Targeting the Sleep-Glymphatic-Vascular Continuum in Cerebral Small Vessel Disease: A Nutritional Perspective on Neuroprotective Potential of Tocotrienols (T3).

Cerebral small vessel disease (CSVD) is a leading cause of stroke, cognitive impairment, and vascular dementia, yet disease-modifying therapeutic strategies remain limited. Emerging evidence suggests that sleep fragmentation (SF), a common and often under-recognized feature of aging and cardiometabolic disorders, plays a pivotal role in CSVD pathogenesis by disrupting the glymphatic system, the brain's primary waste clearance pathway. Sleep-dependent glymphatic function facilitates the removal of neurotoxic metabolites and maintains neurovascular homeostasis. In contrast, SF impairs cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange, promotes perivascular space enlargement, endothelial dysfunction, blood-brain barrier (BBB) breakdown, and chronic neuroinflammation, hallmarks of CSVD. This review synthesizes current mechanistic, preclinical, and clinical evidence linking SF to glymphatic dysfunction and small vessel pathology, framing these interactions as a sleep-glymphatic-vascular continuum underlying CSVD progression and cognitive decline. We further explore the emerging therapeutic potential of tocotrienols (T3), vitamin E isoforms with potent antioxidant, anti-inflammatory, and vasculoprotective properties, as modulators of neurovascular integrity within this continuum. Although direct evidence linking T3 to glymphatic regulation remains limited, converging data support their capacity to preserve endothelial function, attenuate oxidative stress, and stabilize astrocytic and BBB dynamics, mechanisms highly relevant to glymphatic and microvascular health. By integrating sleep biology, glymphatic neuroscience, and nutritional vascular protection, this review highlights hypothesis-generating preventive and therapeutic avenues for CSVD and delineates key knowledge gaps, including the need for longitudinal human studies, standardized glymphatic imaging, objective sleep phenotyping, and interventional trials to establish causal and translational relevance.