Morphology and Distribution of TDP-43 Pre-inclusions in Primary Progressive Aphasia

Abstract

This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS085770), National Institute on Deafness and Other Communication Disorders (DC008552), the Louis Family Foundation, Alzheimer's Disease Center Grant from the National Institute on Aging (AG013854), National Institute on Aging (T32 AG20506), and the Florane and Jerome Rosenstone Fellowship. Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive “pre-inclusions” have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.