1,721,047 research outputs found
Juvenile Huntington's disease: Does a dosage-effect pathogenic mechanism differ from the classical adult disease?
No full textHuntington's disease (HD) is caused by a CAG repeat mutation translating as a polyglutamine (poly(Q)) expansion in the huntingtin protein, whose main pathogenic mechanism is a gain of toxic function. In the case of large expansions beyond 60 repeats onset may result in juvenile HD (JHD, onset before 20 years of age). However, the triplet number does not represent the only onset modifier even in case of large expansions, mechanisms other than the size of the mutation contribute to the phenotype. In this review we discuss the possibility that some of the pathogenic mechanisms contributing to age at onset and progression may differ in the early onset HD compared with the classical adult pathology. (c) 2005 Elsevier Ireland Ltd. All rights reserved
Task-switching abilities in pre-manifest Huntington's disease subjects
No full textIntroduction: Huntington's Disease (HD) cognitive dysfunction occurs before unequivocal motor signs become apparent. The predominant early cognitive abnormal domains may include deficits in psychomotor speed, negative emotion recognition and executive functioning. Our study is aimed to investigate the executive control of cognition in pre-manifest (pre) HD subjects, by means of a task-switching protocol. Methods: We recruited 30 pre-HD subjects and 18 age-, sex- and education-matched Healthy Controls (HC). Subjects were assigned to two experimental groups: 15 pre-HD1 with a Total Motor Score (TMS) ≤4 (far from onset) and 15 pre-HD2 with a 5 ≤ TMS≤9 (near to onset and Diagnostic Confidence Level (DCL) still<4). Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called Switch Cost (SC). Results: Pre-HD subjects had worse performance than HC in the switch and repetition trials, as indicated by increased SC and reaction times. In particular, pre-HD2 showed impaired switching abilities with reaction times slower than pre-HD1 and HC. Conclusions: Our study highlighted a task-switching impairment since HD was still at a pre-manifest stage. Such abnormalities worsen when pre-HD subjects start to show subtle motor manifestations, still nonspecific and insufficient to define the clinical diagnosis of HD (DCL<4). Considering that such abilities have obvious implications for activities of daily living, early cognitive rehabilitation programs addressing such deficits might be useful in the premanifest stage of the disease
Virtual reality tolerability, sense of presence and usability in Huntington disease: a pilot study
No full textIntroduction: Several studies demonstrated the utility of immersive virtual reality (VR) as a complementary approach to conventional therapy for improving motor, psychological and cognitive impairment in some pathological conditions. Our pilot study aims to evaluate for the first time: 1) sense of presence, tolerability and usability of VR immersive experience in patients with early stages of Huntington disease (eHDp) compared to healthy controls (HC); 2) correlation between the use of technology/cybersickness and the variables of presence/usability; 3) correlation between clinical characteristics (genetic, motor, functional and cognitive) and VR’s variables. Method: We recruited 10 eHDp and 10 age, gender and education matched HC. Participants completed questionnaires about sense of presence, usability, tolerability and technology use profile. Subjects were exposed to different VR scenarios from a first-person perspective through a standalone VR headset. Results: Our results showed no significant statistical difference between eHDp and HC for the sense of presence (p=0.910), usability (p=0.744) and tolerability (p=0.730) during the VR experience. Familiarity with the use of technology was also comparable between groups (p=0.676). Regarding correlations in eHDp group, our results showed no correlations between use of technology/tolerability and the sense of presence/usability. Moreover, clinical characteristics of eHDp (genetic, motor, functional and cognitive scores) did not influence the sense of presence, tolerability and usability. Conclusion: Our research presents preliminary evidence for the applicability of VR in eHDp. These results open up the possibility to explore future applications of this methodology in rehabilitation (i.e., cognitive training, physiotherapy), diagnosis and psychological support in Huntington disease patients
The search for cerebral biomarkers of Huntington's disease: a review of genetic models of age at onset prediction
No full textThe mutation causing Huntington's disease is an expanded CAG trinucleotide repeat number beyond 35 in the 5' translated region of the gene. The mutation penetrance varies widely and depends on the CAG expansion length, the low pathological triplet range (36-41) showing a very low penetrance, possibly associated with late ages at onset. No research has so far yielded biomarkers for accurately predicting either age at onset or disease progression in at risk individuals. Specific markers able to follow-up mutation carrier subjects from the pre-symptomatic stages of life are crucial for testing experimental neuroprotective preventive therapies. Nevertheless, the factor accounting for the largest percentage of age at onset variation is the expanded repeat number within the gene. Over the years, this factor has helped in setting up models for genetically predicting age at onset. Once available for practical application in clinics, such models allowed phenotype-genotype correlations that were hitherto inconceivable. In this review, we discuss how these genetic models have been applied in clinical practice and comment on their potential value in searching for cerebral biomarkers of disease onset and severity and in designing trials of therapeutic drugs
Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease
No full textWe studied the anatomic and functional changes in various brain areas during the course of Huntington's disease (HD) in a large cohort of mutation-positive individuals (n = 71) encompassing the complete range of disability (presymptomatic through stage V), and in healthy controls, for the purpose of defining both degenerative and dysfunctional brain changes in the same subjects. Methods: We used an MRI and unsupervised multiparametric segmentation procedure based on a relaxometric approach to measure in vivo brain volumes in 71 subjects with presymptomatic to advanced HD. The same population was evaluated by F-18-FDG PET to assess variations in brain glucose metabolism. To predict age at onset in unaffected mutation carriers, we considered the estimated number of years from each subject's age to manifested HD symptoms, for a given expanded triplet number. Results: Age-adjusted analyses confirmed that the 71 subjects as a group, as well as the subgroup of 24 unaffected presymptomatic subjects at risk for HD, had significantly smaller gray-matter and white-matter volumes and larger cerebrospinal fluid volumes than did controls (P < 0.0001). In the 24 presymptomatic subjects, we observed a significant inverse linear correlation between white-matter volume reduction and the estimated time to symptom onset (r(2) = 0.39; P = 0.0011). Both clinically unaffected subjects at risk for HD and symptomatic patients had significantly decreased glucose uptake in the cortex (frontal and temporal lobes) and striatum (caudate and putamen). HD subjects who were followed up longitudinally showed progressive white-matter reduction in the preclinical subjects (n = 10) and decreased glucose uptake in the cortex and striatum in affected (n = 21) and preclinical (n = 10) subjects. Conclusion: White-matter volume loss may precede gray-matter atrophy and may be associated with neuronal dysfunction in early disease
Adenosine A2A receptor dysfunction correlates with age at onset anticipation in blood platelets of subjects with Huntington's disease.
No full textHuntington's disease (HD) may manifest at an earlier age in affected offspring than in transmitting parents. Earlier onset in successive generations (anticipation) only partially depends on intergenerational parent-child elongation of the CAG expanded mutation. An aberrant amplification of adenosine A(2A) receptor signaling documented in peripheral blood cells of subjects with HD implies that this cellular dysfunction may be related to clinical and genetic features. Prompted by evidence of higher receptor densities in siblings of HD subjects with stronger onset anticipation, in this study we investigated a possible relationship between A(2A) receptor densities and age at onset. We measured adenosine A(2A) receptor densities in blood cell platelets from 32 patients with HD and healthy control siblings, and sought a possible linear correlation between maximum platelet A(2A) receptor binding (B(max)) values for the whole cohort of HD subjects and anticipation in years. The increased B(max) values for the 32 subjects with HD (220 in patients vs. 137 in healthy control subjects, P = 0.0001) correlated significantly with anticipation in years (r2, 0.48, P = 0.0001 by linear correlation analysis). An increased platelet A(2A) receptor B(max) may belong in a cascade of toxic events leading to earlier onset of HD: as such it could be a useful marker of onset anticipation
DNA instability in replicating Huntington's disease lymphoblasts
No full textBACKGROUND: The expanded CAG repeat in the Huntington's disease (HD) gene may display tissue-specific variability (e.g. triplet mosaicism) in repeat length, the longest mutations involving mitotic (germ and glial cells) and postmitotic (neurons) cells. What contributes to the triplet mutability underlying the development of HD nevertheless remains unknown. We investigated whether, besides the increased DNA instability documented in postmitotic neurons, possible environmental and genetic mechanisms, related to cell replication, may concur to determine CAG repeat mutability. To test this hypothesis we used, as a model, cultured HD patients' lymphoblasts with various CAG repeat lengths. RESULTS: Although most lymphoblastoid cell lines (88%) showed little or no repeat instability even after six or more months culture, in lymphoblasts with large expansion repeats beyond 60 CAG repeats the mutation size and triplet mosaicism always increased during replication, implying that the repeat mutability for highly expanded mutations may quantitatively depend on the triplet expansion size. None of the investigated genetic factors, potentially acting in cis to the mutation, significantly influence the repeat changes. Finally, in our experiments certain drugs controlled triplet expansion in two prone-to-expand HD cell lines carrying large CAG mutations. CONCLUSION: Our data support quantitative evidence that the inherited CAG length of expanded alleles has a major influence on somatic repeat variation. The longest triplet expansions show wide somatic variations and may offer a mechanistic model to study triplet drug-controlled instability and genetic factors influencing it
CM-Pf deep brain stimulation and the long term management of motor and psychiatric symptoms in a case of Tourette syndrome
No full textTourette syndrome is a rare neuropsychiatric disorder affecting the cortico-striato-thalamo-cortical system. The disease manifests in childhood with tics and various psychiatric comorbidities. Cases of refractory Tourette syndrome are valuable candidates for functional neurosurgery. The thalamic centromedian-parafascicular complex is an experimental target that shows a promising role in Tourette syndrome deep brain stimulation, due to pathophysiologic evidences. We have shown on a long term follow-up, that thalamic deep brain stimulation, targeted on the centromedian-parafascicular complex, could modulate motor (i.e. tics) symptoms and owns a putative effect on various psychiatric aspects. Non-responding psychiatric symptoms could be due to the aberrant developmental environment of young Tourette patients more than disease itself. Centromedian-parafascicular complex is intriguingly embedded in motor, associative and limbic pathways and should be further investigated in his role for neuromodulation of human movement and behavior
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