{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T14:39:53Z","timestamp":1793025593081,"version":"4.5.0"},"reference-count":177,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Higher Education (MoHE) Malaysia, under the Fundamental Research Grant Scheme","award":["FRGS\/1\/2025\/WAS04\/UNISZA\/03\/1"],"award-info":[{"award-number":["FRGS\/1\/2025\/WAS04\/UNISZA\/03\/1"]}],"id":[{"id":"https:\/\/ror.org\/05mcs2t73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Ajman University, United Arab Emirates","id":[{"id":"https:\/\/ror.org\/01j1rma10","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>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\u2019s 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)\u2013interstitial fluid (ISF) exchange, promotes perivascular space enlargement, endothelial dysfunction, blood\u2013brain 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\u2013glymphatic\u2013vascular 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.<\/jats:p>","DOI":"10.3390\/life16030393","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:06:59Z","timestamp":1772467619000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting the Sleep\u2013Glymphatic\u2013Vascular Continuum in Cerebral Small Vessel Disease: A Nutritional Perspective on Neuroprotective Potential of Tocotrienols (T3)"],"prefix":"10.3390","volume":"16","author":[{"given":"Dena Farysah","family":"Mazli","sequence":"first","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7621-7132","authenticated-orcid":false,"given":"Zaw Myo","family":"Hein","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates"},{"name":"Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-4565","authenticated-orcid":false,"given":"Che Mohd Nasril","family":"Che Mohd Nassir","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu 20400, Terengganu, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ain Hafizah","family":"Alias","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9452-9065","authenticated-orcid":false,"given":"Sint Sint","family":"Win","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Medicine 1, Yangon, No. 245, Myoma-Kyaung Street, Lanmadaw Township, Yangon 11131, Myanmar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Farris Iman Leong","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu 20400, Terengganu, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-6458","authenticated-orcid":false,"given":"Muhammad Zulfadli","family":"Mehat","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5333-4694","authenticated-orcid":false,"given":"Hafizah","family":"Abdul Hamid","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3259-2074","authenticated-orcid":false,"given":"Gehan","family":"El-Akabawy","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates"},{"name":"Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates"},{"name":"Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menofia 6132720, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1161\/STROKEAHA.122.038265","article-title":"Cerebral small vessel disease-related dementia: More questions than answers","volume":"54","author":"Elahi","year":"2023","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.2147\/NDT.S352651","article-title":"Prevalence and consequences of cerebral small vessel diseases: A cross-sectional study based on community people plotted against 5-year age strata","volume":"18","author":"Mu","year":"2022","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Liu, X., Sun, P., Yang, J., and Fan, Y. (2022). 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