Pathological 43-kDa Transactivation Response DNA-Binding Protein in Older Adults With and Without Severe Mental Illness

Abstract

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. To examine patients with chronic psychiatric diseases, mainly schizophrenia, for evidence of neurodegenerative TDP-43 pathology in comparison with controls. 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. University health system. One hundred fifty-one subjects including 91 patients with severe mental illness (mainly schizophrenia) and 60 controls. Clinical medical record review, neuronal and glial TDP-43 pathology, and TARDP and GRN genotyping status. 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. 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.