{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T14:04:27Z","timestamp":1782137067603,"version":"3.54.5"},"reference-count":47,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS107131"],"award-info":[{"award-number":["NS107131"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["HD 036071"],"award-info":[{"award-number":["HD 036071"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["NS107131"],"award-info":[{"award-number":["NS107131"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD 036071"],"award-info":[{"award-number":["HD 036071"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shriners Hospitals","award":["NS107131"],"award-info":[{"award-number":["NS107131"]}]},{"name":"Shriners Hospitals","award":["HD 036071"],"award-info":[{"award-number":["HD 036071"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fragile X-associated tremor\/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects older premutation carriers (55\u2013200 CGG repeats) of the fragile X gene. Despite the high prevalence of the FXTAS disorder, neuropathology studies of individuals affected by FXTAS are limited. We performed hematoxylin and eosin (H&amp;E) staining in the hippocampus of 26 FXTAS cases and analyzed the tissue microscopically. The major neuropathological characteristics were white matter disease, intranuclear inclusions in neurons and astrocytes, and neuron loss. Astrocytes contained more and larger inclusions than neurons. There was a negative correlation between age of death and CGG repeat length in cases over the age of 60. The number of astroglial inclusions (CA3 and dentate gyrus) and the number of CA3 neuronal inclusions increased with elevated CGG repeat length. In the two cases with a CGG repeat size less than 65, FXTAS intranuclear inclusions were not present in the hippocampus, while in the two cases with less than 70 (65\u201370) CGG repeat expansion, neurons and astrocytes with inclusions were occasionally identified in the CA1 sub-region. These findings add hippocampus neuropathology to the previously reported changes in other areas of the brain in FXTAS patients, with implications for understanding FXTAS pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms242417266","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T08:47:26Z","timestamp":1702025246000},"page":"17266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neurodegeneration of White and Gray Matter in the Hippocampus with FXTAS"],"prefix":"10.3390","volume":"24","author":[{"given":"Maryam","family":"Kargar","sequence":"first","affiliation":[{"name":"Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA"},{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-8448","authenticated-orcid":false,"given":"Randi J.","family":"Hagerman","sequence":"additional","affiliation":[{"name":"MIND Institute, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Mart\u00ednez-Cerde\u00f1o","sequence":"additional","affiliation":[{"name":"Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA"},{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"MIND Institute, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1097\/AOG.0b013e318163be0b","article-title":"Prevalence and instability of fragile X alleles: Implications for offering fragile X prenatal diagnosis","volume":"111","author":"Cronister","year":"2008","journal-title":"Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1126\/science.252.5009.1097","article-title":"Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome","volume":"252","author":"Rousseau","year":"1991","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1080\/13854046.2016.1202239","article-title":"Fragile X-associated Tremor\/Ataxia Syndrome: Phenotypic comparisons with other Movement Disorders","volume":"30","author":"Robertson","year":"2016","journal-title":"Clin. Neuropsychol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/(SICI)1097-4547(19980101)51:1<41::AID-JNR4>3.0.CO;2-L","article-title":"Overexpression of fragile X gene (FMR-1) transcripts increases cAMP production in neural cells","volume":"51","author":"Ciurlionis","year":"1998","journal-title":"J. Neurosci. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1086\/367713","article-title":"Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles","volume":"72","author":"Nolin","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s12311-016-0800-2","article-title":"Molecular Pathophysiology of Fragile X-Associated Tremor\/Ataxia Syndrome and Perspectives for Drug Development","volume":"15","author":"Tartaglia","year":"2016","journal-title":"Cerebellum"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/B978-0-444-63233-3.00025-7","article-title":"Chapter 25\u2014Fragile X syndrome and fragile X-associated tremor ataxia syndrome","volume":"Volume 147","author":"Hall","year":"2018","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Valor, L.M., Morales, J.C., Herv\u00e1s-Corpi\u00f3n, I., and Mar\u00edn, R. (2021). Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168368"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1399-0004.2011.01723.x","article-title":"CGG repeat in the FMR1 gene: Size matters","volume":"80","author":"Willemsen","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/ajmg.b.30910","article-title":"The FMR1 Gene and Fragile X-Associated Tremor\/Ataxia Syndrome","volume":"150B","author":"Brouwer","year":"2009","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.neuron.2013.03.026","article-title":"CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome","volume":"78","author":"Todd","year":"2013","journal-title":"Neuron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1002\/ajmg.a.36511","article-title":"Epidemiology of fragile X syndrome: A systematic review and meta-analysis","volume":"164A","author":"Hunter","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1097\/gme.0b013e3181a06a37","article-title":"Premature ovarian failure and fragile X female premutation carriers: No evidence for a skewed X-chromosome inactivation pattern","volume":"16","author":"Madrigal","year":"2009","journal-title":"Menopause"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/ana.20360","article-title":"Fragile X-associated tremor\/ataxia syndrome in sisters related to X-inactivation","volume":"57","author":"Potanos","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1007\/s00415-004-0558-1","article-title":"FMR1 premutation as a rare cause of late onset ataxia evidence for FXTAS in female carriers","volume":"251","author":"Budnik","year":"2004","journal-title":"J. Neurol."},{"key":"ref_16","first-page":"tre-02-56-352-1","article-title":"Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment","volume":"2","author":"Hall","year":"2012","journal-title":"Tremor Other Hyperkinet. Mov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1212\/NXG.0000000000000045","article-title":"X-inactivation in the clinical phenotype of fragile X premutation carrier sisters","volume":"2","author":"Hall","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/ana.20542","article-title":"Magnetic resonance imaging study in older fragile X premutation male carriers","volume":"58","author":"Loesch","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1001\/archneur.63.8.1189","article-title":"Essential tremor associated with pathologic changes in the cerebellum","volume":"63","author":"Louis","year":"2006","journal-title":"Arch. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1002\/mds.21493","article-title":"Fragile X-associated tremor\/ataxia syndrome: Clinical features, genetics, and testing guidelines","volume":"22","author":"Abrams","year":"2007","journal-title":"Mov. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1080\/13854046.2016.1192134","article-title":"Neuropsychiatry of fragile X-premutation carriers with and without fragile X-associated tremor-ataxia syndrome: Implications for neuropsychology","volume":"30","author":"Bourgeois","year":"2016","journal-title":"Clin. Neuropsychol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"830","DOI":"10.2310\/JIM.0b013e3181af59c4","article-title":"Fragile X-associated Tremor\/Ataxia Syndrome (FXTAS): Clinical Phenotype, Diagnosis and Treatment","volume":"57","author":"Leehey","year":"2009","journal-title":"J. Investig. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/brain\/awh683","article-title":"Neuropathology of fragile X-associated tremor\/ataxia syndrome (FXTAS)","volume":"129","author":"Greco","year":"2006","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/ajmg.b.31046","article-title":"Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers","volume":"153B","author":"Adams","year":"2010","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101","DOI":"10.5582\/irdr.2014.01029","article-title":"Current research, diagnosis, and treatment of fragile X-associated tremor\/ataxia syndrome","volume":"3","author":"Muzar","year":"2014","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tassone, F., and Hall, D.A. (2016). FXTAS, FXPOI, and Other Premutation Disorders, Springer International Publishing. [2nd ed.].","DOI":"10.1007\/978-3-319-33898-9"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1097\/NEN.0b013e31821d3194","article-title":"Rare intranuclear inclusions in the brains of 3 older adult males with fragile x syndrome: Implications for the spectrum of fragile X-associated disorders","volume":"70","author":"Hunsaker","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/j.1601-183X.2012.00779.x","article-title":"Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS","volume":"11","author":"Tassone","year":"2012","journal-title":"Genes Brain Behav."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/2047-9158-2-10","article-title":"Intranuclear inclusions in a fragile X mosaic male","volume":"2","author":"Pretto","year":"2013","journal-title":"Transl. Neurodegener."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1080\/13854046.2016.1184652","article-title":"The fragile X mental retardation 1 gene (FMR1): Historical perspective, phenotypes, mechanism, pathology, and epidemiology","volume":"30","author":"Grigsby","year":"2016","journal-title":"Clin. Neuropsychol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1093\/brain\/awh256","article-title":"The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy","volume":"127","author":"Moore","year":"2004","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1172\/JCI119538","article-title":"Fragile-X: Neuropsychological test performance, CGG triplet repeat lengths, and hippocampal volumes","volume":"100","author":"Laakso","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, Y., Shen, M., Stockton, M.E., and Zhao, X. (2019). Hippocampal deficits in neurodevelopmental disorders. Neurobiol. Learn. Mem., 165.","DOI":"10.1016\/j.nlm.2018.10.001"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3389\/fnhum.2012.00297","article-title":"Male carriers of the FMR1 premutation show altered hippocampal-prefrontal function during memory encoding","volume":"6","author":"Wang","year":"2012","journal-title":"Front. Hum. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1590\/S0004-282X2010000500023","article-title":"The fragile x-associated tremor and ataxia syndrome (FXTAS)","volume":"68","author":"Capelli","year":"2010","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1177\/1756285612454323","article-title":"White matter dementia","volume":"5","author":"Filley","year":"2012","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.neurobiolaging.2012.12.001","article-title":"Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor\/ataxia syndrome","volume":"34","author":"Battistella","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1093\/brain\/awr053","article-title":"Hippocampal sclerosis in advanced age: Clinical and pathological features","volume":"134","author":"Nelson","year":"2011","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s00401-014-1302-2","article-title":"Differential clinicopathologic and genetic features of late-onset amnestic dementias","volume":"128","author":"Murray","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40478-015-0209-z","article-title":"Disease-related microglia heterogeneity in the hippocampus of Alzheimer\u2019s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging","volume":"3","author":"Bachstetter","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1111\/bpa.12556","article-title":"Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population","volume":"28","author":"Hokkanen","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/ng0693-147","article-title":"Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain","volume":"4","author":"Abitbol","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1093\/hmg\/ddv216","article-title":"Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS","volume":"24","author":"Hukema","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S0896-6273(03)00533-6","article-title":"RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila","volume":"39","author":"Jin","year":"2003","journal-title":"Neuron"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s40478-019-0818-z","article-title":"Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology","volume":"7","author":"Sacino","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1093\/hmg\/ddg114","article-title":"The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor\/ataxia syndrome","volume":"12","author":"Willemsen","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1002\/mds.27060","article-title":"Two FMR1 premutation cases without nuclear inclusions","volume":"32","author":"Lechpammer","year":"2017","journal-title":"Mov. Disord."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:35:40Z","timestamp":1760132140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,8]]},"references-count":47,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417266"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417266","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,8]]}}}