{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T03:19:38Z","timestamp":1789960778139,"version":"4.0.1"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Agence r\u00e9gionale de sant\u00e9 Auvergne-Rh\u00f4ne-Alpes"},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program","award":["667696"],"award-info":[{"award-number":["667696"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program","award":["667696"],"award-info":[{"award-number":["667696"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-23371-7","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T10:48:39Z","timestamp":1762166919000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Heterogeneity of white matter hyperintensities in Alzheimer\u2019s disease captured by multimodal neuroimaging"],"prefix":"10.1038","volume":"15","author":[{"given":"Antoine","family":"Garnier-Crussard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Landeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Mezenge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Gonneaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Roquet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Cotton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebl","family":"Chetelat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"23371_CR1","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/nrneurol.2015.10","volume":"11","author":"ND Prins","year":"2015","unstructured":"Prins, N. D. & Scheltens, P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat. Rev. Neurol. 11, 157\u2013165 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"23371_CR2","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1186\/s13195-020-00669-4","volume":"12","author":"A Garnier-Crussard","year":"2020","unstructured":"Garnier-Crussard, A. et al. White matter hyperintensities across the adult lifespan: relation to age, A\u03b2 load, and cognition. Alzheimers Res. Ther. 12, 127 (2020).","journal-title":"Alzheimers Res. Ther."},{"key":"23371_CR3","doi-asserted-by":"publisher","first-page":"e001140","DOI":"10.1161\/JAHA.114.001140","volume":"4","author":"JM Wardlaw","year":"2015","unstructured":"Wardlaw, J. M., Vald\u00e9s Hern\u00e1ndez, M. C. & Mu\u00f1oz-Maniega, S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J. Am. Heart Assoc. 4, e001140 (2015).","journal-title":"J. Am. Heart Assoc."},{"key":"23371_CR4","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s00401-017-1738-2","volume":"134","author":"KE McAleese","year":"2017","unstructured":"McAleese, K. E. et al. Parietal white matter lesions in alzheimer\u2019s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol. 134, 459\u2013473 (2017).","journal-title":"Acta Neuropathol."},{"key":"23371_CR5","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1007\/s00401-021-02376-2","volume":"142","author":"KE McAleese","year":"2021","unstructured":"McAleese, K. E. et al. Frontal white matter lesions in alzheimer\u2019s disease are associated with both small vessel disease and AD-associated cortical pathology. Acta Neuropathol. 142, 937\u2013950 (2021).","journal-title":"Acta Neuropathol."},{"key":"23371_CR6","doi-asserted-by":"publisher","first-page":"3738","DOI":"10.1002\/alz.13057","volume":"19","author":"A Garnier-Crussard","year":"2023","unstructured":"Garnier-Crussard, A., Cotton, F., Krolak-Salmon, P. & Ch\u00e9telat, G. White matter hyperintensities in alzheimer\u2019s disease: beyond vascular contribution. Alzheimers Dement. 19, 3738\u20133748 (2023).","journal-title":"Alzheimers Dement."},{"key":"23371_CR7","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1161\/STROKEAHA.120.033225","volume":"52","author":"G Kuchcinski","year":"2021","unstructured":"Kuchcinski, G. & Wright, C. B. Show me your white Matter, I will tell you who you are \u2026. Stroke 52, 631\u2013633 (2021).","journal-title":"Stroke"},{"key":"23371_CR8","doi-asserted-by":"publisher","first-page":"4260","DOI":"10.1002\/alz.13371","volume":"19","author":"AM Brickman","year":"2023","unstructured":"Brickman, A. M. & Rizvi, B. White matter hyperintensities and alzheimer\u2019s disease: an alternative view of an alternative hypothesis. Alzheimers Dement. 19, 4260\u20134261 (2023).","journal-title":"Alzheimers Dement."},{"key":"23371_CR9","doi-asserted-by":"publisher","first-page":"4262","DOI":"10.1002\/alz.13372","volume":"19","author":"A Garnier-Crussard","year":"2023","unstructured":"Garnier-Crussard, A. & Ch\u00e9telat, G. White matter hyperintensities in alzheimer\u2019s disease: beyond (but not instead of) the vascular contribution. Alzheimers Dement. 19, 4262\u20134263 (2023).","journal-title":"Alzheimers Dement."},{"key":"23371_CR10","doi-asserted-by":"publisher","first-page":"fcac150","DOI":"10.1093\/braincomms\/fcac150","volume":"4","author":"L Lorenzini","year":"2022","unstructured":"Lorenzini, L. et al. Regional associations of white matter hyperintensities and early cortical amyloid pathology. Brain Commun. 4, fcac150 (2022).","journal-title":"Brain Commun."},{"key":"23371_CR11","doi-asserted-by":"publisher","first-page":"4414","DOI":"10.1093\/brain\/awad188","volume":"146","author":"H Hampel","year":"2023","unstructured":"Hampel, H. et al. Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain 146, 4414\u20134424 (2023).","journal-title":"Brain"},{"key":"23371_CR12","doi-asserted-by":"publisher","first-page":"362","DOI":"10.14283\/jpad.2023.30","volume":"10","author":"J Cummings","year":"2023","unstructured":"Cummings, J. et al. Lecanemab: appropriate use recommendations. J. Prev. Alz Dis. 10, 362\u2013377 (2023).","journal-title":"J. Prev. Alz Dis."},{"key":"23371_CR13","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1093\/jnen\/nlad026","volume":"82","author":"TG Beach","year":"2023","unstructured":"Beach, T. G. et al. Cerebral white matter rarefaction has both neurodegenerative and vascular causes and May primarily be a distal axonopathy. J. Neuropathol. Exp. Neurol. 82, 457\u2013466 (2023).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"23371_CR14","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1212\/WNL.0b013e3182a43e45","volume":"81","author":"D Erten-Lyons","year":"2013","unstructured":"Erten-Lyons, D. et al. Neuropathologic basis of white matter hyperintensity accumulation with advanced age. Neurology 81, 977\u2013983 (2013).","journal-title":"Neurology"},{"key":"23371_CR15","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/s00401-011-0851-x","volume":"122","author":"R Schmidt","year":"2011","unstructured":"Schmidt, R. et al. Heterogeneity in age-related white matter changes. Acta Neuropathol. 122, 171\u2013185 (2011).","journal-title":"Acta Neuropathol."},{"key":"23371_CR16","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1007\/s00259-021-05493-y","volume":"49","author":"A Moscoso","year":"2021","unstructured":"Moscoso, A. et al. 18F-florbetapir PET as a marker of Myelin integrity across the alzheimer\u2019s disease spectrum. Eur. J. Nucl. Med. Mol. Imaging. 49, 1242\u20131253 (2021).","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"23371_CR17","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1177\/0271678X231152001","volume":"43","author":"J Ottoy","year":"2023","unstructured":"Ottoy, J. et al. Amyloid-PET of the white matter: relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease. J. Cereb. Blood Flow. Metab. 43, 921\u2013936 (2023).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"23371_CR18","doi-asserted-by":"publisher","first-page":"7228","DOI":"10.1038\/s41598-024-57287-5","volume":"14","author":"SN Lee","year":"2024","unstructured":"Lee, S. N., Woo, S. H., Lee, E. J., Kim, K. K. & Kim, H. R. Association between T1w\/T2w ratio in white matter and cognitive function in alzheimer\u2019s disease. Sci. Rep. 14, 7228 (2024).","journal-title":"Sci. Rep."},{"key":"23371_CR19","doi-asserted-by":"publisher","first-page":"fcad279","DOI":"10.1093\/braincomms\/fcad279","volume":"5","author":"O Parent","year":"2023","unstructured":"Parent, O. et al. Assessment of white matter hyperintensity severity using multimodal magnetic resonance imaging. Brain Commun. 5, fcad279 (2023).","journal-title":"Brain Commun."},{"key":"23371_CR20","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1177\/0271678X20957604","volume":"41","author":"L P\u00e5lhaugen","year":"2021","unstructured":"P\u00e5lhaugen, L. et al. Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns. J. Cereb. Blood Flow. Metab. 41, 1162\u20131174 (2021).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"23371_CR21","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1002\/alz.12410","volume":"18","author":"A Garnier-Crussard","year":"2022","unstructured":"Garnier-Crussard, A. et al. White matter hyperintensity topography in alzheimer\u2019s disease and links to cognition. Alzheimers Dement. 18, 422\u2013433 (2022).","journal-title":"Alzheimers Dement."},{"key":"23371_CR22","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1161\/STROKEAHA.120.031641","volume":"52","author":"Jung Keun-Hwa","year":"2021","unstructured":"Jung Keun-Hwa et al. Heterogeneity of cerebral white matter lesions and clinical correlates in older adults. Stroke 52, 620\u2013630 (2021).","journal-title":"Stroke"},{"key":"23371_CR23","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/S1474-4422(23)00131-X","volume":"22","author":"M Duering","year":"2023","unstructured":"Duering, M. et al. Neuroimaging standards for research into small vessel disease\u2014advances since 2013. Lancet Neurol. 22, 602\u2013618 (2023).","journal-title":"Lancet Neurol."},{"key":"23371_CR24","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/S1474-4422(13)70124-8","volume":"12","author":"JM Wardlaw","year":"2013","unstructured":"Wardlaw, J. M. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822\u2013838 (2013).","journal-title":"Lancet Neurol."},{"key":"23371_CR25","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1177\/0271678X18761438","volume":"39","author":"Y Jiaerken","year":"2019","unstructured":"Jiaerken, Y. et al. Microstructural and metabolic changes in the longitudinal progression of white matter hyperintensities. J. Cereb. Blood Flow. Metab. 39, 1613\u20131622 (2019).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"23371_CR26","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.neurobiolaging.2018.12.004","volume":"76","author":"M Dadar","year":"2019","unstructured":"Dadar, M., Maranzano, J., Ducharme, S. & Collins, D. L. White matter in different regions evolves differently during progression to dementia. Neurobiol. Aging. 76, 71\u201379 (2019).","journal-title":"Neurobiol. Aging"},{"key":"23371_CR27","doi-asserted-by":"publisher","first-page":"102616","DOI":"10.1016\/j.nicl.2021.102616","volume":"30","author":"L Melazzini","year":"2021","unstructured":"Melazzini, L. et al. White matter hyperintensities classified according to intensity and Spatial location reveal specific associations with cognitive performance. Neuroimage Clin. 30, 102616 (2021).","journal-title":"Neuroimage Clin."},{"key":"23371_CR28","first-page":"18","volume":"53","author":"N Nowaczyk","year":"2019","unstructured":"Nowaczyk, N. et al. Spatial distribution of white matter degenerative lesions and cognitive dysfunction in relapsing-remitting multiple sclerosis patients. Neurol. Neurochir. Pol. 53, 18\u201325 (2019).","journal-title":"Neurol. Neurochir. Pol."},{"key":"23371_CR29","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1093\/brain\/awn265","volume":"131","author":"AA Gouw","year":"2008","unstructured":"Gouw, A. A. et al. Heterogeneity of white matter hyperintensities in alzheimer\u2019s disease: post-mortem quantitative MRI and neuropathology. Brain 131, 3286\u20133298 (2008).","journal-title":"Brain"},{"key":"23371_CR30","doi-asserted-by":"crossref","unstructured":"Kalheim, L. F. et al. Amyloid dysmetabolism relates to reduced glucose uptake in white matter hyperintensities. Front Neurol 7\u00a0(2016).","DOI":"10.3389\/fneur.2016.00209"},{"key":"23371_CR31","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13195-020-00759-3","volume":"13","author":"M Gaubert","year":"2021","unstructured":"Gaubert, M. et al. Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of alzheimer\u2019s disease. Alzheimers Res. Ther. 13, 29 (2021).","journal-title":"Alzheimers Res. Ther."},{"key":"23371_CR32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neurobiolaging.2014.07.019","volume":"36","author":"AM Brickman","year":"2015","unstructured":"Brickman, A. M. et al. Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts alzheimer\u2019s disease incidence. Neurobiol. Aging. 36, 27\u201332 (2015).","journal-title":"Neurobiol. Aging"},{"key":"23371_CR33","doi-asserted-by":"crossref","unstructured":"Gaubert, M. et al. Performance evaluation of automated white matter hyperintensity segmentation algorithms in a multicenter cohort on cognitive impairment and dementia. Front Psychiatry 13\u00a0(2023).","DOI":"10.3389\/fpsyt.2022.1010273"},{"key":"23371_CR34","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1007\/s00259-021-05195-5","volume":"48","author":"A Moscoso","year":"2021","unstructured":"Moscoso, A., Grothe, M. J. & Sch\u00f6ll, M. Alzheimer\u2019s disease neuroimaging Initiative. Reduced [18F]flortaucipir retention in white matter hyperintensities compared to normal-appearing white matter. Eur. J. Nucl. Med. Mol. Imaging. 48, 2283\u20132294 (2021).","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"23371_CR35","doi-asserted-by":"publisher","first-page":"10402","DOI":"10.1523\/JNEUROSCI.0150-15.2015","volume":"35","author":"FL Besson","year":"2015","unstructured":"Besson, F. L. et al. Cognitive and brain profiles associated with current neuroimaging biomarkers of preclinical alzheimer\u2019s disease. J. Neurosci. 35, 10402\u201310411 (2015).","journal-title":"J. Neurosci."},{"key":"23371_CR36","doi-asserted-by":"publisher","first-page":"16265","DOI":"10.1523\/JNEUROSCI.2170-12.2012","volume":"32","author":"R La Joie","year":"2012","unstructured":"La Joie, R. et al. Region-Specific hierarchy between Atrophy, Hypometabolism, and \u03b2-Amyloid (A\u03b2) load in alzheimer\u2019s disease dementia. J. Neurosci. 32, 16265\u201316273 (2012).","journal-title":"J. Neurosci."},{"key":"23371_CR37","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1001\/archneur.58.12.1985","volume":"58","author":"RC Petersen","year":"2001","unstructured":"Petersen, R. C. et al. Current concepts in mild cognitive impairment. Arch. Neurol. 58, 1985 (2001).","journal-title":"Arch. Neurol."},{"key":"23371_CR38","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1212\/WNL.34.7.939","volume":"34","author":"G McKhann","year":"1984","unstructured":"McKhann, G. et al. Clinical diagnosis of alzheimer\u2019s disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on alzheimer\u2019s disease. Neurology 34, 939\u2013944 (1984).","journal-title":"Neurology"},{"key":"23371_CR39","unstructured":"Schmidt, P. Bayesian Inference for Structured Additive Regression Models for large-scale Problems with Applications To Medical Imaging (Ludwig-Maximilians-Universit\u00e4t, 2017)."},{"key":"23371_CR40","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1002\/hbm.10123","volume":"19","author":"A Hammers","year":"2003","unstructured":"Hammers, A. et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the Temporal lobe. Hum. Brain Mapp. 19, 224\u2013247 (2003).","journal-title":"Hum. Brain Mapp."},{"key":"23371_CR41","first-page":"142","volume":"11","author":"C Andr\u00e9","year":"2019","unstructured":"Andr\u00e9, C. et al. Brain and cognitive correlates of sleep fragmentation in elderly subjects with and without cognitive deficits. Alzheimers Dement. 11, 142\u2013150 (2019).","journal-title":"Alzheimers Dement."},{"key":"23371_CR42","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.jalz.2016.08.005","volume":"13","author":"CR Jack","year":"2017","unstructured":"Jack, C. R. et al. Defining imaging biomarker cut points for brain aging and alzheimer\u2019s disease. Alzheimers Dement. 13, 205\u2013216 (2017).","journal-title":"Alzheimers Dement."},{"key":"23371_CR43","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","volume":"12","author":"MF Folstein","year":"1975","unstructured":"Folstein, M. F., Folstein, S. E. & McHugh, P. R. Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr Res. 12, 189\u2013198 (1975).","journal-title":"J. Psychiatr Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23371-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23371-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23371-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T23:03:00Z","timestamp":1762210980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23371-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["23371"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-23371-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,3]]},"assertion":[{"value":"23 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"No disclosure to report.Independent of this work, A.G.-C. is an unpaid sub-investigator or local principal investigator in NCT04867616 (UCB Pharma), NCT04241068 (Biogen), NCT05310071 (Biogen), NCT03446001 (TauRx Therapeutics), NCT03444870 (Roche), NCT04374253 (Roche), NCT04777396 (Novo Nordisk), NCT04777409 (Novo Nordisk), NCT04770220 (Alzheon), NCT05423522 (Medesis Pharma), NCT06079190 (GlaxoSmithKline).Independent of this work, F.C. has received consulting and lecturing fees, travel grants and unconditional research support from Alexion, Biogen, Bracco, Guerbet, Philips Medical imaging, Novartis, Telediag and Roche.Independent of this work, G.C. has received research support from the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement number 667696), Fondation d\u2019entreprise MMA des Entrepreneurs du Futur, Fondation Alzheimer, R\u00e9gion Normandie, Association France Alzheimer et maladies apparent\u00e9es, Fondation Vaincre Alzheimer, Fondation Recherche Alzheimer, Fondation Bettencourt Schueller and Fondation pour la Recherche M\u00e9dicale (all to Inserm), and personal fees from Fondation Alzheimer and Lilly.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38433"}}