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

Abstract

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 preinclusions (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.

Signature laminar distributions of pathology in frontotemporal lobar degeneration

“…An alternative hypothesis is that the same clinically relevant networks are disrupted by different types of neurons, circuits, or regions [ 21 , 88 , 101 , 104 ]. In support of this latter hypothesis, recent investigations by our lab and others have found different regional patterns of peak tau and TDP-43 histopathologic burden within the language network in PPA [ 29 , 27 , 48 , 49 ] and frontotemporal networks in bvFTD [ 43 , 45 ]. FTLD proteinopathies may also display different laminar distributions of pathology in the same clinical syndrome and network, but comparative examinations of tau and TDP-43 pathology in cortical laminae are lacking.…”

TDP‐43 and tau concurrence in the entorhinal subfields in primary age‐related tauopathy and preclinical Alzheimer's disease

“…In addition, our sample set contained a mixture of right and left hemispheres. While some reports found that TDP‐43 in some forms of dementia favors the language‐dominant hemisphere [ 58 , 59 , 60 ], the result has not consistently been replicated [ 48 ], and it is not yet known if it holds true for typical limbic AD. Finally, while we evaluated pathology on the same subfields on adjacent tissue slides, we did not perform double‐staining to assess the co‐localization of pathology at the individual neuron level.…”

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance

“…Based on the predominance of one or more of the three types of inclusions, the length of dystrophic neurites, and the laminar distribution of cortical inclusions, TDP‐43 pathology is categorized into subtypes A–E (Lee et al., 2017; Mackenzie et al., 2011). TDP‐43 inclusions appear to be preceded by preinclusions of smooth or granular staining in neurons (Kim et al., 2019).…”