{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:45:45Z","timestamp":1785743145387,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University","award":["KFU264110"],"award-info":[{"award-number":["KFU264110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurol. Int.","Neurology International"],"abstract":"<jats:p>Background and objectives: Cerebrovascular strokes and transient ischemic attacks (TIAs) remain leading causes of global mortality and long-term disability. Emerging evidence suggests that pre-existing structural brain frailty\u2014driven by chronic cerebral small vessel disease (CSVD)\u2014critically limits neuroplastic compensation and determines overall recovery potential. This systematic review aims to synthesize current evidence evaluating brain frailty as an independent determinant of functional and cognitive outcomes. Methods: Following PRISMA and Cochrane SWiM guidelines, a comprehensive literature search was conducted across PubMed, Web of Science, Embase, and Scopus. Methodological quality was evaluated using the Newcastle\u2013Ottawa Scale (NOS). Due to anticipated clinical and methodological heterogeneity, data were synthesized via a structured narrative approach. A total of 15 studies comprising more than 18,000 participants met the inclusion criteria, including prospective cohorts, retrospective cohorts, registry analyses, pooled cohort studies, and post hoc analyses of randomized controlled trials. Results: Structural disconnection burden emerged as one of the strongest predictors of post-stroke cognitive impairment, demonstrating remarkably large effect sizes at both 6 months (OR 9.96, 95% CI 2.21\u201352.40) and 36 months (OR 12.27, 95% CI 2.80\u201363.40). Additionally, blood\u2013brain barrier (BBB) leakage was significantly associated with longitudinal cognitive decline (\u03b2 \u22123.62 to \u22120.16, p &lt; 0.001). Pre-existing brain frailty was also consistently associated with poorer functional recovery following acute ischemic stroke, even among patients undergoing advanced reperfusion strategies such as endovascular thrombectomy or intravenous thrombolysis. Conclusions: Brain frailty should be integrated into clinical prognostic frameworks as a key marker for predicting long-term cognitive function and functional independence in stroke patients. However, the substantial methodological and clinical heterogeneity observed across the included literature must be acknowledged as a key limitation of the current evidence base. Large-scale, prospective, multicenter longitudinal studies are required to better standardize brain frailty metrics and validate their utility in clinical practice.<\/jats:p>","DOI":"10.3390\/neurolint18080147","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T06:17:40Z","timestamp":1785737860000},"page":"147","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Brain Frailty in Stroke Outcomes: A Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"given":"Hussain","family":"Almohammed","sequence":"first","affiliation":[{"name":"College of Medicine, King Faisal University, Al Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husna Irfan","family":"Thalib","sequence":"additional","affiliation":[{"name":"General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3297-729X","authenticated-orcid":false,"given":"Samiya","family":"Khanam","sequence":"additional","affiliation":[{"name":"General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9410-5759","authenticated-orcid":false,"given":"Kawthar Faisal","family":"Kushara","sequence":"additional","affiliation":[{"name":"College of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1518-3685","authenticated-orcid":false,"given":"Wejdan Ahmed","family":"Aldawsari","sequence":"additional","affiliation":[{"name":"College of Medicine, Tabuk University, Tabuk 47918, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala Omar","family":"Algazzawi","sequence":"additional","affiliation":[{"name":"General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimas Warid","family":"Aljuaid","sequence":"additional","affiliation":[{"name":"College of Medicine, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Ibrahim","family":"Almuhaysin","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Groningen, 9712 Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hams Akram","family":"Alharbi","sequence":"additional","affiliation":[{"name":"College of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alia","family":"Alokley","sequence":"additional","affiliation":[{"name":"Departments of Clinical Neuroscience, College of Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","unstructured":"GBD 2016 Stroke Collaborators (2019). Global, regional, and national burden of stroke, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 18, 439\u2013458."},{"key":"ref_2","unstructured":"GBD 2019 Stroke Collaborators (2021). Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 20, 795\u2013820."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1161\/CIRCRESAHA.116.308398","article-title":"Stroke risk factors, genetics, and prevention","volume":"120","author":"Boehme","year":"2017","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s11883-022-01067-x","article-title":"A contemporary review of epidemiology, risk factors, etiology, and outcomes of premature stroke","volume":"24","author":"Potter","year":"2022","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jocn.2019.12.032","article-title":"Current aspects of TIA management","volume":"72","author":"Clissold","year":"2020","journal-title":"J. Clin. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1161\/CIRCULATIONAHA.123.065446","article-title":"Long-term incidence of ischemic stroke after transient ischemic attack: A nationwide study from 2014 to 2020","volume":"148","author":"Vinding","year":"2023","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lin, C.J., Huang, H.C., Tsai, J.Y., Liu, T.C., Liu, H.Y., Chi, N.F., Hsu, L.-C., Lee, I.-H., Leu, H.-B., and Chung, C.-P. (2026). Heterogeneous recovery trajectories and prognostic factors after ischemic stroke. Cerebrovasc. Dis., Epub ahead of print.","DOI":"10.1159\/000550328"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jphys.2013.12.012","article-title":"National Institutes of Health Stroke Scale (NIHSS)","volume":"60","author":"Kwah","year":"2014","journal-title":"J. Physiother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1161\/STROKEAHA.111.620336","article-title":"Validation of the Stroke Prognostic Instrument-II in a Large, Modern, Community-Based Cohort of Ischemic Stroke Survivors","volume":"42","author":"Navi","year":"2011","journal-title":"Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1161\/01.STR.31.2.456","article-title":"The Stroke Prognosis Instrument II (SPI-II): A clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke","volume":"31","author":"Kernan","year":"2000","journal-title":"Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1747-4949.2012.00872.x","article-title":"Validation of the Totaled Health Risks in Vascular Events (THRIVE) score for outcome prediction in endovascular stroke treatment","volume":"9","author":"Flint","year":"2014","journal-title":"Int. J. Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1177\/003693305700200504","article-title":"Cerebral vascular accidents in patients over the age of 60: II","volume":"2","author":"Rankin","year":"1957","journal-title":"Progn. Scott. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1161\/01.STR.0000258355.23810.c6","article-title":"Outcomes validity and reliability of the modified Rankin scale: Implications for stroke clinical trials: A literature review and synthesis","volume":"38","author":"Banks","year":"2007","journal-title":"Stroke"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1161\/STROKEAHA.109.571562","article-title":"Improving modified Rankin Scale assessment with a simplified questionnaire","volume":"41","author":"Bruno","year":"2010","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e439","DOI":"10.1212\/WNL.0000000000008881","article-title":"Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke","volume":"94","author":"Appleton","year":"2020","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e039790","DOI":"10.1161\/JAHA.124.039790","article-title":"Imaging-based brain frailty predicts unfavorable outcomes in acute ischemic stroke","volume":"14","author":"Cheng","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S1474-4422(10)70104-6","article-title":"Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges","volume":"9","author":"Pantoni","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1177\/0963689718795148","article-title":"Cerebral small vessel disease","volume":"27","author":"Li","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/j.1750-3639.2002.tb00450.x","article-title":"Hypertensive cerebral small vessel disease and stroke","volume":"12","author":"Lammie","year":"2002","journal-title":"Brain Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1136\/jnnp.2009.201665","article-title":"Cortical and frontal atrophy are associated with cognitive impairment in age-related confluent white-matter lesion","volume":"82","author":"Mok","year":"2011","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.neurobiolaging.2009.05.005","article-title":"Brain atrophy and cognition: Interaction with cerebrovascular pathology?","volume":"32","author":"Muller","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/brain\/awq343","article-title":"Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease","volume":"134","author":"Tuladhar","year":"2011","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1161\/STROKEAHA.120.029841","article-title":"Imaging markers of brain frailty and outcome in patients with acute ischemic stroke","volume":"52","author":"Bu","year":"2021","journal-title":"Stroke"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2534941","DOI":"10.1001\/jamanetworkopen.2025.34941","article-title":"Brain frailty and functional outcomes after thrombolysis for acute ischemic stroke","volume":"8","author":"Loewen","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1177\/23969873231186480","article-title":"Physical and brain frailty in ischaemic stroke or TIA: Shared occurrence and outcomes. A cohort study","volume":"8","author":"Hafdi","year":"2023","journal-title":"Eur. Stroke J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108539","DOI":"10.1016\/j.clineuro.2024.108539","article-title":"The effect of frailty on mortality and functional outcomes in spontaneous intracerebral haemorrhage","volume":"246","author":"Ong","year":"2024","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1159\/000541701","article-title":"Frailty and early mortality following intracerebral hemorrhage","volume":"54","author":"Lewis","year":"2025","journal-title":"Cerebrovasc. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1159\/000542386","article-title":"Prevalence of Frailty in the Transient Ischaemic Attack Clinic and Its Associations with Mortality","volume":"54","author":"Elliott","year":"2025","journal-title":"Cerebrovasc. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1001\/jama.284.22.2901","article-title":"Short-term prognosis after emergency department diagnosis of TIA","volume":"284","author":"Johnston","year":"2000","journal-title":"JAMA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur. J. Epidemiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hong, S., Giese, A.K., Schirmer, M.D., Bonkhoff, A.K., Bretzner, M., Rist, P., Dalca, A.V., Regenhardt, R.W., Etherton, M.R., and Donahue, K.L. (2021). Excessive white matter hyperintensity increases susceptibility to poor functional outcomes after acute ischemic stroke. Front. Neurol., 12.","DOI":"10.1161\/str.52.suppl_1.MP16"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Munthe-Kaas, R., Aam, S., Saltvedt, I., Wyller, T.B., Pendlebury, S.T., Lydersen, S., Hagberg, G., Schellhorn, T., Rostoft, S., and Ihle-Hansen, H. (2022). Is Frailty Index a better predictor than pre-stroke modified Rankin Scale for neurocognitive outcomes 3-months post-stroke?. BMC Geriatr., 22.","DOI":"10.1186\/s12877-022-02840-y"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e70138","DOI":"10.1002\/hbm.70138","article-title":"Long-term post-stroke cognition in patients with minor ischemic stroke is related to tract-based disconnection induced by white matter hyperintensities","volume":"46","author":"Lopes","year":"2025","journal-title":"Hum. Brain Mapp."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zilioli, A., Busi, G., Genovese, A., Avola, G., Angeli, M.C., Ferraro, C., Corradi, L., Pancaldi, B., Spallazzi, M., and Abrignani, G. (2026). Regional brain atrophy, white matter lesions, and functional outcome after endovascular thrombectomy for acute ischemic stroke. J. Neurointerv. Surg., Epub ahead of print.","DOI":"10.1136\/jnis-2026-024941"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1177\/17474930241252530","article-title":"Strategic white matter hyperintensity locations associated with post-stroke cognitive impairment: A multicenter study in 1568 stroke patients","volume":"19","author":"Coenen","year":"2024","journal-title":"Int. J. Stroke"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"22567","DOI":"10.1038\/s41598-024-71936-9","article-title":"Effects of white matter hyperintensity burden on functional outcome after mild versus moderate-to-severe ischemic stroke","volume":"14","author":"Gwak","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.jalz.2016.09.006","article-title":"Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: Evidence from a cohort study","volume":"13","author":"Wardlaw","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1159\/000487668","article-title":"Impact of brain atrophy on early neurological deterioration and outcome in severe ischemic stroke treated by intravenous thrombolysis","volume":"79","author":"Tschirret","year":"2018","journal-title":"Eur. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1007\/s00415-019-09624-2","article-title":"White matter burden does not influence the outcome of mechanical thrombectomy","volume":"267","author":"Mechtouff","year":"2020","journal-title":"J. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1177\/1747493016676612","article-title":"White matter hyperintensity volume predicts persistent cognitive impairment in transient ischemic attack and minor stroke","volume":"12","author":"Sivakumar","year":"2017","journal-title":"Int. J. Stroke"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1521","DOI":"10.1212\/WNL.0000000000207700","article-title":"Association of brain atrophy with functional outcome and recovery trajectories after thrombectomy: Post hoc analysis of the ESCAPE-NA1 trial","volume":"101","author":"Benali","year":"2023","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1159\/000509071","article-title":"Effects of white matter hyperintensities on 90-day functional outcome after large vessel and non-large vessel stroke","volume":"49","author":"Griessenauer","year":"2020","journal-title":"Cerebrovasc. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e213619","DOI":"10.1212\/WNL.0000000000213619","article-title":"Impact of brain frailty on clinical presentation and neurologic recovery in acute ischemic stroke patients undergoing thrombectomy","volume":"104","author":"Fladt","year":"2025","journal-title":"Neurology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16038","DOI":"10.1038\/s41598-021-95265-3","article-title":"Quantitative susceptibility mapping in ischemic stroke patients after successful recanalization","volume":"11","author":"Probst","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1161\/STROKEAHA.123.044606","article-title":"Longitudinal changes in iron and myelination within ischemic lesions associate with neurological outcomes: A pilot study","volume":"55","author":"Uchida","year":"2024","journal-title":"Stroke"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Uchida, Y., Kan, H., Inoue, H., Oomura, M., Shibata, H., Kano, Y., Kuno, T., Usami, T., Takada, K., and Yamada, K. (2022). Penumbra detection with oxygen extraction fraction using magnetic susceptibility in patients with acute ischemic stroke. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.752450"}],"container-title":["Neurology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8377\/18\/8\/147\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:02:58Z","timestamp":1785740578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8377\/18\/8\/147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":48,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["neurolint18080147"],"URL":"https:\/\/doi.org\/10.3390\/neurolint18080147","relation":{},"ISSN":["2035-8377"],"issn-type":[{"value":"2035-8377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]}}}