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 DIAGNOSIS DEMENTIA 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 Kurz A. Eur J Neurol 1998; 5(Suppl 4): S1-8 Wimo A et al. Int J Geriatr Psychiatry 1997; 12: 841-56 1% 2% 4% 8% 16% 30% 50%

7. Ref: Doraiswamy et al, 1998. 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

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. Brain atrophy Senile plaques Neurofibrillary tangles Katzman, 1986; Cummings and Khachaturian, 1996 AD: a progressive CNS disorder with a characteristic pathology

13. Natural history of Alzheimer’s disease 123456789123456789 0 5 10 15 20 25 30 Time (years) Symptoms Diagnosis Loss of functional independence Behavioural problems Nursing home placement Death Mini-Mental State Examination (MMSE) Early diagnosisMild-to-moderate Severe Feldman and Gracon. The Natural History of Alzheimer’s Disease. London: Martin Dunitz, 1996

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

15. Treating Alzheimer’s Disease

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

17. Cholinesterase inhibitors: a rational therapeutic approach in AD NH 2 N Mechanism: AChE/BuChE-I Inhibition: reversible Tacrine O O O N Mechanism: AChE-I Inhibition: reversible Donepezil N O O N N H Mechanism: AChE/BuChE-I Inhibition: pseudo-irreversible Physostigmine O O O OH P Cl O O O O P Mechanism: AChE/BuChE-I Inhibition: irreversible Metrifonate O O H H N OH Mechanism: AChE-I Inhibition: reversible Galantamine O O N N Mechanism: AChE/BuChE-I Inhibition: pseudo-irreversible Rivastigmine 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. C ognition A ctivities of daily living B ehaviour ABC: the key symptom domains affected in AD

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

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 Neurodegeneration Neurofibrillary tangles  -amyloid Environmental risk factors Genetic risk factors Apo-E Pathogenetic mutations APP PS1,2 Cholinergic dysfunction TAU hypophosphorylation

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.”