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Cited by 518Parkinson's Disease Mechanisms and TreatmentsDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Neuropathologic substrates of Parkinson disease dementia

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Irwin, David J., White, Matthew T., Toledo, Jon B., Xie, Sharon X., Robinson, John L., Van Deerlin, Vivianna, Lee, Virginia M.‐Y., Leverenz, James B. +4 more·2012·Annals of Neurology
DOI 10.1002/ana.23659PMC PMC3484250
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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.

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  • Progression of dementia in Parkinson's disease shows a correlation with spread of the neuropathological changes to cortical brain structures.

    “Progression of the dementia shows a correlation with spread of the neuropathological changes to cortical brain structures (Irwin et al. 2012).”

    From The clinical symptoms of Parkinson's disease. (2016) · cites this paper as Irwin et al. 2012

    The Introduction (page unavailable) describes a proposed spread of Lewy body and neurite pathology from the brainstem to the cerebral cortex. The Results and Discussion (pages unavailable) associate greater cortical pathology with dementia in Parkinson’s disease, but do not establish that progression of dementia itself correlates with the spread over time. (LLM, conf=0.83)

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Authors
Irwin, D. J., White, M. T., Toledo, J. B., Xie, S. X., Robinson, J. L., Van Deerlin, V., Lee, V. M. ‐., Leverenz, J. B., Montine, T. J., Duda, J. E., Hurtig, H. I., & Trojanowski, J. Q.
Affiliations
  • Institute on Aging (US)
  • University of Pennsylvania (US)
  • University of Washington (US)
  • Philadelphia VA Medical Center (US)
Corresponding author
Trojanowski, John Q.
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2012-10
Volume
72
Issue
4
Pages
587-598
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.23659
PMC
PMC3484250
OpenAlex
W2400155502
Cited by
518
References
9
Citations by year
2026: 20 · 2025: 31 · 2024: 34 · 2023: 32 · 2022: 41 · 2021: 49 · 2020: 47 · 2019: 34 · 2018: 46 · 2017: 36 · 2016: 33 · 2015: 33 · 2014: 43 · 2013: 33 · 2012: 5
FWCI
23.84
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3 d)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG 05136, P50AG005136, T32AG000255)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK060455)
  • National Institute of Neurological Disorders and Stroke (P50NS062684, P50NS053488, NS062684)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Parkinson's disease dementia, Parkinson's disease, Lewy bodies, Lewy neurites, neurofibrillary tangles, amyloid plaques, APOE ε4, cerebral amyloid angiopathy, cognitive impairment, dementia risk factors, neuropathology, alpha-synuclein, tau protein, amyloid-beta, genetic risk
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Cerebral Cortex, Dementia, DNA, Female, Humans, Longitudinal Studies, Male, Middle Aged, Models, Neurological, Movement Disorders, Parkinson Disease, ROC Curve, Models, Statistical, Cohort Studies, Confidence Intervals, Logistic Models, Odds Ratio, Neurites, Disease Progression, Lewy Body Disease, Apolipoprotein E4

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