Region-specific variations in the cerebrovasculature underlie disease progression in Parkinson’s disease

Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by motor dysfunction, dopaminergic neuronal loss in the substantia nigra and abnormal accumulation of α-synuclein Lewy bodies. Research suggests that the cerebrovascular system plays a role in fluid dynamics, waste clearance, and removal of abnormal proteins. Imaging studies show that this waste clearance system, known as the glymphatic system, is disrupted in Parkinson’s disease, highlighting its involvement in the disease. This immunohistochemical human brain tissue study quantified changes in the cerebrovascular system (perivascular space, string vessels, pericytes, aquaporin-4 and astrocytes) in Parkinson’s disease (n=18) cases with variable disease durations (median=14, range= 19) compared to age and post-mortem matched ( P >0.05) control cases (n=7). Analysis was carried out in brain regions variably affected by cell loss (substantia nigra) and protein deposition (substantia nigra and medial temporal cortex). The occipital cortex was included, as this region is not affected by cell loss or protein deposition. Group differences were analysed and the relationship with protein deposition (Lewy body stage, amyloid score, neurofibrillary tangle score) was assessed. Although total astrocyte density did not change ( P >0.05), Parkinson’s disease cases exhibited reduced aquaporin-4 in astrocytic endfeet and enlargement of the arteriolar and venular perivascular space. Significant changes in the capillary network were also observed with increased string vessel formation ( P <0.001) and pericyte loss ( P <0.001), changes likely to impact blood flow and its regulation. The formation of string vessels significantly correlated with disease duration ( P <0.05), especially in the occipital cortex. The occipital cortex demonstrated the greatest decreases in pericytes ( P <0.001) and aquaporin-4 mislocalisation ( P <0.05), while changes in pericyte density were also significant in the substantia nigra. In contrast, these changes were not significant in the medial temporal cortex despite protein deposition in this region. Although no Lewy pathology was detected in the occipital cortex, there was a positive relationship between Lewy body stage and perivascular space size (Rho =0.6, P <0.05). These findings reveal progressive, region-specific alterations in the cellular components of the glymphatic system and vascular integrity in Parkinson’s disease. Notably, the correlation between string vessel formation and disease duration, even in a region unaffected by protein deposition, suggests that vascular changes may play an important role in disease progression. These results emphasize the need for further investigation into the interplay between regional vascular changes and Parkinson’s disease progression, which may offer novel insights for therapeutic strategies.