BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

Evidence from magnetic resonance imaging (MRI) suggests early structural and functional brain changes in individuals with the Huntington's disease (HD) gene mutation who are presymptomatic for the motor symptoms of the disorder (pre-HD subjects). The objective of this study was to investigate the functional neuroanatomy of verbal working memory (WM) in pre-HD subjects. By means of event-related functional MRI, we studied healthy controls (n = 16) and pre-HD subjects (n = 16) with a parametric WM paradigm comprising three different WM load levels. Voxel-based morphometry (VBM) was used to control potentially confounding brain atrophy. Although WM performance did not significantly differ between pre-HD subjects and healthy controls, pre-HD subjects showed a significantly decreased activation of the left dorsolateral prefrontal cortex (DLPFC) at intermediate and high WM load levels only. This region was not affected by early cortical atrophy, as revealed by VBM. Pre-HD individuals close to the onset of motor symptoms showed an increased activation of the left inferior parietal lobule and the right superior frontal gyrus compared with both pre-HD subjects far from symptom onset and healthy controls. In addition, the activation level in the left DLPFC was positively correlated with the UHDRS cognitive subscore in pre-HD subjects. Our findings demonstrate that early functional brain changes in pre-HD subjects may occur in the DLPFC before manifest cortical atrophy, and support a role of this region in the expression of clinical symptoms. Compensatory brain responses in pre-HD individuals may occur with closer proximity to the onset of manifest clinical symptoms.

The pattern of motor, behavioral and cognitive symptoms in Huntington's disease (HD) implicates dysfunction of basal-ganglia-thalamo-cortical circuits. This study explored if cognitive performance in HD is correlated with localized cerebral changes. Psychomotor functions were investigated by verbal fluency, Stroop color word and Digit Symbol tests in 44 HD patients and 22 controls. Three-dimensional magnetic resonance imaging (MRI) data were analyzed with regard to regional gray matter changes by use of the observer-independent whole-brain-based approach of voxel-based morphometry (VBM). Using statistical parametric mapping, the MRI data of the HD patients were analyzed in an ANCOVA including the individual results of the neuropsychological tests. Besides striatal areas, symmetrical regional atrophy of the thalamus was found to co-vary significantly with cognitive performance (P < 0.001, corrected for multiple comparisons). In particular, thalamic subnuclei projecting to prefrontal areas (dorsomedial subnucleus) and connected to the striatum (centromedian/parafascicular and ventrolateral nuclear complex) displayed volume loss, in agreement with neuropathological studies. These results suggest that thalamic degeneration contributes in an important way to the impairment of executive function in early HD. Patients who are impaired in executive tests display structural double lesions of the basal-ganglia-thalamo-cortical circuitry both at the striatal and at the thalamic level.

Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

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