Understanding Glymphatic’s Role In Proteinopathies (GRIP): A single centre case-control study protocol

Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) are proteinopathies characterized by pathological accumulation of amyloid beta, phosphorylated-tau, and alpha-synuclein. Impaired clearance of these proteins is thought to contribute to disease pathogenesis, whereas preserved or enhanced clearance may be compensatory. Beyond intracellular degradation within neurons and glial cells, an extracellular clearance pathway, the glymphatic system, facilitates cerebrospinal fluid flow into perivascular spaces, exchange with interstitial fluid, and subsequent clearance from the brain. Glymphatic transport may therefore be critical for removal of excess proteins and metabolic waste, and its dysfunction could promote protein aggregation and neurodegeneration. The Glymphatic's Role In Proteinopathies (GRIP) study is an observational case-control imaging and biomarker study comparing glymphatic clearance in patients with AD, PD, and DLB versus healthy controls. We aim to recruit 70 participants: PD (n = 20), DLB (n = 10), AD (n = 20), and age- and sex-matched healthy controls (n = 20). The AD group will be stratified by pathology, with half amyloid-positive/tau-negative (A + T-) and half amyloid- and tau-positive (A + T+). The PD group will be stratified by disease duration. Participants will undergo baseline MRI followed by intrathecal injection of gadobutrol (0.25 mmol) and serial MRI at 5, 24, 48, and 72 hours. Influx and efflux of tracer will be modeled from T1 signal changes. Blood will be sampled repeatedly from 1 to 72 hours; cerebrospinal fluid will be collected at baseline. Individual glymphatic clearance will be estimated using population pharmacokinetic methods, where gadobutrol serves as a tracer. Sleep will be monitored with triaxial accelerometry and sleep diaries. The primary outcome is group differences in glymphatic clearance metrics between each disease group and controls; secondary analyses will explore associations with cognition, disease severity and duration, sleep quality, and cerebrospinal fluid protein levels.