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

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ObjectivesTo explore the relationship between insufficient ipsilateral cerebral venous drainage and the development of perihematomal edema (PHE) and functional outcome in patients with acute intracerebral hemorrhage (ICH).MethodsWe retrospectively reviewed our prospectively collected database for patients with acute spontaneous supratentorial ICH and analyzed patients who underwent baseline CT perfusion (CTP) within 6 hours of onset and noncontrast CT at 24 hours. Absence of filling of 1 or more of the ipsilateral superficial middle cerebral vein, vein of Trolard, vein of Labbé, basal vein of Rosenthal, and internal cerebral vein, evaluated on venous maps generated from baseline CTP, was identified as absent ipsilateral venous filling (AIVF). Relative PHE (rPHE) was calculated as the ratio of PHE volume to hematoma volume on follow-up CT.ResultsA total of 138 patients were included. Median absolute PHE volume on follow-up CT was 3.5 (1.0–9.3) mL and rPHE was 24.3% (9.0%–49.4%). One absent ipsilateral vein was observed in 38 (27.5%) patients, and 2 absent veins were observed in 5 (3.6%) patients. Multivariate analysis showed that AIVF was independently associated with large rPHE at 24 hours (odds ratio [OR] 4.032, 95% confidence interval [CI] 1.739–9.347, p < 0.001). Large PHE volume was independently associated with poor outcome (OR 1.109, 95% CI 1.009–1.218, p = 0.031).ConclusionAIVF was observed in about one-third of patients with acute ICH, which might be attributed to hypoperfusion after ICH and was strongly related to the development of PHE. Identification of cerebral venous filling status might be a promising imaging marker for PHE and a potential therapeutic target in ICH.

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.

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