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Background Major psychiatric diseases such as schizophrenia and mood disorders have not been linked to a specific pathology, but their clinical features overlap with some aspects of the behavioral variant of frontotemporal lobar degeneration. Although the significance of pathological 43-kDa (transactivation response) DNA-binding protein (TDP-43) for frontotemporal lobar degeneration was appreciated only recently, the prevalence of TDP-43 pathology in patients with severe mental illness vs controls has not been systematically addressed. Objective To examine patients with chronic psychiatric diseases, mainly schizophrenia, for evidence of neurodegenerative TDP-43 pathology in comparison with controls. Design Prospective longitudinal clinical evaluation and retrospective medical record review, immunohistochemical identification of pathological TDP-43 in the central nervous system, and genotyping for gene alterations known to cause TDP-43 proteinopathies including the TDP-43 ( TARDBP ) and progranulin ( GRN ) genes. Setting University health system. Participants One hundred fifty-one subjects including 91 patients with severe mental illness (mainly schizophrenia) and 60 controls. Main Outcome Measures Clinical medical record review, neuronal and glial TDP-43 pathology, and TARDP and GRN genotyping status. Results Significant TDP-43 pathology in the amygdala/periamygdaloid region or the hippocampus/transentorhinal cortex was absent in both groups in subjects younger than 65 years but present in elderly subjects (29% [25 of 86] of the psychiatric patients and 29% [10 of 34] of control subjects). Twenty-three percent (8 of 35) of the positive cases showed significant TDP-43 pathology in extended brain scans. There were no evident differences between the 2 groups in the frequency, degree, or morphological pattern of TDP-43 pathology. The latter included (1) subpial and subependymal, (2) focal, or (3) diffuse lesions in deep brain parenchyma and (4) perivascular pathology. A new GRN variant of unknown significance (c.620T>C, p.Met207Thr) was found in 1 patient with schizophrenia with TDP-43 pathology. No known TARDBP mutations or other variants were found in any of the subjects studied herein. Conclusions The similar findings of TDP-43 pathology in elderly patients with severe mental illness and controls suggest common age-dependent TDP-43 changes in limbic brain areas that may signify that these regions are affected early in the course of a cerebral TDP-43 multisystem proteinopathy. Finally, our data provide an age-related baseline for the development of whole-brain pathological TDP-43 evolution schemata.

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.Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.An academic medical center.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.Neuronal and glial TDP-43 pathology.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.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.

Background Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. Objective To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS. Design Performance of an immunohistochemical whole–central nervous system scan for evidence of pathological TDP-43 in ALS patients. Setting An academic medical center. Participants We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. Main Outcome Measures Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology. Results In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls. Conclusions These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.