ABSTRACT/PROJECT SUMMARY Several preclinical & clinical studies have implicated that acceleration/deceleration forces to the brain beyond a certain threshold can lead to disruption of both axonal microtubules and vascular endothelium. The consequences of such injury include diffuse axonal injury and transitory blood flow impairment at the acute stage and the accumulation of toxic protein species such as phosphorylated tau over time, a key factor in the development of vascular cognitive impairment and dementia. In addition, it is thought that the AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric symptoms, attention deficits, sleep disturbances, oculomotor dysfunctions and altered pain perception. A brain wide “glymphatic system”, driven by arterial pulsatility, comprised of paravascular pathways and meningeal lymphatic channels is now recognized as a major pathway of clearance of these proteins from the brain. This pathway, tightly temporally correlated to sleep, has recently shown to be affected by TBI. The thalamus plays a well- known role in sleep regulation. We therefore posit that a likely “vicious cycle” exists wherein glymphatic pathways disrupted by TBI fail to clear toxic protein species from the thalamus, affecting its structure and function, resulting in sleep dysregulation and thereby, impaired glymphatic efflux. As a supplement to the parent grant which is focused on examining the longitudinal changes in the structural and functional connectivity of the thalamus after TBI, we wish to examine, using advanced MRI techniques, whether symptoms of TBI arise from an interplay between thalamic injury and impaired glymphatic efflux. We hypothesize that vascular impairments following TBI include not only endothelial damage but also extend to glymphatic disruption and meningeal lymphatic injury and that such disruption will differentially affect thalamic structural and functional connectivity. Using advanced imaging techniques, we propose to address this using the following two aims: (1) we wish to examine in vivo, using MRI, differences in the structure and function of the human glymphatic system spanning the perivascular space to the meningeal lymphatics between patients with mild TBI and age and gender matched control subjects both at the early (~6mo) and late stages of injury (~5y after initial injury). In Aim 2 we will assess the influence of glymphatic dysfunction upon global thalamic and individual thalamic nuclear structure and thalamocortical structural and functional connectivity and upon performance on neuropsychological assessments. The results from this study will provide a unified framework to understand mechanisms that lead to not only TBI related dementia, vascular cognitive impairment and Alzheimer’s disease but also those that arise from toxic protein accumulation such as Frontotemporal dementia and Lewy Body Disease among others.