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Neuropathologic substrates of Parkinson disease dementia

Authors

  • David J. Irwin MD,

    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
    2. Department of Neurology, Parkinson's Disease and Movement Disorders Clinic, Philadelphia, PA
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  • Matthew T. White MS, MPH,

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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  • Jon B. Toledo MD,

    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
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  • Sharon X. Xie PhD,

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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  • John L. Robinson BS,

    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
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  • Vivianna Van Deerlin MD, PhD,

    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
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  • Virginia M.-Y. Lee PhD, MBA,

    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
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  • James B. Leverenz MD,

    1. Mental Illness, VA-Puget Sound Health Care System (Seattle Division)
    2. Parkinson's Disease Research Education and Clinical Centers, VA-Puget Sound Health Care System (Seattle Division)
    3. Department of Neurology, University of Washington, Seattle WA
    4. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle WA
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  • Thomas J. Montine MD, PhD,

    1. Department of Pathology, University of Washington, Seattle, WA. 98195, USA
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  • John E. Duda MD,

    1. Department of Neurology, Parkinson's Disease and Movement Disorders Clinic, Philadelphia, PA
    2. Parkinson's Disease Research, Education and Clinical Center, Philadelphia VA Medical Center, Philadelphia, PA 19104, USA
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  • Howard I. Hurtig MD,

    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
    2. Department of Neurology, Parkinson's Disease and Movement Disorders Clinic, Philadelphia, PA
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  • John Q. Trojanowski MD, PhD

    Corresponding author
    1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K. Udall Parkinson's Disease Center of Excellence, Institute on Aging, Philadelphia, PA
    • Center for Neurodegenerative Disease Research and Institute on Aging, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA 19104-4283
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Abstract

Objective:

A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD).

Methods:

One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined.

Results:

Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87–8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28–13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04–1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06–5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13–15.30).

Interpretation:

CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid β could potentially improve cognitive performance in PD. ANN NEUROL 2012;72:587–598

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