Professional Documents
Culture Documents
Dementia
Introduction and epidemiology
The leading causes of disability for both sexes in
developed countries
Prevalence (%)
50
40
30
20
10
0
50 60 70 80 90 100
Age (years)
Hofman et al (1991)
Alzheimers disease is becoming even more common
Alzheimers disease
5% Vascular dementia
5%
Dementia with Lewy bodies
Pure DLB 3% Frontotemporal dementia
Other dementias
white matter dementias
DLB with subcortical (secondary) dementias
AD 12% transmissible encephalopathies
Mixed
vascular
dementia
and AD 10% 60%
Pure vascular
dementia 5%
Smoking and AD
APOE is associated with AD
e3/e4 OR = 3.2
e4/e4 OR = 14.9
e2/e2 OR = 0.6
e2/e3 OR = 0.6
APOE gene Genotype and phenotype at the APOE locus Farrer et al (1997)
Vascular risk factors
Hypertension
Evidence of cardiac disease
Peripheral atherosclerosis
. . . increase risk of AD
Snowdon et al (1996)
The Aetiology and pathogenesis
of the dementias
The process of Alzheimers disease is also nearly
understood
Genes
Environment
Plaques
? GSK-3
3
Bringing it all together (1)
5
Oxidative
damage
6
Inflammatory
response
Mutations in
APOE4
APP/PS-1
Age
Bringing it all together (2)
Tangle
Plaque
Alzheimers
PKC GSK-3 Tau phosphorylation
disease
Dementia with Lewy bodies as for AD, but with additional subcortical pathology
Language Perceptuospatial
Memory function
Clinical symptoms of AD
Amnesia
memory loss is early and invariable
recent memory loss before remote memory
Aphasia
nominal dysphasia early
both expressive and receptive dysphasia in moderate stages
severely disrupted speech in late phases
Apraxia
functional difficulties, initially instrumental, subsequently basic activities of daily living
special dyspraxias, including topographical dyspraxia
Agnosia
difficult to assess, but probably more prevalent than often realised
includes autoprosopagnosia (one cause of mirror sign)
Behavioural and psychiatric symptoms (BPSD)
depression
psychotic features
personality change
activity disturbance
NINCDSADRDA criteria for AD
progressive
no disturbance of consciousness
Alzheimers disease
Vascular dementia
Dementia with Lewy bodies
Time
Discovery of a new disorder
Newcastle criteria for DLB
visual hallucinations
parkinsonism
Features supporting diagnosis DLB less likely in the presence of McKeith et al (1996)
Clinical symptoms of FTD
Neuropsychiatric symptoms
inertia and loss of motivation
loss of organisational abilities
lack of insight
restlessness
Speech problems
early loss of expressive speech
stereotyped phrases
late mutism and amimia
Disputed entity
onset age 5070 years
depression
rigidity
neurogenic bladder
Bradyphrenia
Perseveration
Mild amnesia
Routine investigations
full blood count
serum electrolytes
glucose
renal function
liver function
thyroid function tests
vitamin B12/folate
syphilis serology
Neuroimaging
CT
MRI
SPECT
Special investigations
EEG
LP
Evaluation of the elderly patient
Psychological tests
Laboratory investigations
The confused patient
Poor self-esteem
Pessimism
Loss of interest
Physical complaints
Psychomotor retardation
Sadness
Background
pathological process results in atrophy are also expressed elsewhere
hippocampus is affected first by neuropathology
Hypothesis
could regional atrophy visible on structural imaging be used as a biomarker of
AD?
Findings
medial temporal lobe atrophy can be detected by axial CT scan and MRI
an early change in AD
might distinguish AD from VaD
correlates with disease
Reservations
questionable specificity and sensitivity
Tau in CSF as a biomarker
Background
highly phosphorylated tau accumulates in tangles
highly phosphorylated tau is one of the earliest neuropathological changes in
AD
neurons are lost in AD, releasing tau into the extracellular space
Hypothesis
could tau be a biomarker of AD?
Finding
tau is elevated in CSF in AD
Reservations
no clear correlation with disease progression
questionable specificity and sensitivity
requires LP (invasive)
Why use scales in dementia assessment?
Standardisation
Multidisciplinary working
Quantification
Clinical management of dementia
Alzheimers disease is a costly disorder
Costs to sufferers
Costs to carers
Costs to services
Alzheimers disease is a treatable disorder
80
60
40
20
0
OConnor et al (1988)
Acetylcholinesterase inhibitors
Correcting cholinergic loss in AD
Muscarinic receptor
Nicotinic receptor
ACh
ACh metabolites
4 3
1 Choline
Lecithin Acetyl
CoA AChE
AChEIs 2
Donepezil
Cochrane review
Donepezil
Donepezil-treated
ADAS-cog Estimated decline without donepezil
+2
+4
+6
+8
12 26 50 62 74 86 98
Weeks
Rogers and Friedhoff (1998); Rogers et al (2000)
Rivastigmine
Pseudo-irreversibility
Galantamine
voltage dependency
rapid unblocking kinetics
BUT
Glutamate
Magnesium
M Memantine
Pathological activation of Possible neuroprotection Memantine improves
NMDA-receptors by memantine plastic processes
Signal
detected
Signal
Memantine
Placebo
Mean rating
4.0
4.2
4.4 Worsening
4.6 p = 0.025
4.8
5.0
12 28 Week
ADCS-ADL FAST SIB Clinical studies of memantine
Treatment in practice
Improvement or no change
To detect side-effects
To ensure compliance
A. Alzheimer (1907)
Types of activity disturbance in AD
Psychiatric
Changes in activity
symptoms
(e.g. increased activity,
(e.g. depression,
sleeplessness)
psychosis)
Behavioural
complications
Carer stress
Putting it together ABC and PAID
A Antecedents
B Behaviour
C Consequences
P Physical
A Activity
I Intrinsic
D Depression and delusions
The ABC approach to assessment
A antecedents
B behaviour
C consequences
Antecedents
Activity related
Aggression
Psychosis
Hope et al 1997
Consequences
Carer response
Patient response
Services response
Clinical assessment of cause
P Physical
A Activity
I Intrinsic
Cummings and Back (1998); Farlow and Cyrus (2000); Shannon et al (2000)
Cholinesterase inhibitors and behavioural
management
a common problem
a treatable problem
Burke et al (1997)
LUNDBECK INSTITUTE