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Squitieri F.,Center for Neurogenetics and Rare Diseases | Landwehrmeyer B.,University of Ulm | Reilmann R.,University of Munster | Rosser A.,University of Cardiff | And 5 more authors.
Neurology | Year: 2013

Objective: To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease. Methods: Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day). Results: Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported ≥1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and ≥1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported ≥1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified. Conclusion: Pridopidine (≤90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year. Classification of evidence: This study provides Class IV evidence that pridopidine (≤90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year. © 2013 American Academy of Neurology. Source


Ramos E.M.,Massachusetts General Hospital | Ramos E.M.,University of Porto | Latourelle J.C.,Boston University | Lee J.-H.,Massachusetts General Hospital | And 26 more authors.
Human Genetics | Year: 2012

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modiWer of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these Wndings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratiWcation. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modiWer of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratiWcation among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reXect population diVerences in genetic or environmental factors that warrant further investigation. © The Author(s) 2012. Source


Sanchez-Castaneda C.,IRCCS Santa Lucia Foundation | Sanchez-Castaneda C.,University of Barcelona | Squitieri F.,Center for Neurogenetics and Rare Diseases | Di Paola M.,IRCCS Santa Lucia Foundation | And 4 more authors.
Human Brain Mapping | Year: 2015

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P=0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P<0.05). Volume instead decreases in basal ganglia, starting from the caudate (P<0.0001) and extending to the putamen and globus pallidus (P≤0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P<0.027); extending to premotor and parieto-temporo-occipital areas in patients (P<0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P<0.023) and SS (P<0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P<0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex. Hum Brain Mapp, 36:-66, 2015. © 2014 Wiley Periodicals, Inc. Source


Sanchez-Castaneda C.,Autonomous University of Barcelona | Squitieri F.,Center for Neurogenetics and Rare Diseases | Di Paola M.,University of LAquila | Petrollini M.,Center for Neurogenetics and Rare Diseases
Human Brain Mapping | Year: 2014

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P=0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P<0.05). Volume instead decreases in basal ganglia, starting from the caudate (P<0.0001) and extending to the putamen and globus pallidus (P≤0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P<0.027); extending to premotor and parieto-temporo-occipital areas in patients (P<0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P<0.023) and SS (P<0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P<0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex. © 2014 Wiley Periodicals, Inc. Source


Ramos E.M.,Massachusetts General Hospital | Ramos E.M.,University of Porto | Latourelle J.C.,Boston University | Gillis T.,Massachusetts General Hospital | And 40 more authors.
Neurogenetics | Year: 2013

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations. © 2013 The Author(s). Source

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