LUNDBECK INSTITUTE

Dementia
Introduction and epidemiology
The leading causes of disability for both sexes in
developed countries

Total number of cases of disability = 75,389

Both sexes

Rank Disease or Injury Total (millions) % of total

1 Unipolar major depression 9.8 13.0

2 Alcohol use 6.1 8.1

3 Osteoarthritis 4.7 6.2

Dementia and other degenerative and hereditary
4 3.2 4.3
CNS disorders

5 Schizophrenia 3.0 4.0

6 Bipolar disorder 2.5 3.3

7 Cerebrovascular disease 2.3 3.1

8 Obsessive-compulsive disorder 2.1 2.8

9 Road traffic accidents 2.0 2.7

10 Diabetes mellitus 2.0 2.6

Murray and Lopez (1996)

Alzheimers disease: a prevalent disorder

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

Large increase in the oldest-old

in industrialised countries

Large increase in the young-old

in developing countries
Relative frequencies of the main dementias

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%

Gearing et al (1995); Kosunen et al (1996); Nagy et al (1998)

Risk factors and protective
factors
Using epidemiology to understand aetiology

Risk-modifying factors for AD

age
family history
head injury
vascular factors
diabetes
education
depression
dietary factors
heavy metals
maternal age
?smoking

Smoking and AD
APOE is associated with AD

APOEe4 increases risk

APOEe2 decreases risk
e2/e4 OR = 2.6

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

What does this mean for vascular dementia?

Breteler et al (1994); Tariska et al (1997)

Education

Low educational level increases risk of dementia and probably AD

Demonstrated by prospective studies and the Nun Study

Snowdon et al (1996)
The Aetiology and pathogenesis
of the dementias
The process of Alzheimers disease is also nearly
understood

Genes

Environment
Plaques

Central amyloid core

Degenerating peripheral neurites

Contents of a plaque Evolution of a plaque Distribution of plaques

Tangles

Intraneuronal accumulations of paired helical filaments

Paired helical filaments formed from highly phosphorylated tau

Other locations Filaments

Tau phosphorylation and the amyloid cascade
hypothesis

1. APP mutations give rise to plaques and tangles

2. Tau mutations give rise to tangles only
3. Tau mutations do not give rise to plaques
4. Plaque pathology therefore causes tangle formation

APP / PS-1 TAU

mutations mutations
4
1 2

? GSK-3

3
Bringing it all together (1)

5
Oxidative
damage

6
Inflammatory
response

Mutations in
APOE4
APP/PS-1

Increased Ab42 Tau phosphorylation Neuronal

Environment formation and and aggregation death
deposition
3
2 4
1

Age
Bringing it all together (2)

Tangle

Transentorhinal cortex Temporal/parietal cortex

Plaque

Increased non-amyloidogenic metabolism

Normal PKC GSK-3 Tau phosphorylation

Alzheimers
PKC GSK-3 Tau phosphorylation
disease

Increased amyloidogenic metabolism

Regional distribution of pathology

Distribution of pathology in AD is not random, but starts in

transentorhinal cortex and ends in neocortex

Braak staging Braak et al (1994); Delacourte et al (1999); Duyckaerts et al (1998)

Diagnosis and assessment
Regional distribution of atrophy in the common
dementias

Alzheimers disease predominantly parietal and temporal

Frontotemporal dementia predominantly frontal and temporal

Dementia with Lewy bodies as for AD, but with additional subcortical pathology

Vascular dementia vascular distribution

Executive Praxia Functional regions

functions FTD
AD

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

Criteria for clinical diagnosis of AD include

dementia

deficits in two or more areas of cognition

progressive

no disturbance of consciousness

onset ages 4090 years

absence of other systemic or brain disease that could account for

the condition

Other (1) Other (2) Unlikely Possible AD Definite AD McKhann et al (1984)

 Natural history of dementia with Lewy bodies
(DLB)

Onset may be gradual, but may also be sudden; in retrospect,

onset may have been first diagnosed as delirium
Progression fluctuating
Duration some evidence suggests total duration of illness shorter
than for AD
Cognitive function

Alzheimers disease
Vascular dementia
Dementia with Lewy bodies

Time
Discovery of a new disorder
Newcastle criteria for DLB

Progressive cognitive decline and two of three core features

fluctuation

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

Cherrier et al (1997); Duara et al (1999); Neary et al (1998)

Manchester and Lund criteria for FTD

Core diagnostic features

insidious onset and gradual progression

early decline in social interpersonal conduct

early impairment in regulation of personal conduct

early emotional blunting

early loss of insight

Behavioural Language Physical signs Investigations Neary et al (1998)

Natural history of vascular dementia

Vascular dementia is classically described as a disorder of

sudden onset
stepwise deterioration

However, there are problems with the notion as

vascular factors are risk factors for AD
mixed disease is common (and may be more common than vascular dementia alone)
relationship between degree of vascular damage and dementia is not direct
progression in vascular dementia is similar to that in AD (although mixed disease may be
different from both by showing more rapid decline) (Bowler et al 1997)
vascular dementia is found in many forms (Loeb and Meyer 1996)
NINDSAIREN criteria for probable vascular dementia

Dementia (according to ICD10)

Cerebrovascular disease evident on history, examination or

imaging

Two disorders must be related by

onset of dementia within 3 months or
abrupt, fluctuating or stepwise progression

Features of VaD Uncertain Possible VaD Definite VaD Roman et al (1993)

Binswanger's disease

Disputed entity
onset age 5070 years

evidence of hypertension or systemic vascular disease

progressive dementia (with predominant subcortical features)

depression

gait abnormalities (especially small stepping gait)

rigidity

neurogenic bladder

Cummings (1994); Pantoni and Garcia (1995)

Clinical symptoms of subcortical dementias

Bradyphrenia

Perseveration

Executive function deficits

Language and visuospatial preservation

Mild amnesia

Social functioning often preserved

Neurological symptoms of the primary disorder

Cummings (1994); Cummings and Benson (1984); Savage (1997)

Parkinson's disease and dementia

Occurs in 2040% patients

Usually occurs after motor disorder
Mild amnesia
Severe slowing of thought
Depression common
Part of Lewy body disease spectrum

Elwan et al (1996); Hughes et al (1993)

Parkinson Plus: common clinical features

Parkinsonism without rest tremor

Subcortical / frontal dementia
Emotional disturbances or depression
Other neurological or neuropsychiatric features characteristic of
each of the syndromes
Overlap between syndromes
Investigations

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

Differentiate the following conditions

depression
dementia
pseudodementia
concurrent depression and dementia

Identify and treat physical disease / contributory factors

Specialist investigations CT, EEG

Psychological tests

Laboratory investigations
The confused patient

Confusion is the inability to think with one's customary clarity and

coherence (Lishman 1987)

Primary causes of confusion include dementia and delirium

Confusion also arises as a consequence of other events and

pathologies

It may be the doctor and not the patient who is confused

DSM-IV: features of delirium DSM-IV: features of dementia

Clinical features of depression in AD

Lack of reactivity to pleasant events

Poor self-esteem

Pessimism

Loss of interest

Physical complaints

Psychomotor retardation

Sadness

Harwood et al (1998); Katz (1998);

Assessment Difficulties
Longsdon and Teri (1995)
Structural imaging

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?

Reliability and validity

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

Treating the symptoms

Treating the carers

Treating the environment

Treating the symptoms

Alzheimers disease goes unrecognised and
untreated

Dementia in the community

Dementia recognised by GPs

Population (%)
Dementia referred for treatment
100

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

Reversible acetylcholinesterase (AChE) inhibitor

Half life < 70 hours
Once-daily dosing
Two doses: 5 mg/day and 10 mg/day
Greater efficacy at 10 mg/day
Subjected to Cochrane review
Evidence for improvement in cognition, global state and possibly
function
Side-effects similar to other AChEIs nausea and vomiting most
common
Side-effects often mild and attenuate with time
Nightmares may occur

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-irreversible acetylcholinesterase (AChE) inhibitor

Half life ~2 hours / effects on AChE ~10 hours
Twice-daily dosing
Dose-titration regimen
Greater efficacy (and more side-effects) at higher doses
Evidence for improvements in cognition, global state and possibly
function
Evidence for benefits in those with vascular risk factors
Side-effects similar to other AChEIs nausea and vomiting most
common
Few interactions with other drugs
Pharmacoeconomic modelling suggests modest cost savings

Pseudo-irreversibility
Galantamine

Competitive reversible acetylcholinesterase (AChE) inhibitor

Allosteric modulator of nicotinic receptors
Half life ~2 hours / effects on AChE ~10 hours
Slow dose-titration reduces side-effects
Evidence for improvement in cognition, global state and possibly
function
No effect of APOE
Benefit maintained to 12 months
Side-effects similar to other AchEIs nausea and vomiting most
common

Allosteric modulation of nicotinic receptors

NMDA-receptor antagonism
Glutamatergic hypothesis of dementia

Glutamate is the main fast excitatory transmitter in regions

associated with cognition and memory

Cortical and subcortical structures that contain glutamatergic

receptors are structurally damaged in AD

Glutamate acts as an excitotoxin, causing neuronal death when

chronically released

Animal data suggest that NMDA-receptor antagonists provide

neuroprotection

Clinical signs of dementia correlate with deficits of glutamatergic

association fibres
Mechanism of action of memantine (1)

Both memantine and magnesium allow the physiological

activation of the NMDA-receptor due to their:

voltage dependency
rapid unblocking kinetics

BUT

Memantine does not leave the NMDA-receptor channel as easily as

magnesium following tonic low level activation of NMDA-receptors
Memantines voltage-dependency is not as pronounced as
magnesiums
Mechanism of action of memantine (2)

Glutamate
Magnesium
M Memantine
Pathological activation of Possible neuroprotection Memantine improves
NMDA-receptors by memantine plastic processes

Rest Rest Learning

M

Ca2+ M Ca2+ Ca2+

Signal
detected

Signal

Noise Noise Noise

Clinicians Interview-Based Impression of Change
(CIBIC)-plus

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

Four patterns of response

Improvement or no change

Improvement followed by deterioration after one year

Stabilisation followed by deterioration after one year

Deterioration from start

Improvement Deterioration Stabilisation Deterioration from start

Purpose of monitoring therapy

To ensure correct targeting of compounds

To detect side-effects

To ensure compliance

To ensure responders differentiated from non-responders

To ensure compound stopped when providing no benefit

Treating behavioural disturbance
Alzheimers disease is a disorder with behavioural
symptoms

The first noticeable symptom of

illness shown by this 51-year-old
woman was suspiciousness of her
husband. [At times] believing that
people were out to murder her,
[she] started to scream loudly. At
times she. . .seems to have
auditory hallucinations.

A. Alzheimer (1907)
Types of activity disturbance in AD

Activity disturbance is common and persistent

It may be broadly divided into apathy/withdrawal, social/sexual
impropriety and agitation
Agitation may be non-aggressive or aggressive
Non-aggressive Aggressive
Restlessness Hitting
Repetitive behaviours Pushing
Pacing Scratching
Wandering Grabbing
Bossiness Kicking
Complaining and whining Biting
Verbal interruptions Cursing
Constant demands for attention Temper outbursts
Noisiness
Screaming
Disturbance and psychopathology Haupt et al (1998); Devanand et al (1997)
Importance of treating BPSD

Reduction in carer stress

Improvement in ability of carers to care

Reduction in service costs

Improvement in quality of life

Carer stress Improvement Cost reduction Quality of life

Impact of specific behaviours on carers

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

What was the patient doing?

What was the carer doing?

What was the environment doing?

Behaviours

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

D Depression and delusions

Physical Activity Intrinsic Depression and delusions

Acetylcholine and BPSD

Dementia with Lewy bodies characterised by cholinergic deficit

and by hallucinations

Loss of cholinergic presynaptic markers, but not post-synaptic

receptors, in AD

Preservation of cholinergic system in frontal lobes

Anticholinergic compounds induce psychosis

Acetylcholinesterase inhibitors reduce behavioural abnormalities

in AD

Cummings and Back (1998); Farlow and Cyrus (2000); Shannon et al (2000)
Cholinesterase inhibitors and behavioural
management

Cholinesterase inhibitors reduce behavioural disturbance in AD

Cholinesterase inhibitors may be a safer alternative to

neuroleptics in DLB

Muscarinic agonists reduce BPSD despite little or no effect on

cognition

Bodick et al (1997); McKeith et al (2000); Tariot et al (2000)

Benzodiazepines in dementia

Frequently used, rarely studied

Considerable adverse effects

falls
confusion
oversedation
disinhibition

If absolutely unavoidable, use short term only

Short half-life, hepatic metabolism, no active metabolites are

favourable qualities (e.g. lorazepam, temazepam)

McCarten et al (1995); Sunderland et al (1989)

Psychosis as a target for therapy

Psychosis is highly prevalent in AD

delusions ~ 30%
hallucinations ~ 20%

Lewy body dementia is particularly associated with visual

hallucinations

Psychosis is associated with aggression and increased activities

Treat the patient, not the symptom!

Antipsychotics as a therapeutic tool

Have been used to treat

behavioural disturbance
sleeplessness
psychosis
aggression
the nursing home

Good practice suggests

define the target symptom
choose the antipsychotic carefully with respect to side-effect profile
start low, go slow
assess response
withdraw medication as soon as possible
Overview

Untreated BPSD may hasten caregiver burnout and patient

institutionalisation
Researchers from multiple disciplines are involved in developing
psychosocial interventions
Occupational therapists, nurses, psychologists, social workers,
physicians, and formal and informal caregivers are aided by these
interventions
The American Psychiatric Association practice guidelines for
patients with dementia and their families emphasise behavioural
management of patient symptoms and supportive therapies for
their families
Psychosocial interventions in dementia (PSID)
Depression and dementia

a common problem

a treatable problem

a problem causing carer stress

a problem reducing quality of life

SSRIs for dementia in depression

Well tolerated in the elderly

Few anticholinergic side-effects

Serotonin function lost in AD

Burke et al (1997)
LUNDBECK INSTITUTE