**4. Discussion**

In this study, we have utilized a novel neuroimaging method to demonstrate that metabolic abnormalities likely affect the caudate, putamen, globus pallidus, and thalamus in patients with JOHD. However, there were no significant group differences for the mean T1ρ relaxation time in the anterior cerebellum, an area which also controls motor function. Similarly, there were no significant differences in T1ρ relaxation times in the hippocampus between the JOHD and control groups. These results are interesting because the cerebellum is thought to be spared in HD and has even been found to be proportionally enlarged in JOHD [2]. The cerebellum has been hypothesized to play a compensatory role in HD and potentially in JOHD and these results may provide additional support for this theory [24].

The increases in subcortical T1ρ relaxation times were directly related to CAG repeat length in the JOHD group, increasing the likelihood that these findings are related to pathological changes. The disease burden score significantly predicted T1ρ relaxation times in the caudate and thalamus, but did not reach the level of significance for predicting relaxation times in the putamen and globus pallidus, despite a trend in that direction. Again, these findings indicate that T1ρ relaxation times seem to be indicative of disease severity and may be used as a unique measure of disease progression in JOHD. This is further supported by the finding that the longer duration of disease of JOHD was associated with significantly higher T1ρ relaxation times in the caudate, putamen, and globus pallidus.

Patients with JOHD often experience unique motor symptoms. Specifically, patients with JOHD may have less chorea, but more hypokinetic symptoms, including bradykinesia and dystonia [25]. These symptoms can be very di fficult to treat and the underlying pathology of this di fference between JOHD and AOHD is poorly understood. All of the subcortical regions that we analyzed were significantly and positively associated with the total motor score on the UHDRS. Additionally, relaxation times in the caudate and putamen significantly predicted total scores on the JOHD-specific motor assessment scale. This suggests that metabolic abnormalities in the striatum may drive the unique hypokinetic motor deficits of JOHD.

There are some potential limitations to this study. T1ρ MRI abnormalities in JOHD are not indicative of a specific metabolic dysfunction since it is sensitive to changes in several factors including pH, glucose, glutamate, water, and proteins. Further research using magnetic resonance spectroscopy may investigate specific molecular imbalances in the brain regions identified within this study. Additionally, T1ρ MRI images were captured last in a series of di fferent neuroimaging tests, so JOHD participants with more severe symptoms were not able to complete T1ρ imaging. However, participants with very severe symptoms may have significantly diminished the striatum that is di fficult to measure. Finally, the current study was limited by its small sample size due to the rarity of JOHD. As a result, further studies are required to confirm these results in an expanded patient population.
