TDP-43 deposition in prospectively followed, cognitively normal elderly individuals: correlation with argyrophilic grains but not other concomitant pathologies

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. Several studies have also sought to investigate the frequency of TDP-43 deposition in other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, but there has been relatively little work focused on the prevalence, distribution and histopathological associations of abnormal TDP-43 deposits in the brains of cognitively normal elderly subjects. We screened thick, free-floating coronal sections of mesial temporal lobe from 110 prospectively followed and autopsied cognitively normal subjects (age range 71-100 years) using an immunohistochemical method for phosphorylated TDP-43. We found a 36.4 % prevalence of pathologic TDP-43, mostly in the form of neurites while perikaryal cytoplasmic neuronal inclusions were uncommon and intranuclear inclusions were rare. With respect to other concomitant pathologies commonly found in elderly individuals, cases with TDP-43 had a greater prevalence of argyrophilic grains (ARG) (40 vs. 18.6 %) and overall ARG density (moderate vs. sparse). There were no additional associations with other concomitant pathologies, including cerebral white matter rarefaction, incidental Lewy bodies, neurofibrillary tangles or amyloid plaques. These results indicate deposition of TDP-43 occurs in a substantial subset of cognitively normal elderly subjects and is more common in those with ARG, supporting some previous studies linking pathological TDP-43 deposition with ARG and other pathological tau protein deposits.