Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases
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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.
KeywordsFrontotemporal lobar degeneration TDP-43 Dementia with Lewy bodies Parkinson’s disease
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.
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