TDP-43 Deposition in Prospectively Followed, Cognitively Normal Elderly Individuals: A Correlative Study

Abstract

TAR DNA-binding protein 43 (TDP-43) has been heavily researched in recent years due to its involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Numerous studies have also sought to investigate the frequency of TDP-43 deposition in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, with very few studies focusing on the relationship of TDP-43 to pathological and clinical parameters within cognitively normal subjects. We sought to explore the deposition of TDP-43 and its relation to pathological and clinical parameters in a series of prospectively followed, cognitively normal, elderly individuals whom have come to autopsy. We screened thick, coronal sections of mesial temporal lobe; containing hippocampus and/or amygdalar regions from a series of 110 cognitively normal subjects (age range 71-100 years) using immunohistochemical methods for phosphorylated TDP-43. Consistent with previous results, we found a 36.4% incidence of pathologic TDP-43. Deposition was detected in the form of dendritic neurites, intranuclear inclusions, and perikaryal cytoplasmic neuronal inclusions. With respect to other concomitant pathologies commonly found in elderly individuals, cases with TDP-43 had a greater proportion of cases with argyrophilic grains (ARG) (40% vs. 18.6%). There was not greater prevalence or densities of other concomitant pathologies, including cerebral white matter rarefaction, incidental Lewy bodies, neurofibrillary tangles or amyloid plaques in TDP-43 positive cases. These results indicate deposition of TDP-43 occurs in a substantial subset of cognitively normal elderly subjects and is more common in those with argyrophilic grains.