Relationship of subclinical lung injury to chronic airway inflammation in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is one of the most prevalent hereditary neurodegenerative disorders, with respiratory failure being the leading cause of mortality. Nevertheless, pulmonary function in SCA3 has not been thoroughly characterized, and the underlying mechanisms remain unclear. We conducted pulmonary function tests in both patients and healthy controls, as well as in SCA3 mice and wild-type mice. In participants, we used diaphragm ultrasonography to evaluate diaphragmatic dysfunction. We examined clinical features and inflammatory biomarkers to identify independent associations with pulmonary function. We also performed histopathological and immunohistochemical analyses on lung tissues from SCA3 mice to assess the presence of chronic airway inflammation. We enrolled 102 patients and 91 healthy controls for pulmonary function testing. For blood biomarker analyses, SCA3 participants with available blood data were drawn from the same patient cohort and were compared with an independent cohort of 88 age- and sex-matched healthy controls, distinct from the pulmonary-function controls. Compared with controls, patients showed significant reductions in FVC (P < 0.001), FEV1 (P < 0.001), DLco-SB (P = 0.015), and small-airway flow indices (P < 0.05), along with an increased RV/TLC ratio (P < 0.001), indicating subclinical pulmonary dysfunction. Impaired pulmonary function, defined according to prespecified criteria, was identified in 71/102 (69.6%) patients versus 0/91 controls (P < 0.001). Pulmonary impairment was associated with ataxia severity (SARA: OR = 1.196, 95% CI 1.038–1.376; P = 0.013). Diaphragm ultrasound showed preserved diaphragmatic function, whereas systemic inflammatory markers were associated with reduced pulmonary function, with NLR inversely correlated with MEF25 (ρ =–0.272, P = 0.010). In SCA3 mice (n = 4) compared with wild-type mice (n = 3), pulmonary function abnormalities and lung pathology were consistent with airway inflammatory changes. SCA3 is associated with early, subclinical pulmonary dysfunction that worsens with disease progression. Chronic inflammation in the small airways may be involved in this process. Our findings underscore the need for early intervention with chest physiotherapy and respiratory training as part of the clinical management of SCA3.