Glymphatic Dysfunction And Its Mechanism In Patients With Vascular Cognitive Impairment

Background and aims With the aging of the world’s population,the prevalence of dementia is increasing year by year,and it has become one of the serious public health problems worldwide.Alzheimer’s Disease(AD)and Vascular dementia(Va D)are the two most common causes of dementia in the elderly.Given the failure of therapeutic drugs against AD pathologies,there is growing evidence that vascular pathogenic factors may be the most preventable and treatable factors in dementia.Therefore,improved prevention and treatment strategies for vascular cognitive impairment(VCI)will be key to reducing the incidence of dementia and cognitive impairment.However,since VCI is a heterogeneous group of diseases,including a variety of different vascular pathologies.In this case,clarifying the underlying common pathophysiological mechanism of VCI is of great significance for finding effective VCI biomarkers and guiding the treatment of VCI.The glymphatic system is a functional waste cleaning system of the brain that has only been discovered in recent years.Its association with neurodegenerative diseases such as AD has been demonstrated and may link cerebrovascular pathology with neurodegenerative pathology.Therefore,in order to explore the potential role and mechanism of glymphatic function in VCI,this study measured changes in glymphatic function in VCI patients using the noninvasive "diffusion tensor imaging analysis along the perivascular space"(DTI-ALPS)technique.Since VCI is gradually recognized as a network disorder,we used graph theory to study the topological properties of the brain structural network of VCI patients,and analyzed the correlation between the structural network topology and glymphatic function by means of correlation analysis and causal mediation analysis,and possible mediating effect of network topology in the process of cognitive impairment caused by glymphatic dysfunction.Finally,in order to further explore the mechanism of glymphatic dysfunction in VCI,we measured cerebral blood flow(CBF)in CSVD and post-stroke subjects using Arterial spin labeling(ASL)technology,and analyzed its relationship with cognitive function and ALPS index.Methods 1.We recruited 79 patients with mild VCI,including 40 with cerebral small vessel disease cognitive impairment(SVCI)and 39 with post-stroke cognitive impairment(PSCI);and,77 normal cognitive(NC)subjects were recruited.All subjects received neuropsychological assessments and multimodal magnetic resonance imaging scans.ALPS-index was calculated and structural networks were constructed by deterministic tractography,and then,the topological metrics of these structural connectivity were evaluated.2.Thirty-five patients with cerebral small vessel disease(CSVD)and 35 subjects 6 months after stroke were recruited.All subjects underwent neuropsychological assessments and multimodal magnetic resonance imaging scans.The ALPS index was calculated by DTI,and the cerebral blood flow in different brain regions was obtained using arterial spin labeling(ASL)images,and correlation and regression analysis were performed.Results 1.The ALPS-index of VCI patients was significantly lower than that of NC subjects(P < 0.001).Multiple linear regression analysis showed that ALPS-index affects cognitive function independently(β = 0.411,P < 0.001).The results of correlation analysis showed that the ALPS-index was correlated with overall vascular risk factor burden(r =-0.263,P = 0.001)and multiple cerebrovascular pathologies(P < 0.05).In addition,global efficiency(Eg)of network was correlated with ALPS-index in both SVCI(r = 0.348,P = 0.028)and PSCI(r =0.732,P < 0.001)patients.Finally,the results of mediation analysis showed that Eg partially mediated in the impact of glymphatic dysfunction on cognitive impairment(indirect effect =7.46,95% CI 4.08-11.48).2.Frontal CBF in CSVD patients is related to cognitive function(r = 0.570,P < 0.001).CBF in cortex(r = 0.380,P = 0.024),frontal lobe(r = 0.499,P = 0.002),parietal lobe(r = 0.492,P= 0.003)and limbic lobe(r =-0.463,P = 0.009)were associated with ALPS-index,and frontal CBF was independently associated with ALPS index(β = 0.447,P = 0.013).In post-stroke patients,the CBF(P < 0.001)and ALPS-index(P < 0.001)in the ipsilateral side of the infarction were significantly lower than those in the contralateral side of the infarction.The CBF in the ipsilateral side of the infarction was associated with ALPS-index(r = 0.569,P < 0.001)and cognitive function(r = 0.467,P = 0.005).After controlling for confounding factors,CBF in ipsilateral side of the infarction was independently associated with the ALPS index(β = 0.434,P = 0.009).Conclusions 1.In both major subtypes of VCI,the ALPS-index was decreased,indicating impaired glymphatic function in VCI.Glymphatic dysfunction may affect cognitive function in VCI by disrupting network connectivity,and,may be a potential common pathological mechanism of VCI.ALPS-index is expected to become an emerging imaging marker for VCI.2.Frontal lobe CBF in CSVD patients and CBF ipsilateral to the infarct in post-stroke patients were independently associated with glymphatic function.Decreased CBF may lead to glymphatic dysfunction.CBF and glymphoatic function may influence each other and participate in the cognitive impairment of VCI patients.