AXONAL LOSS, MYELIN DAMAGE, AND PROTEIN AGGREGATES CONVERGE IN THE ANTERIOR INSULAR CORTEX IN PARKINSON’S DISEASE AND DEMENTIA WITH LEWY BODIES
- Yasmine Y. Fathy, Netherlands
Abstract
Aims
Axons are crucial for impulse transmission, transportation of organelles, and clearance of proteins necessary for neuronal and synaptic survival. In Parkinson’s disease (PD), axonal degeneration occurs early and contributes to spread of pathology. The aim of this study is to assess features of axonal degeneration and protein aggregation in the anterior insular sub-regions in PD and dementia with Lewy bodies (DLB).
Methods
The post-mortem anterior insula was collected from 25 PD, PD dementia (PDD), and DLB donors. Axonal loss was evaluated using modified Bielschowsky silver staining and unbiased stereology. Pathology load was semi-quantified on sections stained for α-synuclein, hyperphosphorylated (HPF)-tau, and amyloid-β proteins. For cytoskeletal damage, immunofluorescent multi-labelling with neurofilament (NFL), myelin, and α-synuclein was analyzed using confocal laser-scanning microscopy. Parametric tests and linear mixed model were used for data analysis.
Results
The anterior agranular insula showed a significantly higher load of α-synuclein (t(21)=5.3;p<0.001), HPF-tau pathology (t(19)=5.1;p<0.001) and axonal loss (t(23)=-5.7;p<0.001) compared to the anterior dysgranular insula. The dysgranular insula alternatively showed a significant higher load of amyloid-β pathology (t(9)=-2.5;p=0.03). In mixed model analysis, HPF-tau significantly contributed to axonal loss (b=-3.45x10-5;F(1,42)=4.2;p=0.046). NFL showed fragmentation and swellings; while myelin showed axon-myelin disruption in both sub-regions. The DLB group showed most severe axonal loss, cytoskeletal damage and protein aggregates.
Conclusions
The agranular and dysgranular insular sub-regions were differentially vulnerable to axonal loss and pathological aggregates, most pronounced in DLB. Our results highlight the selective vulnerability of the anterior insula to various converging pathologies disrupting axonal integrity, potentially contributing to non-motor deficits in PD and DLB.