Axonal degeneration in the anterior insular cortex in Parkinson’s disease and Dementia with Lewy bodies: more than just an α-synuclein story

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 as 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 and burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB. Methods α-Synuclein (α-syn), phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insula (agranular and dysgranular) subregions of brain donors (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(D), DLB showed significantly higher α-syn and p-tau pathology load, argyrophilic grains, and most severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significant higher load of amyloid-β pathology. Using mixed model analysis, p-tau contributed most to axonal loss in the DLB group, highest in the anterior agranular insula. 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 agranular insular sub-region to various converging pathologies, leading to impaired axonal integrity in PD(D) and DLB, disrupting its functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.