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Seventy\u2010six people diagnosed with MS were scanned using a SIEMENS Prisma Fit 3T magnetic resonance imaging (MRI), employing both conventional (T1w and fluid\u2010attenuated inversion recovery) and advanced diffusion MRI sequences from which fractional anisotropy (FA) and microscopic FA (\u03bcFA) maps were generated. Using automated fiber quantification (AFQ), we assessed diffusion profiles across multiple white matter (WM) pathways to measure the sensitivity of anisotropy diffusion metrics in detecting localized tissue damage. In parallel, we analyzed structural brain connectivity in a specific patient cohort to fully grasp its relationships with cognitive and physical clinical outcomes. This evaluation comprehensively considered different patient categories, including cognitively preserved (CP), mild cognitive deficits (MCD), and cognitively impaired (CI) for cognitive assessment, as well as groups distinguished by physical impact: those with mild disability (Expanded Disability Status Scale [EDSS] &lt;=3) and those with moderate\u2013severe disability (EDSS &gt;3). In our initial objective, we employed Ridge regression to forecast the presence of focal MS lesions, comparing the performance of \u03bcFA and FA. \u03bcFA exhibited a stronger association with tissue damage and a higher predictive precision for focal MS lesions across the tracts, achieving an <jats:italic>R<\/jats:italic>\u2010squared value of .57, significantly outperforming the <jats:italic>R<\/jats:italic>\u2010squared value of .24 for FA (<jats:italic>p<\/jats:italic>\u2010value &lt;.001). In structural connectivity, \u03bcFA exhibited more pronounced differences than FA in response to alteration in both cognitive and physical clinical scores in terms of effect size and number of connections. Regarding cognitive groups, FA differences between CP and MCD groups were limited to 0.5% of connections, mainly around the thalamus, while \u03bcFA revealed changes in 2.5% of connections. In the CP and CI group comparison, which have noticeable cognitive differences, the disparity was 5.6% for FA values and 32.5% for \u03bcFA. Similarly, \u03bcFA outperformed FA in detecting WM changes between the MCD and CI groups, with 5% versus 0.3% of connections, respectively. When analyzing structural connectivity between physical disability groups, \u03bcFA still demonstrated superior performance over FA, disclosing a 2.1% difference in connectivity between regions closely associated with physical disability in MS. In contrast, FA spotted a few regions, comprising only 0.6% of total connections. In summary, \u03bcFA emerged as a more effective tool than FA in predicting MS lesions and identifying structural changes across patients with different degrees of cognitive and global disability, offering deeper insights into the complexities of MS\u2010related impairments.<\/jats:p>","DOI":"10.1002\/hbm.26706","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T07:30:54Z","timestamp":1718263854000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Microscopic fractional anisotropy outperforms multiple sclerosis lesion assessment and clinical outcome associations over standard fractional anisotropy tensor"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6409-1197","authenticated-orcid":false,"given":"F.","family":"Viv\u00f3","sequence":"first","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit Laboratory of Advanced Imaging in Neuroimmunological Diseases (ImaginEM), Hospital Clinic Barcelona Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona\u2010Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer and Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7973-2439","authenticated-orcid":false,"given":"E.","family":"Solana","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit Laboratory of Advanced Imaging in Neuroimmunological Diseases (ImaginEM), Hospital Clinic Barcelona Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona\u2010Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer and Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1953-2803","authenticated-orcid":false,"given":"A.","family":"Calvi","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit Laboratory of Advanced Imaging in Neuroimmunological Diseases (ImaginEM), Hospital Clinic Barcelona Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona\u2010Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer and Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2183-8094","authenticated-orcid":false,"given":"E.","family":"Lopez\u2010Soley","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit Laboratory of Advanced Imaging in Neuroimmunological Diseases (ImaginEM), Hospital Clinic Barcelona Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona\u2010Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer and Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3585-8141","authenticated-orcid":false,"given":"L. B.","family":"Reid","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Francisco  San Francisco California USA"},{"name":"Department of Radiology University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-5867","authenticated-orcid":false,"given":"S.","family":"Pascual\u2010Diaz","sequence":"additional","affiliation":[{"name":"Institute of Neurosciences, Department of Medicine, School of Medicine and Health Sciences University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Garrido","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Imaging Core Facility Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4060-5824","authenticated-orcid":false,"given":"L.","family":"Planas\u2010Tardido","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit Laboratory of Advanced Imaging in Neuroimmunological Diseases (ImaginEM), Hospital Clinic Barcelona Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona\u2010Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer and Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6984-1209","authenticated-orcid":false,"given":"J. 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