Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

Hanae Nakashima-Yasuda; Kunihiro Uryu; John Robinson; Sharon X. Xie; Howard Hurtig; John E. Duda; Steven E. Arnold; Andrew Siderowf; Murray Grossman; James B. Leverenz; Randy Woltjer; Oscar L. Lopez; Ronald Hamilton; Debby W. Tsuang; Douglas Galasko; Eliezer Masliah; Jeffrey Kaye; Christopher M. Clark; Thomas J. Montine; Virginia M.Y. Lee; John Q. Trojanowski

doi:10.1007/s00401-007-0261-2

Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

Hanae Nakashima-Yasuda, Kunihiro Uryu, John Robinson, Sharon X. Xie, Howard Hurtig, John E. Duda, Steven E. Arnold, Andrew Siderowf, Murray Grossman, James B. Leverenz, Randy Woltjer, Oscar L. Lopez, Ronald Hamilton, Debby W. Tsuang, Douglas Galasko, Eliezer Masliah, Jeffrey Kaye, Christopher M. Clark, Thomas J. Montine, Virginia M.Y. LeeJohn Q. Trojanowski

Neurology

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

364 Scopus citations

Abstract

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Original language	English (US)
Pages (from-to)	221-229
Number of pages	9
Journal	Acta Neuropathologica
Volume	114
Issue number	3
DOIs	https://doi.org/10.1007/s00401-007-0261-2
State	Published - Sep 2007

Keywords

Dementia with Lewy bodies
Frontotemporal lobar degeneration
Parkinson's disease
TDP-43

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1007/s00401-007-0261-2

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Nakashima-Yasuda, H., Uryu, K., Robinson, J., Xie, S. X., Hurtig, H., Duda, J. E., Arnold, S. E., Siderowf, A., Grossman, M., Leverenz, J. B., Woltjer, R., Lopez, O. L., Hamilton, R., Tsuang, D. W., Galasko, D., Masliah, E., Kaye, J., Clark, C. M., Montine, T. J., ... Trojanowski, J. Q. (2007). Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathologica, 114(3), 221-229. https://doi.org/10.1007/s00401-007-0261-2

Nakashima-Yasuda, H, Uryu, K, Robinson, J, Xie, SX, Hurtig, H, Duda, JE, Arnold, SE, Siderowf, A, Grossman, M, Leverenz, JB, Woltjer, R, Lopez, OL, Hamilton, R, Tsuang, DW, Galasko, D, Masliah, E, Kaye, J, Clark, CM, Montine, TJ, Lee, VMY & Trojanowski, JQ 2007, 'Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases', Acta Neuropathologica, vol. 114, no. 3, pp. 221-229. https://doi.org/10.1007/s00401-007-0261-2

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title = "Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases",

abstract = "Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.",

keywords = "Dementia with Lewy bodies, Frontotemporal lobar degeneration, Parkinson's disease, TDP-43",

author = "Hanae Nakashima-Yasuda and Kunihiro Uryu and John Robinson and Xie, {Sharon X.} and Howard Hurtig and Duda, {John E.} and Arnold, {Steven E.} and Andrew Siderowf and Murray Grossman and Leverenz, {James B.} and Randy Woltjer and Lopez, {Oscar L.} and Ronald Hamilton and Tsuang, {Debby W.} and Douglas Galasko and Eliezer Masliah and Jeffrey Kaye and Clark, {Christopher M.} and Montine, {Thomas J.} and Lee, {Virginia M.Y.} and Trojanowski, {John Q.}",

note = "Funding Information: Acknowledgments We thank colleagues for technical support and advice in the Center for Neurodegenerative Disease Research. We thank the families of patients whose generosity made this research possible. This work was supported by grants from the National Institutes of Health (AG-09215, AG-10124, AG-17586). V.M.-Y.L. is the John H. Ware III Professor of Alzheimer{\textquoteright}s disease research; and J.Q.T. is the William Maul Measey-Truman G. Schnabel Jr, Professor of Geriatric Medicine and Gerontology.",

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doi = "10.1007/s00401-007-0261-2",

language = "English (US)",

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T1 - Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

AU - Nakashima-Yasuda, Hanae

AU - Uryu, Kunihiro

AU - Robinson, John

AU - Xie, Sharon X.

AU - Hurtig, Howard

AU - Duda, John E.

AU - Arnold, Steven E.

AU - Siderowf, Andrew

AU - Grossman, Murray

AU - Leverenz, James B.

AU - Woltjer, Randy

AU - Lopez, Oscar L.

AU - Hamilton, Ronald

AU - Tsuang, Debby W.

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Kaye, Jeffrey

AU - Clark, Christopher M.

AU - Montine, Thomas J.

AU - Lee, Virginia M.Y.

AU - Trojanowski, John Q.

N1 - Funding Information: Acknowledgments We thank colleagues for technical support and advice in the Center for Neurodegenerative Disease Research. We thank the families of patients whose generosity made this research possible. This work was supported by grants from the National Institutes of Health (AG-09215, AG-10124, AG-17586). V.M.-Y.L. is the John H. Ware III Professor of Alzheimer’s disease research; and J.Q.T. is the William Maul Measey-Truman G. Schnabel Jr, Professor of Geriatric Medicine and Gerontology.

PY - 2007/9

Y1 - 2007/9

N2 - Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

AB - Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

KW - Dementia with Lewy bodies

KW - Frontotemporal lobar degeneration

KW - Parkinson's disease

KW - TDP-43

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Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

Abstract

Keywords

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