Background The pathological burden of spinocerebellar ataxia type 3, also known as Machado–Joseph disease (SCA3/MJD), accumulates before the beginning of symptoms. Our study aims at validating biomarkers for disease progression since pre‐ataxic periods. We report on baseline findings of clinical scales and oculomotor neurophysiology. Methods Ataxic (Scale for the Assessment and Rating of Ataxia > 2.5) and at 50% risk subjects were included. The latter were subdivided into noncarriers, pre‐ataxic carriers near (PAN), or pre‐ataxic carriers far from (PAFF) ataxia onset (AO), with 4 years from the predicted age at onset being the cutoff. The subjects were assessed by Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), International Cooperative Ataxia Rating Scale (ICARS), Inventory of Non‐Ataxic Signs (INAScount), Composite Cerebellar Functions Score and SCA Functional Index, and video‐oculography, including the regression slope of vestibulo‐ocular reflex gain (VORr), main sequence of volitional and reflexive vertical saccades, slow‐phase velocity of central and gaze‐evoked (SPV‐GE) nystagmus, and vertical pursuit gain. Correction for multiple comparisons was performed; the threshold for statistical significance was P < 0.05. Results A total of 35 ataxic, 14 PAN, 24 PAFF, and 22 noncarriers were included. All variables showed significant differences between groups and correlated to time to onset or time after onset, among all 73 SCA3/MJD carriers; none significantly changed with age in controls. NESSCA, ICARS, INAScount, VORr, main sequence of volitional saccades, and SPV‐GE not only distinguished PAN from controls but also correlated with time left to AO. Conclusions Clinical scales and video‐oculography variables were already altered in pre‐ataxic SCA3/MJD carriers and worsened with time. NESSCA, ICARS, INAScount, VORr, main sequence of vertical volitional saccades, and SPV‐GE are good candidates to measure preclinical changes in SCA3/MJD. © 2021 International Parkinson and Movement Disorder Society

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Background Little is known about preclinical stages of Machado‐Joseph disease, a polyglutamine disorder characterized by progressive adult‐onset ataxia. Objective We aimed to describe the longitudinal progression of clinical and oculomotor variables in the preataxic phase of disease. Methods Carriers and noncarriers were assessed at three visits. Preataxic carriers (Scale for Assessment and Rating of Ataxia score < 3) expected to start ataxia in ≤4 years were considered near onset (PAN). Progressions of ataxic and preataxic carriers, considering status at the end of the study, were described according to the start (or its prediction) of gait ataxia (TimeToAfterOnset) and according to the study time. Results A total of 35 ataxics, 38 preataxics, and 22 noncarriers were included. The “TimeToAfterOnset” timeline showed that Neurological Examination Scale for Spinocerebellar Ataxias (NESSCA; effect size, 0.09), Inventory of Non‐Ataxia Symptoms (INAS0.07), and the vestibulo‐ocular reflex gain (0.12) progressed in preataxic carriers, and that most slopes accelerate in PAN, turning similar to those of ataxics. In the study time, NESSCA (1.36) and vertical pursuit gain (1.17) significantly worsened in PAN, and 6 of 11 PANs converted to ataxia. For a clinical trial with 80% power and 2‐year duration, 57 PANs are needed in each study arm to detect a 50% reduction in the conversion rate. Conclusions NESSCA, INAS, vestibulo‐ocular reflex, and vertical pursuit gains significantly worsened in the preataxic phase. The “TimeToAfterOnset” timeline unveiled that slopes of most variables are small in preataxics but increase and reach the ataxic slopes from 4 years before the onset of ataxia. For future trials in preataxic carriers, we recommend recruiting PANs and using the conversion rate as the primary outcome. © 2022 International Parkinson and Movement Disorder Society.