Objective Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. Methods In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1‐weighted imaging was performed to assess the function of the glymphatic pathway and head high‐resolution T2–fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. Results In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). Interpretation We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357–369

Our purpose is to assess the role of deep medullary veins (DMVs) in pathogenesis of MRI-visible perivascular spaces (PVS) in patients with cerebral small vessel disease (cSVD). Consecutive patients recruited in the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) were included. Susceptibility Weighted Imaging-Phase images were used to evaluate DMVs based on a brain region-based visual score. T2 weighted images were used to evaluate PVS based on the five-point score, and PVS in basal ganglia (BG-PVS), centrum semiovale (CSO-PVS) and hippocampus (H-PVS) were evaluated separately. 270 patients were included. The severity of BG-PVS, CSO-PVS and H-PVS was positively related to the increment of age (all p < 0.05). The severity of BG-PVS and H-PVS was positively related to DMVs score (both p < 0.05). Patients with more severe BG-PVS had higher Fazekas scores in both periventricle and deep white matter (both p < 0.001) and higher frequency of hypertension ( p = 0.008). Patients with more severe H-PVS had higher frequency of diabetes ( p < 0.001). Besides, high DMVs score was an independent risk factor for more severe BG-PVS ( β = 0.204, p = 0.001). Our results suggested that DMVs disruption might be involved in the pathogenesis of BG-PVS.

Objective: Choroid plexus (CP) is a key regulator in cerebrospinal fluid production, but its contribution to glymphatic clearance function and association with white matter hyperintensity (WMH) remains unclear. Methods: This retrospective study included 2 prospective 3.0-T magnetic resonance imaging (MRI) cohorts. In cohort 1, patients with indications for lumbar puncture underwent 3-dimensional T1-weighted sequence (3D-T1) before and at 39 hours after intrathecal administration of contrast agent (glymphatic MRI). In cohort 2, patients with WMH were enrolled from the CIRCLE study and had a median follow-up time of 1.4 years. WMH and CP of the lateral ventricles were automatically segmented on T2 fluid-attenuated inversion recovery (FLAIR) and 3D-T1, respectively. CP volume was expressed as a ratio to intracranial volume. Glymphatic clearance was measured as signal percentage change from baseline to 39 hours at 8 brain locations based on glymphatic MRI in the first cohort, or as noninvasive diffusion tensor image analysis along the perivascular space (DTI-ALPS) index based on DTI in the second cohort. Results: In cohort 1, a total of 52 patients were included. Higher CP volume was correlated with slower glymphatic clearance rate in all brain locations. In cohort 2, a total of 197 patients were included. Baseline CP volume was positively associated with WMH volume and its growth. Furthermore, DTI-ALPS index partially mediated the association of CP with both WMH load and growth. Interpretations: Enlarged CP volume could be an indicator for larger growth of WMH, potentially involving impaired glymphatic clearance function. The exploration of CP may provide a novel perspective to clarify the mechanism of WMH pathogenesis, as well as other glymphatic-related disorders.

Background: The benefit of alteplase in minor non-disabling acute ischemic stroke (AIS) is unknown. We aimed to explore the clinical efficacy of alteplase-treatment in minor non-disabling stroke in clinical practice. Methods: We used a prospectively collected database of AIS patients who were being assessed for thrombolysis with alteplase. Minor non-disabling AIS was identified as patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 and a score 0 or 1 on each baseline NIHSS score item (items 1a to 1c being 0). Results: A total of 461 patients with minor non-disabling AIS were included and among them 240 (52.1%) patients were treated with alteplase and 113 (24.5%) patients had severe stenosis/occlusion of large vessels. No significant association of 90-day excellent outcome was found with alteplase-treatment (77.1% vs. 80.5%, p 1 = 0.425; OR 0.911, 95% CI 0.428 to 1.940; p 2 = 0.808). However, among patients with severe stenosis/occlusion of large vessels, alteplase-treatment was independently associated with excellent outcome (74.4% vs. 45.7%, p 1 = 0.005; OR 4.709, 95% CI 1.391 to 11.962; p 2 = 0.010). Conclusion: Although alteplase-treatment did not result in an excellent outcome in general minor non-disabling stroke patients, it may work in those specific patients who had severe stenosis/occlusion of large vessels.

Objective The glymphatic pathway, characterised as a cerebral drainage system, influences cognitive function in neurodegenerative diseases; however, evidence is limited in a normal ageing population. The aim of this study was to investigate the effect of glymphatic function on ageing-related cognitive decline. Methods We retrospectively reviewed the Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly (CIRCLE) study, and participants with multi-model magnetic resonance imaging (MRI) scans and Mini-Mental State Examinations (MMSE) were enrolled. Glymphatic function was evaluated via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Regression models were used to estimate the impact of the DTI-ALPS index on cognitive decline cross-sectionally and longitudinally. We further analysed the mediation effect of the DTI-ALPS on age and cognitive function. Results A total of 633 participants were included in this study (48.2% female; mean age, 62.8 ± 8.9 years). The DTI-ALPS index was positively associated with cognitive function cross-sectionally (β = 0.108, P = 0.003), and was an independent protective factor for cognitive decline longitudinally (odds ratio (OR) = 0.029, P = 0.007). The DTI-ALPS index declined progressively with ageing (r = −0.319, P &lt;0.001), and the decrease was more pronounced after 65 years of age. Furthermore, the DTI-ALPS index mediated the relationship between age and MMSE score (β = −0.016, P &lt;0.001). The mediation effect accounted for 21.3%, which was higher in subjects aged over 65 years (25.3%) compared with those aged under 65 years (5.3%). Conclusion Glymphatic function played a protective role in normal ageing-related cognitive decline, which may serve as a potential therapeutic target against cognitive decline in future.