Wednesday, April 2, 2025
4/2/2025
Intrinsic CSF outflow metrics for mild cognitive impairment and Alzheimer's disease - One in 10 Americans aged 65 and older (10%) has Alzheimer’s disease (AD), with prevalence increasing with age. AD is a slowly progressive, irreversible neurodegenerative disease with a long preclinical phase. The pathophysiology of AD is not fully understood but is likely to be multifactorial. One postulated contributor is impaired glymphatic clearance. The glymphatic system is conceptualized as a system by which soluble proteins and metabolites are eliminated from the central nervous system via cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the perivascular space (PVS). In rodent models, sleep and physical activity have been reported to accelerate glymphatic clearance using invasive methods. During sleep, a nearly 60% increase in clearance of brain waste was observed in rats, caused by expansion and contraction of the extracellular space. Glymphatic clearance was transiently increased in aged mice by physical activity, and physical activity has been reported to improve clearance of brain Aβ in rats. Although animal studies suggest that reduced glymphatic clearance is important for cognitive function in aging, translation of findings from rodents to humans is limited because rodent models do not fully capture the human experience. In humans, use of a gadolinium-based contrast agent (GBCA) via intrathecal injection allows for observation of glymphatic clearance, albeit over a long period. However, this method is limited by its invasiveness, and by the unknown effect of the GBCA tracer on the in vivo time-course of glymphatic clearance. Using a novel, noninvasive, non-contrast 3D MRI technique, we have shown intrinsic glymphatic clearance or CSF outflow metrics decreases with age using a single-tagged method. The intrinsic CSF metrics decrease drastically over 60 years old. Thus, we will develop an advanced double-tagged method from both brain hemispheres. Using the double-tagged method, we propose to study healthy older adults, mild cognitive impairment (MCI), and AD patients on intrinsic CSF outflow metrics by segmenting various regions of interest (ROI) such as upper, middle, and lower parasagittal dura (PSD), superior sagittal sinus (SSS), and entire SSS region. Because CSF outflow is influenced by physical activity, we will monitor their activity level using actigraphy. Our challenges include segmentation of these small ROIs, and measurement of subtle changes in CSF outflow metrics in each ROI. To overcome these challenges, our aims of the project are i) identify the detailed CSF outflow egress pathways; ii) obtain quantitative measures at each ROI from both sides of brain hemispheres; iii) compare quantitative measures of intrinsic CSF outflow in MCI and AD patients to age-, and sex-matched cognitively healthy adults; iv) investigate any preference of intrinsic CSF outflow metrics from the right- and left-brain hemispheres; and compare with their physical activity level. We expect that intrinsic CSF outflow will decrease with cognitive decline; that clearance pathways may be altered in MCI and AD patients from healthy individuals.
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