Transcript Psychotic symptoms in Parkinson`s disease

Mental Health Issues
In Parkinson’s
Dr. Duncan Forsyth
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust
Cambridge
Difficult areas in older people
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Diagnosis
Assessment
Hospitalisation
Drug Treatment & Therapies
Neuropsychiatry
Addenbrooke’s Hospital
5Hydroxytryptamine and Noradrenaline
Depression
Lewy
bodies
Oxidative stress
Dementia
Acetylcholine
Oxidative stress
Parkinson’s
Dopamine
Addenbrooke’s Hospital
What is Parkinson’s Disease?
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Parkinson’s disease …
is an insidious and progressive
neurodegenerative disorder
leads to a disruption of smooth and
coordinated motion
affects 1% of those over 60
results in premature death (mean
duration of disease at death 17yrs)
contributes to a substantial burden on
individuals, their families, medical
services and society as a whole
Addenbrooke’s Hospital
Diagnostic criteria for Parkinson’s disease -1
The UK Parkinson’s Disease Society Brain Bank has
devised a diagnostic criteria with a predictive accuracy of
82-84% (formal confirmation is only possible at post
mortem):
NB: Queens Square error rate 24% (1992) 10% (2001) - mainly MSA & PSP
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Bradykinesia (slowness and progressive decrease of amplitude of
movement).
Plus at least one of the following: resting tremor; rigidity; disorders of
posture, balance and gait.
None of the following: recent neuroleptic, toxin, designer drug
exposure; past history of encephalitis/oculogyric crisis: stepwise
progression of stroke; cerebellar or pyramidal signs; early severe
autonomic failure; supranuclear down gaze paresis; cerebellar/frontal
tumours/communicating hydrocephalus.
Addenbrooke’s Hospital
Diagnostic criteria for Parkinson’s disease -2
Clinical signs that may distinguish PD from the three other
parkinsonian disorders (MSA, PSP, and dementia with Lewy bodies)
commonly confused with PD include:
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Asymmetric onset of parkinsonism
Good response to levodopa and development of dyskinesias
Absence of pyramidal or oculomotor symptoms
Absence of early (usually 2 years) memory disturbances,
hallucinations, confusional episodes not related to treatment
Absence of early postural instability, particularly falls
Addenbrooke’s Hospital
Conditions to exclude
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Essential tremor
Drug induced Parkinsonism
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Arteriosclerotic pseudoParkinsonism
Multisystem atrophy (MSA)
Progressive Supranuclear Palsy (PSP)
Other causes of tremor
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phenothiazines
prochlorperazine
metoclopramide
tetrabenazine
drugs:
lithium, amiodarone, SSRIs,
anxiety
hyperthyroidism
MPTP exposure
Old age!
Addenbrooke’s Hospital
Signs and symptoms – motor
Hypokinesia
•shuffling, hesitant gait
•mask-like face
•drooling
•soft, mumbled speech
•micrographia
Rigidity
•cramp-like pain
•expressionless face
•cog-wheel rigidity
Resting
tremor
•tremor at rest but
not when moving or
sleeping
Addenbrooke’s Hospital
Causes of diagnostic uncertainty in determining the
presence of Parkinsonism in older people
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The presence of co-morbidities (such as arthritis, depression,
dementia, muscle weakness, involuntary movements
Non specific presentation (falls, depression, slowing down,
fatigue)
Atypical presentation (dysphagia, pain, dysarthria)
Tremor is common in older people and may be atypical and
difficult to classify
Tremor dominant Parkinson’s disease
Minor signs of extrapyramidal disturbance in older people
associated with cognitive impairment.
Addenbrooke’s Hospital
Reasons for diagnostic uncertainty in determining the
cause of Parkinsonism in older people
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There are more causes of Parkinsonism in older people
Drug induced Parkinsonism increases in frequency with age
Levodopa responsiveness is unreliable in older people as a marker
for Parkinson’s disease
Vascular Parkinsonism and Parkinsonism associated with dementia
become more prevalent with age and create diagnostic difficulty
Addenbrooke’s Hospital
Signs and symptoms – non-motor
Autonomic problems
in < 71% (recorded in @ 23%)
• orthostatic hypotension (21-58%)
• constipation (43-72%)
• bladder dysfunction (14-45%)
• increased sweating
• impotence (20-60%)
• altered thermoregulation (22%)
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Depression
in < 40%
• lifetime risk @ 70%
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Dementia
20-40%
• <80% at 10yrs
•
Addenbrooke’s Hospital
Prevalence of Parkinson’s Disease
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Approximately 1.5% of the population over the
age of 65 is estimated to suffer from Parkinson’s
Disease
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6.3 million people worldwide
120 000 in UK
Emre M 2003
European Parkinson’s Disease Association 2003
Parkinson's Disease Society Media Briefing Sheet
Addenbrooke’s Hospital
Progression of Parkinson’s disease
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Not a uniform prognosis
At least 10% still in Hoehn & Yahr stage I at 10yrs
23% in NH at 10yrs (Sydney Multicentre Study. 1999)
Rate of progression different in younger onset
Effect of Rx on progression unclear - ?DA neuroprotective
Impact of Rx on global prognosis unclear
Co-morbidities influence prognosis
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dementia
dysphagia
falls
Addenbrooke’s Hospital
Addenbrooke’s Hospital
Olive – 78yrs
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Slow recovery (poor mobility) post pneumonia
Blunted facial expression
Questionable increase tone in upper limbs
Bilateral hand tremor
Hallucinating
MMSE 26/30
Would she benefit from levodopa therapy?
Addenbrooke’s Hospital
Welcome to Geriatric Medicine!
(Comprehensive Geriatric Assessment)
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Check vision
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Cataracts
Senile macular degeneration
Check hearing
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Wax
Hearing aid
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In use
Functioning
Score MMSE correctly!
Co-morbidities
Take a good history and review the notes
Addenbrooke’s Hospital
Olive – 78yrs
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Slow recovery (poor mobility) post pneumonia
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Blunted facial expression
Questionable increase tone in upper limbs
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Arthritis and poor visual acuity
Widespread osteoarthritis (wrists, knees, shoulders)
Bilateral hand tremor
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(50yrs)
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Visual misintrepretations – bilateral cataracts
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Actually 26/28
Hallucinating
MMSE 26/30
Would she benefit from levodopa therapy?
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This is not PD
Addenbrooke’s Hospital
The slippery slope to psychosis
Reduced sleep
Excessive daytime somnolence
Illusions
Vivid dreams
Hallucinations
Delusions
Organic confusional psychosis
Addenbrooke’s Hospital
John – 74yrs
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Parkinson’s symptoms for 5 years untreated
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Distrusts doctors (he trained most of them!)
Denial
Frustration
Resentment
Reluctantly attended clinic after getting stuck in the bath
and agreed to start on levodopa
Benefitted from levodopa but still undertreated
Started on dopamine agonist
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By end of 1st week developed visual, auditory and tactile
hallucinations
Addenbrooke’s Hospital
Let’s discuss John’s case
Addenbrooke’s Hospital
Psychosis - 1
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30% develop hallucinations in first 5 years after
diagnosis
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These may become permanent in >80%
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Fenelon G, et al. Brain 2000; 123: 733-45
Graham JM, et al. J. Neurol. Neurosurg. Psychiatry 1997; 63: 434-40.
Hallucinations rarely (14%) go away
Addenbrooke’s Hospital
Psychosis - 2
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Hallucinations may be associated with excessive
dopaminergic and serotonergic activity, and
cholinergic deficit
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Factor SA, et al. Advances in Neurology 1995: 115-38.
Dopaminergic therapies may only precipitate
psychosis in those with limbic predominance of
Lewy bodies
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Holroyd S, et al. J Neurol Neurosurg Psychiatry 2001; 70: 734-8.
Addenbrooke’s Hospital
Comparison of 214 Consecutive Patients with Parkinson
Disease with and without visual Hallucinations
Characteristic
Mean (+SD) age, yrs
Male, %
Mean (+SD) disease duration, yrs
P
.007
.05
.008
Hallucinators
n = 56
Non hallucinators
(n= 158)
70+10.3
66+9.18
73
57
8.6+5.6 (n=47) 6.3+5.4 (n=100)
Mean (+SD) Hoehn and Yahr stage
<0.001
3.2+0.9
2.3+0.8
Mean (+SD) Folstein MMSE score
<0.001
.002
21.8+6.6
(n=46)
43 (n=50)
27.3+2.4
(n=116)
17 (n=100)
History of sleep disturbance, %
<0.001
40 (n=54)
18.3 (n=100)
Mean (+SD) daily levodopa dose, mg
Mean (+SD) anticholinergic dose, mg
.7
<0.001
426+216
2.3+0.45 (n=5)
443+310
4.0+0.5 (N=15)
Mean (+SD) selegiline hydrocholoride
dose, mg
Mean (+SD) bromocriptine dose, mg
.50
6.75+0.6
(n=14)
6.2+0.65 (n=7)
7.33+0.45
(n=46)
7.5+1.0 (n=4)
History of depression, %
.03
Addenbrooke’s Hospital
David – 76yrs
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Presents to OAP with low mood, paranoia and delusions
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No fluctuations in either physical or mental state
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Thinks his wife is having multiple affairs
Deluded
Poor engagement with staff
Poor nutritional intake
Poor sleep pattern
Constipated
B12, folate, TFTs, FBC, LFTs, U&Es normal
CT head scan normal
Noted to have rest tremor of left hand, cog-wheel rigidity
of left limbs, is bradykinetic (walking, dressing)
Addenbrooke’s Hospital
Let’s discuss David’s case
Addenbrooke’s Hospital
Psychotic depression
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May present for as first episode in old age
Beware co-existent pathologies
Beware interaction between:
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Psychiatric and physical symptoms
Psychiatric and dopaminergic medications
Don’t let him fall between
Addenbrooke’s Hospital
Outcome
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Mood improved
Delusions resolved
Eating and sleeping normally
Quetiapine
Citalopram
Walking speed increased (0.4 – 0.8 m/sec)
Tremor decreased
Rigidity decreased
Sinemet
Shared care but NOT shared notes!
Addenbrooke’s Hospital
Depression in Parkinson’s - 1
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Common and potentially treatable
GDS-15 sensitivity @ 90%, specificity @ 70%
Prevalence @ 40% in hospital based population
Prevalence @ 26-33% in community based population
Addenbrooke’s Hospital
Depression in Parkinson’s - 2
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1 in 3 carers depressed when screened with GDS-15
Distress in carers predicted by motor impairment and level of
depression in PD sufferer
Depression in PD sufferer correlates with severity of disease
Treating depression in PD sufferer may reduce carer stress
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Meara et al. Age & Ageing 1999; 28: 35-8
Addenbrooke’s Hospital
Depression in Parkinson’s - 3
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QOL most affected by depression and level of disability
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1 in 3 depressed
2/3 of these untreated for depression
Of those on Rx for depression 50% inadequately Rxd and still
clinically depressed
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Weintraub et al 2003
SAM (S-adenosyl methionine) improves depression in PD (open
label study – 13 pts)
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DiRocco et al 2000
Pramipexole improves MADRS in 50% pts cf pergolide in 19%
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Rektorova et al. Eur J Neurol 2003
Addenbrooke’s Hospital
Marion – 76yrs
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Parkinson’s for 10yrs
Complex phase with dyskinesias and motor fluctuations
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Fall
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Apomorphine s/c infusion 0800hrs – 2000hrs
Pergolide overnight
Sinemet tds
# R NOF diagnosed 1 week later when still poorly mobile in sheltered
housing complex
Operation then delayed 4 days pending echocardiogram
Post-op
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nurses complain of Marion’s criticisms about their management of her
medication
Admits to having hallucinations
Evidence of problems with strategies, organisation, abstraction and
planning – all increase risk of further falls
Addenbrooke’s Hospital
Let’s discuss Marion’s case
Addenbrooke’s Hospital
Delirium
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Is medication being given correctly
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Fluid and hydrational status
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UTI
Constipation
Pain management
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Doses
Timing
ApoGo presents a level of complexity for some staff
Lack of
Constipation
Side-effects
Operative delay
Have we unmasked fronto-temporal dementia?
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Dementia as a predisposing factor for delirium
Addenbrooke’s Hospital
Management of psychosis
Addenbrooke’s Hospital
Psychosis - management
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Exclude and prevent delirium
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Reduce sensory deprivation / overload
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Optimise vision and hearing
Minimise drugs (motion-emotion conundrum)
Explain to carer(s) – they are more bothered!
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Manage sleep
Avoid constipation
Nutrition and hydration
Avoid anaesthesia where possible
Avoid hospitalisation / institutions
Avoid neuroleptics
Review support needs (care package, respite, etc)
Liaison between PD service and OAP
Atypical antipsychotics
Acetylcholinesterase inhibitors
Addenbrooke’s Hospital
Stay CCALM - 1
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Carer support
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Cognitive strategies
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Appropriate, timely social and respite care, support
groups
Cueing and attentional strategies for movement and
memory
Assessment
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Cognition, capacity
Mood, psychosis
Motor, ADL and social function
Addenbrooke’s Hospital
Stay CCALM - 2
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Liaison
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OAP, Social Services, Primary Care, PDNS, CPN
Medical care
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Manage sleep
Avoid constipation
Optimise vision
Avoid anaesthesia where possible
Avoid hospitalisation / institutions
Avoid neuroleptics
Manage hallucinosis (motion – emotion conundrum)
Consider cholinesterase inhibitors
Addenbrooke’s Hospital
Atypical antipsychotics in PD psychosis - 1
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6 week open label study of olanzapine in 5 PDD
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4 withdrew due to worsening motor function, sedation, paranoia
No improvemnet in psychotic symptoms
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Marsh L, et al. Psychosomatics 2001; 42: 477-81.
In an open label retrospective analysis of the effects of
quetiapine:
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80% PDD & 90% DLB patients had partial-complete resolution of
psychosis
72% of both groups remained on quetiapine for a mean duration
of 14 months
Motor function worsened slightly in 32% PDD & 27% DLB
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Fernandez HH, et al. J Clin Psychiatry 2002; 63: 513-5.
Addenbrooke’s Hospital
Atypical antipsychotics in PD psychosis - 2
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14 week DBRCT clozapine in PD psychosis
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60 pts mean age 72yrs
Mean dose of clozapine 24.7mg daily
CGI, BPRS both improved p < 0.001 and p = 0.002
Neutropaenia in 1 case
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Parkinson’s Study Group. New Engl J Med 1999; 340: 757-63.
Addenbrooke’s Hospital
The Challenge of Treating the Psychotic
Symptoms Associated with PD
Agents used to
Conventional
treat motor symptoms Antipsychotics
No improvements in
cognitive function
Atypical
Antipsychotics
EPS, sedation, EPS, Anticholinergic
confusion, falls,
effects, sedation,
sensitivity reactions
CVAs
Need for alternative therapies to treat the cognitive
and behavioural symptoms of these populations
Emre M. Lancet Neurol 2003;2:229–37
McKeith I et al. Lancet Neurol 2004;3:19–28
Burn DJ, McKeith IG. Mov Disord 2003;18 (Suppl 6):S72–9
Addenbrooke’s Hospital
Fanny – 88yrs
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Takes to bed on a regular basis in her sheltered housing
complex and won’t eat or engage with carers for several
days at a time
Often hallucinates – sees children in her flat
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GP treated with olanzapine and she became much worse
In between times ambulant, eats, enjoys company, hard
to complete MMSE (very deaf) but daughter reports
mother’s memory has declined over last year.
Daughter says “it is like having two mothers!”
No tremor
Shuffles around flat
Widespread arthritis makes assessment of tone
impossible
Addenbrooke’s Hospital
Let’s discuss Fanny’s case
Addenbrooke’s Hospital
Dementia Associated with PD
Prevalence of 40% of PD patients
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% PD patients developing dementia
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In PD patients without dementia almost 80%
develop dementia over an 8-year period
90
80
70
60
50
40
30
Aarsland D et al. Arch Neurol 2003;60:387–92
20
Emre M. Lancet Neurol 2003;2:229–37
10
0
Year 0
Year 4
Year 8
Addenbrooke’s Hospital
Parkinson’s Disease with Dementia
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More common
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(6x) At all ages than age-matched controls
with age of onset of PD > 60yrs
In later stages of PD
With more severe EPS
If develop psychosis and confusion with levodopa
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Levy G, et al. Ann Neurol 2002; 51: 722-9
Depression frequently co-exists (Rx if in doubt)
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Poor attention, poor initiation, poor construction, increased
perseveration all mimic Parkinson’s dementia
Addenbrooke’s Hospital
Dementia in Parkinson’s
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27% newly diagnosed Parkinson’s have executive deficit,
65% do not
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Foltynie 2004
Frontal dysexecutive syndrome is best predictor for risk of
developing dementia
Prevalence of dementia
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40% all PD population
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Cummings 1988
Correlates with age (0% <50yrs; 69% >80yrs)
29% after 3yrs
78% after 8yrs
60-80% after 10-15yrs
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Aarsland 2003
Addenbrooke’s Hospital
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Cognitive deficits in PD are commonly
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Executive function (most prominent and may be earliest)
Higher order attention
Memory
Spatial skills (visuo-motor processing and visual attention)
Executive dysfunction underlies
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Memory dysfunction
Problems with verbal fluency
Problems with reasoning
Problems with spatial skills
Problems with complex attention
Addenbrooke’s Hospital
Dementia in Parkinson’s
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Dysexecutive frontal syndrome reflects dopaminergic
deficits
Impairment of verbal fluency & clock drawing reflects
cholinergic deficit in limbic system
Severe cortical cholinergic deficits in PDD correlate with
cognitive deficit
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Dopaminergic loss
Cholinergic loss
Noradrenergic loss
Serotonergic loss
Perry 1985, 1987, 1993
dysexecutive
dementia (memory)
attention deficit
depression
Addenbrooke’s Hospital
Parkinson’s Disease with Dementia:
Early detection?
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May be predicted early by abnormalities of:
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Verbal fluency
Picture completion section of WAIS
Interference section of the STROOP test of divided
attention
Fluoro-L-dopa PET shows impaired mesolimbic
& caudate dopaminergic function in PDD
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Ito K, et al. Brain 2002; 125: 1358-65
Addenbrooke’s Hospital
Dementia with Lewy bodies
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15-20% of all dementias in older people
Mean age onset 75yrs (50-83yrs)
Fluctuations
@ 80%
Hallucinations
@ 70%
EPS
@ 75%
Addenbrooke’s Hospital
Lewy Bodies
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Lewy bodies are intracytoplasmic inclusions found in
nerve cells in patients with PD and DLB
Addenbrooke’s Hospital
Lewy bodies
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Dementia with Lewy bodies (DLB) may represent 1520% of all dementia cases
DLB is associated with increasing density of Lewy
bodies widespread throughout the cortex.
There may be a direct correlation between density of synuclein cortical Lewy bodies and severity of dementia
in PD.
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91% sensitivity 90% specificity
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Hurtig HI. et al. Neurology 2000; 54: 1916-21
> 2 Lewy bodies in parahippocampus has 93% positive
predictive value for dementia
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Harding AJ & Halliday GM. Acta Neuropathol 2001; 102: 355-63
Addenbrooke’s Hospital
Differentiating DLB from PDD - 1
PD
DLB
EPS
100%
70-100%
Executive dysfunction
YES
YES
Visuo-spatial dysfunction
YES
YES
Hallucinations
14% (54% PDD)
76%
Delusions
7% (29% PDD)
57%
Addenbrooke’s Hospital
Revised criteria for DLB
Central
feature
Core features
Suggestive features
Supportive features
Central
feature plus:
2 or more core
1 core + 1 suggestive
1 core feature
1 or more suggestive
= probable DLB
= probable DLB
= possible DLB
= possible DLB
McKeith et al Neurology 2005; 65: 1863 -1872
Addenbrooke’s Hospital
DLB: Central feature
Progressive
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deterioration of cognitive function
- mandatory requirement
Different
cognitive profile compared to AD
-In early stages memory impairment not always prominent
-Prominent
deficit of:
--
attention
-- visuospatial abilities
-- psychomotor speed
-- verbal fluency
-- executive functions
McKeith et al Neurology 2005; 65: 1863 -1872
Addenbrooke’s Hospital
DLB: Core features
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1. Fluctuating cognition
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- Variation in attention and alertness (50-75%)
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2. Persistent complex visual hallucinations
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- Generally present in early stages of illness
- Associated with more marked visuo-perceptual dysfunction
- More LB in temporal lobe and amygdala
- Greater deficit in cortical acetylcholine
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3. Spontaneous extrapyramidal features
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- 25-50% at presentation
- Gait abnormality / postural instability
- Rigidity
- Bradykinesia / akinesia
- Rest-tremor (less common than in PD)
- Less levodopa responsiveness than in uncomplicated PD
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McKeith et al Neurology 2005; 65: 1863 -1872
Addenbrooke’s Hospital
DLB: Suggestive features
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1. REM sleep behavioural disorder (RBD)
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- Frightening dreams during REM sleep
- Accompanied by talking and shouting
- Thrashing around the bed
- Vivid visual images
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2. Severe neuroleptic sensitivity
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- Present in up to 50% of exposed patients
- Severe exacerbation of parkinsonism
- Impairment of consciousness
- May be induced by both typical and atypical neuroleptics
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3. Low (FP-CIT) tracer uptake in striatal dopamine transporters
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McKeith et al Neurology 2005; 65: 1863 -1872
Addenbrooke’s Hospital
Differentiating AD from PDD and DLB
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Parkinsonian features uncommon in AD (6.7-30%) and
usually a late manifestation.
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PDD more apathetic on the Frontal Systems Behaviour
Scale
AD worse on memory subscale of DRS
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Cahn-Weiner DA, et al. Neuropsychiatry Neuropsychol Behav Neurol 2002; 15: 79-87
DLB worse on attention @ construction subsets of
MMSE than AD
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Ala TA, et al. Int J Geriatr Psychiatry 2002; 17: 503-9.
Visual hallucinations, altered consciousness
Parkinsonism commoner in DLB than AD
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and
Ballard CG, et al. Age & Ageing 1998; 27: 631-6
Addenbrooke’s Hospital
Differentiating DLB and AD
DLB
DLB
AD
AD
Presentation (%)
Ever (%)
Presentation (%)
Ever (%)
Dementia
82
100
100
100
Fluctuations
58
75
6
12
Visual hallucinations
33
46
13
20
Auditory hallucinations
19
19
1
4
Depression
29
38
16
16
EPS
43
77
12
23
Falls
28
37
9
18
Neuroleptic sensitivity
61
15
Addenbrooke’s Hospital
In-vivo demonstration of dopaminergic
degeneration in dementia with Lewy bodies
Zuzana Walker, Durval C Costa, Paul Ince, Ian G McKeith, Cornelius L E Katona
The Lancet: August 21 1999; 354:646-647
Addenbrooke’s Hospital
DAT scans and dementias

88% sensitivity, 85% specificity in differentiating DLB
from AD

DLB equal loss caudate and putamen
PDD putamen > caudate




DLB loss tends to be symmetrical
PDD loss tends to be asymmetrical with greater scatter
Lower uptake of radioactivity in caudate and putamen in
PD and DLB cf AD (Walker et al. J Neurol Neurosurg Psychiatry 2002; 73: 134-40)
Addenbrooke’s Hospital
Why use DaTSCAN in suspected DLB?

Neuroleptic sensitivity

Cholinergic response

Dopaminergic response

Patient/carer awareness

Confident management
AD patient:
hallucinating
with
extra-pyramidal
features
DLB patient:
hallucinating
with
Parkinsonian
features
Images courtesy of Southampton General Hospital
Addenbrooke’s Hospital
Differentiation of dementia with Lewy
bodies from Alzheimer's disease using a
dopaminergic presynaptic ligand
Z Walker1, D C Costa1, R W H Walker2, K Shaw1, S Gacinovic1, T Stevens1, G
Livingston1, P Ince3, I G McKeith4 and C L E Katona1
JNNP 2002; 73 134-140
Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of
Alzheimer's disease (AD). Key pathological features of patients with DLB are not only
the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving
neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of
Parkinson's disease (PD). In DLB there is 40–70% loss of striatal dopamine.
Objective: To determine if detection of this dopaminergic degeneration can help to
distinguish DLB from AD during life.
Addenbrooke’s Hospital
Potential use:
• pre-clinical changes
• support Δ in early disease
• confidence
• support ΔΔ
• change management
• monitor disease progression
Abnormal scan supports Δ provided
structural imaging normal. Normal
scan argues against Δ
10-13% clinically diagnosed PD have
normal scans (Calm-PD, Real-PET,
ELLDOPA) – SWEDDs (subjects
without evidence
transporter deficit)
of
dopamine
Once a SWEDD always a SWEDD!
? Negative
SWEDDs
predictive
value
of
Addenbrooke’s Hospital
Do PDD and AD share aetiology?
PDD
AD
NO
YES
Inverse
Inverse
Head Injury
NO
YES
Smoking
YES
YES
Hypertension
NO
YES
Diabetes
NO
YES
Depressive symptoms
YES
Severity of EPS
YES
L-DOPA psychosis
YES
APOE4 genotype
HRT
Levy et al. Mov Dis 2002;
17: 250-7
Addenbrooke’s Hospital
Parkinson’s Disease with Dementia:
Cholinergic deficit


Dopaminergic stimulation has only weak positive
effect on cognition.
Cognitive deficits increase with reduced cortical
cholinergic, especially nicotinic receptor binding.


Newhouse PE, et al. Drugs Ageing 1997; 11: 206-28.
Extent of reduction in Choline acetyltransferase
activity in prefrontal areas correlates with degree of
cognitive impairment and with number of Lewy bodies

Mattila PM, et al. Acta Neuropathol 2001; 102: 160-6.
Addenbrooke’s Hospital
Cholinergic Deficits in Dementia
Associated with PD, DLB and AD
300
250
200
150
100
50
0
Controls
Dementia
associated
with PD
DLB
AD
Tiraboschi P et al. Neurology 2000;54:407–11
Addenbrooke’s Hospital
Cholinesterase Inhibitor Studies in
Dementia Associated with PD
Double-blind, placebo-controlled studies
multi-center
DLB
rivastigmine
(McKeith et al 2000)
n = 120
donepezil
(Aarsland et al 2002)
n = 14
(Leroi et al 2004)
n = 16
(Brashear et al 2004)
n = 24
single-center
PDD
Smaller, open-label studies
PDD
rivastigmine, donepezil, galantamine
n = 5–28
DLB
rivastigmine, donepezil
n = 7–17
Addenbrooke’s Hospital
Cholinesterase inhibitors in DLB

Open study of rivastigmine (11pts) over 12 weeks





73% had reduction in delusions
61% less apathetic
52% less agitated
75% had fewer hallucinations (37.5% lost them altogether)
Overall 45% experienced significant clinical improvement


Samuel W, et al. Int J Geriatr Psychiatry 2000; 15: 794-802.
Placebo controlled trial of rivastigmine (127pts)

>30% reduction in psychiatric symptoms occurred in 63% of
rivastigmine group vs 30% controls

McKeith IG, et al. Lancet 2000; 356: 2031-6.
Addenbrooke’s Hospital
Cholinesterase inhibitors in PDD

Open study of tacrine (7pts) and donepezil (4 pts)




3.2 point improvement on ADAS-cog
p<0.012
1.2 point improvement in MMSE
NS
0.2 point improvement in GDS
NS
5 individuals had motor improvement, none worsened


Werber & Rabey. J Neural Transm 2001; 108: 1319-25.
Donepezil <10mg/day in 6 PDD with psychosis



5 clinically significant improvement in psychosis (>53%)
1 non-clinically significant improvement in psychosis (24%)
No side-effects or withdrawals

Bergman & Lerner. Clin Neuropharmacol 2002; 25: 107-10.
Addenbrooke’s Hospital
Efficacy of rivastigmine in PDD (mean dose 8.6mg/day)
Emre et. al. New Engl J Med 2004; 351: 2509-18
Addenbrooke’s Hospital
EXPRESS Open-Label Extension
Effect of Rivastigmine on ADAS-cog
-4
Open-label extension
(all patients receiving rivastigmine)
Change from baseline,
ADAS-cog
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
Week: 0
Double-blind phase
Rivastigmine, n = 176
Placebo, n = 97
Improvement
Rivastigmine
Placebo
Baseline
16
24
48
176
95
174
94
162
93
OC analysis
n values show numbers of patients in each group providing ADAS-cog data at each time point
On the ADAS-cog, lower scores indicate improvements in cognitive performance
Addenbrooke’s Hospital
So what happened to Fanny?
Addenbrooke’s Hospital
Addenbrooke’s Hospital
Thank you for your attention!
Addenbrooke’s Hospital
Basal ganglia - cognition
Pre-frontal
Supplementary
Motor
Pre-motor
Caudate
Putamen
Cerebellum
Medial
Lateral
Substantia nigra pars compacta
Addenbrooke’s Hospital
Basal ganglia - unconscious motor
Pre-frontal
Supplementary
Motor
Pre-motor
Caudate
Putamen
Cerebellum
Medial
Lateral
Substantia nigra pars compacta
Addenbrooke’s Hospital
Basal ganglia – conscious motor
Pre-frontal
Supplementary
Motor
Pre-motor
Caudate
Putamen
Cerebellum
Medial
Lateral
Substantia nigra pars compacta
Addenbrooke’s Hospital