title: Neuropathologic substrates of Parkinson disease dementia.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Matthew T
authors.initials: MT
authors.lastname: White
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
authors.forename: John L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Vivianna
authors.initials: V
authors.lastname: Van Deerlin
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: John E
authors.initials: JE
authors.lastname: Duda
authors.forename: Howard I
authors.initials: HI
authors.lastname: Hurtig
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D053327:Apolipoprotein E4 / Q000378:metabolism; D001344:Autopsy; D002540:Cerebral Cortex / Q000473:pathology; D015331:Cohort Studies; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics; D003704:Dementia / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000473:pathology; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D015233:Models, Statistical; D009069:Movement Disorders / Q000473:pathology / Q000523:psychology; D016501:Neurites / Q000473:pathology; D016017:Odds Ratio; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D012372:ROC Curve
chemical_list: D053327:Apolipoprotein E4; D004247:DNA