Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra-strong gradient MRI

Abstract

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

Keywords: MRI; axon; myelin; premanifest Huntington disease; white matter microstructure.

FIGURE 1

Callosal segmentation. For each segment, the corresponding anatomical label is reported, together with the cortical area it connects to

FIGURE 2

The TBCA analysis pipeline. After all images have been normalized to a common anatomical space, statistics maps are produced based on the voxel‐level analysis of the data; this is done by using a nonparametric approach based on a permutation test strategy (Winkler et al., 2014). The statistic maps are thresholded by a value of p = .01. Next, the significant voxel level statistic results are projected on a hypervoxel template. Finally, significant clusters of hypervoxels are identified. Figure from Luque Laguna (2019)

FIGURE 3

PCA of the cognitive data with varimax rotation. Plot summarizing how each variable is accounted for in the extracted PC. The absolute correlation coefficient is plotted. Color intensity and the size of the circles are proportional to the loading. This PC accounted for 38.7% of the total variance and included measures from all test domains, except for the digit span. Four patients were excluded from the PCA because of missing data. The final sample size for the PCA was n = 21 patients

FIGURE 4

PCA of the microstructure metrics with varimax rotation. Left: Plot summarizing how each variable is accounted for in every principal component. The absolute correlation coefficient is plotted. Color intensity and the size of the circles are proportional to the loading. The final sample size for the PCA was n = 25 for the HD group and n = 24 for the control group. Right: Segment clustering based on PC1 and PC2. The horizontal axis shows increasing restriction or hindrance perpendicular to the main axis of the bundles. The vertical axis represents an increase in MTR. Each point represents one subject. Concentration ellipsoids cover 95% confidence around the mean. Segment 7 appears to encompass most of the data variability

FIGURE 5

Callosal magnetization transfer: patient‐control differences across callosal segments (top), and relationship between age and inter‐individual variability in the magnetization transfer component (bottom). A group‐by‐segment interaction effect (p = .04) was observed for callosal magnetization transfer, indicating that the effect of group was different for different callosal segments. Patients presented significantly higher magnetization transfer compared to controls in segment 1 (p = .016), and significantly lower in segment 7 (p = .034). Overall, scores on the magnetization transfer component for the patient group were higher than controls in the more anterior portions of the CC but lower in posterior portions. Additionally, a significant interaction effect between group and age indicated that, while older HD patients presented significantly lower magnetization transfer than age‐matched controls, the opposite was true for younger HD patients. *p < .05, **p < .01, ***p < .001, Bonferroni‐corrected

FIGURE 6

Relationship between magnetization transfer in each callosal segment and CAG repeat length in patients

FIGURE 7

Results of the cluster‐analysis obtained with TBCA between patients and controls (a), Spearman correlations between significant TBCA clusters in patients (b) (*p < .05, **p <0.01, ***p < .001, Bonferroni‐corrected), and plot of MTR in the posterior callosum versus FR in the CST in patients (c)