Brain diffusion tensor imaging changes in cerebrotendinous xanthomatosis reversed with
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1 Brain diffusion tensor imaging changes in cerebrotendinous xanthomatosis reversed with treatment Claudia B. Catarino, MD, PhD, 1*, Christian Vollmar, MD, PhD, 2,3* Clemens Küpper, MD, 1,4 Klaus Seelos, MD, 3 Constanze Gallenmüller, MD, 1 Joanna Bartkiewicz, PhD, 2 Saskia Biskup, MD, 5 Konstanze Hörtnagel, MD, 5 Thomas Klopstock, MD 1,4,6,# 1 Department of Neurology, Friedrich Baur Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich; 2 Department of Neurology, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany; 3 Department of Neuroradiology, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany; 4 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 5 CeGaT GmbH und Praxis für Humangenetik, Tübingen, Germany 6 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; * These authors contributed equally to the manuscript. # Corresponding Author: Thomas.Klopstock@med.LMU.de
2 Supplementary Material Methods MRI studies 3-Tesla brain MRI scans were performed, before starting treatment and at 6 and 18 months of follow-up. The acquisition was performed on a 3-Tesla GE Excite HDx scanner and included conventional structural T1, T2 and FLAIR images and a DTI acquisition with 64 diffusion-weighted directions. DTI data analysis DTI image pre-processing was done using FSL software [1, 2], including correction for head movement and eddy-current artifacts, diffusion tensor fitting and calculation of fractional anisotropy (FA) maps. Whole-brain streamline tractography was performed, using the diffusion toolkit software, and cerebellar tract-density and volume were determined before and after treatment. Trackvis 0.6 software was used for visualization [3]. For quantitative analysis of the DTI data, FA maps were spatially normalized to a template in MNI space and statistically compared between each single patient and a group of 35 healthy controls. Difference images were created and analysed using a one-sample t-tests in SPM software [4], as previously described [5]. The resulting t-score reflects the degree of FA reduction in comparison to the healthy controls. T-scores above 15 were statistically significant and were colourencoded and 3D-rendered on the surface of the brain template. 2
3 References 1. Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. FSL. NeuroImage. 2012;62: Analysis Group, FMRIB, Oxford, UK (2017). FMRIB Software Library v Accessed 01 September Wang R, Wedeen Van J., Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital (2015). Trackvis 0.6 software. 01 September FIL Methods group SPM, (1991, ) September Henson R(2006).Comparing a single patient versus a group of controls (and SPM). Accessed 01 September
4 Supplementary Fig. 1 Neuropsychological tests,before and after treatment with CDCA. (a, b) Brother: The performance in the trail-making test (a) and clock-drawing (b) is shown before treatment (above) and after 6 months of CDCA therapy (below), with the patient performing faster and without mistakes (correct response, green circle; wrong response, red triangle) on CDCA therapy 4
5 Supplementary Fig. 2 DTI and tractography, before and after treatment with CDCA. (a, b) Proband: DTI tractography, with a seed slice in the cerebellum before treatment (a) shows less tracts originating from that slice than in healthy controls (data not shown). After 6 months of CDCA therapy (b) there was a 17% increase in tract number and 20% increase in tract volume in relation to baseline. The same pattern was seen for her brother, and paralleled the clinical improvement in coordination, gait and cognition (c-e) Proband, 3D brain images rendered on the surface of the MNI template view from above. Colour bars show the degree of FA reduction compared to the healthy control population. Before treatment (c), significant and widespread cerebral reductions of fractional anisotropy (FA) compared to a group of 35 healthy controls. After 6 months of treatment, the cortical reductions of FA became less (d), and even less after 18 months (e) 5
6 Supplementary Table 1 Raw FA values before and after treatment Proband Brother Baseline 6-Months- 18-Months- 6-Months- 18-Months- Baseline Follow-up Follow-up Follow-up Follow-up Left superior frontal gyrus Right superior frontal gyrus Left cerebellar peduncle Left dentate nucleus FA values were measured from anatomically defined regions of interest with a diameter of 10 mm after smoothing the FA maps with a 4mm FWHM kernel to reduce noise. 6
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