- : Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease. - pubmed: huntington's or hunt...
Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease.
Neuroimage Clin. 2017;15:502-512
Authors: Vaca-Palomares I, Coe BC, Brien DC, Munoz DP, Fernandez-Ruiz J
The ability to inhibit automatic versus voluntary saccade commands in demanding situations can be impaired in neurodegenerative diseases such as Huntington's disease (HD). These deficits could result from disruptions in the interaction between basal ganglia and the saccade control system. To investigate voluntary oculomotor control deficits related to the cortico-basal circuitry, we evaluated early HD patients using an interleaved pro- and anti-saccade task that requires flexible executive control to generate either an automatic response (look at a peripheral visual stimulus) or a voluntary response (look away from the stimulus in the opposite direction). The impairments of HD patients in this task are mainly attributed to degeneration in the striatal medium spiny neurons leading to an over-activation of the indirect-pathway thorough the basal ganglia. However, some studies have proposed that damage outside the indirect-pathway also contribute to executive and saccade deficits. We used the interleaved pro- and anti-saccade task to study voluntary saccade inhibition deficits, Voxel-based morphometry and Tract-based spatial statistic to map cortico-basal ganglia circuitry atrophy in HD. HD patients had voluntary saccade inhibition control deficits, including increased regular-latency anti-saccade errors and increased anticipatory saccades. These deficits correlated with white-matter atrophy in the inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior corona radiata and superior longitudinal fasciculus. These findings suggest that cortico-basal ganglia white-matter atrophy in HD, disrupts the normal connectivity in a network controlling voluntary saccade inhibitory behavior beyond the indirect-pathway. This suggests that in vivo measures of white-matter atrophy can be a reliable marker of the progression of cognitive deficits in HD.
PMID: 28649493 [PubMed - in process]
- : Integrating personalized gene expression profiles into predictive disease-associated gene pools. - pubmed: huntington's or hunt...
Integrating personalized gene expression profiles into predictive disease-associated gene pools.
NPJ Syst Biol Appl. 2017;3:10
Authors: Menche J, Guney E, Sharma A, Branigan PJ, Loza MJ, Baribaud F, Dobrin R, Barabási AL
Gene expression data are routinely used to identify genes that on average exhibit different expression levels between a case and a control group. Yet, very few of such differentially expressed genes are detectably perturbed in individual patients. Here, we develop a framework to construct personalized perturbation profiles for individual subjects, identifying the set of genes that are significantly perturbed in each individual. This allows us to characterize the heterogeneity of the molecular manifestations of complex diseases by quantifying the expression-level similarities and differences among patients with the same phenotype. We show that despite the high heterogeneity of the individual perturbation profiles, patients with asthma, Parkinson and Huntington's disease share a broadpool of sporadically disease-associated genes, and that individuals with statistically significant overlap with this pool have a 80-100% chance of being diagnosed with the disease. The developed framework opens up the possibility to apply gene expression data in the context of precision medicine, with important implications for biomarker identification, drug development, diagnosis and treatment.
PMID: 28649437 [PubMed - in process]
- : Functional neuroimaging and chorea: a systematic review. - pubmed: huntington's or hunt...
Functional neuroimaging and chorea: a systematic review.
J Clin Mov Disord. 2017;4:8
Authors: Ehrlich DJ, Walker RH
Chorea is a hyperkinetic movement disorder consisting of involuntary irregular, flowing movements of the trunk, neck or face. Although Huntington's disease is the most common cause of chorea in adults, chorea can also result from many other neurodegenerative, metabolic, and autoimmune conditions. While the pathophysiology of these different conditions is quite variable, recent advances in functional imaging have enabled the development of new methods for analysis of brain activity and neuronal dysfunction. In this paper we review the growing body of functional imaging data that has been performed in chorea syndromes and identify particular trends, which can be used to better understand the underlying network changes within the basal ganglia. While it can be challenging to identify whether changes are primary, secondary, or compensatory, identification of these trends can ultimately be useful in diagnostic testing and treatment in many of the conditions that cause chorea.
PMID: 28649394 [PubMed - in process]
- : Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis. - pubmed: huntington's or hunt...
Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis.
Neurology. 2017 Jun 06;88(23):2216-2224
Authors: Silva MA, Duarte GS, Camara R, Rodrigues FB, Fernandes RM, Abreu D, Mestre T, Costa J, Trenkwalder C, Ferreira JJ
OBJECTIVE: To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants.
METHODS: Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable in the placebo arm. Placebo response was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. Nocebo response was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Statistical heterogeneity was assessed with I(2) statistic. Several predetermined subgroup and sensitivity analysis were performed. PROSPERO registration number is CRD42015027992.
RESULTS: We included 85 randomized controlled trials (5,046 participants). Pooled placebo response effect size was -1.41 (95% confidence interval [CI] -1.56 to -1.25, 64 trials, I(2) = 88.1%), corresponding to -6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95% CI 40.47%-50.29%, 72 trials; I(2) = 89.8%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacologic interventions and idiopathic RLS, and in industry-funded and unpublished studies. The placebo response was considerably smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors.
CONCLUSIONS: The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.
PMID: 28490647 [PubMed - indexed for MEDLINE]
- : Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. - pubmed: huntington's or hunt...
Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice.
Biochim Biophys Acta. 2016 11;1860(11 Pt A):2345-54
Authors: Larkin PB, Sathyasaikumar KV, Notarangelo FM, Funakoshi H, Nakamura T, Schwarcz R, Muchowski PJ
BACKGROUND: In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo.
METHODS: Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions.
RESULTS AND CONCLUSIONS: Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.
PMID: 27392942 [PubMed - indexed for MEDLINE]