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

Objective This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. Methods SCA1 or SCA3...

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Published in:Annals of neurology 2023-04, Vol.93 (4), p.686-701
Main Authors: Chandrasekaran, Jayashree, Petit, Emilien, Park, Young Woo, Montcel, Sophie Tezenas, Joers, James M., Deelchand, Dinesh K., Považan, Michal, Banan, Guita, Valabregue, 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 O., Paulson, Henry, Durr, Alexandra, Klockgether, Thomas, Ashizawa, Tetsuo, Lenglet, Christophe, Öz, Gülin, Rosenthal, Liana, Burns, Matthew, Grobe‐Einsler, Marcus, Oender, Demet, Kimmich, Okka, Roy, Nina, Ewenczyk, Claire, Heinzmann, Anna, Lallemant, Pauline, Heide, Solveig, Charles, Perrine, Coarelli, Giulia, Cunha, Paulina, Sayah, Sabrina, Wilmot, George, Scorr, Laura, Opal, Puneet, Sha, Sharon, Santini, Veronica, Sampson, Jacinda, Perlman, Susan, Geschwind, Michael, Nelson, Alexandra, Dietiker, Cameron, Gomez, Christopher, Hawkins, Trevor, Morrison, Peter
Format: Article
Language:English
Subjects:
Abnormalities
Activities of Daily Living
Ataxia
Ataxin
Atrophy
Brain damage
Brain stem
Cerebellar Ataxia - genetics
Cerebellum
Humans
Life Sciences
Machado-Joseph disease
Magnetic resonance imaging
Magnetic Resonance Imaging - methods
Magnetic Resonance Spectroscopy
Neuroimaging
Pons
Santé publique et épidémiologie
Sensory neurons
Signs and symptoms
Spinocerebellar ataxia
Spinocerebellar Ataxias - diagnostic imaging
Spinocerebellar Ataxias - genetics
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Summary:Objective This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. Methods SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US‐European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. Results Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). Interpretation Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2023;93:686–701
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.26573