Center for Neurogenetics and Rare Diseases

Pozzilli, Italy

Center for Neurogenetics and Rare Diseases

Pozzilli, Italy

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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.


Sanchez-Castaneda C.,Autonomous University of Barcelona | Squitieri F.,Center for Neurogenetics and Rare Diseases | Di Paola M.,University of L'Aquila | 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.


Ramos E.M.,Massachusetts General Hospital | Ramos E.M.,University of Porto | Latourelle J.C.,Boston University | Gillis T.,Massachusetts General Hospital | And 41 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).


Eatough V.,Birkbeck, University of London | Santini H.,Huntingtons Disease Association | Eiser C.,University of Sheffield | Goller M.-L.,Uppsala University Hospital | And 11 more authors.
European Journal of Human Genetics | Year: 2013

The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington's disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington's disease; living with the disease; other people's knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe. © 2013 Macmillan Publishers Limited.


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.


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.


Di Paola M.,IRCCS Santa Lucia Foundation | Di Paola M.,University of L'Aquila | Phillips O.R.,IRCCS Santa Lucia Foundation | Sanchez-Castaneda C.,IRCCS Santa Lucia Foundation | And 7 more authors.
Human Brain Mapping | Year: 2014

Increased iron in subcortical gray matter (GM) structures of patients with Huntington's disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*-weighted gradient echo-planar imaging for MR-based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well-defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD. © 2013 Wiley Periodicals, Inc.


Sanchez-Castaneda C.,IRCCS Santa Lucia | Sanchez-Castaneda C.,University of Barcelona | Cherubini A.,IRCCS Santa Lucia | Elifani F.,Center for Neurogenetics and Rare Diseases | And 7 more authors.
Human Brain Mapping | Year: 2013

Neurodegeneration of the striatum in Huntington disease (HD) is characterized by loss of medium-spiny neurons, huntingtin nuclear inclusions, reactive gliosis, and iron accumulation. Neuroimaging allows in vivo detection of the macro- and micro-structural changes that occur from presymptomatic stages of the disease (preHD). The aim of our study was to evaluate the reliability of multimodal imaging as an in vivo biomarker of vulnerability and development of the disease and to characterize macro- and micro-structural changes in subcortical nuclei in HD. Macrostructure (T1-weighted images), microstructure (diffusion tensor imaging), and iron content (R2*relaxometry) of subcortical nuclei and medial temporal lobe structures were evaluated by a 3 T scanner in 17 preHD carriers, 12 early-stage patients and 29 matched controls. We observed a volume reduction and microstructural changes in the basal ganglia (caudate, putamen, and globus pallidus) and iron accumulation in the globus pallidus in both preHD and symptomatic subjects; all these features were significantly more pronounced in patients, in whom degeneration extended to the other subcortical nuclei (i.e., thalamus and accumbens). Mean diffusivity (MD) was the most powerful predictor in models explaining more than 50% of the variability in HD development in the caudate, putamen, and thalamus. These findings suggest that the measurement of MD may further enhance the well-known predictive value of striatal volume to assess disease progression as it is highly sensitive to tissue microimpairment. Multimodal imaging may detect brain changes even in preHD stages. © 2012 Wiley Periodicals, Inc.


Ciarmiello A.,S Andrea Hospital | Giovacchini G.,S Andrea Hospital | Orobello S.,Center for Neurogenetics and Rare Diseases | Bruselli L.,S Andrea Hospital | And 2 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2012

Purpose: To test in a longitudinal follow-up study whether basal glucose metabolism in subjects with a genetic risk of Huntington disease (HD) may influence the onset of manifest symptoms. Methods: The study group comprised 43 presymptomatic (preHD) subjects carrying the HD mutation. They underwent a 18F-FDG PET scan and were prospectively followed-up for at least 5 years using the unified HD rating scale to detect clinical changes. Multiple regression analysis included subject's age, CAG mutation size and glucose uptake as variables in a model to predict age at onset. Results: Of the 43 preHD subjects who manifested motor symptoms, suggestive of HD, after 5 years from the PET scan, 26 showed a mean brain glucose uptake below the cut-off of 1.0493 in the caudate, significantly lower than the 17 preHD subjects who remained symptom-free (P<0.0001). This difference was independent of mutation size. Measurement of brain glucose uptake improved the CAG repeat number and age-based model for predicting age at onset by 37 %. Conclusion: A reduced level of glucose metabolism in the brain caudate may represent a predisposing factor that contributes to the age at onset of HD in preHD subjects, in addition to the mutation size. © 2012 Springer-Verlag.


PubMed | Center for Neurogenetics and Rare Diseases
Type: Journal Article | Journal: Neurology | Year: 2013

To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease.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).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.Pridopidine (90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year.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.

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