Neurobiology of disease · 2026
The fT3/fT4 ratio as a candidate marker of motor progression in SCA3.
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Dong Mengyuan, Ding Ziyan, Chen Zhao, Wan Na, Peng Linliu, Huang Qinlin, Hu Jian, Cui Ziting, Peng Rongfan, Zeng Daren, Zou Ying, Gong Yiqing, Tan Yan, Chen Daji, Jiang Qian, He Jiawei, Pei Zhuan, Ding Siyu, Shen Xiaokai, Wu Qi, Deng Qi, Yuan Hongyu, Wang Chunrong, Wan Linlin, He Lang, Peng Huirong, Shi Yuting, Qiu Rong, Jiang Hong
Аннотация
BACKGROUND: Motor severity and progression in spinocerebellar ataxia type 3 (SCA3) vary across individuals, yet physiological factors contributing to this heterogeneity remain incompletely understood. Thyroid hormones are central regulators of systemic metabolism and are associated with motor function and frailty in physiological conditions and neurodegenerative diseases, but their relevance to SCA3 is unclear.
OBJECTIVES: To investigate whether thyroid-related measures are associated with progression-related motor measures in SCA3.
METHODS: Thyroid function tests, including free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), together with derived hypothalamic-pituitary-thyroid (HPT) homeostatic indices were analyzed in pre-ataxic and ataxic ATXN3 carriers. Cross-sectional analyses were performed to examine associations between thyroid-related measures and motor outcomes. In the longitudinal cohort, linear mixed-effects models were used to assess whether baseline fT3/fT4 ratio was associated with subsequent motor progression trajectories.
RESULTS: Euthyroid ATXN3 carriers showed reduced TSH and fT3/fT4 ratio, together with elevated thyroid's secretory capacity (SPINA-GT), compared with controls. Both SPINA-GT elevation and fT3/fT4 reduction were already detectable in pre-ataxic carriers, and at this stage fT3/fT4 was positively associated with expanded CAG repeat length. In euthyroid symptomatic carriers, lower fT3/fT4 ratios were associated with less favorable cross-sectional annualized progression estimates, including higher Scale for the Assessment and Rating of Ataxia (SARA)/year and International Cooperative Ataxia Rating Scale (ICARS)/year. In the longitudinal cohort, patients in the lower baseline fT3/fT4 group showed steeper subsequent SARA worsening in the prespecified baseline-anchored linear mixed-effects model (β = -1.68, 95% CI -2.812 to -0.554, p = 0.007), whereas the corresponding ICARS effect was not significant.
CONCLUSIONS: Our findings suggest that altered thyroid hormone homeostasis, particularly a reduced fT3/fT4 ratio, is associated with progression-related motor heterogeneity in SCA3. The reduction in fT3/fT4 ratio was detectable in pre-ataxic carriers and was associated with subsequent SARA worsening in the longitudinal cohort. These findings support a possible link between thyroid-related metabolic alterations and disease heterogeneity in SCA3.
OBJECTIVES: To investigate whether thyroid-related measures are associated with progression-related motor measures in SCA3.
METHODS: Thyroid function tests, including free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), together with derived hypothalamic-pituitary-thyroid (HPT) homeostatic indices were analyzed in pre-ataxic and ataxic ATXN3 carriers. Cross-sectional analyses were performed to examine associations between thyroid-related measures and motor outcomes. In the longitudinal cohort, linear mixed-effects models were used to assess whether baseline fT3/fT4 ratio was associated with subsequent motor progression trajectories.
RESULTS: Euthyroid ATXN3 carriers showed reduced TSH and fT3/fT4 ratio, together with elevated thyroid's secretory capacity (SPINA-GT), compared with controls. Both SPINA-GT elevation and fT3/fT4 reduction were already detectable in pre-ataxic carriers, and at this stage fT3/fT4 was positively associated with expanded CAG repeat length. In euthyroid symptomatic carriers, lower fT3/fT4 ratios were associated with less favorable cross-sectional annualized progression estimates, including higher Scale for the Assessment and Rating of Ataxia (SARA)/year and International Cooperative Ataxia Rating Scale (ICARS)/year. In the longitudinal cohort, patients in the lower baseline fT3/fT4 group showed steeper subsequent SARA worsening in the prespecified baseline-anchored linear mixed-effects model (β = -1.68, 95% CI -2.812 to -0.554, p = 0.007), whereas the corresponding ICARS effect was not significant.
CONCLUSIONS: Our findings suggest that altered thyroid hormone homeostasis, particularly a reduced fT3/fT4 ratio, is associated with progression-related motor heterogeneity in SCA3. The reduction in fT3/fT4 ratio was detectable in pre-ataxic carriers and was associated with subsequent SARA worsening in the longitudinal cohort. These findings support a possible link between thyroid-related metabolic alterations and disease heterogeneity in SCA3.