{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T03:19:43Z","timestamp":1789960783459,"version":"4.0.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Frontal lobe structures decline faster than most other brain regions in older adults. Age-related change in the frontal lobe is associated with poorer executive function (e.g., working memory, switching\/set-shifting, and inhibitory control). The effects and presence of frontal lobe white matter hyperintensities (WMH) on executive function in normal aging is relatively unknown. The current study assessed relationships between region-specific frontal WMH load and cognitive performance in healthy older adults using three executive function tasks from the NIH Toolbox (NIHTB) Cognition Battery. A cohort of 279 healthy older adults ages 65\u201388 completed NIHTB and 3T T1-weighted and FLAIR MRI. Lesion Segmentation Toolbox quantified WMH volume and generated lesion probability maps. Individual lesion maps were registered to the Desikan-Killiany atlas in FreeSurfer 6.0 to define regions of interest (ROI). Independent linear regressions assessed relationships between executive function performance and region-specific WMH in frontal lobe ROIs. All models included age, sex, education, estimated total intracranial volume, multi-site scanner differences, and cardiovascular disease risk using Framingham criteria as covariates. Poorer set-shifting performance was associated with greater WMH load in three frontal ROIs including bilateral superior frontal (left \u03b2 = \u22120.18, FDR-\n                    <jats:italic>p<\/jats:italic>\n                    = 0.02; right \u03b2 = \u22120.20, FDR-\n                    <jats:italic>p<\/jats:italic>\n                    = 0.01) and right medial orbitofrontal (\u03b2 = \u22120.17, FDR-\n                    <jats:italic>p<\/jats:italic>\n                    = 0.02). Poorer inhibitory performance associated with higher WMH load in one frontal ROI, the right superior frontal (right \u03b2 = \u22120.21, FDR-\n                    <jats:italic>p<\/jats:italic>\n                    = 0.01). There were no significant associations between working memory and WMH in frontal ROIs. Our study demonstrates that location and pattern of frontal WMH may be important to assess when examining age-related differences in cognitive functions involving switching\/set-shifting and inhibition. On the other hand, working memory performance was not related to presence of frontal WMH in this sample. These data suggest that WMH may contribute selectively to age-related declines in executive function. Findings emerged beyond predictors known to be associated with WMH presence, including age and cardiovascular disease risk. The spread of WMH within the frontal lobes may play a key role in the neuropsychological profile of cognitive aging. Further research should explore whether early intervention on modifiable vascular factors or cognitive interventions targeted for executive abilities may help mitigate the effect of frontal WMH on executive function.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2021.672535","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T03:48:35Z","timestamp":1624852115000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Frontal White Matter Hyperintensities and Executive Functioning Performance in Older Adults"],"prefix":"10.3389","volume":"13","author":[{"given":"Emanuel M.","family":"Boutzoukas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"O'Shea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Albizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole D.","family":"Evangelista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna K.","family":"Hausman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N.","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Van Etten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradyumna K.","family":"Bharadwaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha G.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Porges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Hishaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T.","family":"DeKosky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel S.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Marsiske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene E.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Woods","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.trci.2019.02.001","article-title":"White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): knowledge gaps and opportunities","volume":"5","author":"Alber","year":"2019","journal-title":"Alzheimer's Dementia Transl. Res. Clin. Intervent."},{"key":"B2","doi-asserted-by":"publisher","first-page":"159","DOI":"10.3389\/fnagi.2014.00159","article-title":"Interactive effects of vascular risk burden and advanced age on cerebral blood flow","volume":"6","author":"Bangen","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1097\/WAD.0000000000000215","article-title":"Baseline white matter hyperintensities and hippocampal volume are associated with conversion from normal cognition to mild cognitive impairment in the framingham offspring study","volume":"32","author":"Bangen","year":"2018","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"B4","doi-asserted-by":"publisher","first-page":"P1148","DOI":"10.1016\/j.jalz.2019.06.3508","article-title":"P3-473: regional white matter hyperintensity volume distinguishes among mild cognitive impairment subtypes and predicts decline in daily functioning","volume":"15","author":"Bangen","year":"2019","journal-title":"Alzheimer's Dementia"},{"key":"B5","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.neurobiolaging.2013.10.072","article-title":"Regional white matter hyperintensities: aging, Alzheimer's disease risk, and cognitive function","volume":"35","author":"Birdsill","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"B6","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/1471-2377-12-126","article-title":"The association between cognitive function and white matter lesion location in older adults: a systematic review","volume":"12","author":"Bolandzadeh","year":"2012","journal-title":"BMC Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.jalz.2014.07.155","article-title":"APOE \u03b54 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role?","volume":"10","author":"Brickman","year":"2014","journal-title":"Alzheimer's Dementia"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1016\/j.neurobiolaging.2009.10.013","article-title":"White matter hyperintensities and cognition: testing the reserve hypothesis","volume":"32","author":"Brickman","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2012","DOI":"10.1007\/s11682-019-00151-2","article-title":"Patterns of white matter hyperintensities associated with cognition in middle-aged cognitively healthy individuals","volume":"14","author":"Brugulat-Serrat","year":"2020","journal-title":"Brain Imag. Behav."},{"key":"B10","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.neurobiolaging.2010.01.021","article-title":"MRI predictors of cognitive change in a diverse and carefully characterized elderly population","volume":"33","author":"Carmichael","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"B11","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1002\/hbm.20118","article-title":"Exploring the unity and diversity of the neural substrates of executive functioning","volume":"25","author":"Collette","year":"2005","journal-title":"Hum. Brain Map."},{"key":"B12","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1080\/13803395.2014.985636","article-title":"Posterior brain white matter abnormalities in older adults with probable mild cognitive impairment","volume":"37","author":"Cooley","year":"2015","journal-title":"Null"},{"key":"B13","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.neurobiolaging.2018.12.004","article-title":"White matter in different regions evolves differently during progression to dementia","volume":"76","author":"Dadar","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"B14","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1006\/nimg.1998.0395","article-title":"Cortical surface-based analysis: I. Segmentation and surface reconstruction","volume":"9","author":"Dale","year":"1999","journal-title":"NeuroImage"},{"key":"B15","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.neuroimage.2017.09.011","article-title":"Performance of five research-domain automated WM lesion segmentation methods in a multi-center MS study","volume":"163","author":"de Sitter","year":"2017","journal-title":"NeuroImage"},{"key":"B16","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1212\/WNL.0b013e318227b227","article-title":"Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline","volume":"77","author":"Debette","year":"2011","journal-title":"Neurology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.neuroimage.2006.01.021","article-title":"An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest","volume":"31","author":"Desikan","year":"2006","journal-title":"NeuroImage"},{"key":"B18","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1159\/000049151","article-title":"Cognition and white matter lesions","volume":"13","author":"Desmond","year":"2002","journal-title":"Cerebrovasc. Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1002529","DOI":"10.1371\/journal.pmed.1002529","article-title":"Cerebral white matter disease and functional decline in older adults from the Northern Manhattan Study: a longitudinal cohort study","volume":"15","author":"Dhamoon","year":"2018","journal-title":"PLoS Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.nicl.2016.11.020","article-title":"MRI FLAIR lesion segmentation in multiple sclerosis: does automated segmentation hold up with manual annotation?","volume":"13","author":"Egger","year":"2017","journal-title":"NeuroImage Clin."},{"key":"B21","doi-asserted-by":"publisher","first-page":"11050","DOI":"10.1073\/pnas.200033797","article-title":"Measuring the thickness of the human cerebral cortex from magnetic resonance images","volume":"97","author":"Fischl","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B22","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1006\/nimg.1998.0396","article-title":"Cortical surface-based analysis: II: inflation, flattening, and a surface-based coordinate system","volume":"9","author":"Fischl","year":"1999","journal-title":"NeuroImage"},{"key":"B23","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1093\/cercor\/bhg087","article-title":"Automatically parcellating the human cerebral cortex","volume":"14","author":"Fischl","year":"2004","journal-title":"Cereb. Cortex"},{"key":"B24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.neuroimage.2009.06.060","article-title":"Accurate and robust brain image alignment using boundary-based registration","volume":"48","author":"Greve","year":"2009","journal-title":"NeuroImage"},{"key":"B25","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/978-1-4419-9863-7_1215","article-title":"Benjamini\u2013Hochberg method","volume-title":"Encyclopedia of Systems Biology","author":"Haynes","year":"2013"},{"key":"B26","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1017\/S1355617714000241","article-title":"Reliability and validity of composite scores from the NIH toolbox cognition battery in adults","volume":"20","author":"Heaton","year":"2014","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"B27","doi-asserted-by":"publisher","first-page":"373","DOI":"10.3389\/fnagi.2017.00373","article-title":"Executive functions in healthy older adults are differentially related to macro- and microstructural white matter characteristics of the cerebral lobes","volume":"9","author":"Hirsiger","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1006\/nimg.2002.1132","article-title":"Improved optimization for the robust and accurate linear registration and motion correction of brain images","volume":"17","author":"Jenkinson","year":"2002","journal-title":"NeuroImage"},{"key":"B29","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/S1361-8415(01)00036-6","article-title":"A global optimisation method for robust affine registration of brain images","volume":"5","author":"Jenkinson","year":"2001","journal-title":"Med. Image Anal."},{"key":"B30","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.nicl.2018.03.035","article-title":"The association of regional white matter lesions with cognition in a community-based cohort of older individuals","volume":"19","author":"Jiang","year":"2018","journal-title":"NeuroImage Clin."},{"key":"B31","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1016\/j.neuropsychologia.2009.01.001","article-title":"Aging white matter and cognition: differential effects of regional variations in diffusion properties on memory, executive functions, and speed","volume":"47","author":"Kennedy","year":"2009","journal-title":"Neuropsychologia"},{"key":"B32","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1037\/a0030548","article-title":"Formulation of the age\u2013education index: measuring age and education effects in neuropsychological performance","volume":"25","author":"Lam","year":"2013","journal-title":"Psychol. Assess."},{"key":"B33","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1177\/0271678X17740501","article-title":"Lesion location matters: the relationships between white matter hyperintensities on cognition in the healthy elderly","volume":"39","author":"Lampe","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B34","volume-title":"Neuropsychological Assessment","author":"Lezak","year":"2004"},{"key":"B35","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.arr.2016.11.006","article-title":"Aging of cerebral white matter","volume":"34","author":"Liu","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3389\/fnhum.2012.00056","article-title":"Episodic memory function is associated with multiple measures of white matter integrity in cognitive aging","volume":"6","author":"Lockhart","year":"2012","journal-title":"Front. Hum. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1017\/S1355617712000227","article-title":"White matter predictors of cognitive functioning in older adults","volume":"18","author":"Meier","year":"2012","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"B38","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1006\/cogp.1999.0734","article-title":"The unity and diversity of executive functions and their contributions to complex \u201cfrontal lobe\u201d tasks: a latent variable analysis","volume":"41","author":"Miyake","year":"2000","journal-title":"Cogn. Psychol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ijcha.2018.04.006","article-title":"Cardiovascular disease and brain health: focus on white matter hyperintensities","volume":"19","author":"Moroni","year":"2018","journal-title":"IJC Heart Vasculat."},{"key":"B40","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1055\/s-0035-1555115","article-title":"The impact of age on cognition","volume":"36","author":"Murman","year":"2015","journal-title":"Semin. Hear."},{"key":"B41","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/nrneurol.2015.10","article-title":"White matter hyperintensities, cognitive impairment and dementia: an update","volume":"11","author":"Prins","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"B42","first-page":"1","article-title":"Aging of the brain and its impact on cognitive performance: integration of structural and functional findings","volume-title":"The Handbook of Aging and Cognition, 2nd Edn","author":"Raz","year":"2000"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1093\/cercor\/bhi044","article-title":"Regional brain changes in aging healthy adults: general trends, individual differences and modifiers","volume":"15","author":"Raz","year":"2005","journal-title":"Cereb. Cortex"},{"key":"B44","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.mri.2020.11.008","article-title":"Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: a European multi-site 3T study","volume":"76","author":"Ribaldi","year":"2021","journal-title":"Magnet. Resonanc. Imag."},{"key":"B45","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.neurobiolaging.2017.12.006","article-title":"The effect of white matter hyperintensities on cognition is mediated by cortical atrophy","volume":"64","author":"Rizvi","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"B46","doi-asserted-by":"publisher","first-page":"3774","DOI":"10.1016\/j.neuroimage.2011.11.032","article-title":"An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis","volume":"59","author":"Schmidt","year":"2012","journal-title":"NeuroImage"},{"key":"B47","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1212\/01.wnl.0000316799.86917.37","article-title":"Impact of white matter hyperintensity volume progression on rate of cognitive and motor decline","volume":"71","author":"Silbert","year":"2008","journal-title":"Neurology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1212\/WNL.0b013e318217e7c8","article-title":"Correlations between MRI white matter lesion location and executive function and episodic memory","volume":"76","author":"Smith","year":"2011","journal-title":"Neurology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.neurobiolaging.2004.12.008","article-title":"Cerebral changes on MRI and cognitive function: the CASCADE study","volume":"27","author":"S\u00f6derlund","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1016\/j.neuropsychologia.2004.02.009","article-title":"Memory and executive function in older adults: relationships with temporal and prefrontal gray matter volumes and white matter hyperintensities","volume":"42","author":"Van Petten","year":"2004","journal-title":"Neuropsychologia"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.3233\/JAD-180285","article-title":"Subjective cognitive decline is associated with greater white matter hyperintensity volume","volume":"66","author":"van Rooden","year":"2018","journal-title":"J. Alzheimer's Dis."},{"key":"B52","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1111\/j.1532-5415.2009.02699.x","article-title":"White matter hyperintensities predict functional decline in voiding, mobility, and cognition in older adults","volume":"58","author":"Wakefield","year":"2010","journal-title":"J. Am. Geriatr. Soc."},{"key":"B53","doi-asserted-by":"publisher","first-page":"S54","DOI":"10.1212\/WNL.0b013e3182872ded","article-title":"Cognition assessment using the NIH Toolbox","volume":"80","author":"Weintraub","year":"2013","journal-title":"Neurology"},{"key":"B54","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.cct.2017.11.017","article-title":"Augmenting cognitive training in older adults (The ACT Study): design and methods of a Phase III tDCS and cognitive training trial","volume":"65","author":"Woods","year":"2018","journal-title":"Contemp. Clin. Trials"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2021.672535\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T03:48:39Z","timestamp":1624852119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2021.672535\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,28]]},"references-count":54,"alternative-id":["10.3389\/fnagi.2021.672535"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2021.672535","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,28]]},"article-number":"672535"}}