through the touch of a hand rather than through technology.”