Atrophy and microglial distribution in primary progressive aphasia with transactive response DNA-binding protein-43 kDa.

OBJECTIVE: To quantitatively determine the density and distribution of activated microglia across cortical regions and hemispheres in the brains of primary progressive aphasia (PPA) participants with pathological diagnoses of frontotemporal lobar degeneration with transactive response DNA-binding protein-43 (TDP-43) inclusions and to examine the relationships between microglial densities, patterns of focal atrophy, (TDP-43) inclusions, and clinical phenotype. METHODS: Activated microglia and TDP-43 inclusions were visualized in whole-hemisphere brain sections using immunohistochemical methods from five participants with PPA-TDP. Unbiased stereology was used to bilaterally quantify human leuckocyte antigen/D related-positive activated microglia and TDP-43 inclusions across five language-related regions. Density and distribution of both markers were compared across cortical regions and hemispheres, and their relationships to patterns of focal atrophy and clinical phenotype were determined. RESULTS: Activated microglia displayed asymmetric distribution favoring the language-dominant hemisphere, consistent with greater postmortem and/or in vivo atrophy in that hemisphere, in PPA-TDP. In one participant with no asymmetric atrophy, quantitative distribution of microglia also lacked asymmetry. Patterns of microglial activation also showed variation that favored areas of high atrophy in regions affiliated with language function, demonstrating concordance between patterns of microglial activation, atrophy, and clinical phenotype. TDP-43 also showed higher inclusion densities in areas of high atrophy than in regions with low atrophy, but no clear relationship with microglia density at a regional level. INTERPRETATION: The initial activation of microglia is most likely a response to cortical abnormalities in PPA-TDP, which contribute to atrophy. The patterns of microglial activation, TDP-43 inclusion deposition, atrophy, and clinical phenotype suggest that activated microglia may make unique contributions to cortical thinning and TDP-43 inclusion formation. Ann Neurol 2018;83:1096-1104.

Distribution of TDP-43 Pathology in Hippocampal Synaptic Relays Suggests Transsynaptic Propagation in Frontotemporal Lobar Degeneration.

Hyperphosphorylation, nuclear depletion, and aggregation of TDP-43 in ubiquitinated inclusions is a hallmark of frontotemporal lobar degeneration (FTLD-TDP). Evidence of potential spread of TDP-43 along synaptic connections in the human is largely limited to qualitative and semiquantitative observations. We quantitatively investigated potential transsynaptic propagation of TDP-43 across the well-established chain of single synaptic connections of the hippocampus. Hippocampi from 5 participants with clinical diagnoses of primary progressive aphasia and 2 participants with behavioral variant frontotemporal dementia, all with postmortem diagnoses of FTLD-TDP, were examined. TDP-43-positive mature (darkly stained) and pre-inclusions (diffuse puncta or fibrillar staining) in the granule cell layer of dentate gyrus (DG) and pyramidal cell layers of Cornu Ammonis (CA)3, CA2, and CA1 were quantified using unbiased stereology. The density of mature TDP-43 inclusions was higher in the DG than in the CA fields (p < 0.05). There were no differences in inclusion densities across the CA fields. TDP-43 pre-inclusions densities were not different across the 4 subregions. There was significantly higher preinclusion density than mature inclusions in CA3, but not in other subregions. Analysis of normalized total counts in place of densities revealed virtually identical results. Our finding of greatest mature inclusion deposition in the DG, coupled with more preinclusions than mature inclusions at the next relay station (CA3), and reduced densities of both in CA2-CA1, provide evidence in support of a sequential transsynaptic propagation mechanism of TDP-43 aggregates.

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

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.

Activated Microglia in Cortical White Matter Across Cognitive Aging Trajectories.

Activation of microglia, the primary mediators of inflammation in the brain, is a major component of gliosis and neuronal loss in a number of age-related neurodegenerative disorders, such as Alzheimer's disease (AD). The role of activated microglia in white matter, and its relationship with cognitive decline during aging are unknown. The current study evaluated microglia densities in the white matter of postmortem specimens from cognitively normal young adults, cognitively normal older adults, and cognitive "SuperAgers," a unique group of individuals over age 80 whose memory test scores are at a level equal to or better than scores of 50-to-65-year-olds. Whole hemisphere sections from cognitively normal old, young, and "SuperAgers" were used to quantify densities of human leukocyte antigen-D related (HLA-DR)-positive activated microglia underlying five cortical regions. Statistical findings showed a significant main effect of group on differences in microglia density where cognitively normal old showed highest densities. No difference between SuperAgers and young specimens were detected. In two autopsied SuperAgers with MRI FLAIR scans available, prominent hyperintensities in periventricular regions were observed, and interestingly, examination of corresponding postmortem sections showed only sparse microglia densities. In conclusion, activated microglia appear to respond to age-related pathologic changes in cortical white matter, and this phenomenon is largely spared in SuperAgers. Findings offer insights into the relationship between white matter neuroinflammatory changes and cognitive integrity during aging.