Concomitant TAR-DNA-Binding Protein 43 Pathology Is Present in Alzheimer Disease and Corticobasal Degeneration but Not in Other Tauopathies

TLDR

TAR‑DNA‑binding protein 43 (TDP‑43) is a disease protein implicated in frontotemporal lobar degeneration with ubiquitin‑positive inclusions and amyotrophic lateral sclerosis. The study aimed to determine the presence, frequency, distribution, and clinical impact of TDP‑43 pathology in a cohort of clinically well‑characterized tauopathy brains, including Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, and Pick disease. Immunohistochemistry and biochemical analyses were employed to assess TDP‑43 pathology across these cases. TDP‑43 pathology was present in 25.8 % of Alzheimer’s disease cases, mainly confined to the dentate gyrus and entorhinal cortex but more widespread in a quarter of cases, and was linked to longer disease duration without altering clinical presentation; it was absent in progressive supranuclear palsy and Pick disease, whereas 15.4 % of corticobasal degeneration cases showed a distinct glial TDP‑43 pattern with biochemical changes resembling FTLD‑U, underscoring the broader burden and clinical relevance of TDP‑43 pathology beyond FTLD‑U and ALS.

Abstract

Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.