Glymphatics Imaging to Probe Sleep in Veterans with the Polytrauma Clinical Triad (GLIMPSE-PCT)

About This Grant

There is increasing recognition for the association between traumatic brain injury (TBI) and neurodegenerative conditions, and further amplification of this signal with additional co-existing chronic overlapping conditions (e.g., post-traumatic stress disorder, PTSD, and chronic pain; defining the “polytrauma clinical triad”, PCT). Veterans with the PCT, estimated to be present in ~40% of those returning from OEF/OIF/OND and subsequent conflicts, are often highly disabled suffering from severe symptomatology and chronic sequela disproportionate to their singular conditions. For example, sleep disturbances, one of the principle complicating factors in Veterans with the PCT are frequently intensified compared to their singular conditions. While obviously sleep-wake disturbances impair quality of life, exacerbate commonly comorbid conditions (e.g., mood, cognitive dysfunction, chronic pain), and impede effective clinical care and rehabilitation, impaired sleep has also been identified as a driver of neurodegeneration. However, mechanistically, the link between the PCT, sleep disturbances, and risk for neurodegeneration is not well defined, and objective prognostic biomarkers are lacking; a prominent goal of the VA RR&D service line. We propose the glymphatic system as a promising, mechanistic-based biomarker of potential prognostic value to Veterans with the PCT. The glymphatic system, initially defined by investigators in our group, Nedergaard, and colleagues in 2012, supports the convective exchange of fluid between the cerebrospinal fluid and brain interstitial compartments along perivascular spaces, clearing pathogenic proteins including amyloid-β, tau, and α-synuclein. Importantly, the glymphatic system functions preferentially during sleep, and is impaired following TBI (and in the PCT) and in sleep disruption, supporting the mechanistic implication for glymphatic function to potentially underly the association between neurotrauma, sleep, and neurodegeneration. Accordingly, the proposed experimental paradigm will define the role of sleep-active glymphatic function as the mechanistic link between neurotrauma and neurodegeneration. We propose to deeply phenotype sleep and glymphatic function in n=60 Veterans with the PCT, compared to n=60 age- and sex- matched controls without TBI, PTSD, or chronic pain, using novel approaches of non-contrast MRI-based glymphatic measures in combination with objective and subjective continuous sleep monitoring. MRI sequences include 1) quantifying MRI visible perivascular space burden (volume x number), 2) intra-voxel incoherent motion examining slow/long range interstitial flow, 3) fast frequency functional MRI measuring low- frequency cerebral spinal fluid pulsations, and 4) multi-echo arterial spin labeling MRI measuring glial-vascular water exchange. Sleep monitoring innovatively combines wrist-based actigraphy, a low-burden text messaging based daily sleep diary, and validated questionnaires. Glymphatic function will be assessed following 4-weeks of continuous sleep monitoring. Primary outcomes in this proposal center around cross-sectional analyses, demonstrating glymphatic impairment in Veterans with the PCT compared to controls (Aim 1), an association between glymphatic function and sleep impairment (Aim 2), and an association between glymphatic function and PCT relevant symptomology (Aim 3). Collectively these data will also establish precedent for the continued monitoring and longer-term imaging via competitive renewal and/or de novo VA merit proposals.