Association Between Motor Symptoms and Brain Metabolism in Early Huntington Disease

Abstract

Importance: Brain hypometabolism is associated with the clinical consequences of the degenerative process, but little is known about regional hypermetabolism, sometimes observed in the brain of patients with clinically manifest Huntington disease (HD). Studying the role of regional hypermetabolism is needed to better understand its interaction with the motor symptoms of the disease.

Objective: To investigate the association between brain hypometabolism and hypermetabolism with motor scores of patients with early HD.

Design, setting, and participants: This study started in 2001, and analysis was completed in 2016. Sixty symptomatic patients with HD and 15 healthy age-matched control individuals underwent positron emission tomography to measure cerebral metabolism in this cross-sectional study. They also underwent the Unified Huntington's Disease Rating Scale motor test, and 2 subscores were extracted: (1) a hyperkinetic score, combining dystonia and chorea, and (2) a hypokinetic score, combining bradykinesia and rigidity.

Main outcomes and measures: Statistical parametric mapping software (SPM5) was used to identify all hypo- and hypermetabolic regions in patients with HD relative to control individuals. Correlation analyses (P < .001, uncorrected) between motor subscores and brain metabolic values were performed for regions with significant hypometabolism and hypermetabolism.

Results: Among 60 patients with HD, 22 were women (36.7%), and the mean (SD) age was 44.6 (7.6) years. Of the 15 control individuals, 7 were women (46.7%), and the mean (SD) age was 42.2 (7.3) years. In statistical parametric mapping, striatal hypometabolism was significantly correlated with the severity of all motor scores. Hypermetabolism was negatively correlated only with hypokinetic scores in the cuneus (z score = 3.95, P < .001), the lingual gyrus (z score = 4.31, P < .001), and the crus I/II of the cerebellum (z score = 3.77, P < .001), a region connected to associative cortical areas. More severe motor scores were associated with higher metabolic values in the inferior parietal lobule, anterior cingulate, inferior temporal lobule, the dentate nucleus, and the cerebellar lobules IV/V, VI, and VIII bilaterally corresponding to the motor regions of the cerebellum (z score = 3.96 and 3.42 in right and left sides, respectively; P < .001).

Conclusions and relevance: Striatal hypometabolism is associated with clinical disease severity. Conversely, hypermetabolism is likely compensatory in regions where it is associated with decreasing motor scores. Hypermetabolism might be detrimental in other structures in which it is associated with more severe motor symptoms. In the cerebellum, both compensatory and detrimental contributions seem to occur. This study helps to better understand the motor clinical relevance of hypermetabolic brain regions in HD.

Figure 1.. Flowchart Depicting Study Design

SPM indicates statistical parametric mapping.

Figure 2.. Statistical Parametric Mapping Presenting Correlations of Motor Scores With Regional Metabolism

t Statistics maps of the correlation analyses computed between the extracted glucose metabolism values and clinical motor scores (P < .001, uncorrected) using the hypometabolic and hypermetabolic masks are overlaid on 3 intersecting slices of a glass brain. Clusters of these maps are overlaid on the mean gray matter volume with axial, sagittal, and coronal views. Correlations with hypokinetic motor scores (A, C, and E) and correlations with hyperkinetic motor scores (B, D, and F).

Figure 3.. Correlation of Motor Scores With Hypermetabolism in the Cerebellum

A, Left: clusters overlaid on axial slice (z = −36) from a canonical brain T1 image showing negative correlations. Hypokinetic motor scores correlated with hypermetabolic values in the left crus II of the cerebellum. Right: correlation plot on the left crus II region (R² = 0.98). B, Left: clusters overlaid on coronal slices at 2 different y coordinates showing positive correlations between hypermetabolic values and hyperkinetic motor scores bilaterally in the lobules IV-V, VI, VIII, and IX in the cerebellum. Right: correlation plot on the right lobules IV, V, VI, VIII, and IX (R² = 0.95).