{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:38:14Z","timestamp":1786441094437,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,10]]},"group-title":"Neurology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["P41EB029460"],"award-info":[{"award-number":["P41EB029460"]}],"id":[{"id":"https:\/\/ror.org\/00372qc85","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1AG087306-01"],"award-info":[{"award-number":["RF1AG087306-01"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100029129","name":"Fishman Family Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100029129","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Paramagnetic rim lesions are a subset of focal white matter lesions specific to multiple sclerosis that are chronically inflamed and are associated with increased tissue injury, brain atrophy, and clinical disability. The molecular mechanisms linking paramagnetic rim lesions to these progressive biological outcomes remain unclear. Glutamatergic dysregulation has been hypothesized as a mechanism of multiple sclerosis progression potentially via excitotoxicity, but lesion-specific involvement is unknown. Here, 7T MRI was used to investigate glutamate-related metabolic alterations in paramagnetic rim lesions. Glutamate-weighted chemical exchange saturation transfer, together with T\n                  <jats:sub>1<\/jats:sub>\n                  mapping and quantitative susceptibility mapping, was evaluated across paramagnetic rim lesions, non-paramagnetic rim lesions, and normal-appearing tissues in participants with multiple sclerosis (n=20) and healthy controls (n=11). Glutamate-weighted chemical exchange saturation transfer contrast was significantly higher in paramagnetic rim lesions compared to non-paramagnetic rim lesions (+10.7%) and normal-appearing white matter (+13%), while no differences were observed in normal-appearing tissue between multiple sclerosis and healthy controls. Additionally, reduced glutamate-weighted chemical exchange saturation transfer contrast in normal-appearing tissues was associated with worse motor and dexterity performance, linking observed metabolic abnormalities to clinical disability. These results identify a distinct metabolic phenotype of paramagnetic rim lesions marked by elevated glutamate-weighted signal consistent with localized excitotoxic stress. This work also implicates lesion-specific glutamatergic dysregulation in paramagnetic rim lesion-related neurodegeneration and demonstrates the potential of metabolic MRI to probe pathogenic mechanisms in multiple sclerosis.\n                <\/jats:p>","DOI":"10.64898\/2026.08.06.26359875","type":"posted-content","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:35:17Z","timestamp":1786368917000},"source":"Crossref","is-referenced-by-count":0,"title":["Altered Glutamate Homeostasis in Paramagnetic Rim Lesions of Patients with Multiple Sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3566-4010","authenticated-orcid":false,"given":"Paul S.","family":"Jacobs","sequence":"first","affiliation":[{"name":"Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Spangler","sequence":"additional","affiliation":[{"name":"Penn Statistics in Imaging and Visualization Endeavor (PennSIVE), Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikka","family":"Bakhtiar","sequence":"additional","affiliation":[{"name":"Penn Statistics in Imaging and Visualization Endeavor (PennSIVE), Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Elkady","sequence":"additional","affiliation":[{"name":"McConnell Bain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, QC, Canada"},{"name":"Department of Biomedical Engineering, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil E.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshuman","family":"Swain","sequence":"additional","affiliation":[{"name":"Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Horwath","sequence":"additional","affiliation":[{"name":"Penn Statistics in Imaging and Visualization Endeavor (PennSIVE), Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina M.","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Division of Multiple Sclerosis and Related Disorders, Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Center of Neuroinflammation and Experimental Therapeutics, Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell T.","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Penn Statistics in Imaging and Visualization Endeavor (PennSIVE), Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Center for Artificial Intelligence and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Thebault","sequence":"additional","affiliation":[{"name":"Division of Multiple Sclerosis and Related Disorders, Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Center of Neuroinflammation and Experimental Therapeutics, Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7179-0335","authenticated-orcid":false,"given":"Amit","family":"Bar-Or","sequence":"additional","affiliation":[{"name":"Division of Multiple Sclerosis and Related Disorders, Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Center of Neuroinflammation and Experimental Therapeutics, Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Detre","sequence":"additional","affiliation":[{"name":"Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Rudko","sequence":"additional","affiliation":[{"name":"McConnell Bain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, QC, Canada"},{"name":"Department of Biomedical Engineering, McGill University, Montreal, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew K.","family":"Schindler","sequence":"additional","affiliation":[{"name":"Division of 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