Transcript MEMORY LOSS - IS IT ALZHEIMER’S DISEASE?

AGEING, MEMORY LOSS
AND ALZHEIMER’S
DISEASE?
Dr JANE HECKER
Dept Internal Medicine, Royal Adelaide
Hospital
College Grove Hospital
MEMORY
• Age
• health (chronic pain, exercise, diet,
alcohol,)
• attitudes(anxiety, poor selfconfidence)
• lifestyle (participation in cognitive
activities)
• lifestyle (stress, workload, fatigue,
relationship problems)
DIFFERENTIAL DIAGNOSIS
DEMENTIA
•
•
•
•
Depression
Delirium
Drugs
Decline in memory
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
Prevalence of Alzheimer’s disease
Prevalence (%)
60
50%
50
40
30%
30
20
16%
10
0
1%
2%
4%
8%
60-64 65-69 70-74 75-79 80-84
85+
95+
Age (years)
Kurz A. Eur J Neurol 1998; 5(Suppl 4): S1-8
Wimo A et al. Int J Geriatr Psychiatry 1997; 12: 841-56
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.
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
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
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
AD: a progressive CNS disorder
with a characteristic pathology
Brain
atrophy
Senile
plaques
Neurofibrillary
tangles
Katzman, 1986; Cummings and Khachaturian, 1996
Mini-Mental State Examination (MMSE)
Natural history of Alzheimer’s
disease
Early diagnosis
Severe
Mild-to-moderate
30
Symptoms
25
Diagnosis
20
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
Cholinergic Deficit underlies clinical
symptoms
Cholinergic deficit
– progressive loss of
cholinergic neurones
N. basalis Meynert
– progressive decrease in
available ACh
– impairment in ADL,
behaviour and cognition
Cortex
Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978
Hippocampus
Treating Alzheimer’s Disease
Central Cholinergic Synapse
Acetyl CoA
+
Choline
ChAT
ACh
Cholinesterase
Inhibitors
M2
(-)
ACh
X
AChE
(+)
Post synaptic
Muscarinic 1
receptor
Choline
+
Acetate
Cholinesterase inhibitors:
a rational therapeutic approach in AD
OH
H
NH2
H
O
O
O
N
N
Tacrine
O
N
O
Galantamine
Donepezil
Mechanism: AChE/BuChE-I
Inhibition: reversible
Mechanism: AChE-I
Inhibition: reversible
Mechanism: AChE-I
Inhibition: reversible
O
O
N
O
O
H
O
Physostigmine
Mechanism: AChE/BuChE-I
Inhibition: pseudo-irreversible
OH
O
P
Cl
N
N
O
O
N
N
Rivastigmine
Mechanism: AChE/BuChE-I
Inhibition: pseudo-irreversible
O Cl
P
O
Cl
O
Cl
Cl
Metrifonate
Mechanism: AChE/BuChE-I
Inhibition: irreversible
Weinstock, 1999
CHOLINESTERASE INHIBITORS
-Second Generation
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Reminyl)
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
ABC: the key symptom domains
affected in AD
Cognition
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.’
Change from baseline in daily time
spent assisting with ADL (min)
Mean change in daily time spent by
caregiver assisting with ADL at 6 months:
GAL-INT-1
30
*
20
10
0
-10
-20
-30
-40
-50
Galantamine 24
mg/day
Placebo
* p < 0.05 vs baseline
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”
Therapeutic Dilemmas:
Alzheimer’s Disease
• Which drug?
• Who to treat?
• When to start treatment?
• How long to treat?
• By whom?
• Whether to treat?
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
PREVENTION?
AN OUNCE OF PREVENTION IS
WORTH A POUND OF CURE
Benjamin Franklin
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
The pathological cascade of AD
Clinical symptoms
Cholinergic dysfunction
Neurodegeneration
Neurofibrillary
tangles
TAU hypophosphorylation
-amyloid
Apo-E
PS1,2
Environmental
risk factors
APP
Genetic
risk
factors
Pathogenetic
mutations
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.”