Brain Network Changes Appear Decades Before Motor Symptoms in Huntington Disease

New longitudinal data from the Huntington's Disease Young Adult Study (HD-YAS) show that functional connectivity (FC) changes in the brain are already detectable in gene-expanded individuals who are, on average, more than two decades from predicted clinical motor onset. The study, published in Movement Disorders, followed 43 Huntington disease gene-expanded (HDGE) adults and 28 matched controls over approximately 4.8 years using resting-state fMRI seeded on the bilateral caudate and putamen.¹

The findings revealed a mixed picture. In the study, HDGE participants showed reduced connectivity between the putamen and cerebellar/brainstem regions, alongside increased connectivity between the putamen and parietal hubs of the default mode network. Over time, the right caudate showed progressively declining connectivity with frontal, occipital, and intra-striatal regions in HDGE individuals, a trajectory that diverged from the pattern seen in controls.

Recently, NeurologyLive^® spoke with Michela Leocadi, PhD, research fellow in the Department of Neurodegenerative Disease of the Huntington's Disease Centre at UCL Queen Square Institute of Neurology and first author of the study. She talked about what these results from the study mean for clinical trial design, how to interpret the seemingly contradictory connectivity changes, and what comes next in this line of research.

NeurologyLive: What do these findings mean for how clinical trials in HD should be designed, given the changes are already there decades before symptoms start?

Michela Leocadi, PhD: Our findings add to a growing body of evidence suggesting that subtle changes already occur many years (decades even) before the appearance of overt clinical symptoms. In our cohort, participants were on average more than 2 decades from predicted clinical motor onset, yet we could already detect longitudinal changes in brain functional connectivity.

For clinical trials, this reinforces the idea that the optimal window for disease-modifying interventions may be much earlier than we traditionally considered. As therapies designed to slow or prevent neurodegeneration become available, there is increasing interest in identifying sensitive biomarkers that can detect disease progression during these very early stages, when individuals remain clinically well.

Our findings do not immediately support using functional connectivity as a trial outcome measure. However, they highlight specific neural circuits, particularly striatal-cerebellar and striatal-frontal networks, that may be informative to track alongside established biomarkers in HD, such as striatal atrophy, fluid markers, and cognitive/clinical measures. Ultimately, multimodal approaches will likely be needed to determine whether interventions are altering disease trajectories long before symptoms emerge.

More broadly, our results support a shift towards studying and treating the disease during its earliest phases, when neural systems may still retain the capacity to adapt and compensate for ongoing pathological processes.

How should clinicians think about the increased connectivity you saw? Is it a good sign of the brain adapting, or an early warning sign?

The short answer is that we do not yet know, and it is probably a combination of both.

One of the most interesting findings was the coexistence of reduced connectivity in some circuits, particularly between the putamen and cerebellar/brainstem regions, and increased connectivity in others, including between the putamen and regions of the Default Mode Network.

One possible interpretation is that the increased connectivity reflects compensatory or adaptive brain responses. In other words, as some neural systems begin to show subtle dysfunction, other networks may reorganize to help maintain normal behavior and clinical function. This would be consistent with the fact that our participants remained clinically asymptomatic despite showing evidence of underlying disease-related changes, including striatal atrophy and alterations in biofluid biomarkers.

This could be viewed as encouraging, as it suggests that the brain retains some capacity to adapt in the face of early pathology. At the same time, however, these changes may also represent an early warning sign that these compensatory mechanisms are becoming increasingly challenged and may eventually become insufficient.

Increased connectivity should not automatically be interpreted as beneficial. Hyperconnectivity may also reflect network stress or instability, representing an early sign that the brain is responding to underlying pathology. In addition, our longitudinal findings in the right caudate suggest that these patterns are not necessarily sustained over time. Compared with controls, gene-expanded participants showed progressive reductions in connectivity, raising the possibility that early compensatory responses may diminish as neurodegeneration progresses.

Rather than classifying these changes as either "good" or "bad", I think it is more accurate to view them as evidence that the brain is actively responding to disease processes long before symptoms develop.

What's the next step to figure out whether these connectivity changes actually predict who will develop symptoms sooner?

The crucial next step is longer-term follow-up. The HD-Young Adult Study is ongoing, and we are continuing to collect valuable longitudinal data over a much longer period than the 2 visits described in this publication.

To determine whether these connectivity changes have predictive value, we need studies that follow individuals over many years and relate early connectivity patterns to subsequent changes in motor, cognitive, psychiatric, and functional outcomes. If individuals with greater network disruption go on to experience faster clinical decline, that would provide evidence that these measures may have prognostic value.

Another important direction will be integrating functional connectivity with other biomarkers. HD research is increasingly moving toward multimodal models that combine imaging, fluid biomarkers, genetics, and clinical measures. Connectivity changes are unlikely to tell the whole story on their own, but they may provide unique information about how the brain is functioning as a network, complementing measures of structural degeneration.

Ultimately, the goal is to determine whether these early network changes are simply markers of disease presence or whether they can help predict the timing and pace of disease progression in individual patients.

Transcript edited for clarity. Click here to view more of our HD coverage.

REFERENCES
1. Leocadi M, Hobbs NZ, Farag M, et al. Early Longitudinal Brain Network Changes in Huntington's Disease Before Clinical Motor Onset. Mov Disord. Published online August 9, 2026. doi:10.1002/mds.70461