Glymphatic clearance function in patients with cerebral small vessel disease.

Few studies have focused on the connection between glymphatic dysfunction and cerebral small vessel disease (CSVD), partially due to the lack of non-invasive methods to measure glymphatic function. We established modified index for diffusion tensor image analysis along the perivascular space (mALPS-index), which was calculated on diffusion tensor image (DTI), compared it with the classical detection of glymphatic clearance function calculated on Glymphatic MRI after intrathecal administration of gadolinium (study 1), and analyzed the relationship between CSVD imaging markers and mALPS-index in CSVD patients from the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) (study 2). Among 39 patients included in study 1, mALPS-index were significantly related to glymphatic clearance function calculated on Glymphatic MRI ( r  = -0.772~-0.844, p < 0.001). A total of 330 CSVD patients were included in study 2. Severer periventricular and deep white matter hyperintensities (β = -0.332, p < 0.001; β = -0.293, p < 0.001), number of lacunas (β = -0.215, p < 0.001), number of microbleeds (β = -0.152, p = 0.005), and severer enlarged perivascular spaces in basal ganglia (β = -0.223, p < 0.001) were related to mALPS-index. Our results indicated that non-invasive mALPS-index might represent glymphatic clearance function, which could be applied in clinic in future. Glymphatic clearance function might play a role in the development of CSVD.

Zhang W ，Zhou Y ，Wang J ，Gong X ，Chen Z ，Zhang X ，Cai J ，Chen S ，Fang L ，Sun J ，Lou M ... -  《-》

Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study.

This study aims to investigate the associations of glymphatic system with the presence, severity and neuroimaging phenotypes of cerebral small vessel disease (CSVD) in a community-based population. This report included 2219 community-dwelling people aged 50-75 years who participated in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events cohort. The diffusivity along perivascular spaces based on diffusion tensor imaging (DTI-ALPS index) was measured to assess glymphatic pathway. The presence and severity of CSVD were estimated using a CSVD score (points from 0 to 4) and a modified CSVD score (points from 0 to 4), which were driven by 4 neuroimaging features of CSVD, including white matter hyperintensity (WMH), enlarged perivascular spaces (EPVS), lacunes, cerebral microbleeds. Brain atrophy (BA) was also evaluated. Binary or ordinal logistic regression analyses were carried out to investigate the relationships of DTI-ALPS index with CSVD. The mean age was 61.3 (SD 6.6) years, and 1019 (45.9%) participants were men. The average DTI-ALPS index was 1.67±0.14. Individuals in the first quartile (Q1) of the DTI-ALPS index had higher risks of the presence of CSVD (OR 1.77, 95% CI 1.33 to 2.35, p<0.001), modified presence of CSVD (odds ratio (OR) 1.80, 95% CI 1.38 to 2.34, p<0.001), total burden of CSVD (common OR (cOR) 1.89, 95% CI 1.43 to 2.49, p<0.001) and modified total burden of CSVD (cOR 1.95, 95% CI 1.51 to 2.50, p<0.001) compared with those in the fourth quartile (Q4). Additionally, individuals in Q1 of the DTI-ALPS index had increased risks of WMH burden, modified WMH burden, lacunes, basal ganglia-EPVS and BA (all p<0.05). A lower DTI-ALPS index underlay the presence, severity and typical neuroimaging markers of CSVD, implying that glymphatic impairment may interact with CSVD-related pathology in the general ageing population. NCT03178448.

Tian Y ，Cai X ，Zhou Y ，Jin A ，Wang S ，Yang Y ，Mei L ，Jing J ，Li S ，Meng X ，Wei T ，Liu T ，Wang Y ，Pan Y ，Wang Y ... -  《-》

Arterial Stiffness Is Associated With Basal Ganglia Enlarged Perivascular Spaces and Cerebral Small Vessel Disease Load.

We assessed whether the load of cerebral small vessel disease (cSVD) and its individual markers, including lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces (EPVS), are associated with arterial stiffness. We evaluated cSVD markers in a cohort of 782 hypertensive individuals without history of stroke or dementia. The load of the disease was calculated using an ordinal scale ranging from 0 to 4 (1 point was given for each of the 4 markers examined). The arterial stiffness was tested by measuring the carotid-femoral pulse wave velocity with an oscillometric automatic device. The mean age of the participants (49.6% women) was 62.7±5.4 years, and the mean systolic/diastolic blood pressure was 142.9/77.3 mm Hg (55.5% of the participants had poor blood pressure control). We found 7.2% cases with lacunes, 6.4% with microbleeds, 6.7% with extensive white matter hyperintensities, 24.5% with extensive basal ganglia EPVS, and 40.1% with extensive EPVS in the centrum semiovale. Regarding the cSVD load, 19.7% of the participants scored 1, 6.5% scored 2, and 1.4% scored ≥3. The median carotid-femoral pulse wave velocity was 10.5 m/s (interquartile range, 9.2-11.9) and was associated with lacunes (odds ratio per carotid-femoral pulse wave velocity SD increase, 1.51; 95% confidence interval, 1.13-2.03), extensive basal ganglia EPVS (odds ratio, 1.39; 95% confidence interval, 1.16-1.67), and cSVD load (common odds ratio, 1.42; 95% confidence interval, 1.19-1.68). We found that, in a cohort of hypertensive individuals, the arterial stiffness is associated with the total load of the cSVD, especially with lacunes and basal ganglia EPVS.

Riba-Llena I ，Jiménez-Balado J ，Castañé X ，Girona A ，López-Rueda A ，Mundet X ，Jarca CI ，Álvarez-Sabin J ，Montaner J ，Delgado P ... -  《-》

Evaluation of glymphatic-meningeal lymphatic system with intravenous gadolinium-based contrast-enhancement in cerebral small-vessel disease.

To investigate the feasibility of using noninvasive neuroimaging methods in visualizing and evaluating the clearance of the glymphatic-meningeal lymphatic system (GMLS) in patients with arteriosclerotic cerebral small-vessel disease (CSVD) and controls. This observational study recruited patients with high-burden CSVD and controls (age 50-80 years). At multiple time points before and after intravenous administration of a contrast agent, three-dimensional (3D) brain volume T1-weighted imaging and 3D Cube T2-fluid attenuated inversion recovery imaging were performed to visualize and assess the clearance of the glymphatics and meningeal lymphatic vessels (mLVs). We measured the signal intensity ratio (SIR) of four regions of interest representing the glymphatics and mLVs at each time point. The clearance rate at 24 h (CR24h) and changes in the SIR from baseline to 24 h (∆SIR) were defined as the clearance function. The analysis of variance was used to evaluate the group differences after adjusting for hypertension. A total of 20 CSVD patients and 15 controls were included. Cortical periarterial enhancement and the enhancement of enlarged perivascular spaces in the basal ganglia were respectively observed in 11 (55.00%) and 16 (80.00%) CSVD patients, but in none of controls. All CSVD patients and most of controls (80.00%) showed cortical perivenous enhancement. Para-sinus enhancement was observed in all participants. CSVD patients showed lower CR24h and higher ∆SIR of the glymphatics and mLVs (all p < 0.05). The impaired drainage of the GMLS in patients with high-burden CSVD could be visually evaluated using noninvasive neuroimaging methods with intravenous gadolinium-based contrast-enhancement. Dynamic intravenous contrast-enhanced MRI could visually evaluate the impaired drainage of the glymphatic-meningeal lymphatic system in patients with high-burden cerebral small-vessel disease and could help to explore a new therapeutic target. • Signal intensity changes in regions representing the glymphatic-meningeal lymphatic system (GMLS) can reflect the drainage function based on contrast-enhanced 3D-FLAIR and 3D T1-weighted MRI. • Impaired drainage of the GMLS in patients with high-burden CSVD can be visually evaluated using dynamic intravenous contrast-enhanced MRI. • This direct, noninvasive technique could serve as a basis for further GMLS studies and could help to explore a new therapeutic target in CSVD patients.

Zhang M ，Tang J ，Xia D ，Xue Y ，Ren X ，Huang Q ，Shi L ，Tang W ，Fu J ... -  《-》

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer's disease continuum participants.

Glymphatic dysfunction is a crucial pathway for dementia. Alzheimer's disease (AD) pathologies co-existing with cerebral small vessel disease (CSVD) is the most common pathogenesis for dementia. We hypothesize that AD pathologies and CSVD could be associated with glymphatic dysfunction, contributing to cognitive impairment. Participants completed with amyloid PET, diffusion tensor imaging (DTI), and T2 fluid-attenuated inversion-recovery (FLAIR) sequences were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). White matter hyperintensities (WMH), the most common CSVD marker, was evaluated from T2FLAIR images and represented the burden of CSVD. Amyloid PET was used to assess Aβ aggregation in the brain. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, the burden of enlarged perivascular spaces (PVS), and choroid plexus volume to reflect glymphatic function. The relationships between WMH burden/Aβ aggregation and these glymphatic markers as well as the correlations between glymphatic markers and cognitive function were investigated. Furthermore, we conducted mediation analyses to explore the potential mediating effects of glymphatic markers in the relationship between WMH burden/Aβ aggregation and cognition. One hundred and thirty-three participants along the AD continuum were included, consisting of 40 CN - , 48 CN + , 26 MCI + , and 19 AD + participants. Our findings revealed that there were negative associations between whole-brain Aβ aggregation (r =  - 0.249, p = 0.022) and WMH burden (r =  - 0.458, p < 0.001) with DTI-ALPS. Additionally, Aβ aggregation (r = 0.223, p = 0.041) and WMH burden (r = 0.294, p = 0.006) were both positively associated with choroid plexus volume. However, we did not observe significant correlations with PVS enlargement severity. DTI-ALPS was positively associated with memory (r = 0.470, FDR-p < 0.001), executive function (r = 0.358, FDR-p = 0.001), visual-spatial (r = 0.223, FDR-p < 0.040), and language (r = 0.419, FDR-p < 0.001). Conversely, choroid plexus volume showed negative correlations with memory (r =  - 0.315, FDR-p = 0.007), executive function (r =  - 0.321, FDR-p = 0.007), visual-spatial (r =  - 0.233, FDR-p = 0.031), and language (r =  - 0.261, FDR-p = 0.021). There were no significant correlations between PVS enlargement severity and cognitive performance. In the mediation analysis, we found that DTI-ALPS acted as a mediator in the relationship between WMH burden/Aβ accumulation and memory and language performances. Our study provided evidence that both AD pathology (Aβ) and CSVD were associated with glymphatic dysfunction, which is further related to cognitive impairment. These results may provide a theoretical basis for new targets for treating AD.

Hong H ，Hong L ，Luo X ，Zeng Q ，Li K ，Wang S ，Jiaerken Y ，Zhang R ，Yu X ，Zhang Y ，Lei C ，Liu Z ，Chen Y ，Huang P ，Zhang M ，Alzheimer’s Disease Neuroimaging Initiative (ADNI) ... -  《-》