RESUMEN
Inferior frontal sulcal hyperintensity (IFSH) on FLAIR sequence may indicate elevated cerebrospinal fluid (CSF) wastes. The objective of this study was to investigate its association with the clearance function of putative meningeal lymphatic vessels (mLVs). We included patients who underwent FLAIR sequence and dynamic contrast MRI with intrathecal administration of contrast agent. The visibility of IFSH was quantitatively assessed by measuring the mean signal intensity of inferior frontal sulci on 2D FLAIR. The clearance function of putative mLVs was defined as the percentage change of signal unite ratio in the parasagittal dura from baseline to 4.5, 15 and 39 hours after intrathecal injection on dynamic contrast MRI. Additionally, imaging markers of cerebral small vessel disease, including white matter hyperintensities and enlarged perivascular spaces, were measured. Correlation analysis and linear regression were employed to verify the association of IFSH with the clearance function of mLVs. A total of 76 patients were included in the study. The visibility of IFSH was found to be associated with the percentage change of signal unite ratio in parasagittal dura from baseline to 15 and 39 hours in adjusted analyses. Furthermore, the visibility of IFSH was positively related to the age, scores of both periventricular and deep white matter hyperintensities, and the grade of enlarged perivascular spaces in centrum semiovale. These findings suggest that the visibility of IFSH on 2D FLAIR may serve as an indicator of clearance dysfunction of mLVs and may be implicated in the development of cerebral small vessel disease.
RESUMEN
White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.
RESUMEN
BACKGROUND: Animal experiments have demonstrated the dependency of cerebrospinal fluid clearance function on age and sleep, which partially underlay the cognitive decline in the elderly. However, human evidence is lacking, which could be mainly attributed to the limited methods of cerebrospinal fluid clearance function assessment. METHOD: Serial T1-weighted and T2-fluid attenuated inversion recovery imaging were performed in 92 patients before and at multiple time points including 4.5 h, 15 h and 39 h after intrathecal injection of contrast agent to visualize the putative meningeal lymphatic pathway, peri-olfactory nerve pathway, and peri-optic nerve pathway. We defined the clearance function as the percentage change in signal unit ratio of critical locations in these pathways from baseline to 39 h after intrathecal injection, and further analysed their relationships with age, sleep, and cognitive function. FINDINGS: Cerebrospinal fluid clearance through the putative meningeal lymphatic and perineural pathways were clearly visualized. The clearance function of putative meningeal lymphatic and perineural pathways were impaired with ageing (all P < 0.05). The clearance function through peri-olfactory nerve pathway in inferior turbinate was positively correlated with sleep quality and cognitive function (both P < 0.05), and mediated the association of sleep quality with cognitive function (percent change in ß [bootstrap 95% CI]: 33% [-0.220, -0.007]). INTERPRETATION: The impaired clearance through putative peri-olfactory nerve pathway may explain the cognitive decline in patients with sleep disturbance. The study shows a promising method to assess cerebrospinal fluid clearance function of putative peri-neural pathways via dynamic magnetic resonance imaging with intrathecal injection of contrast agent. FUNDING: This work was supported by the National Natural Science Foundation of China (81971101, 82171276 and 82101365).