{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:26:10Z","timestamp":1791599170758,"version":"4.3.4"},"reference-count":48,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2022,3,22]]},"abstract":"<jats:p>Background: Vascular pathology is an important partner of Alzheimer\u2019s disease (AD). Both total cerebral small vessel disease (CSVD) score and white matter free water (FW) are useful markers that could reflect cerebral vascular injury. Objective: We aim to investigate the efficacy of these two metrics in predicting cognitive declines in patients with mild cognitive impairment (MCI). Methods: We enrolled 126 MCI subjects with 3D T1-weighted images, fluid-attenuated inversion recovery images, T2* images, diffusion tensor imaging images, cerebrospinal fluid biomarkers and neuropsychological tests from the Alzheimer\u2019s Disease Neuroimaging Initiative database. The total CSVD score and FW values were calculated. Simple and multiple linear regression analyses were applied to explore the association between vascular and cognitive impairments. Linear mixed effect models were constructed to investigate the efficacy of total CSVD score and FW on predicting cognitive decline. Results: FW was associated with baseline cognition and could predict the decline of executive and language functions in MCI subjects, while no association was found between total CSVD score and cognitive declines. Conclusion: FW is a promising imaging marker for investigating the effect of CSVD on AD progression.<\/jats:p>","DOI":"10.3233\/jad-215541","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T19:18:32Z","timestamp":1644347912000},"page":"741-751","source":"Crossref","is-referenced-by-count":7,"title":["White Matter Free Water Outperforms Cerebral Small Vessel Disease Total Score in Predicting Cognitive Decline in Persons with Mild Cognitive Impairment"],"prefix":"10.1177","volume":"86","author":[{"given":"Zili","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"},{"name":"Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingze","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaicheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China"},{"name":"Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-215541_ref1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease","volume":"25","author":"Lane","year":"2018","journal-title":"Eur J Neurol"},{"key":"10.3233\/JAD-215541_ref2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00401-016-1570-0","article-title":"Brain imaging of neurovascular dysfunction in Alzheimer\u2019s disease","volume":"131","author":"Montagne","year":"2016","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215541_ref3","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nrn3114","article-title":"Neurovascular pathways to neurodegeneration in Alzheimer\u2019s disease and other disorders","volume":"12","author":"Zlokovic","year":"2011","journal-title":"Nat Rev Neurosci"},{"key":"10.3233\/JAD-215541_ref4","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.jalz.2019.06.001","article-title":"Preventing dementia by preventing stroke: The Berlin Manifesto","volume":"15","author":"Hachinski","year":"2019","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215541_ref5","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1177\/1747493017731947","article-title":"Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination","volume":"13","author":"Blair","year":"2018","journal-title":"Int J Stroke"},{"key":"10.3233\/JAD-215541_ref6","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/S1474-4422(13)70124-8","article-title":"Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration","volume":"12","author":"Wardlaw","year":"2013","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-215541_ref7","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.jalz.2017.08.017","article-title":"Cerebral small vessel disease in middle age and genetic predisposition to late-onset Alzheimer\u2019s disease","volume":"14","author":"Stefaniak","year":"2018","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215541_ref8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.arr.2018.06.002","article-title":"Cerebral small vessel disease and the risk of Alzheimer\u2019s disease: A systematic review","volume":"47","author":"Liu","year":"2018","journal-title":"Ageing Res Rev"},{"key":"10.3233\/JAD-215541_ref9","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1212\/WNL.0000000000000837","article-title":"Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden","volume":"83","author":"Staals","year":"2014","journal-title":"Neurology"},{"key":"10.3233\/JAD-215541_ref10","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1161\/STROKEAHA.113.002545","article-title":"Ambulatory blood pressure in patients with lacunar stroke: Association with total MRI burden of cerebral small vessel disease","volume":"44","author":"Klarenbeek","year":"2013","journal-title":"Stroke"},{"key":"10.3233\/JAD-215541_ref11","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/gps.4747","article-title":"Total cerebral small vessel disease score and cognitive performance in community-dwelling older adults. Results from the Atahualpa Project","volume":"33","author":"Del Brutto","year":"2018","journal-title":"Int J Geriatr Psychiatry"},{"key":"10.3233\/JAD-215541_ref12","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1016\/j.neurobiolaging.2015.06.024","article-title":"Total MRI load of cerebral small vessel disease and cognitive ability in older people","volume":"36","author":"Staals","year":"2015","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-215541_ref13","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3233\/JAD-181135","article-title":"Total cerebral small vessel disease burden is related to worse performance on the Mini-Mental State Examination and incident dementia: A prospective 5-year follow-up","volume":"69","author":"Jiang","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-215541_ref14","doi-asserted-by":"crossref","first-page":"72","DOI":"10.3389\/fnagi.2013.00072","article-title":"Accumulation of MRI markers of cerebral small vessel disease is associated with decreased cognitive function. A study in first-ever lacunar stroke and hypertensive patients","volume":"5","author":"Huijts","year":"2013","journal-title":"Front Aging Neurosci"},{"key":"10.3233\/JAD-215541_ref15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3389\/fnagi.2016.00301","article-title":"Total cerebral small vessel disease MRI score is associated with cognitive decline in executive function in patients with hypertension","volume":"8","author":"Uiterwijk","year":"2016","journal-title":"Front Aging Neurosci"},{"key":"10.3233\/JAD-215541_ref16","doi-asserted-by":"crossref","first-page":"695732","DOI":"10.3389\/fnagi.2021.695732","article-title":"Higher total cerebral small vessel disease burden was associated with mild cognitive impairment and overall cognitive dysfunction: A propensity score-matched case-control study","volume":"13","author":"Li","year":"2021","journal-title":"Front Aging Neurosci"},{"key":"10.3233\/JAD-215541_ref17","doi-asserted-by":"crossref","first-page":"698035","DOI":"10.3389\/fnagi.2021.698035","article-title":"Total cerebral small vessel disease burden on MRI correlates with medial temporal lobe atrophy and cognitive performance in patients of a memory clinic","volume":"13","author":"Fan","year":"2021","journal-title":"Front Aging Neurosci"},{"key":"10.3233\/JAD-215541_ref18","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1523\/JNEUROSCI.4437-12.2013","article-title":"Brain microstructure reveals early abnormalities more than two years prior to clinical progression from mild cognitive impairment to Alzheimer\u2019s disease","volume":"33","author":"Douaud","year":"2013","journal-title":"J Neurosci"},{"key":"10.3233\/JAD-215541_ref19","doi-asserted-by":"crossref","first-page":"e2221","DOI":"10.1212\/WNL.0000000000007449","article-title":"Cerebral white matter free water: A sensitive biomarker of cognition and function","volume":"92","author":"Maillard","year":"2019","journal-title":"Neurology"},{"key":"10.3233\/JAD-215541_ref20","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.jalz.2017.12.007","article-title":"Free water determines diffusion alterations and clinical status in cerebral small vessel disease","volume":"14","author":"Duering","year":"2018","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215541_ref21","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/alz.12150","article-title":"Small vessel disease more than Alzheimer\u2019s disease determines diffusion MRI alterations in memory clinic patients","volume":"16","author":"Finsterwalder","year":"2020","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215541_ref22","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.neuroimage.2019.06.065","article-title":"Development of a transcallosal tractography template and its application to dementia","volume":"200","author":"Archer","year":"2019","journal-title":"Neuroimage"},{"key":"10.3233\/JAD-215541_ref23","doi-asserted-by":"crossref","first-page":"4749","DOI":"10.1038\/s41598-019-41363-2","article-title":"White matter microstructural abnormalities and default network degeneration are associated with early memory deficit in Alzheimer\u2019s disease continuum","volume":"9","author":"Ji","year":"2019","journal-title":"Sci Rep"},{"key":"10.3233\/JAD-215541_ref24","doi-asserted-by":"crossref","first-page":"101985","DOI":"10.1016\/j.nicl.2019.101985","article-title":"Free-water imaging of the hippocampus is a sensitive marker of Alzheimer\u2019s disease","volume":"24","author":"Ofori","year":"2019","journal-title":"Neuroimage Clin"},{"key":"10.3233\/JAD-215541_ref25","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.nicl.2018.09.027","article-title":"Microstructural brain changes track cognitive decline in mild cognitive impairment","volume":"20","author":"Reas","year":"2018","journal-title":"Neuroimage Clin"},{"key":"10.3233\/JAD-215541_ref26","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3233\/JAD-190871","article-title":"Associations between microstructure, amyloid, and cognition in amnestic mild cognitive impairment and dementia","volume":"73","author":"Reas","year":"2020","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-215541_ref27","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/ana.21610","article-title":"Cerebrospinal fluid biomarker signature in Alzheimer\u2019s disease neuroimaging initiative subjects","volume":"65","author":"Shaw","year":"2009","journal-title":"Ann Neurol"},{"key":"10.3233\/JAD-215541_ref28","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s00401-011-0808-0","article-title":"Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI","volume":"121","author":"Shaw","year":"2011","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215541_ref29","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1161\/STROKEAHA.110.591586","article-title":"Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: A population-based study","volume":"41","author":"Zhu","year":"2010","journal-title":"Stroke"},{"key":"10.3233\/JAD-215541_ref30","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2214\/ajr.149.2.351","article-title":"MR signal abnormalities at 1.5 T in Alzheimer\u2019s dementia and normal aging","volume":"149","author":"Fazekas","year":"1987","journal-title":"AJR Am J Roentgenol"},{"key":"10.3233\/JAD-215541_ref31","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1002\/mrm.28599","article-title":"Free-water DTI estimates from single b-value data might seem plausible but must be interpreted with care","volume":"85","author":"Golub","year":"2021","journal-title":"Magn Reson Med"},{"key":"10.3233\/JAD-215541_ref32","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s13195-020-00657-8","article-title":"Association of glial and neuronal degeneration markers with Alzheimer\u2019s disease cerebrospinal fluid profile and cognitive functions","volume":"12","author":"Teitsdottir","year":"2020","journal-title":"Alzheimers Res Ther"},{"key":"10.3233\/JAD-215541_ref33","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3233\/JAD-170627","article-title":"Executive and language subjective cognitive decline complaints discriminate preclinical Alzheimer\u2019s disease from normal aging","volume":"61","author":"Valech","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-215541_ref34","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13195-017-0292-4","article-title":"Distinct white matter microstructural abnormalities and extracellular water increases relate to cognitive impairment in Alzheimer\u2019s disease with and without cerebrovascular disease","volume":"9","author":"Ji","year":"2017","journal-title":"Alzheimers Res Ther"},{"key":"10.3233\/JAD-215541_ref35","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1002\/hbm.25273","article-title":"White matter hyperintensities at critical crossroads for executive function and verbal abilities in small vessel disease","volume":"42","author":"Camerino","year":"2021","journal-title":"Hum Brain Mapp"},{"key":"10.3233\/JAD-215541_ref36","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.neurobiolaging.2020.05.001","article-title":"Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline","volume":"94","author":"Archer","year":"2020","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-215541_ref37","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1017\/S135561770999035X","article-title":"Ecological assessment of executive functions in mild cognitive impairment and mild Alzheimer\u2019s disease","volume":"15","author":"Espinosa","year":"2009","journal-title":"J Int Neuropsychol Soc"},{"key":"10.3233\/JAD-215541_ref38","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s13195-021-00848-x","article-title":"Correlating natural language processing and automated speech analysis with clinician assessment to quantify speech-language changes in mild cognitive impairment and Alzheimer\u2019s dementia","volume":"13","author":"Yeung","year":"2021","journal-title":"Alzheimers Res Ther"},{"key":"10.3233\/JAD-215541_ref39","doi-asserted-by":"crossref","first-page":"e0242696","DOI":"10.1371\/journal.pone.0242696","article-title":"Free water: A marker of age-related modifications of the cingulum white matter and its association with cognitive decline","volume":"15","author":"Edde","year":"2020","journal-title":"PLoS One"},{"key":"10.3233\/JAD-215541_ref40","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1159\/000320491","article-title":"Diffusion tensor imaging changes correlate with cognition better than conventional MRI findings in patients with subcortical ischemic vascular disease","volume":"30","author":"Xu","year":"2010","journal-title":"Dement Geriatr Cogn Disord"},{"key":"10.3233\/JAD-215541_ref41","doi-asserted-by":"crossref","first-page":"e0173982","DOI":"10.1371\/journal.pone.0173982","article-title":"Microstructural white matter alterations in preclinical Alzheimer\u2019s disease detected using free water elimination diffusion tensor imaging","volume":"12","author":"Hoy","year":"2017","journal-title":"PLoS One"},{"key":"10.3233\/JAD-215541_ref42","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/ana.23802","article-title":"Diffusion changes predict cognitive and functional outcome: The LADIS study","volume":"73","author":"Jokinen","year":"2013","journal-title":"Ann Neurol"},{"key":"10.3233\/JAD-215541_ref43","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1161\/STROKEAHA.119.026170","article-title":"Global burden of small vessel disease\u2013related brain changes on MRI predicts cognitive and functional decline","volume":"51","author":"Jokinen","year":"2020","journal-title":"Stroke"},{"key":"10.3233\/JAD-215541_ref44","doi-asserted-by":"crossref","first-page":"e1294","DOI":"10.1212\/WNL.0000000000009141","article-title":"Simple MRI score aids prediction of dementia in cerebral small vessel disease","volume":"94","author":"Al Olama","year":"2020","journal-title":"Neurology"},{"key":"10.3233\/JAD-215541_ref45","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s12975-021-00899-0","article-title":"White matter free water is a composite marker of cerebral small vessel degeneration","volume":"13","author":"Huang","year":"2022","journal-title":"Transl Stroke Res"},{"key":"10.3233\/JAD-215541_ref46","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/alz.12221","article-title":"Cognitive impairment in sporadic cerebral small vessel disease: A systematic review and meta-analysis","volume":"17","author":"Hamilton","year":"2021","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-215541_ref47","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1001\/2013.jamaneurol.405","article-title":"The aging brain and cognition: Contribution of vascular injury and abeta to mild cognitive dysfunction","volume":"70","author":"Marchant","year":"2013","journal-title":"JAMA Neurol"},{"key":"10.3233\/JAD-215541_ref48","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1002\/acn3.51048","article-title":"The A4 study: Beta-amyloid and cognition in 4432 cognitively unimpaired adults","volume":"7","author":"Insel","year":"2020","journal-title":"Ann Clin Transl Neurol"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-215541","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:05:18Z","timestamp":1777370718000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-215541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,22]]},"references-count":48,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.3233\/jad-215541","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,22]]}}}