Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3

Abstract

Background and Objective:In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations or biomarkers modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxias type 1 and 3 to provide essential markers for therapeutic interventions. We looked for clinical, imaging or biological markers that are present at an early-stage of the disease.Methods:We enrolled carriers of a pathologicalATXN1orATXN3expansion and controls from 18 US and two European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between mutation carriers with and without ataxia and controls.Results:We enrolled 200 participants: 45 carriers of a pathologicalATXN1expansion (31 patients with ataxia (median SARA: 9 [7;10]), 14 mutation carriers without ataxia (1 [0;2])) and 116 carriers of a pathologicalATXN3expansion (80 patients with ataxia (7 [6;9]), 36 mutation carriers without ataxia (1 [0;2])). In addition, we enrolled 39 controls who did not carry a pathological expansion inATXN1orATXN3. Plasma NfL levels were significantly higher in mutation carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL (P <0.0001), SCA3: 19.8 pg/mL (P<0.0001). Mutation carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 P=0.0003, SCA3 P=0.003) and by the presence of sensor impairment and diplopia in SCA3 (P=0.0448, and 0.0445 respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in mutation carriers with ataxia than those without ataxia. Ataxic SCA3 subjects showed extrapyramidal signs, urinary dysfunction and lower motor neuron signs significantly more often than mutation carriers without ataxia.Discussion:READISCA showed the feasibility of harmonized data acquisition in a multi-national network. NfL alterations, early sensory ataxia and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and mutation carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study

“…Despite that, supporting evidence comes from a recent study from the READISCA consortium, which reported sensory deficits to be conspicuous and precocious in both ataxic and preataxic SCA1 and SCA3 cohorts. 18 Moreover, results from electrophysiological studies-particularly evoked potentialsare also supportive of our hypothesis. Indeed, patients with SCA1 typically present motor-evoked potentials with prolonged central conduction times, and patients with SCA1, SCA2 and SCA3 all present abnormal somatosensory-evoked potentials.…”

“… 4 Indeed, Tezenas du Montcel and colleagues showed that pyramidal signs and posterior column signs precede ataxia in SCA1 and SCA3, suggesting that spinal cord is damaged early in these disorders. 18 Spinal MRI research undertaken in SCAs to-date has been restricted to a small number of studies that have relied on modest sample sizes, limiting the sensitivity, reliability and generalisability of available evidence. 11–13 15 17 19 Furthermore, magnitude of spinal cord damage in each SCA and how it progresses along the disease course, including in preataxic disease stages, remains unknown.…”

Serum Neurofilament Light Chain in Replication Factor Complex Subunit 1 CANVAS and Disease Spectrum

“…Elevated NfL levels were observed in various clinical phenotypes, including isolated sensory neuropathy, which is more common in early disease stages. NfL levels demonstrated excellent discriminatory power, supporting its potential as a reliable biomarker in various neurodegenerative ataxias, 12,13,17‐19 as well as in hereditary neuropathies 8,10 …”

“…An explanation of this phenomenon is that NfL may increase rapidly in the initial stages of the disease and then reach a plateau above a certain degree of severity, as observed in other genetic ataxias. 12 , 13 , 18 Other possible explanations entail the difficulty in accurately defining the onset of the disease, because neuropathy symptoms may remain unnoticed for a long time, or the chronologically variable involvement of the cerebellum in early or late disease stages relative to onset, due to factors yet to be explored, including the repeat size and additional genetic modifiers. Also, no significant difference in serum NfL levels was found based on vestibular involvement.…”