AGEING, MEMORY LOSS AND ALZHEIMERS DISEASE

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AGEING, MEMORY LOSS AND ALZHEIMERS DISEASE?

• Dr JANE HECKER
• Dept Internal Medicine, Royal Adelaide Hospital
• College Grove Hospital

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MEMORY

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

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DIFFERENTIAL DIAGNOSISDEMENTIA

• Depression
• Delirium
• Drugs
• Decline in memory

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DEMENTIA

• Alzheimers disease 60
• Vascular dementia 20
• Dementia with Lewy bodies 10-15
• Fronto-temporal dementia 10
• Dementia associated with other neurological
  conditions e.g. Parkinsons disease
• Mixed dementia

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Prevalence of Alzheimers disease
50
30
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8
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Kurz A. Eur J Neurol 1998 5(Suppl 4) S1-8 Wimo
A et al. Int J Geriatr Psychiatry 1997 12 841-56
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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.
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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

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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

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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

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AD a progressive CNS disorderwith a
characteristic pathology
Brainatrophy
Senileplaques
Neurofibrillary tangles
Katzman, 1986 Cummings and Khachaturian, 1996
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Natural history of Alzheimers disease
Severe
Early diagnosis
Mild-to-moderate
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Symptoms
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Diagnosis
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Mini-Mental State Examination (MMSE)
Loss of functional independence
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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
Alzheimers Disease. London Martin Dunitz, 1996
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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
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Treating Alzheimers Disease
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Central Cholinergic Synapse
Acetyl CoA Choline
Post synaptic
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Cholinesterase inhibitors a rational
therapeutic approach in AD
Weinstock, 1999
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CHOLINESTERASE INHIBITORS-Second Generation

• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Reminyl)

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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

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

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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 lt 0.05 vs baseline
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NICE RECOMMENDATIONSCOST 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

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Therapeutic Dilemmas Alzheimers Disease

• Which drug?
• Who to treat?
• When to start treatment?
• How long to treat?
• By whom?
• Whether to treat?

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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

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PREVENTION?

• AN OUNCE OF PREVENTION IS WORTH A POUND OF
  CURE
• Benjamin Franklin

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Protective Factors?

• NSAIDs (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

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The pathological cascade of AD
Clinical symptoms
Cholinergic dysfunction
Neurodegeneration
Neurofibrillary tangles
Genetic risk factors
?-amyloid
Apo-E
TAU hypophosphorylation
PS1,2
Environmental risk factors
Pathogenetic mutations
APP
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Post and Whitehouse - Guidelines on Ethics of
Care of People with Alzheimers 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.