Transcript VanessaHinson_Cognitive Impairment in Parkinson`s Disease

Cognitive Impairment
in Parkinson’s Disease
Vanessa K. Hinson, MD, PhD
Medical University of South Carolina
PD: “More than a Movement
Disorder”
 Non-motor
symptoms often precede the
development of motor-symptoms

Olfactory dysfunction, constipation,
depression, sleep disorders
 Early
PD stages spare dopaminergic
nuclei
 Late stage development of levodopa
refractory symptoms
Braak Stages of PD

Stage I

Stage II

Stage III

Stage IV

Stages V,VI
Olfactory bulb
Nuclei IX and X in medulla
Intermediate reticular zone,
lower raphe, coeruleus-complex
Substantia
nigra,amygdala,hippocampus
Temporal mesocortex and
allocortex
High order sensory
association areas of neocortex
and prefrontal cortex.
Braak H et al. Staging of brain pathology related to sporadic Parkinson’s
disease. Neurobiol Aging 2003
Nonmotor
signs
Motor
signs
Cognition,
emotion
Typical course of PD
Honeymoon
Resistant
symptoms
Onset
Diagnosis
Death
3y
8y
Motor
complications
15y
Dementia
Cognitive Decline
Non-Motor Symptoms in PD
 Dementia
 Dysphagia
 Depression
 Drooling
 Anxiety
 Constipation
 Hallucinations
 Sleep
 Pain
problems
 Communication
Disorders
Symptoms
Median
frequency
%rated symptom
moderate or
severe
Difficulty eating
3
72
Difficulty
communicating
3
79
Physical discomfort 3
70
Confusion
3
68
Depression
3
60
Insomnia
2
47
Shortness of breath 2
40
Choking
2
47
Anxiety
2
60
1=never, 2= a few times, 3= frequently, 4=almost all the time, 5=constantly
Goy ER, Carter JH, Ganzini L. Parkinson’s Disease at the End of Life: Caregiver
Perspectives. Neurology 2007;69:611-12.
Impact of PD symptoms on
Quality of Life

Survey amongst 228 patients with > 5 year
disease duration
 Non-motor symptoms were rated to have
greater impact on quality of life than motor
symptoms
 PD end-of-life caregiver survey confirms
impact of non-motor symptoms
 Non-motor symptoms impact risk for nursing
home placement and mortality
PD nursing home follow-up
study
 55%
of nursing home patients had died on
follow-up 1 (mean, 40.2 m after data collection)
 Compared to 14% of those in the
community
 All living patients remained permanently in
the nursing home
1: Goetz CG, Stebbins GT. Risk factors for nursing home placement in
advanced Parkinson’s disease. Neurology 1993
Dementia in PD
~
40% of patients
 More common in late-onset PD (>70 y)
 Onset after years of PD motor
symptoms
 Important risk factor for more rapidly
worsening disability and reduced
survival
Dementia and PD mortality
 Louis
et al.1 showed mortality in PD 1.6 >
than non-demented elderly subjects
 Those with PD and dementia had mortality
risk ratio of 4.9
1: Louis E, Marder K, Cote L, et al. Mortality From Parkinson’s Disease. Arch Neurol 1997
PD dementia
Clinical features
 “Subcortical
dementia”
 Executive dysfunction
 Difficulties with planning, sequencing,
complex goal-directed behavior
 Impaired attention and concentration
 Decreased processing speed
 Problems with free recall, help from
external cuing
Parkinson’s Dementia
Dementia with Lewy bodies
 Traditionally
viewed as clinically distinct
disorders
 Based on chronology of events and
additional clinical features
 Single biologic entity? Synucleinopathy
Clinical Distinction
PDD
DLB

> 1 year history of
motor symptoms
before onset of
dementia*
 Visual hallucinations
late phenomenon
 Dysautonomia mild

< 1 year history of
motor symptoms
before onset of
dementia *
 Visual hallucinations
early
 Dysautonomia
prominent
* McKeith criteria
Can MRI make the difference?
 VBM
study Meyer et al. Neurology 2007
 DLB compared to PDD:
 Greater temporal, parietal and occipital
atrophy
Neuropathological differences
 Ballard
et al. (Neurology 2006): 57
prospectively assessed patients with DLB
or PDD
 Confirmed at autopsy
 PDD: threefold reduction in frequency of
abundant plaques
 20% less cortical synuclein pathology
 30% greater cholinergic deficit
PDD/DLB conclusion
 Key
substrates are the same
 Differences in cortical pathologic lesions
and neurochemical deficits
 DLB/PDD Working Group:


Single biologic entity (synucleinopathy) for
research purposes targeting basic molecular
processes
Distinction retained for clinical practice and
treatment
Risk factors for PD Dementia
 Advanced
age at onset of motor
symptoms
 Early occurrence of levodopa related
confusion or psychosis
 Presence of speech and axial involvement
 Depression
 REM sleep behavior disorder
Neurochemical deficits
Dopaminergic deficit?





Cognitive dysfunction correlates strongly with
non-levodopa responsive motor symptoms
Levodopa dose not reverse cognitive
dysfunction
No correlation between cell loss in substantia
nigra and dementia
Suggestive mainly of involvement of nondopaminergic systems
In neocortical areas however: decrease in
dopamine correlates with dementia
Neurochemical deficits
Noradrenergic/serotinergic
pathways?

Locus coeruleus damaged in PD
 Neuronal loss and norepinephrine depletion
more severe in PDD
 Pilot data on α1 and α2 agonists improving
attention and spatial memory*
 Serotinergic deficit and cell loss in raphe
nucleus has been described, but so far no
correlated with dementia
*Riekkinen et al Neuroscience 1999, Bedard et al. Clin neuropharm 1998
Neurochemical deficits
Cholinergic deficit?
 Severe
cellular loss in nucleus basalis of
Meynert
 Decrease in cholinergic innervation of the
cerebral cortex
 These deficits are correlated with
dementia
 PDD>DLB>AD
 Does this predict clinical response to
cholinergic therapy?
Unifying hypothesis
 Dopaminergic
deficit:
dysexecutive
syndrome
 Cholinergic deficit:
memory, frontal
lobe dysfunction
 Noradrenergic deficit: impaired attention
 Serotinergic deficit:
depression
Treatment implications?
Treatment (Donezepil)
Ravina et al. JNNP 2005;76:934-939
 Randomized
double blind, placebo
controlled, crossover study in 22 subjects
with PDD.
 Donepezil was well tolerated and did not
worsen PD.
 There was a modest (not stat. sign.)
benefit on aspects of cognitive function.
Treatment (Donezepil)
Aarsland et al.: JNNP 2002;72:708-712
 Double
blind, randomized, placebo
controlled, crossover study in 14 patients
with PD and cognitive impairment
 Donezepil: Mean MMSE score improved
by 2.1 (SD 2.7) points (baseline/week 10)
 Placebo: 0.3 (SD 3.2) point difference.
 Significant effect of donepezil on the
MMSE score compared with placebo
(p=0.013).
Dementia in PD
Treatment
 Cholinesterase
inhibitors have been
studied in randomized clinical trials
 Generally considered safe
 May exacerbate tremor
 Modest efficacy
 Role of memantine uncertain
Neuroimaging correlates
 Conventional
structural MRI: minimal or no
cortical or hippocampal atrophy
 Some studies have shown increased
incidence of small vessel ischemic disease
 Voxel based morphometry: automated,
unbiased method for voxel-wise
comparison of high resolution MRI data
Figure: Areas of reduced grey matter in PD MCI compared with PD
Significant changes are found in the (A) left superior temporal gyrus, (B) left
frontal lobe (precentral gyrus) and (C) right temporal lobe (inferior temporal
gyrus) and left temporal lobe (superior temporal gyrus) at p< 0.001.
Beyer, M. K et al. J Neurol Neurosurg Psychiatry 2007;78:254-259
Copyright ©2007 BMJ Publishing Group Ltd.
Functional Neuroimaging
 PET
to study abnormal functional
connectivity
 PD at rest: increased pallidothalamic and
pontine activity, reduced activity in cortical
motor and association regions*
 This network can be modulated by
therapeutic interventions such as DBS
* Eckert et. Al. Lancet Neurology 2007.
Parkinson’s Disease related cognitive pattern. A:PET. B:
Correlation PDCP expression/CVLT. C: PDCP/MCI. D: PDCP
expression over time (Eckert et al., Lancet Neurol 2007)
Pathology in PD dementia
Diffuse Lewy bodies
Senile plaques,
neurofibrillary tangles
Vascular disease
 Vascular
Disease and PDD
Role of homocysteine
Elevated Homocysteine in PD pts treated
with levodopa
Cts/pts
Hcy/cts
Hcy/pts
Kuhn
2001
54/132
13.1
17.3
Rogers
2003
32/205
12.2
16.1
Yasui
2000
50/90
10.2
16.3
Blandini
2001
31/30
10.8
16.9
Homocysteine metabolism and
effects of levodopa
SAM= S-Adenosylmethionine. SAH= S-Adenosylhomocysteine. MTHFR:
Methylenetetrahydrofolate reductase. CBS= Cystathionine
betasynthase. Vitamin cofactors in parenthesis.
Homocysteine
 Risk
factor for vascular disease and
dementia
 Potential neurotoxic effects
 Hcy could adversely affect cognition in PD
through vascular and neurotoxic effects
Vascular effects of homocysteine
 Enhanced
carotid atherosclerosis in PD,
correlation of severity of atherosclerosis
with duration of levodopa treatment and
degree of Hcy elevation (Nakaso et al.)
 Alteration of LDL receptors, enhanced
rate of plaque formation, proliferation of
vascular smooth muscle and impaired
endothelial activity.
 Silent brain infarcts and white matter
hyperintensities have been linked to
elevations in Hcy.
Vascular effects of homocysteine

Rotterdam Scan Study: Hcy is independent risk
factor for the presence of silent brain infarcts
and white matter lesions. Highest Hcy group: 3
times the risk for small vessel disease compared
to the lowest quintile.
 Neuropathological study of 13 cases of PDD:
presence of large and small vessel ischemic
disease in all patients (Apaydin et al.).
 Increase in white matter intensities on MRI in
PDD compared to PD (Beyer et al.).
Neurotoxic effects of
homocysteine
 Oxidative
injury
 Impaired DNA-repair
 NMDA-mediated excitotoxic effects
 Interaction with inflammatory
mechanisms
Clinical data on Hcy and PD
 Rogers:
Hcy elevation correlated with
presence of CAD in PD patients
 O’Suilleabhain: study of Hcy levels,
cognition, mood, and motor function in 97
subjects with PD.

Hyperhomocysteinemia was correlated with
worse cognition and mood, but motor function
unaffected.
Potential treatment of
hyperhomocysteinemia
 Vitamin
supplementation
 COMT inhibitors (entacapone, tolcapone)
Summary
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PD dementia is common and clinically distinct
from DLB
Impacts quality of life and mortality
Cholinergic deficit
Lewy body/AD/vascular pathology
Role of levodopa induced
hyperhomocysteinemia?
Research emphasizes the non-dopaminergic
features of PD including PD dementia
Antisyncuclein therapies