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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.

Purpose: To compare MR axon radius estimation in human white matter using a multiband spiral sequence combined with field monitoring to the current state‐of‐the‐art echo‐planar imaging (EPI)‐based approach. Methods: A custom multiband spiral sequence was used for diffusion‐weighted imaging at ultra‐high b$$ b $$‐values. Field monitoring and higher order image reconstruction were employed to greatly reduce artifacts in spiral images. Diffusion weighting parameters were chosen to match a state‐of‐the art EPI‐based axon radius mapping protocol. The spiral approach was compared to the EPI approach by comparing the image signal‐to‐noise ratio (SNR) and performing a test–retest study to assess the respective variability and repeatability of axon radius mapping. Effective axon radius estimates were compared over white matter voxels and along the left corticospinal tract. Results: Increased SNR and reduced artifacts in spiral images led to reduced variability in resulting axon radius maps, especially in low‐SNR regions. Test–retest variability was reduced by a factor of approximately 1.5 using the spiral approach. Reduced repeatability due to significant bias was found for some subjects in both spiral and EPI approaches, and attributed to scanner instability, pointing to a previously unknown limitation of the state‐of‐the‐art approach. Conclusion: Combining spiral readouts with field monitoring improved mapping of the effective axon radius compared to the conventional EPI approach. [ABSTRACT FROM AUTHOR]

Background: Clinical trials for upcoming disease‐modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes. Objectives: READISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations. Methods: A total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3‐T MR scanning at baseline and a median [interquartile range] follow‐up of 6.2 [5.9–6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6‐month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate. Results: Rate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls (P < 0.005), with high effect sizes (Cohen's d = 1–2) and moderate‐to‐high responsiveness (|standardized response mean| = 0.6–0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups. Conclusions: Diffusion MRI is sensitive to disease progression at very early‐stage SCA1 and SCA3 and may provide a >5‐fold reduction in sample sizes relative to SARA as endpoint for 6‐month‐long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Purpose: This work demonstrates a new variant of the 3DREAM sequence for whole‐brain B1+$$ {\mathrm{B}}_1^{+} $$ mapping employing a three‐dimensional (3D) stack‐of‐spirals readout. The spiral readout reduces the echo train length after the STEAM preparation in order to overcome the significant blurring in STE* images due to the decreasing STE* signal with each excitation pulse. Methods: The 3DREAM sequence rapidly acquires two contrasts to calculate whole‐brain flip angle maps. In the proposed spiral 3DREAM sequence, the Cartesian readout scheme is replaced by an accelerated 3D stack‐of‐spirals readout with a CAIPIRINHA sampling scheme. Phantom experiments were conducted to compare flip angle maps of the spiral 3DREAM sequence to a Cartesian 3DREAM sequence, an actual flip‐angle‐imaging (AFI) sequence, the dual‐angle method, and the Bloch–Siegert shift method. Afterwards, the results were validated in vivo acquiring flip angle maps from five subjects. Results: Flip angle maps of the spiral 3DREAM sequences showed high agreement with the reference methods both in phantom and in vivo experiments. Blurring in STE* images and flip angle maps was reduced compared to the Cartesian 3DREAM sequence. Conclusion: The spiral 3DREAM sequence utilizes a fast readout minimizing the echo train length of the imaging train. This reduces blurring in STE* images as well as the total acquisition time and increases the effective resolution of B1+$$ {\mathrm{B}}_1^{+} $$ maps. [ABSTRACT FROM AUTHOR]

We propose to utilize the rich information content about microstructural tissue properties entangled in asymmetric balanced steady‐state free precession (bSSFP) profiles to estimate multiple diffusion metrics simultaneously by neural network (NN) parameter quantification. A 12‐point bSSFP phase‐cycling scheme with high‐resolution whole‐brain coverage is employed at 3 and 9.4 T for NN input. Low‐resolution target diffusion data are derived based on diffusion‐weighted spin‐echo echo‐planar‐imaging (SE‐EPI) scans, that is, mean, axial, and radial diffusivity (MD, AD, and RD), fractional anisotropy (FA), as well as the spherical coordinates (azimuth Φ and inclination ϴ) of the principal diffusion eigenvector. A feedforward NN is trained with incorporated probabilistic uncertainty estimation. The NN predictions yielded highly reliable results in white matter (WM) and gray matter structures for MD. The quantification of FA, AD, and RD was overall in good agreement with the reference but the dependence of these parameters on WM anisotropy was somewhat biased (e.g. in corpus callosum). The inclination ϴ was well predicted for anisotropic WM structures, while the azimuth Φ was overall poorly predicted. The findings were highly consistent across both field strengths. Application of the optimized NN to high‐resolution input data provided whole‐brain maps with rich structural details. In conclusion, the proposed NN‐driven approach showed potential to provide distortion‐free high‐resolution whole‐brain maps of multiple diffusion metrics at high to ultrahigh field strengths in clinically relevant scan times. [ABSTRACT FROM AUTHOR]