Human Glymphatic Function Declines with Age, Correlates with Cognitive Decline
Drainage of cerebrospinal fluid from the brain into the body is reduced with age. The known pathways become impaired. Firstly, drainage holes in the cribriform plate behind the nose ossify and close up. Secondly the glymphatic system that carries away fluid from the brain loses lymphatic vessel density and vessel function. The outcome of reduced fluid flow leaving the brain is that metabolic wastes build up, causing inappropriate changes in cell behavior, including an increase in inflammatory signaling produced by the innate immune cells called microglia. Neurodegenerative conditions are characterized by chronic inflammation in the brain, disruptive to tissue structure and function.
As a companion to yesterday's paper on VEGF-C gene therapy to restore glymphatic drainage of cerebrospinal fluid in aged mice, today I'll point out a study that assesses glymphatic fluid flow in aged humans. The researchers correlate reduced flow with both loss of cognitive function and structural changes in the brain characteristic of aging. A relatively recently developed imaging technique known as Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) was employed. This uses MRI to obtain an assessment of how much water is flowing out of the brain via lymphatic vessels and perivascular spaces in a region where a number of vessels are conveniently lined up in parallel. The technique doesn't actually measure flow, but rather measures the direction and extent of local diffusion of water molecules in many small volumes. If there is flow, one would expect a very unbalanced "diffusion", with a lot of movement in the direction of the flow. So far the technique appears to be producing good results.
Glymphatic function decline as a mediator of core memory-related brain structures atrophy in aging
This study aimed to elucidate the role of the glymphatic system - a crucial pathway for clearing waste in the brain - in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function. Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined.
As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex (r = 0.258), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness (r = 0.414). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline.
In conclusion, this study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline.