Estado del arte o antecedentes

prodromal stages (and in fact did so better than any of the cognitive measures). However, consistent with the baseline findings, UHDRS-TMS changed at a different rate than WM in the High group, in which it underperformed in its similarity to WM compared to all the cognitive measures. In fact, UHDRS-TMS was the only clinical variable with no non-significant High slope differences from WM components. This different presentation in the High group reinforces the cross-sectional finding of similarities between UHDRS-TMS and WM that

exceed those observed with any of the cognitive variables until the late prodrome.

More surprisingly, TMTA also exhibited strong similarity to WM both cross-sectionally and longitudinally. Like UHDRS-TMS, TMTA changes were most similar to earlier prodromal WM changes. However, unlike UHDRS-TMS, TMTA slope also aligned well with High component slopes, indicating that TMTA may be the most reliable cognitive measure for

representing ongoing prodromal WM changes. Notably, of the cognitive variables, Stroop

Interference shared the most similarities with High group WM changes; however, WM changes were more consistent with TMTA change overall (i.e., robust similarities were observed at various prodromal stages).

The overall patterns of alignment among component and clinical variable

trajectories suggest that distinct regional changes accompany changes in different clinical functioning domains (Figure 5.5—3) and that these underlying changes differ across the

prodrome (especially in the late prodrome). Throughout prodromal progression, different

suggest that parietal areas may change the most steadily with both cognitive and motor functioning across the prodrome.

Figure 5.5-3. WM Changes and Clinical Functioning across the Prodrome

Simplified schematic depicting areas in which rates of change are most similar to changing motor (UHDRS-TMS) and cognitive functioning in each CAP group (yellow = Low, orange = Medium, red = High).

Some components reflected changing function in multiple clinical variables at certain prodromal stages (Figures 5.4.5—1 and 5.4.5—2), the most poignant example of which was seen in the Control group; postcentral gyral component J’s trajectory of change did not differ from that of any clinical measure in Controls, and was either the only effect (SDMT, SC, SI, TMTA) or the most robust effect (UHDRS-TMS, TMTB) observed in Controls. This postcentral

component displayed a relatively flat slope across control and prodromal groups, whereas the clinical functioning slopes revealed minimal change in controls (as expected) but substantial prodromal change; these discrepancies between Control and prodromal clinical change are the basis of the selective similarity between component J and clinical change trajectories in the

Control group. The Low group overall exhibited clinical changes that aligned well with parietal changes (components A, B, and D), but similarity was also observed in occipital (components A, B, and D) and temporal (components A and U) regions, as well as in the striatum (component U), corpus callosum (component E), cingulum (component E), and limbic lobe (components E and U). By the Medium prodromal stage, many of the same parietal, occipital, and temporal areas were changing at a rate similar to clinical measure changes, with more frontal areas (component K) changing similarly as well. By the High stage, fewer occipital components changed with clinical functioning, whereas many parietal, some frontal and more striatal components aligned with clinical changes. In the High group, the strongest WM-cognition links were observed in the absence of significant effects in any other group, indicating that regions most strongly

underlying cognitive changes may differ in the late compared to early and middle prodrome.

5.5.6 Summary

There were overlaps and differences among WM regions that most readily changed with prodromal progression (unstacked analyses) and those most implicated in cognitive and motor functioning across the prodrome (stacked analyses). Two components (A and B) stood out in both sets of analyses (Figure 5.5—4). One of these (A) is a mixture of parietal, temporal (especially middle) and to a lesser extent, occipital areas; the other (B) is mostly parietal (superior and inferior) and occipital (superior and middle). Notably, both of these components have strong representation from angular gyrus, the site of most parietal projections to striatal convergence zones (171). These components displayed prominent differences and changes across the prodrome as well as similarity with clinical changes.

Figure 5.5-4. Components with Robust Effects Across Analyses

Two WM profiles containing angular gyrus exhibited robust baseline and longitudinal group differences in addition to reliably aligning well with clinical functioning measures.

WM components that aligned most with clinical functioning typically also exhibited many significant group differences cross-sectionally and over time, indicating that areas essential for prodromal clinical functioning also differ across prodromal stages as well as between prodromal and control individuals.

5.6 Conclusions

Overall, these results support the hypothesis that largely distinct regions most underlie cognitive compared to motor impairments in the HD prodrome, and further suggest that regions underlying these processes differ at different prodromal stages.

These findings portray a widespread prodromal pattern of WM changes marked by intense, early motor cortical and middle frontal gyral (in additional to striatal) changes that increasingly extend sub-gyrally with increased prodromal progression.

The results are also in keeping with previous reports highlighting UHDRS-TMS as the best indicator of prodromal WM changes. However, at the High prodromal stage, cognitive variables (particularly Stroop Interference) outperformed UHDRS-TMS, and TMTA exhibited the most similarity to WM profiles overall across groups (especially cross-sectionally).

Many observations were in keeping with predictions; WM in the High and Low groups respectively differed most and least drastically from the Control group, and the most robust longitudinal changes in clinical functioning were also observed in the High group. The prediction that motor performance would most resemble striatal and motor-implicated frontal change was partially supported, but indicated a stronger frontal involvement in the early prodrome;

supplementary motor and striatal component changes most agreed with changing UHDRS-TMS performance in the Low and High groups, respectively.

Other findings contradicted predictions. Frontal WM changes did not align most with cognitive changes across the prodrome. Instead, many components that best reflected changing clinical functioning highlighted regions with prominent striatal connections as well as essential roles in cognition, such as the angular gyrus and middle frontal gyrus.

5.7 Limitations

Because HD is a rare condition, there is an unavoidable tradeoff between maximizing power (afforded by a large sample) and data homogeneity (enabled by uniform data collection). Like most studies involving many participants with an uncommon condition, PREDICT-HD collected data from multiple sites using unique MRI scanners. Several steps were taken to minimize the complications of analyzing multi-site data. Before data collection, PREDICT-HD established uniform protocols across sites. Following data collection, sites were examined for

outliers and unbalanced participant demographics. For analyses, random site intercepts were included to account for correlations due to inherent scanner or site-specific features. Notably, the SBM method itself has also been shown to eradicate site effects (100), and the reliability of DWI data collected across these sites has also been previously demonstrated (172).

5.8 Future Directions

Reports regarding the chronology of brain structural changes in prodromal HD are conflicting, and it is still unclear whether WM and gray matter (GM) changes occur mostly simultaneously or if robust changes in WM precede those in GM (or vice versa); thus, a

promising future direction for this work is to directly compare WM changes with those in GM, which could be achieved by applying SBM to the GM segmentations extracted in the first phase of this study and performing similar stacked LMM analyses to compare WM and GM trajectories from the same participants and scans. It is also possible that prodromal GM change more aptly reflects cognitive or motor changes, which could similarly be addressed in an analogous LMM study assessing GM in conjunction with clinical variables.

6 DISCUSSION