Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington's disease

Abstract

The aim of this study was to examine basal ganglia volumes and regional cerebral blood flow in asymptomatic subjects at-risk for Huntington's disease who had undergone genetic testing. We determined which measures were the best 'markers' for the presence of the mutation and for the onset of symptoms. Twenty subjects who were Huntington's disease gene mutation-positive and 24 Huntington's disease gene mutation-negative participants, all of whom had a parent with genetically confirmed Huntington's disease, and were therefore 50% at-risk for inheriting the Huntington's disease gene mutation, were included in the study. To evaluate basal ganglia structure and function, MRI and single photon emission computed tomography (SPECT) were used. Quantitative measures of regional volumes and relative measures of regional perfusion were calculated. SPECT and MRI scans were co-registered so that MRI anatomy could be used accurately to place SPECT regions. Estimated years-to-onset in the mutation-positive subjects was calculated based on a regression formula that included gene (CAG)(n) repeat length and parental age of onset. Changes in imaging measures in relation to estimated years-to-onset were assessed. The imaging measure that was most affected in mutation-positive subjects was putamen volume. This was also the measure that correlated most strongly with approaching onset. In subjects >/=7 years from estimated onset age, the putamen volume measures were similar to those of the mutation-negative subjects. However, in subjects </=6 years from estimated onset age, there were dramatic reductions in putamen volume, resulting in >90% discrimination from both the far-from-onset and the mutation-negative subjects. Caudate volume and bicaudate ratio also showed a significant decline in the close-to-onset subjects, although to a lesser degree than putamen volume reductions. Furthermore, SPECT basal ganglia perfusion deficits were observed in mutation-positive subjects. Imaging markers of neuropathological decline preceding clinical onset are important for assessing the effects of treatments aimed at slowing the course of Huntington's disease. The current study suggests that quantitative assessment of basal ganglia may provide a means to track early signs of decline in individuals with the Huntington's disease gene mutation prior to clinical onset.

Basal ganglia volume and clinical correlates in ‘preclinical’ Huntington’s disease

“…The main new finding is that smaller basal ganglia volumes in gene carriers were associated with subtle motor abnormalities and worse performances on psychomotor tasks. The results confirm previous MRI studies showing that gene carriers in the preclinical stage of HD have a smaller caudate nucleus, putamen and globus pallidus compared to non-gene carriers [9,10,12,20,37]. However, we could not confirm the finding that thalamus volume was reduced in gene carriers [12].…”

“…■ Key words Huntington's disease · preclinical · imaging · cognition made [8][9][10][11][12]. Approaching disease onset globus pallidus volume and thalamus volume was found to be reduced as well [8,9,12].…”

Striatal and extrastriatal atrophy in Huntington's disease and its relationship with length of the CAG repeat

“…There is evidence of distributed gray matter pathology and progressive white matter pathology before the clinical onset of HD (5,19), and loss of basal ganglia volume has also been reported in asymptomatic individuals with HD mutation (20)(21)(22)(23)(24), indicating that striatal neuronal loss occurs before or early during the clinical course.…”

Progress in Huntington’s disease: the search for markers of disease onset and progression

“…There is also evidence of atrophy in many other brain structures including the frontal lobes, thalamus, globus pallidus and insula [2,12,28,42] with abnormalities in both white matter [9,31] and cortical grey matter [39] during the pre-manifest stage. However, there is still discussion about the relationship between these abnormalities and the onset of disease or whether they could also have some developmental basis.…”