Cross-sectional (Intercept) Differences in WM Profiles

Like previous studies, our analyses detected widespread WM differences inclusive of regions in every lobe of the brain. Components most sensitive to differences between Controls and all three CAP groups (i.e., those significant in all three Control group contrasts: X, N, O, AB, and C) were most commonly parietal. Areas of overlap among these components included angular gyrus (in three of the five components), superior temporal gyrus, superior and middle occipital, and inferior parietal lobule. Notably, component X included premotor, primary motor, and supplementary motor cortices, which exhibited the most robust effects in the largest

longitudinal study of prodromal WM tract changes to date (24). Differences between CAP groups were best represented by components T (cerebellar), Q (parietal), and A

(temporal/parietal), which yielded significant differences in every CAP group comparison (Low vs. Medium, Low vs. High, and Medium vs. High); component Q (inferior parietal,

supramarginal gyrus) differed the most across CAP-group comparisons. These substantive cross- sectional results suggest a pattern in which the most reliable group differences begin in superior temporal and parietal (Control > Low) and later extend into inferior parietal in the middle and late prodrome.

Three components (T, Q, and N) exhibited the most robust intercept effects across

prodromal and control group comparisons, with significant differences in five out of six contrasts (no component was significant in every intercept contrast). These components had few

overlapping regions; component T most strongly represented cerebellar posterior lobe (along with cerebellum crus 1 and uvula), component Q sub-gyral inferior parietal WM, and component N superior and middle temporal WM (with weaker parietal and occipital contributions). These

three components are superimposed in Figure 5.5—1. Although the non-significant contrast was different among the three components (Control vs. Low for component T, Control vs. Medium for component Q, Low vs. Medium for component N), it reassuringly never included the High group (i.e., the High group was always different from the other groups for these components). Across components, significant differences were also most common in comparisons with the High group, conforming with the expectation that the most robust cross-sectional differences would be observed in the group closest to HD-onset.

Figure 5.5-1. Components with the strongest cross-sectional group differences

Superimposition of the three components with the strongest cross-sectional (intercept) effects across groups (components T, Q, and N, thresholded at p = 0.05). These components were significant in all but one of the possible CAP-group comparisons, highlighting differences across prodromal groups. Primary regions represented in each component are listed along with corresponding MNI coordinates (x, y, z).

5.5.2 Longitudinal (Slope) Differences in WM Profiles

The longitudinal analysis also highlighted parietal component Q, which was significant in every slope contrast, indicating differences in the rate of change in these regions at each

prodromal time point. As expected, the most rapid prodromal change occurred in the High group and the slowest change in the Low group, with change in the Control group lagging behind that of any prodromal group. Areas within component Q, including the inferior parietal lobe and lobule, supramarginal gyrus/BA40, frontal lobe, and postcentral gyrus, may most readily

undergo WM changes throughout the prodrome. Other components with prominent group

differences in trajectory of change (components AF, T, F, AA and H, which were significant in five out of six contrasts) either: (1) showed robust group differences both cross-sectionally and longitudinally or (2) had a strong slope/longitudinal effect but only one or no significant baseline effect.

(1) In addition to inferior parietal component Q, components T (cerebellum posterior

lobe, cerebellum crus 1, uvula, and other cerebellar areas) and AA (left middle frontal gyrus

and other frontal regions) showed robust effects in both cross-sectional and longitudinal analyses, suggesting that group differences, as well as changes, are detectable in these

regions.

(2) Thalamic component AF (significant only in the High vs. Control intercept contrast) and premotor/supplementary motor/frontal component F (significant only in the Low vs. Control intercept contrast) displayed robust longitudinal effects despite few cross-sectional differences (Figure 5.5—2), suggesting that WM changes in these regions occur throughout the prodrome but may be challenging to detect cross-sectionally.

Figure 5.5-2. Components exhibiting significant change but not baseline differences Examples of white matter profiles that changed at significantly different rates among groups but did not exhibit significant group differences at baseline

Although several components with longitudinal group differences had no intercept differences, the reverse was rarely true; only occipital component AB (cuneus, left calcarine, BA17/V1) lacked slope but not intercept effects (component AB was significant in four intercept contrasts). Fascinatingly, other components with maximum signals from these regions (e.g., components Z and AE) also had fewer slope than intercept effects, which was not a common occurrence across components. In each of these cases, significant differences were observed at baseline but little change was seen over time across groups.

Regarding comparisons with the Control group, frontal components that were most significant longitudinally were least likely to show prominent cross-sectional effects (e.g., components AC and K), and conversely other components like striatal component S and parietal component Q did show significant intercept effects. The comparison with the Control group suggests that prodromal differences from controls in striatal and parietal WM may be easier to detect cross-sectionally than some frontal changes, even though changes in all

regions in previous studies, and is consistent with our findings in gray matter, where SBM probed frontal differences that were not detected by a similar univariate analysis (23).

The suggested patterns of most robust change among the intercept and slope results is similar for the Medium and High groups but distinct for the early prodrome. In other words, cross-sectional and longitudinal findings highlighted many of the same regions in the Medium and High groups, whereas areas most implicated in the Low group differed in the intercept compared to slope results. All results highlighted inferior parietal component Q as strongly representative of changes in the middle and late prodrome. However, the most prominent early (Control and Low) cross-sectional differences manifested in temporal and superior parietal regions, whereas the longitudinal results singled out the most substantial early changes in premotor, supplementary motor and middle frontal component AC (in addition to

commonly reported striatal and sub-gyral areas in component S) and highlighted many

other frontal components in this early contrast. Cross-sectional effects were also weaker

overall, but it is comforting for the sake of study feasibility everywhere that similar

interpretations become apparent across cross-sectional and longitudinal analyses, especially at later prodromal phases when intercept and slope results shared more regional overlap.