CN-1 Neuropathology of Parkinson’s Disease Dementia James B. Leverenz, MD Associate Professor Neurology and Psychiatry and Behavioral Sciences University

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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

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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

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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

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Silver stain: plaques and tangles

Alzheimer’s Disease—Pathology

Silver stain:neuritic plaques

Neurofibrillarytangles

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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.

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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.

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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

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Neuropathology of Parkinson’s Disease

Substantia nigra pathology

Lewy body inclusionsNeuronal loss

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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

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Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex

Cerebral cortex Substantia nigra

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Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459.

Braak Staging of Lewy Bodies

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What Is the Neuropathologic Basis of Dementia in Parkinson’s Disease?

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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.

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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

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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

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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.

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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.

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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.

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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.

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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

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Is the Cholinergic System Dysfunctional in Parkinson’s Disease with Dementia?

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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.

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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

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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.


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

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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.

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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.

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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

Documents

CN-1 Neuropathology of Parkinson’s Disease Dementia James B. Leverenz, MD Associate Professor Neurology and Psychiatry and Behavioral Sciences University