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Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies
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OBJECTIVE: To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment. DESIGN: Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review. SETTING: An academic medical center. PARTICIPANTS: We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment. MAIN OUTCOME MEASURE: Neuronal and glial TDP-43 pathology. RESULTS: We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology. CONCLUSION: These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.
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“TDP‐43 inclusions are also observed in > 95% of ALS, 22 supporting the notion that FTLD‐TDP and ALS are part of a clinicopathological continuum.”
From New developments of biofluid‐based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia (2022) · cites this paper as [23]
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Metadata
- Authors
- Geser, F., Martinez-Lage, M., Robinson, J., Uryu, K., Neumann, M., Brandmeir, N. J., Xie, S. X., Kwong, L. K., Elman, L., McCluskey, L., Clark, C. M., Malunda, J., Miller, B. L., Zimmerman, E. A., Qian, J., Van Deerlin, V., Grossman, M., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Trojanowski, John Q.
- ORCID
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2009-02-01
- Volume
- 66
- Issue
- 2
- Pages
- 180-9
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC2774117
- OpenAlex
- W2117597459
- Cited by
- 267
- References
- 19
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 3 · 2023: 16 · 2022: 11 · 2021: 12 · 2020: 12 · 2019: 9 · 2018: 12 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 19 · 2013: 21 · 2012: 29
- FWCI
- 21.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG 10 124, AG 17586)
- National Institute on Aging (P30AG010124, P01AG017586, AG17586, AG-10124, P01AG019724)
- National Heart, Lung, and Blood Institute (T35HL071483, HL071483)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TDP-43 proteinopathy, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, motor neuron disease, ubiquitinated inclusions, cognitive impairment, extrapyramidal symptoms, neuropsychiatric features, neurodegeneration, clinicopathological correlation
- MeSH terms
- Aged, Amyotrophic Lateral Sclerosis, Brain, Brain Mapping, Inclusion Bodies, Cognition Disorders, Dementia, DNA-Binding Proteins, Female, Humans, Immunohistochemistry, Male, Middle Aged, Movement Disorders, Neuroglia, Neurons, Retrospective Studies, Motor Neuron Disease, Disease Progression, Ubiquitin, Ubiquitination
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