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. 2024 Dec;31(12):e16460.
doi: 10.1111/ene.16460. Epub 2024 Sep 10.

Microstructure of the cerebellum and its afferent pathways underpins dystonia in myoclonus dystonia

Clément Tarrano  1   2   3 , Giuseppe Zito  4 , Cécile Galléa  1   5 , Cécile Delorme  1   2 , Eavan M McGovern  6   7 , Cyril Atkinson-Clement  1   8 , Vanessa Brochard  2 , Stéphane Thobois  9   10 , Christine Tranchant  11   12   13 , David Grabli  1   2 , Bertrand Degos  14 , Jean Christophe Corvol  1   2 , Jean-Michel Pedespan  15 , Pierre Krystkowiak  16 , Jean-Luc Houeto  17 , Adrian Degardin  18 , Luc Defebvre  19   20 , Mélanie Didier  1   5 , Romain Valabrègue  1   5 , Emmanuelle Apartis  1   3 , Marie Vidailhet  1   2 , Emmanuel Roze  1   2 , Yulia Worbe  1   2   3
Affiliations

Microstructure of the cerebellum and its afferent pathways underpins dystonia in myoclonus dystonia

Clément Tarrano et al. Eur J Neurol. 2024 Dec.

Abstract

Background and purpose: Myoclonus dystonia due to a pathogenic variant in SGCE (MYC/DYT-SGCE) is a rare condition involving a motor phenotype associating myoclonus and dystonia. Dysfunction within the networks relying on the cortex, cerebellum, and basal ganglia was presumed to underpin the clinical manifestations. However, the microarchitectural abnormalities within these structures and related pathways are unknown. Here, we investigated the microarchitectural brain abnormalities related to the motor phenotype in MYC/DYT-SGCE.

Methods: We used neurite orientation dispersion and density imaging, a multicompartment tissue model of diffusion neuroimaging, to compare microarchitectural neurite organization in MYC/DYT-SGCE patients and healthy volunteers (HVs). Neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) were derived and correlated with the severity of motor symptoms. Fractional anisotropy (FA) and mean diffusivity (MD) derived from the diffusion tensor approach were also analyzed. In addition, we studied the pathways that correlated with motor symptom severity using tractography analysis.

Results: Eighteen MYC/DYT-SGCE patients and 24 HVs were analyzed. MYC/DYT-SGCE patients showed an increase of ODI and a decrease of FA within their motor cerebellum. More severe dystonia was associated with lower ODI and NDI and higher FA within motor cerebellar cortex, as well as with lower NDI and higher ISOVF and MD within the corticopontocerebellar and spinocerebellar pathways. No association was found between myoclonus severity and diffusion parameters.

Conclusions: In MYC/DYT-SGCE, we found microstructural reorganization of the motor cerebellum. Structural change in the cerebellar afferent pathways that relay inputs from the spinal cord and the cerebral cortex were specifically associated with the severity of dystonia.

Keywords: cerebellum; diffusion tensor imaging; dystonia; myoclonus; neuroimaging.

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Conflict of interest statement

The authors have no conflict of interest concerning the present research. Regarding financial disclosures for the preceding 12 months, C.Ta. has received a PhD grant from the “Fondation pour la Recherche Médicale.” C.D. has received a research grant from the FIA; travel funding from Merz Pharma, Abbvie, Boston Scientific, and Medtronic; and honoraria from Elivie, Merz Pharma, and Medtronic. J.C.C. has served on advisory boards for Biogen, Denali, Idorsia, Prevail Therapeutic, Servier, Theranexus, and UCB and has received grants from Sanofi and the Michael J. Fox Foundation for other projects. S.T. has received grants from France Parkinson and PHRC and honorarium from Abbvie, Boston, and Merz. E.M.M. has received speaking honoraria from AbbVie and the Dutch MDS symposium and travel support from Elivie; has served on an advisory board for AbbVie; and has received research grants from the STAR MD and the RCSI Richard Steeven's Scholarship. D.G. has received grants from AP‐HP (DRC‐PHRC) and France Parkinson; has served on scientific advisory boards for AbbVie and Zambon; received research funding from Air Liquide and Orkyn; has received speech honoraria from Medtronic, AbbVie, Merz, Orkyn, Aguettant, and EverPharma; and has received travel funding from AbbVie and Merz. E.R. has received honoraria for speaking from Orkyn, Aguettant, and Elivie and for participating on an advisory board from Merz Pharma. He has received research support from Merz Pharma, Orkyn, Aguettant, Elivie, Ipsen, Everpharma, Fondation Desmarest, AMADYS, ADCY5.org, Fonds de dotation Patrick Brou de Laurière, Agence Nationale de la Recherche, Societé Française de Médecine Esthétique, and Dystonia Medical Research Foundation. None of the other authors has any disclosure relevant to this work.

Figures

FIGURE 1
FIGURE 1
Neurite orientation dispersion and density imaging and diffusion tensor imaging metrics comparison between groups. (a) Results for orientation dispersion index (ODI). (b) Results for fractional anisotropy (FA). Yellow–red color highlights regions where patients > healthy volunteers, whereas blue indicates regions where patients < healthy volunteers. Statistical significance was determined with a peak threshold of p < 0.001 and a cluster level threshold of p < 0.05, corrected using the false discovery rate method for all analyses.
FIGURE 2
FIGURE 2
Regression analysis of neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) parameters by Burke–Fahn–Marsden Dystonia Rating Scale (BFM) in the patients group. (a) Results for NODDI parameters. (b) Results for DTI parameters. Yellow–red and blue colors highlight regions with respectively a positive and a negative association with BFM. The peak statistical threshold was set to p < 0.001, with a cluster level threshold of p < 0.05 corrected by false discovery rate method for all analyses. FA, fractional anisotropy; ISOVF, isotropic volume fraction; MD, mean diffusivity; NDI, neurite density index; ODI, orientation dispersion index.
FIGURE 3
FIGURE 3
Cluster localization using tractography. Significant white matter clusters of the NODDI and DTI analysis (in yellow–red color) are overlayed with the corticopontocerebellar pathway (CPCP) in green, cerebellothalamic pathway (CTP) in yellow, and spinocerebellar pathway (SCP) in blue. For better readability, the corticostriatal and motor thalamocortical pathways are not displayed. The pie charts represent the overall distribution of significant clusters' voxels across the pathways of interest for each parameter.
See this image and copyright information in PMC

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