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Clinical and pathological continuum of multisystem TDP-43 proteinopathies


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 (2009). Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Archives of Neurology, 66(2):180-189.

Abstract

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.

Abstract

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:February 2009
Deposited On:03 Mar 2010 13:34
Last Modified:03 Aug 2017 15:15
Publisher:American Medical Association
ISSN:0003-9942
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1001/archneurol.2008.558
PubMed ID:19204154

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