{"doi":"10.1002/acn3.70116","title":"Fixel‐Based Analysis of Diffusion Imaging as a Quantitative Marker of Disease State in Spinocerebellar Ataxia","abstract":"OBJECTIVE: Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous neurodegenerative diseases causing progressive deterioration and reduced quality of life. Therapeutic advances have been limited by a lack of sensitive anatomic, functional, or diffusion imaging-based biomarkers. This study aimed to identify white matter differences in the brains of preataxic and early-stage SCA1 and SCA3 mutation carriers using diffusion magnetic resonance imaging data from a multisite trial setting. METHODS: Fixel-based analysis was used to estimate microscopic fiber density, macroscopic fiber-bundle cross-section, and a combined fiber density and fiber-bundle cross-section measure within 45 cerebral and cerebellar tracts. Multivariate ANOVAs compared controls (n = 16), pre-ataxic (n = 10 SCA1, n = 24 SCA3), and ataxic patients (n = 14 SCA1, n = 36 SCA3). Clinical variables were correlated with fixel metrics and receiver operating characteristic analyses identified white matter tracts sensitive to distinguishing controls from pre-ataxic SCA1 and SCA3. RESULTS: We found widespread white matter deficits in pre-ataxic and ataxic patients compared to controls with regard to fiber density, fiber-bundle cross-section, and combined measures, all of which were associated with clinical measures of ataxia severity. We also found the combined fiber density and fiber-bundle cross-section measure from cerebellar tracts distinguished controls from pre-ataxia with high sensitivity and specificity for both SCA1 (receiver operating characteristic area under the curve = 0.96) and SCA3 (area under the curve = 0.97). The receiver operating characteristic analyses revealed that cerebellar tracts resulted in greater area under the curve than cortico-spinal and transcallosal tracts. INTERPRETATION: These results demonstrate that fixel metrics offer sensitive disease-specific measures of early SCA disease state that correlate with standard clinical measures. TRIAL REGISTRATION: Clinical Trial Readiness for SCA1 and SCA3 (READISCA), NCT03487367. https://clinicaltrials.gov/ct2/show/NCT03487367.","journal":"Annals of Clinical and Translational Neurology","year":2025,"id":532681,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT03487367"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":523438,"name":"S. H. Subramony","orcid":"0000-0002-8052-9240","position":1,"is_corresponding":false},{"id":348661,"name":"David E. Vaillancourt","orcid":"0000-0002-5663-6476","position":2,"is_corresponding":false},{"id":380178,"name":"Tetsuo Ashizawa","orcid":"0000-0001-7180-2869","position":3,"is_corresponding":false},{"id":17559,"name":"Alexandra Dürr","orcid":"0000-0002-8921-7104","position":4,"is_corresponding":false},{"id":545376,"name":"Thomas H. Mareci","orcid":"0000-0003-4700-2364","position":5,"is_corresponding":false},{"id":326382,"name":"Thomas Klockgether","orcid":"0000-0001-6174-5442","position":6,"is_corresponding":false},{"id":657253,"name":"Jennifer Faber","orcid":"0000-0003-3265-0262","position":7,"is_corresponding":false},{"id":331940,"name":"Henry L. Paulson","orcid":"0000-0002-0382-7535","position":8,"is_corresponding":false},{"id":262954,"name":"Gülin Öz","orcid":"0000-0002-5769-183X","position":9,"is_corresponding":false},{"id":266310,"name":"Matthew R. Burns","orcid":"0000-0002-9309-7723","position":10,"is_corresponding":false},{"id":520932,"name":"David J. Arpin","orcid":"0000-0002-6442-1205","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:51:27.893975Z","pmid":"40665587","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}