title: Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.
abstract: BACKGROUND
  Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.
  
  
  METHODS
  In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.
  
  
  RESULTS
  On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R20·22, p<0·0001) and with survival (-2·0, -3·2 to -0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.
  
  
  CONCLUSIONS
  Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology.
  
  
  BACKGROUND
  US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: dirwin@mail.med.upenn.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Parkinson's Disease Research, Education and Clinical Center, Michael J Crescenz VA Medical Center, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Hurtig
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Parkinson's Disease Research, Education and Clinical Center, Michael J Crescenz VA Medical Center, Philadelphia, PA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Duda
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Kofler
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Jicha
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Woltjer
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, OR, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kaye
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic Foundation, Cleveland, OH, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Debby
authors.initials: D
authors.lastname: Tsuang
authors.affiliation: Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Northwest Parkinson's Disease Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Katelan
authors.initials: K
authors.lastname: Longfellow
authors.affiliation: Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Yearout
authors.affiliation: Department of Epidemiology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Kukull
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, Standford University, Stanford, CA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Northwest Parkinson's Disease Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
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, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D001344:Autopsy; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology*; D020961:Lewy Body Disease / Q000235:genetics / Q000473:pathology; D016014:Linear Models; D008297:Male; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D039781:PubMed / Q000706:statistics & numerical data; D012372:ROC Curve; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein