cn-1 neuropathology of parkinson's disease dementia
TRANSCRIPT
CN-1
Neuropathology ofParkinson’s Disease Dementia
James B. Leverenz, MD
Associate ProfessorNeurology and Psychiatry and Behavioral Sciences
University of Washington School of Medicine
UW Alzheimer’s Disease Research Center
VA Northwest Network Mental Illness and Parkinson’s Disease Research, Education, and Clinical Centers
CN-2
Overview—Neuropathology of PDD
Dementia in elderly PD patients is primarily due to Lewy body pathology, and not just coexistent AD
– Review of AD pathology
– Review of PD pathology
– Neuropathologic changes in PDD
PDD is associated with severe deficits in the cholinergic system
– Biochemical and neuroimaging data
– Neuropsychologic data
CN-3
Abbreviations and Terminology
PD – Parkinson’s Disease without dementia
PDD – Parkinson’s Disease with dementia
AD – Alzheimer’s Disease
LBP – Lewy Body Pathology
– “classic” Lewy body inclusions
– alpha-synuclein immuno-positive inclusions and neurites
CERAD – Consortium to Establish a Registry for Alzheimer’s Disease
CN-4
Silver stain: plaques and tangles
Alzheimer’s Disease—Pathology
Silver stain:neuritic plaques
Neurofibrillarytangles
CN-5
Pathological Criteria for AD
Staging of AD pathologic change
– Neuritic plaques (CERAD, absent to frequent)
– Neurofibrillary tangles (Braak staging, I - VI)
For pathological diagnosis of AD†
– Integrate CERAD and Braak staging evaluating “likelihood” AD changes led to dementia
• High - CERAD frequent/Braak V or VI
• Intermediate - CERAD moderate/Braak III or IV
• Low - CERAD sparse/Braak I or II
† Neurobiol Aging. 1997;18(4 suppl):S1-2.
CN-6
AD Pathologic Change in Non-Demented Elderly
Knopman et al (JNEN 2003)†
– 39 longitudinally followed non-demented cases
• Mean age 85 years (74 - 95)
– AD pathologic change
• 38 Braak stage I or greater, 4 Braak stage IV or V
• 37 with sparse or absent neuritic plaques, ~50% with moderate to frequent diffuse plaques
– “...cut off points ...Braak stage ≥ IV ...neuritic plaques ≥ moderate...”
† Knopman et al. J Neurol Pathol Exp Neurol. 2003;62:1087-1095.
CN-7
AD Pathologic Change in the Elderly
Knopman et al. J Neuropathol Exp Neurol. 2003;62:1087-1095.
Diffuse plaquesCored plaquesNeuritic plaques
Braak and Braak stage CERAD plaque ratings
0 - I II III IV - V None Sparse Moderate Frequent
Nu
mb
er o
f su
bje
cts
Nu
mb
er o
f su
bje
cts
0
2
6
8
10
12
4
14
0
5
15
20
10
25
CN-8
Neuropathology of Parkinson’s Disease
Substantia nigra pathology
Lewy body inclusionsNeuronal loss
CN-9
Improved Detection of Lewy Body Pathology
Alpha-synuclein mutations in familial PD
Alpha-synuclein immunoreactivity in all Lewy bodies
– Classic brainstem Lewy bodies
– Cortical Lewy bodies
– Lewy neurites
CN-10
Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex
Cerebral cortex Substantia nigra
CN-11
Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459.
Braak Staging of Lewy Bodies
CN-12
What Is the Neuropathologic Basis of Dementia in Parkinson’s Disease?
CN-13
Neuropathology of PDDAD Pathologic Change
“…contrary to published reports, most patients with parkinsonism who exhibit dementia do not have concomitant Alzheimer’s disease…Some pathogenetic mechanism must be sought to account for this increasingly common cause of cognitive decline in the sufferers of Parkinson’s disease.”
—Ball M. Can J Neuro Sci. 1984;11(1 suppl):180-184.
CN-14
Neuropathology of PDDCortical LB Pathology Correlates With Dementia
Author, yr Population Primary correlate of dementia
Kosaka, 1998 11 PDD Cortical LBs
Mattila, 1998 44 PDD Cortical LBs
Mattila, 2000 45 PDD Frontal cortical LBs
Hurtig, 2000 22 PDD vs 20 PD only
Cortical LBs
Apaydin, 2002 13 PDD Cortical LBs
Kovari, 2003 22 PDD LBs in entorhinal cortex andBrodmann 24
Braak, 2005 88 PD Cortical LBs
1-15\DV
CN-15
Neuropathology of PDDAD Pathologic Change
Case selection
– Treatment-responsive PD precedes dementia
Neuropathology
– Alpha-synuclein immunohistochemistry
– Up-to-date criteria for AD diagnosis
• Braak IV to VI and CERAD plaque stage B or C
CN-16
Neuropathology of PDDAD Pathologic Change
Apaydin et al (Arch Neurol, 2002)– Clinical
• 13 PDD cases (mean age 78.1yr, range 64 - 89)
– Pathology• 12 with diffuse or transitional Lewy body
pathology– 1 case with intermediate likelihood of AD
(Braak stage IV, CERAD plaque stage B)• 1 case with PSP (no LBP)
Apaydin H, et al. Arch Neurol. 2002;59:102-112.
CN-17
Neuropathology of PDDAD Pathologic Change
Braak et al (Neurology, 2005)
– 88 clinical PD cases with autopsy confirmation of LBP (mean age 75.9 yr; range 60 - 89)
– 79 with mild to severe cognitive impairment
– MMSE score correlated with stage of LBP (using Braak’s staging of LBP)
– Only 2 cases fulfilled criteria for AD pathologically (VI C and IV B)
Braak H, et al. Neurology. 2005;64:1404-1410.
CN-18
PDD - AD Pathologic Change
Aarsland et al (Ann Neurol, 2005)
– Community-based sample of PD (N = 245)
– Longitudinal follow-up with cognitive evaluation
– 22 autopsied cases (18 demented)
– All with limbic or neocortical stage LBP
• Correlation of LB score to last MMSE
– AD pathology limited (all Braak stage IV or less)
• No correlation of AD pathology and last MMSE
Aarsland D, et al. Ann Neurol. 2005;58:773-776.
CN-19
Summary—Neuropathology of PDDAD Pathologic Change
Total of 110 cases with PDD studied
DSM III or III-R criteria for dementia diagnosis
Age in late 70s at death
Neocortical LB pathology correlates with dementia
Only 7(6%) cases fulfilled pathologic criteriafor AD
Aarsland D, et al. Ann Neurol. 2005;58:773-776.Apaydin H, et al. Arch Neurol. 2002;59:102-112.Braak H, et al. Neurology. 2005;64:1404-1410.
CN-20
Conclusion—Neuropathology of PDDAD Pathologic Change
Clinical diagnosis highly predictive of Lewy body pathology
Significant AD pathology is relatively rare in clinically diagnosed PDD cases
Dementia in elderly PD patients is
primarily due to Lewy body pathology
and not just coexistent AD
CN-21
Is the Cholinergic System Dysfunctional in Parkinson’s Disease with Dementia?
CN-22
Neurochemistry of PDD and AD Cholinergic System
Cholinergic basal forebrain
– Neuronal loss and Lewy body pathology in PD and PDD
– Neuronal loss and neurofibrillary tangles in AD
Pedunculopontine (PPT) nucleus
– Neuronal loss and Lewy body pathology in PD and PDD
– Neuronal loss and neurofibrillary tangles in AD
Jellinger K. J Neurol Neurosurg Psychiatry. 1988;51:540-543.
CN-23
Cholinergic deficitCholinergic deficit
PDDLewy body pathology in cholinergic basal
forebrain and brainstem PPT
ADNeurofibrillary
tangles in cholinergic basal forebrain and
brainstem PPT
Two Distinct Disorders With aCommon Cholinergic Deficit
CN-24
Author Technique
Disease subgroups
AD PD PDD
Perry, 1985 Neurochem (ChAT)
Ruberg, 1986 Neurochem (AChE) N/A / /†
Tiraboschi, 2000 Neurochem (ChAT) N/A
Mattila, 2001 Neurochem (ChAT) N/A ‡ ‡
Bohnen, 2003 PET (AChE activity)
† AChE total/AChE 10S form.‡ Included PD/PDD together.
Neurochemistry of PDD and AD Cholinergic System
CN-25Percentage Reductions of Cerebral Acetylcholinesterase Activity inPD, PDD, and AD
Alzheimer diseasePD without dementiaParkinsonian dementia
Mean cortex
Amygdala
Hippocampus
Inferior temporal
Superior temporal
Parietal
Frontal
Reg
ion
of
the
bra
in, %
Percentage reductions of cerebral acetylcholinesterase (AChE) activity in the various patient groups compared with healthy control subjects.Bohnen NI, et al. Arch Neurol. 2003;60:1745-1748.
0 –5 –10 –15 –20 –25 –30
% reduction in AChE activity
CN-26Correlation Coefficients Between Individual Cognitive Tests and Cortical AChE Activities in the Combined PDD and PD Groups
Cognitive testCorrelation coefficient(significance)
California Verbal Learning Test-STM Rs = 0.13 ns
California Verbal Learning Test-LTM Rs = 0.20 ns
Judgment of Line Orientation Test Rs = 0.43 (p < 0.05)
Stroop Color Word Test Rs = 0.46 (p < 0.05)
Trail Making Test B-A Rs = 0.44 (p < 0.05)
WAIS-III Digit Span Rs = 0.57 (p < 0.005)
Bohnen NI, et al. J Neurol. 2006;253:242-247.
CN-27
Neurochemistry of PDD and AD Cholinergic System
Cholinergic nuclei are pathologically involved in PDD
Reduced cortical cholinergic activity is more severe in PDD than in mild AD‡
Cholinergic dysfunction in PDD is associated with decreased performance on tests of attentional and executive functioning§
† Mattila, et al. Acta Neuropathol. 2001;32:397-402.‡ Bohnen, et al. Arch Neurol. 2003;60:1745-1748.§ Bohnen NI, et al. J Neurol. 2006;253:242-247.
CN-28
Conclusion
Clinical PDD is highly predictive of specific neuropathologic and neurochemical characteristics
– Neuropathology
• Lewy body pathology
• Limited AD pathologic change
– Biochemistry
• Profound loss of cholinergic function
• Cholinergic deficit associated with impairments in attentional and executive functions