Motor cortical dysfunction develops in spinocerebellar ataxia type 3

•Cortical dysfunction is an early feature of SCA3 and associated with motor symptoms and ataxia.•Identifying cortical neuronal dysfunction in SCA3 may be of therapeutic significance.•SCA3 onset is not confined to the cerebellum and brainstem.

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disorder characterized by cerebellar ataxia and variable expression of clinical features beyond the cerebellum. To gain further insights into disease pathophysiology, the present study explored motor cortex function in SCA3 to determine whether cortical dysfunction was present and if this contributed to the development of clinical manifestations.MethodsClinical phenotyping and longitudinal assessments were combined with central (threshold-tracking transcranial magnetic stimulation) and peripheral (nerve excitability) techniques in 11 genetically characterized SCA3 patients.ResultsShort-interval intracortical inhibition was significantly reduced in presymptomatic and symptomatic SCA3 patients (−1.3 ± 1.4%) compared to healthy controls (10.3 ± 0.7%, P < 0.0005), with changes evident prior to clinical onset of ataxia and related to worsening severity (R = −0.78, P < 0.005). Central motor conduction time was also significantly prolonged in presymptomatic and symptomatic SCA3 patients (7.5 ± 0.4 ms) compared to healthy controls (5.3 ± 0.2 ms, P < 0.0005) and related to clinical severity (R = 0.81, P < 0.005). Markers of peripheral motor neurodegeneration and excitability did not correlate with cortical hyperexcitability or ataxia.ConclusionsSimultaneous investigation of clinical status, and central and peripheral nerve function has identified progressive cortical dysfunction in SCA3 patients related to the development of ataxia.SignificanceThese findings suggest alteration in cortical activity is associated with SCA3 pathogenesis and neurodegeneration.