Phosphorylated TDP-43 Staging of Primary Age-Related Tauopathy

Primary age-related tauopathy(PART) is characterized by tau neurofibrillary tangles(NFTs) in the absence of amyloid plaque pathology. In the present study,we analyzed the distribution patterns of phosphorylated43-kDa TAR DNA-binding protein(pTDP-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART,Alzheimer's disease(AD), and aging control cases. We examined the regional distribution patterns of pTDP-43 intraneuronal inclusions in PART with Braak NFT stages[ 0 and B IV, and a Thal phase of 0(no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of pTDP-43 in PART. Stage I was characterized by the presence of pTDP-43 lesions in the amygdala, stage II by such lesions in the hippocampus,stage III by spread of pTDP-43 to the neocortex, and stage IV by pTDP-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of pTDP-43 pathology in PART cases was similar to the early TDP-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of pTDP-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the pTDP-43 stage and density.

Axonal degeneration in the anterior insular cortex is associated with Alzheimer’s co-pathology in Parkinson’s disease and dementia with Lewy bodies

Background:Axons,crucial for impulse transmission and cellular trafficking,are thought to be primary targets of neurodegeneration in Parkinson’s disease(PD)and dementia with Lewy bodies(DLB).Axonal degeneration occurs early,preceeding and exceeding neuronal loss,and contributes to the spread of pathology,yet is poorly described outside the nigrostriatal circuitry.The insula,a cortical brain hub,was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB.The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD,PD with dementia(PDD),and DLB.Methods:α-Synuclein,phosphorylated(p-)tau,and amyloid-βpathology load were evaluated in the anterior insular(agranular and dysgranular)subregions of post-mortem human brains(n=27).Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology.Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.Results:Compared to PD and PDD,DLB showed significantly higherα-synuclein and p-tau pathology load,argyrophilic grains,and more severe axonal loss,particularly in the anterior agranular insula.Alternatively,the dysgranular insula showed a significantly higher load of amyloid-βpathology and its axonal density correlated with cognitive performance.p-Tau contributed most to axonal loss in the DLB group,was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia.Neurofilament and myelin showed degenerative changes including swellings,demyelination,and detachment of the axon-myelin unit.Conclusions:Our results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies,leading to impaired axonal integrity in PD,PDD and DLB,disrupting their functional properties and potentially contributing to cognitive,emotional,and autonomic deficits.