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.
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TDP-43 immunoreactive inclusions are commonly observed in cases with LBD.
“TDP-43 immunoreactive inclusions are observed in the majority of cases of HS (Figure 6) [8,28,40,64], about one-half of cases with FTLD and ubiquitin inclusions with or without motor neuron disease, most sporadic cases of amyotrophic lateral sclerosis, and commonly in cases with AD neuropathologic change [8,9] or with LBD [43], as well as other neurodegenerative diseases [48].”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [43]
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“…DNA-binding protein 43 kDa (TDP-43) are observed in approximately 97% of all patients, including patients with sporadic ALS (sALS) or familial ALS (fALS) (1–3), as well as in subsets of patients with frontotemporal dementia (FTD) (1, 3), Alzheimer’s disease (4), and Parkinson’s disease (5).”
Background
- Authors
- 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., Lee, V. M. Y., & Trojanowski, J. Q.
- Affiliations
- Hospital of the University of Pennsylvania (US)
- University of Pennsylvania (US)
- Philadelphia VA Medical Center (US)
- University of Washington (US)
- University of Pittsburgh (US)
- University of California San Diego (US)
- Oregon Health & Science University (US)
- Corresponding author
- Trojanowski, John Q.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2007-07-25
- Volume
- 114
- Issue
- 3
- Pages
- 221-229
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2136305293
- Cited by
- 468
- References
- 3
- Citations by year
- 2026: 27 · 2025: 25 · 2024: 16 · 2023: 29 · 2022: 50 · 2021: 27 · 2020: 18 · 2019: 23 · 2018: 21 · 2017: 17 · 2016: 9 · 2015: 12 · 2014: 17 · 2013: 16 · 2012: 20
- FWCI
- 25.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG09215, P30AG010124, P01AG009215, P01AG017586, AG17586, AG-10124)
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- TDP-43, Lewy body disease, Parkinson's disease, dementia with Lewy bodies, Parkinson's disease dementia, Alzheimer's disease, comorbidities, proteinopathies, neurodegeneration, TDP-43 inclusions
- MeSH terms
- Aged, Inclusion Bodies, DNA-Binding Proteins, Female, Hippocampus, Humans, Immunohistochemistry, Male, Middle Aged, Parkinson Disease, Comorbidity, tau Proteins, Lewy Body Disease, Ubiquitin, alpha-Synuclein
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