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 H. Adler; Thomas G. Beach; John Q. Trojanowski

doi:10.1007/s00401-015-1526-9

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 H. Adler, Thomas G. Beach, John Q. Trojanowski

Neurology

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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 language	English (US)
Pages (from-to)	393-409
Number of pages	17
Journal	Acta neuropathologica
Volume	131
Issue number	3
DOIs	https://doi.org/10.1007/s00401-015-1526-9
State	Published - Mar 1 2016

Keywords

Alzheimer disease
Classification
Dementia with Lewy bodies
Diagnosis
Neuropathology
Parkinson disease

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1007/s00401-015-1526-9

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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. Y., 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, 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

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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{\textquoteright}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.",

keywords = "Alzheimer disease, Classification, Dementia with Lewy bodies, Diagnosis, Neuropathology, Parkinson disease",

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

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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.

PY - 2016/3/1

Y1 - 2016/3/1

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.

AB - 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.

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KW - Classification

KW - Dementia with Lewy bodies

KW - Diagnosis

KW - Neuropathology

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

Abstract

Keywords

ASJC Scopus subject areas

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