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Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology.
Acta Neuropathol. 2016 Mar; 131(3):393-409.AN

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.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA. jtoledo@mail.med.upenn.edu.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Department of Clinical Neuroanatomy and Neurology, University of Ulm, Ulm, Germany.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.Philadelphia VA Medical Center, Philadelphia, PA, USA.Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26721587

Citation

Toledo, Jon B., et al. "Pathological Α-synuclein Distribution in Subjects With Coincident Alzheimer's and Lewy Body Pathology." Acta Neuropathologica, vol. 131, no. 3, 2016, pp. 393-409.
Toledo JB, Gopal P, Raible K, et al. Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology. Acta Neuropathol. 2016;131(3):393-409.
Toledo, J. B., Gopal, P., Raible, K., Irwin, D. J., Brettschneider, J., Sedor, S., Waits, K., Boluda, S., Grossman, M., Van Deerlin, V. M., Lee, E. B., Arnold, S. E., Duda, J. E., Hurtig, H., Lee, V. M., Adler, C. H., Beach, T. G., & 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
Toledo JB, et al. Pathological Α-synuclein Distribution in Subjects With Coincident Alzheimer's and Lewy Body Pathology. Acta Neuropathol. 2016;131(3):393-409. PubMed PMID: 26721587.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology. AU - Toledo,Jon B, AU - Gopal,Pallavi, AU - Raible,Kevin, AU - Irwin,David J, AU - Brettschneider,Johannes, AU - Sedor,Samantha, AU - Waits,Kayla, AU - Boluda,Susana, AU - Grossman,Murray, AU - Van Deerlin,Vivianna M, AU - Lee,Edward B, AU - Arnold,Steven E, AU - Duda,John E, AU - Hurtig,Howard, AU - Lee,Virginia M-Y, AU - Adler,Charles H, AU - Beach,Thomas G, AU - Trojanowski,John Q, Y1 - 2015/12/31/ PY - 2015/12/08/received PY - 2015/12/13/accepted PY - 2015/12/13/revised PY - 2016/1/2/entrez PY - 2016/1/2/pubmed PY - 2016/11/9/medline KW - Alzheimer disease KW - Classification KW - Dementia with Lewy bodies KW - Diagnosis KW - Neuropathology KW - Parkinson disease SP - 393 EP - 409 JF - Acta neuropathologica JO - Acta Neuropathol VL - 131 IS - 3 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/26721587/Pathological_α_synuclein_distribution_in_subjects_with_coincident_Alzheimer's_and_Lewy_body_pathology_ L2 - https://dx.doi.org/10.1007/s00401-015-1526-9 DB - PRIME DP - Unbound Medicine ER -