Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

David Coughlin; Sharon X. Xie; Mendy Liang; Andrew Williams; Claire Peterson; Daniel Weintraub; Corey T. McMillan; David A. Wolk; Rizwan S. Akhtar; Howard I. Hurtig; H. Branch Coslett; Roy H. Hamilton; Andrew D. Siderowf; John E. Duda; Katya Rascovsky; Edward B. Lee; Virginia M.Y. Lee; Murray Grossman; John Q. Trojanowski; David J. Irwin

doi:10.1002/ana.25392

Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

David Coughlin, Sharon X. Xie, Mendy Liang, Andrew Williams, Claire Peterson, Daniel Weintraub, Corey T. McMillan, David A. Wolk, Rizwan S. Akhtar, Howard I. Hurtig, H. Branch Coslett, Roy H. Hamilton, Andrew D. Siderowf, John E. Duda, Katya Rascovsky, Edward B. Lee, Virginia M.Y. Lee, Murray Grossman, John Q. Trojanowski, David J. Irwin^*

^*Corresponding author for this work

Neurology

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

86 Scopus citations

Abstract

Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN−AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. Results: SYN burden was higher in SYN + AD than SYN−AD in each neocortical region (F_{1, 54} = 5.6–6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F_{1, 43–49} = 0.7–1.7, p > 0.2). SYN + AD performed worse than SYN−AD on a temporal lobe–mediated naming task (t₂₇ = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = −0.39 to −0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F_{1, 43} = 12.8–97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t₄₁ = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t₄₁ = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F_{1, 40–43} = 1.6–2.0, p > 0.1). Interpretation: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1–13 ANN NEUROL 2019;85:259–271.

Original language	English (US)
Pages (from-to)	259-271
Number of pages	13
Journal	Annals of neurology
Volume	85
Issue number	2
DOIs	https://doi.org/10.1002/ana.25392
State	Published - Feb 2019

ASJC Scopus subject areas

Clinical Neurology
Neurology

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10.1002/ana.25392

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Coughlin, D., Xie, S. X., Liang, M., Williams, A., Peterson, C., Weintraub, D., McMillan, C. T., Wolk, D. A., Akhtar, R. S., Hurtig, H. I., Branch Coslett, H., Hamilton, R. H., Siderowf, A. D., Duda, J. E., Rascovsky, K., Lee, E. B., Lee, V. M. Y., Grossman, M., Trojanowski, J. Q., & Irwin, D. J. (2019). Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders. Annals of neurology, 85(2), 259-271. https://doi.org/10.1002/ana.25392

@article{cf48aa27acb74deeaca5bc5e80082c10,

title = "Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders",

abstract = "Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN−AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. Results: SYN burden was higher in SYN + AD than SYN−AD in each neocortical region (F1, 54 = 5.6–6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43–49 = 0.7–1.7, p > 0.2). SYN + AD performed worse than SYN−AD on a temporal lobe–mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = −0.39 to −0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8–97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F1, 40–43 = 1.6–2.0, p > 0.1). Interpretation: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1–13 ANN NEUROL 2019;85:259–271.",

author = "David Coughlin and Xie, {Sharon X.} and Mendy Liang and Andrew Williams and Claire Peterson and Daniel Weintraub and McMillan, {Corey T.} and Wolk, {David A.} and Akhtar, {Rizwan S.} and Hurtig, {Howard I.} and {Branch Coslett}, H. and Hamilton, {Roy H.} and Siderowf, {Andrew D.} and Duda, {John E.} and Katya Rascovsky and Lee, {Edward B.} and Lee, {Virginia M.Y.} and Murray Grossman and Trojanowski, {John Q.} and Irwin, {David J.}",

note = "Funding Information: Research reported in this publication was supported by funding from the NIH National Center for Advancing Translational Sciences (TL1TR001880), National Institute on Aging (AG010124), and National Institute of Neurological Disorders and Stroke (NS088341, NS053488). We thank C. Zhou, J. Robinson, and T. Shuck for their technical assistance; and the patients and families for their participation in the research. Publisher Copyright: {\textcopyright} 2018 American Neurological Association",

year = "2019",

month = feb,

doi = "10.1002/ana.25392",

language = "English (US)",

volume = "85",

pages = "259--271",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "2",

}

Coughlin, D, Xie, SX, Liang, M, Williams, A, Peterson, C, Weintraub, D, McMillan, CT, Wolk, DA, Akhtar, RS, Hurtig, HI, Branch Coslett, H, Hamilton, RH, Siderowf, AD, Duda, JE, Rascovsky, K, Lee, EB, Lee, VMY, Grossman, M, Trojanowski, JQ & Irwin, DJ 2019, 'Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders', Annals of neurology, vol. 85, no. 2, pp. 259-271. https://doi.org/10.1002/ana.25392

TY - JOUR

T1 - Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

AU - Coughlin, David

AU - Xie, Sharon X.

AU - Liang, Mendy

AU - Williams, Andrew

AU - Peterson, Claire

AU - Weintraub, Daniel

AU - McMillan, Corey T.

AU - Wolk, David A.

AU - Akhtar, Rizwan S.

AU - Hurtig, Howard I.

AU - Branch Coslett, H.

AU - Hamilton, Roy H.

AU - Siderowf, Andrew D.

AU - Duda, John E.

AU - Rascovsky, Katya

AU - Lee, Edward B.

AU - Lee, Virginia M.Y.

AU - Grossman, Murray

AU - Trojanowski, John Q.

AU - Irwin, David J.

N1 - Funding Information: Research reported in this publication was supported by funding from the NIH National Center for Advancing Translational Sciences (TL1TR001880), National Institute on Aging (AG010124), and National Institute of Neurological Disorders and Stroke (NS088341, NS053488). We thank C. Zhou, J. Robinson, and T. Shuck for their technical assistance; and the patients and families for their participation in the research. Publisher Copyright: © 2018 American Neurological Association

PY - 2019/2

Y1 - 2019/2

N2 - Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN−AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. Results: SYN burden was higher in SYN + AD than SYN−AD in each neocortical region (F1, 54 = 5.6–6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43–49 = 0.7–1.7, p > 0.2). SYN + AD performed worse than SYN−AD on a temporal lobe–mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = −0.39 to −0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8–97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F1, 40–43 = 1.6–2.0, p > 0.1). Interpretation: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1–13 ANN NEUROL 2019;85:259–271.

AB - Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN−AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. Results: SYN burden was higher in SYN + AD than SYN−AD in each neocortical region (F1, 54 = 5.6–6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43–49 = 0.7–1.7, p > 0.2). SYN + AD performed worse than SYN−AD on a temporal lobe–mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = −0.39 to −0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8–97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F1, 40–43 = 1.6–2.0, p > 0.1). Interpretation: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1–13 ANN NEUROL 2019;85:259–271.

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Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

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