Clinically Meaningful <scp>Magnetic Resonance</scp> Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types <scp>1</scp> and <scp>3</scp>

Chandrasekaran, Jayashree; Petit, Emilien; Park, Young Woo; Montcel, Sophie Tézenas du; Joers, James M.; Deelchand, Dinesh K.; Považan, Michal; Banan, Guita; Valabrègue, Romain; Ehses, Philipp; Faber, Jennifer; Coupé, Pierrick; Onyike, Chiadi U.; Barker, Peter B.; Schmahmann, Jeremy D.; Ratai, Eva‐Maria; Subramony, S. H.; Mareci, Thomas H.; Bushara, Khalaf; Paulson, Henry L.; Dürr, Alexandra; Klockgether, Thomas; Ashizawa, Tetsuo; Lenglet, Christophe; Öz, Gülin

doi:10.1002/ana.26573

Cited by 18 publications

(35 citation statements)

References 61 publications

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“…These observations are in line with autopsy findings that show, unlike most other SCAs, relative sparing of cerebellar cortex in SCA3. 21 The strong involvement of the CWM volume corroborates previous findings of prominent white matter loss in patients with SCA3, 22,23 and is in line with reports of early oligodendrocyte pathology in mouse models of SCA3. 24,25 Pons volume showed an almost linear decline along the entire disease range, denoting it as a potential marker of disease progression.…”

Section: Discussionsupporting

confidence: 83%

“…Further studies including additional fluid and imaging biomarker data, such as MR spectroscopy and diffusion imaging, 11 may allow to further subdivide the biomarker stage. In the present model, we have not introduced a clinical sign or symptom stage preceding the final clinical stage like in the HD model.…”

Section: Discussionmentioning

confidence: 99%

“…These markers reflect key pathological changes of SCA3 and are known to be abnormal before onset of ataxia. [4][5][6][7][10][11][12] To assess the presence and severity of ataxia, we used the Scale for the Assessment and Rating of Ataxia (SARA). 13 Our analysis allowed to propose a staging model of SCA3 based on changes of SARA and the biomarkers under study.…”

Section: Introductionmentioning

confidence: 99%

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Stage-dependent biomarker changes in spinocerebellar ataxia type 3

Faber

Berger

Wilke

et al. 2023

Preprint

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Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stage-dependent biomarker changes in spinocerebellar ataxia type 3

Faber

Berger

Wilke

et al. 2023

Preprint

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“…In addition, among the at-risk participants, 27 did not carry a pathologic expansion in ATXN1 or ATXN3 (0 [0-1]) (Tables 1 and 2). [ [32][33][34][35][36][37][38][39][40][41], p_PA = 0.0001) and the controls (38 [31-47], SCA1: p_CA = 0.0092, SCA3: p_CA = 0.0009) (Tables 1 and 2). As expected, they had significantly more severe cerebellar and functional scores than expansion carriers without ataxia.…”

Section: Resultsmentioning

confidence: 99%

“…Comparisons Between Controls, Expansion Carriers With and Without AtaxiaFor both groups, patients with ataxia were older (SCA1 median: 47 [41-54], SCA3: 49[41][42][43][44][45][46][47][48][49][50][51][52][53][54]) than both the preataxic participants (SCA1: 39[34][35][36][37][38][39][40][41][42][43][44][45][46], p_PA = 0.0619; SCA3: 36…”

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confidence: 99%

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

et al. 2023

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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.

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Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice

McLoughlin

Gundry

Rainwater

et al. 2023

Annals of Neurology

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ObjectiveSpinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti‐ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).MethodsSymptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild‐type vehicle‐treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2‐way analysis of variance mixed‐effects sex‐adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.ResultsMR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N‐acetylaspartate across both regions. Some ASO‐rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO‐corrected motor activity correlated with total choline and total N‐acetylaspartate levels early in disease.InterpretationSCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N‐acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023

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Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Cited by 18 publications

References 61 publications

Stage-dependent biomarker changes in spinocerebellar ataxia type 3

Stage-dependent biomarker changes in spinocerebellar ataxia type 3

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

Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice

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