ageing, memory loss and alzheimer’s disease?
DESCRIPTION
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 self-confidence) lifestyle (participation in cognitive activities) - PowerPoint PPT PresentationTRANSCRIPT
AGEING, MEMORY LOSS AND ALZHEIMER’S
DISEASE?
Dr JANE HECKERDept Internal Medicine, Royal Adelaide
HospitalCollege Grove Hospital
MEMORY• Age• health (chronic pain, exercise, diet,
alcohol,)• attitudes(anxiety, poor self-confidence)• lifestyle (participation in cognitive
activities)• lifestyle (stress, workload, fatigue,
relationship problems)
DIFFERENTIAL DIAGNOSISDEMENTIA
• 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
Kurz A. Eur J Neurol 1998; 5(Suppl 4): S1-8Wimo A et al. Int J Geriatr Psychiatry 1997; 12: 841-56
0
10
20
30
40
50
60
60-64 65-69 70-74 75-79 80-84 85+ 95+
Age (years)
Pre
vale
nce
(%)
1% 2% 4%8%
16%
30%
50%
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
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
Brainatrophy
Senileplaques
Neurofibrillarytangles
Katzman, 1986; Cummings and Khachaturian, 1996
AD: a progressive CNS disorderwith a characteristic pathology
Natural history of Alzheimer’s disease
1 2 3 4 5 6 7 8 9
0
5
10
15
20
25
30
Time (years)
Symptoms
Diagnosis
Loss of functional independence
Behavioural problems
Nursing home placement
DeathMin
i-Men
tal S
tate
Exa
min
atio
n (M
MS
E) Early diagnosis Mild-to-moderate Severe
Feldman and Gracon. The Natural History of Alzheimer’s Disease. London: Martin Dunitz, 1996
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
Treating Alzheimer’s Disease
Post synaptic
Acetyl CoA+
Choline
Choline+
AcetateAChE
ACh
ACh
ChAT
Central Cholinergic Synapse
X
Cholinesterase Inhibitors
(-)
M2
Muscarinic 1receptor
(+)
Cholinesterase inhibitors: a rational therapeutic approach in AD
NH2
N
Mechanism: AChE/BuChE-IInhibition: reversible
Tacrine
O
OON
Mechanism: AChE-IInhibition: reversible
Donepezil
N
O
O
NN
H
Mechanism: AChE/BuChE-IInhibition: pseudo-irreversible
Physostigmine
OO
O
OHP
ClCl Cl
O
OO
O
PCl
Cl
Mechanism: AChE/BuChE-IInhibition: irreversible
Metrifonate
OO
HH
N
OH
Mechanism: AChE-IInhibition: reversible
Galantamine
O
O N
N
Mechanism: AChE/BuChE-IInhibition: pseudo-irreversible
Rivastigmine
Weinstock, 1999
CHOLINESTERASE INHIBITORS-Second Generation
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Reminyl)
A.D. CLINICAL TRIALS9204 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
Cognition
Activi
ties o
f dail
y livi
ng
Behaviour
ABC: the key symptom domainsaffected in AD
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.’
-50
-40
-30
-20
-10
0
10
20
30
Chan
ge fr
om b
asel
ine
in d
aily
tim
e sp
ent a
ssis
ting
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
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 ADClinical symptoms
Neurodegeneration
Neurofibrillary tangles
-amyloid
Environmental risk factors
Genetic risk factors
Apo-E
Pathogenetic mutations
APP
PS1,2
Cholinergic dysfunction
TAU hypophosphorylation
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.”