In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7.

Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy ((1) H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi-LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n=16), SCA2 (n=12), SCA3 (n=21), and SCA7 (n=12) and healthy controls (n=33). Compared with controls, patients displayed lower total N-acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo-Ins), was elevated. Patients also showed higher total creatine as reported in Huntington's disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N-acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo-Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell-specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof-of-concept therapeutic trials. © 2015 International Parkinson and Movement Disorder Society.

The structural correlates of functional deficits in early huntington's disease.

Neuropathological studies in Huntington disease (HD) have demonstrated neuronal loss in the striatum, as well as in other brain regions including the cortex. With diffusion tensor MRI we evaluated the hypothesis that the clinical dysfunction in HD is related to regionally specific lesions of circuit-specific cortico-basal ganglia networks rather than to the striatum only. We included 27 HD and 24 controls from the TRACK-HD Paris cohort. The following assessments were used: self-paced tapping tasks, trail B making test (TMT), University of Pennsylvania smell identification test (UPSIT), and apathy scores from the problem behaviors assessment. Group comparisons of fractional anisotropy and mean diffusivity and correlations were performed using voxel-based analysis. In the cortex, HD patients showed significant correlations between: (i) self paced tapping and mean diffusivity in the parietal lobe at 1.8 Hz and prefrontal areas at 3 Hz, (ii) UPSIT and mean diffusivity in the parietal, and median temporal lobes, the cingulum and the insula, and fractional anisotropy in the insula and the external capsule, (iii) TMT B and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal and post central areas, and (iv) apathy and fractional anisotropy in the white matter of the rectus gyrus. In the basal ganglia, we found correlations between the self paced tapping, UPSIT, TMT tests, and mean diffusivity in the anterior part of the putamen and the caudate nucleus. In conclusion, disruption of motor, associative and limbic cortico-striatal circuits differentially contribute to the clinical signs of the disease.

Critical roles for anterior insula and dorsal striatum in punishment-based avoidance learning.

The division of human learning systems into reward and punishment opponent modules is still a debated issue. While the implication of ventral prefrontostriatal circuits in reward-based learning is well established, the neural underpinnings of punishment-based learning remain unclear. To elucidate the causal implication of brain regions that were related to punishment learning in a previous functional neuroimaging study, we tested the effects of brain damage on behavioral performance, using the same task contrasting monetary gains and losses. Cortical and subcortical candidate regions, the anterior insula and dorsal striatum, were assessed in patients presenting brain tumor and Huntington disease, respectively. Both groups exhibited selective impairment of punishment-based learning. Computational modeling suggested complementary roles for these structures: the anterior insula might be involved in learning the negative value of loss-predicting cues, whereas the dorsal striatum might be involved in choosing between those cues so as to avoid the worst.

Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease.

We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites - C5 ketone bodies - cross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)=33+/-13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and (31)P-NMR spectroscopy (NMRS) in muscle. At baseline, (31)P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205+/-60 ng/ml versus 246+/-68 ng/ml, P=0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD.

Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment.

Reliable and easy to perform functional scales are a prerequisite for future therapeutic trials in cerebellar ataxias. In order to assess the specificity of quantitative functional tests of cerebellar dysfunction, we investigated 123 controls, 141 patients with an autosomal dominant cerebellar ataxia (ADCA) and 53 patients with autosomal dominant spastic paraplegia (ADSP). We evaluated four different functional tests (nine-hole pegboard, click, tapping and writing tests), in correlation with the scale for the assessment and rating of cerebellar ataxia (SARA), the scale of functional disability on daily activities (part IV of the Huntington disease rating scale), depression (the Public Health Questionnaire PHQ-9) and the EQ-5D visual analogue scale for self-evaluation of health status. There was a significant correlation between each functional test and a lower limb score. The performance of controls on the functional tests was significantly correlated with age. Subsequent analyses were therefore adjusted for this factor. The performances of ADCA patients on the different tests were significantly worse than that of controls and ADSP patients; there was no difference between ADSP patients and controls. Linear regression analysis showed that only two independent tests, the nine-hole pegboard and the click test on the dominant side (P < 0.0001), accounted for the severity of the cerebellar syndrome as reflected by the SARA scores, and could be represented by a composite cerebellar functional severity (CCFS) score calculated as follows: [Formula: see text]. The CCFS score was significantly higher in ADCA patients compared to controls (1.12 +/- 0.18 versus 0.85 +/- 0.05, P(c) < 0.0001) and ADSP patients (1.12 +/- 0.18 versus 0.90 +/- 0.08, P(c) < 0.0001) and was correlated with disease duration (P < 0.0001) but independent of self-evaluated depressive mood in ADCA. Among genetically homogeneous subgroups of ADCA patients (Spinocerebellar ataxia 1, 2, 3), SCA3 patients had significantly lower (better) CCFS scores than SCA2 (P(c) < 0.04) and the same tendency was observed in SCA1. Their CCFS scores remained significantly worse than those of ADSP patients with identified SPG4 mutations (P < 0.0001). The pegboard and click tests are easy to perform and accurately reflect the severity of the disease. The CCFS is a simple and validated method for assessing cerebellar ataxia over a wide range of severity, and will be particularly useful for discriminating paucisymptomatic carriers from affected patients and for evaluating disease progression in future therapeutic trials.