Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology

Jon B. Toledo, Pallavi Gopal, Kevin Raible, David J. Irwin, Johannes Brettschneider, Samantha Sedor, Kayla Waits, Susana Boluda, Murray Grossman, Vivianna M. Van Deerlin, Edward B. Lee, Steven E. Arnold, John E. Duda, Howard Hurtig, Virginia M Y Lee, Charles Howard Adler, Thomas G. Beach, John Q. Trojanowski

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher’s input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen. PD cases with AD pathology showed increased LRP. The cluster with occipital LRP was associated with non-AD type dementia clinical diagnosis in the Dem-AD-LB group and a faster progression to dementia in the PD groups. We found that (1) LRP pathology in Dem-AD-LB shows a distribution that differs from PD, without significant brainstem or extracranial LRP in initial phases; (2) coincident AD pathology is associated with increased LRP in PD indicating an interaction; (3) LRP and coincident AD pathology independently predict progression to dementia in PD, and (4) evaluation of LRP needs to acknowledge different LRP spreading patterns and evaluate substantia nigra integrity in the neuropathological assessment and consider the implications of neuropathological heterogeneity for clinical and biomarker characterization.

Original languageEnglish (US)
Pages (from-to)393-409
Number of pages17
JournalActa Neuropathologica
Volume131
Issue number3
DOIs
StatePublished - Mar 1 2016

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Synucleins
Lewy Bodies
Pathology
Alzheimer Disease
Dementia
Substantia Nigra
Brain Stem

Keywords

  • Alzheimer disease
  • Classification
  • Dementia with Lewy bodies
  • Diagnosis
  • Neuropathology
  • Parkinson disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Toledo, J. B., Gopal, P., Raible, K., Irwin, D. J., Brettschneider, J., Sedor, S., ... Trojanowski, J. Q. (2016). Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. Acta Neuropathologica, 131(3), 393-409. https://doi.org/10.1007/s00401-015-1526-9

Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. / Toledo, Jon B.; Gopal, Pallavi; Raible, Kevin; Irwin, David J.; Brettschneider, Johannes; Sedor, Samantha; Waits, Kayla; Boluda, Susana; Grossman, Murray; Van Deerlin, Vivianna M.; Lee, Edward B.; Arnold, Steven E.; Duda, John E.; Hurtig, Howard; Lee, Virginia M Y; Adler, Charles Howard; Beach, Thomas G.; Trojanowski, John Q.

In: Acta Neuropathologica, Vol. 131, No. 3, 01.03.2016, p. 393-409.

Research output: Contribution to journalArticle

Toledo, JB, Gopal, P, Raible, K, Irwin, DJ, Brettschneider, J, Sedor, S, Waits, K, Boluda, S, Grossman, M, Van Deerlin, VM, Lee, EB, Arnold, SE, Duda, JE, Hurtig, H, Lee, VMY, Adler, CH, Beach, TG & Trojanowski, JQ 2016, 'Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology', Acta Neuropathologica, vol. 131, no. 3, pp. 393-409. https://doi.org/10.1007/s00401-015-1526-9
Toledo, Jon B. ; Gopal, Pallavi ; Raible, Kevin ; Irwin, David J. ; Brettschneider, Johannes ; Sedor, Samantha ; Waits, Kayla ; Boluda, Susana ; Grossman, Murray ; Van Deerlin, Vivianna M. ; Lee, Edward B. ; Arnold, Steven E. ; Duda, John E. ; Hurtig, Howard ; Lee, Virginia M Y ; Adler, Charles Howard ; Beach, Thomas G. ; Trojanowski, John Q. / Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. In: Acta Neuropathologica. 2016 ; Vol. 131, No. 3. pp. 393-409.
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