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-β pathology 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 higher α-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-β pathology 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.