{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T13:11:34Z","timestamp":1780665094168,"version":"3.54.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background and objectives<\/jats:title>\n                    <jats:p>\n                      Fragile X\u2013associated tremor\/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects carriers of the\n                      <jats:italic>FMR1<\/jats:italic>\n                      premutation (55\u2013200 CGG repeats). It is characterized by motor and cognitive impairments. However, the mechanisms underlying individual susceptibility to FXTAS among carriers remain poorly understood. Emerging evidence suggests that neuroinflammation and glymphatic dysfunction may interact and play key roles in the pathological cascade leading to neurodegeneration. This study aimed to investigate potential glymphatic and\/or inflammatory dysfunction in\n                      <jats:italic>FMR1<\/jats:italic>\n                      premutation carriers with FXTAS using the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, as well as gene expression and functional enrichment analyses in individuals with FXTAS versus controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed the DTI-ALPS index in 14 participants with FXTAS and 25 age- and sex-matched controls, and assessed the expression and pathway dysregulation of genes related to neuroinflammation and glymphatic function using Reactome analysis in postmortem brain tissue from 3 individuals with FXTAS and 12 controls and skin fibroblasts from 6 individuals with FXTAS and 3 controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The DTI-ALPS index was significantly lower in individuals with FXTAS compared to controls in the right but not left hemisphere (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.0051) and globally in both hemispheres (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.0473). There was no correlation between lower DTI-ALPS index and increasing CGG repeat length but a trend was observed in males. Reactome analysis revealed downregulation of aquaporin-mediated transport in brain tissue and fibroblasts, upregulation of multiple immune-related and inflammatory pathways, predominantly in brain tissue, and increased circadian-related pathway activity in fibroblasts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our findings point at glymphatic system dysfunction and neuroinflammation in FXTAS pathophysiology, as evidenced by\n                      <jats:italic>in vivo<\/jats:italic>\n                      DTI-ALPS metrics and gene pathway dysregulation and expression in fibroblasts and in postmortem FXTAS brains.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2026.1856101","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:20:53Z","timestamp":1779949253000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Glymphatic dysfunction and neuroinflammation in FXTAS: evidence from DTI-ALPS and gene expression analysis"],"prefix":"10.3389","volume":"19","author":[{"given":"Andrea","family":"Elias-Mas","sequence":"first","affiliation":[{"name":"Radiology Department, Hospital Universitari M\u00fatua Terrassa, (HUMT)","place":["Terrassa, Spain"]},{"name":"Institute for Research and Innovation Parc Taul\u00ed (I3PT)","place":["Sabadell, Spain"]},{"name":"Genetics Doctorate Program, Universitat de Barcelona (UB)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther Granell","family":"Moreno","sequence":"additional","affiliation":[{"name":"Radiology Department, Hospital de Santa Creu i Sant Pau","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e8lia Painous","family":"Mart\u00ed","sequence":"additional","affiliation":[{"name":"Unitat de Parkinson i altres Trastorns del Moviment, Servei de Neurologia, Hospital Cl\u00ednic de Barcelona, FRCB-IDIBAPS, Institut de Neurosci\u00e8ncies, CIBERNED, ISCIII, ERN-RND, UBNeuro","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Rubio-Roy","sequence":"additional","affiliation":[{"name":"Institute for Research and Innovation Parc Taul\u00ed (I3PT)","place":["Sabadell, Spain"]},{"name":"Department of Neurology, Parc Taul\u00ed Hospital Universitari","place":["Sabadell, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Aguado-Gracia","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry and Psychology, Hospital Clinic of Barcelona","place":["Barcelona, Spain"]},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Mu\u00f1oz-Moreno","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Hinojosa","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u00f1igo","family":"Herrero","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabel","family":"Alvarez-Mora","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)","place":["Barcelona, Spain"]},{"name":"Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona","place":["Barcelona, Spain"]},{"name":"CIBER of Rare Diseases (CIBERER), Instituto de Salud Carlos III","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randi","family":"Hagerman","sequence":"additional","affiliation":[{"name":"MIND Institute, University of California Davis","place":["Sacramento, CA, United States"]},{"name":"Department of Pediatrics, University of California Davis, School of Medicine","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California Davis, School of Medicine","place":["Sacramento, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idoia","family":"Zaro","sequence":"additional","affiliation":[{"name":"Unitat de Parkinson i altres Trastorns del Moviment, Servei de Neurologia, Hospital Cl\u00ednic de Barcelona, FRCB-IDIBAPS, Institut de Neurosci\u00e8ncies, CIBERNED, ISCIII, ERN-RND, UBNeuro","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia Gonz\u00e1lez","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Radiology Department, Hospital Cl\u00ednic de Barcelona","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy","family":"Krupinski","sequence":"additional","affiliation":[{"name":"Department of Neurology, F.Ass. 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