fMRI detection of early neural dysfunction in preclinical Huntington's disease

Abstract

Neuropsychological and neuroimaging changes have been observed in individuals with the Huntington's disease (HD) gene expansion prior to the onset of manifest HD. This cross-sectional fMRI study of preclinical HD (pre-HD) individuals was conducted to determine if functional brain changes precede deficits in behavioral performance and striatal atrophy. Twenty-six pre-HD and 13 demographically matched healthy participants performed a time reproduction task while undergoing fMRI scanning. Pre-HD participants were divided into two groups (n=13 each): FAR (>12 years to estimated onset [YEO] of manifest HD) and CLOSE (<12 YEO). The CLOSE group demonstrated behavioral deficits, striatal atrophy, and reduced neural activation in the left putamen, SMA, left anterior insula and right inferior frontal gyrus. The FAR group showed reduced neural activation in the right anterior cingulate and right anterior insula. The FAR group also demonstrated increased neural activation in the left sensorimotor, left medial frontal gyrus, left precentral gyrus, bilateral superior temporal gyri and right cerebellum. The fMRI changes in the FAR group occurred in the relative absence of striatal atrophy and behavioral performance deficits. These results suggest that fMRI is sensitive to neural dysfunction occurring more than 12 years prior to the estimated onset of manifest HD.

Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach

“…Indeed, cross-sectional and longitudinal MRI studies have suggested that structural brain changes in carriers of the HD mutation may serve as biomarkers and potentially as surrogate endpoints in clinical trials [2,3,4,5,6]. However, intact brain structure in preHD has also been reported [7,8,9,10]. It is unlikely that these discrepancies can be solely explained by differing sample sizes, since clinical characteristics, such as the proximity to the onset of motor signs [5,11,12], and different analysis procedures [13] may also account for data heterogeneity.…”

Magnetization Transfer Imaging in Premanifest and Manifest Huntington Disease: A 2-Year Follow-Up

“…Two reports exist on increased activation in premanifest HD, which is thought to represent cortical recruitment as a compensatory strategy; this was specifically true for premanifest HD far from expected onset and not in the close to onset group. 33,34 In our view, any of these proposed explanations could be true; however, we should be extremely cautious not to overly interpret the findings because the correction for multiple comparisons reduced the number and strength of the findings. This finding could, however, lead to broader examination of MTI and other MR imaging measures in the premanifest far from disease onset group because this potentially can lead to better understanding of the neuropathology in HD.…”

First use of creatine hydrochloride in premanifest Huntington disease

“…It is now well-documented that cortical degeneration precedes clinical features, which further implicates long-term neuronal dysfunction in pathology 5,[19][20][21] . Neuronal loss, particularly in the striatum and cortex, leads to additional neurological and motor deficits 22,23 .…”

“…Volumetric muscle strength changes in the upper and lower body showed highly significant, progressive increases in total group muscle strength, and significant increases for female (p<0.03) and male (p<0.02) subgroups, in all exercises after 9 months intervention (p<0.0005; Figure 40). [21], and separately for female [11] and male [10] sub-groups to indicate gender response). Highly significant increases in muscle strength were achieved for each of the above exercises after 9 months intervention (p<0.0005).…”