No abstract

No abstract

ObjectiveEmerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking.MethodsIn this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function.ResultsOverall, 289 patients with PD were enrolled in the cross‐sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5‐year follow‐up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid‐high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS‐UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aβ1‐42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5.InterpretationThe ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023

The pathological accumulation of α‐synuclein (α‐Syn) and the transmission of misfolded α‐Syn underlie α‐synucleinopathies. Increased plasma α‐Syn levels are associated with cognitive impairment in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies, but it is still unknown whether the cognitive deficits in α‐synucleinopathies have a common vascular pathological origin. Here, it is reported that combined injection of α‐Syn preformed fibrils (PFFs) in the unilateral substantia nigra pars compacta, hippocampus, and cerebral cortex results in impaired spatial learning and memory abilities at 6 months post‐injection and that this cognitive decline is related to cerebral microvascular injury. Moreover, insoluble α‐Syn inclusions are found to form in primary mouse brain microvascular endothelial cells (BMVECs) through lymphocyte‐activation gene 3 (Lag3)‐dependent α‐Syn PFFs endocytosis, causing poly(ADP‐ribose)‐driven cell death and reducing the expression of tight junction proteins in BMVECs. Knockout of Lag3 in vitro prevents α‐Syn PFFs from entering BMVECs, thereby reducing the abovementioned response induced by α‐Syn PFFs. Deletion of endothelial cell‐specific Lag3 in vivo reverses the negative effects of α‐Syn PFFs on cerebral microvessels and cognitive function. In short, this study reveals the effectiveness of targeting Lag3 to block the spread of α‐Syn fibrils to endothelial cells in order to improve cognition.

No abstract

No abstract