David Hessl PhD, Jun Yi Wang PhD, Glenda Espinal BS, Ellery Santos MD, Flora Tassone PhD, Randi J. Hagerman MD, Susan M. Rivera PhD
{"title":"脆性x射线相关震颤/共济失调综合征的神经放射生物标志物纵向分析及其临床试验意义","authors":"David Hessl PhD, Jun Yi Wang PhD, Glenda Espinal BS, Ellery Santos MD, Flora Tassone PhD, Randi J. Hagerman MD, Susan M. Rivera PhD","doi":"10.1002/ana.27267","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>The objective of this study was to show the capacity of structural brain magnetic resonance imaging (MRI) measures to serve as monitoring biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>From 2 longitudinal studies of male <i>FMR1</i> premutation carriers, 2 brain MRI scans were selected from each participant, collected within a period of 2 years (12 healthy controls, 17 carriers without FXTAS, and 51 carriers with FXTAS; all men, ages 40 to 80 years), along with clinical measurements and <i>FMR1</i> cytosine-guanine-guanine (CGG) repeat numbers. Candidate MRI biomarkers included whole brain white matter hyperintensity (WMH) and cerebellar, brainstem, and whole brain volumes.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>In the FXTAS group, mixed-effects models demonstrated significant volume loss across an average interval of 1.32 years for the whole brain, cerebellum and brain stem volumes, and significant increases in WMH, with large magnitude effects for whole brain and WMH volumes. All MRI measures showed deterioration with advancing FXTAS stage, with the strongest pattern shown in WMH volume. CGG repeat number showed significant nonlinear associations with all 4 brain MRI metrics, with mid-range CGG repeat carriers evidencing the worst brain atrophy and WMHs.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Structural brain MRI measurements, especially those capturing white matter deterioration, are correlated with <i>FMR1</i> premutation size of CGG repeat length and sensitive to FXTAS disease progression across a relatively short interval of less than 2 years, making them potentially suitable as surrogate end points for clinical trials. ANN NEUROL 2025;98:471–481</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 3","pages":"471-481"},"PeriodicalIF":7.7000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27267","citationCount":"0","resultStr":"{\"title\":\"Longitudinal Analysis of Neuroradiological Biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome and Implications for Clinical Trials\",\"authors\":\"David Hessl PhD, Jun Yi Wang PhD, Glenda Espinal BS, Ellery Santos MD, Flora Tassone PhD, Randi J. Hagerman MD, Susan M. Rivera PhD\",\"doi\":\"10.1002/ana.27267\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>The objective of this study was to show the capacity of structural brain magnetic resonance imaging (MRI) measures to serve as monitoring biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>From 2 longitudinal studies of male <i>FMR1</i> premutation carriers, 2 brain MRI scans were selected from each participant, collected within a period of 2 years (12 healthy controls, 17 carriers without FXTAS, and 51 carriers with FXTAS; all men, ages 40 to 80 years), along with clinical measurements and <i>FMR1</i> cytosine-guanine-guanine (CGG) repeat numbers. Candidate MRI biomarkers included whole brain white matter hyperintensity (WMH) and cerebellar, brainstem, and whole brain volumes.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>In the FXTAS group, mixed-effects models demonstrated significant volume loss across an average interval of 1.32 years for the whole brain, cerebellum and brain stem volumes, and significant increases in WMH, with large magnitude effects for whole brain and WMH volumes. All MRI measures showed deterioration with advancing FXTAS stage, with the strongest pattern shown in WMH volume. CGG repeat number showed significant nonlinear associations with all 4 brain MRI metrics, with mid-range CGG repeat carriers evidencing the worst brain atrophy and WMHs.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Interpretation</h3>\\n \\n <p>Structural brain MRI measurements, especially those capturing white matter deterioration, are correlated with <i>FMR1</i> premutation size of CGG repeat length and sensitive to FXTAS disease progression across a relatively short interval of less than 2 years, making them potentially suitable as surrogate end points for clinical trials. ANN NEUROL 2025;98:471–481</p>\\n </section>\\n </div>\",\"PeriodicalId\":127,\"journal\":{\"name\":\"Annals of Neurology\",\"volume\":\"98 3\",\"pages\":\"471-481\"},\"PeriodicalIF\":7.7000,\"publicationDate\":\"2025-06-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27267\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ana.27267\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.27267","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Longitudinal Analysis of Neuroradiological Biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome and Implications for Clinical Trials
Objective
The objective of this study was to show the capacity of structural brain magnetic resonance imaging (MRI) measures to serve as monitoring biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).
Methods
From 2 longitudinal studies of male FMR1 premutation carriers, 2 brain MRI scans were selected from each participant, collected within a period of 2 years (12 healthy controls, 17 carriers without FXTAS, and 51 carriers with FXTAS; all men, ages 40 to 80 years), along with clinical measurements and FMR1 cytosine-guanine-guanine (CGG) repeat numbers. Candidate MRI biomarkers included whole brain white matter hyperintensity (WMH) and cerebellar, brainstem, and whole brain volumes.
Results
In the FXTAS group, mixed-effects models demonstrated significant volume loss across an average interval of 1.32 years for the whole brain, cerebellum and brain stem volumes, and significant increases in WMH, with large magnitude effects for whole brain and WMH volumes. All MRI measures showed deterioration with advancing FXTAS stage, with the strongest pattern shown in WMH volume. CGG repeat number showed significant nonlinear associations with all 4 brain MRI metrics, with mid-range CGG repeat carriers evidencing the worst brain atrophy and WMHs.
Interpretation
Structural brain MRI measurements, especially those capturing white matter deterioration, are correlated with FMR1 premutation size of CGG repeat length and sensitive to FXTAS disease progression across a relatively short interval of less than 2 years, making them potentially suitable as surrogate end points for clinical trials. ANN NEUROL 2025;98:471–481
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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