Objective: Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. Our aim here was to identify factors that can be modified to slow disease progression even before the first symptoms appear.
Methods: We included 2636 presymptomatic individuals (comparison with family controls) drawn from the prospective observational cohort Enroll-HD, with more than 35 CAG repeats and at least two assessments of disease progression measured with the composite Huntington's disease rating Scale (cUHDRS).
Cognitive deficits represent a hallmark of neurodegenerative diseases, but evaluating their progression is complex. Most current evaluations involve lengthy paper-and-pencil tasks which are subject to learning effects dependent on the mode of response (motor or verbal), the countries' language or the examiners. To address these limitations, we hypothesized that applying neuroscience principles may offer a fruitful alternative.
View Article and Find Full Text PDFHuntington's Disease (HD) is an inherited neurodegenerative disease characterized by a combination of motor, cognitive, and behavioral disorders. The social and behavioral symptoms observed in HD patients impact their quality of life and probably explain their relational difficulties, conflicts, and social withdrawal. In this study, we described the development of the Social Relationship Self-Questionnaire (SRSQ), a self-reporting questionnaire that assesses how HD patients perceived their social relationships.
View Article and Find Full Text PDFBackground: Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington's disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes.
Methods: We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females).
Post-traumatic stress disorder (PTSD) is an incapacitating trauma-related disorder, with no reliable therapy. Although PTSD has been associated with epigenetic alterations in peripheral white blood cells, it is unknown where such changes occur in the brain, and whether they play a causal role in PTSD. Using an animal PTSD model, we show distinct DNA methylation profiles of PTSD susceptibility in the nucleus accumbens (NAc).
View Article and Find Full Text PDFGPR88 is an orphan G-protein-coupled receptor (GPCR) highly expressed in striatal medium spiny neurons (MSN), also found in cortical neurons at low level. In MSN, GPR88 has a canonical GPCR plasma membrane/cytoplasmic expression, whereas in cortical neurons, we previously reported an atypical intranuclear localization. Molecular size analysis suggests that GPR88, expressed in plasma membrane of MSN or in nuclear compartment of cortical neurons, corresponds to the full-length protein.
View Article and Find Full Text PDFBackground: The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington's, that is not reliant on clinical expertise for administration.
Methods: One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington's disease completed the Unified Huntington's Disease Rating Scale and the C3t at baseline.
Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity.
View Article and Find Full Text PDFThe European Huntington's Disease Network (EHDN) commissioned an international task force to provide global evidence-based recommendations for everyday clinical practice for treatment of Huntington's disease (HD). The objectives of such guidelines are to standardize pharmacological, surgical and non-pharmacological treatment regimen and improve care and quality of life of patients. A formalized consensus method, adapted from the French Health Authority recommendations was used.
View Article and Find Full Text PDFPrenatal stress defines long-term phenotypes through epigenetic programming of the offspring. These effects are potentially mediated by glucocorticoid release and by sex. We hypothesized that the glucocorticoid receptor (Gr, Nr3c1) fashions the DNA methylation profile of offspring.
View Article and Find Full Text PDFAim: The goal of this study was to test the state of methylation of transcription start positions in DNA that are actively involved in transcription.
Materials & Methods: We used sequential ChIP-bisulfite-sequencing with an antibody to RNpolII-PS5 to map the state of methylation of actively transcribing transcription start sites (TSS).
Results: TSS that RNApolII-PS5 physically bind to, are ubiquitously unmethylated.
Studies in rodents, nonhuman primates, and humans suggest that epigenetic processes mediate between early life experiences and adult phenotype. However, the normal evolution of epigenetic programs during child development, the effect of sex, and the impact of early life adversity on these trajectories are not well understood. This study mapped the genome-wide DNA methylation changes in CD3+ T lymphocytes from rhesus monkeys from postnatal day 14 through 2 years of age in both males and females and determined the impact of maternal deprivation on the DNA methylation profile.
View Article and Find Full Text PDFBackground: Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution.
Methods: Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation.
The effects of social status on human health can be modeled in captive cohorts of nonhuman primates. This study shows that maternal social rank is associated with broad changes in DNA methylation in placentae of rhesus monkeys (N = 10). Differentially methylated genes between social ranks are enriched in signaling pathways playing major roles in placenta physiology.
View Article and Find Full Text PDFGPR88 is a neuronal cerebral orphan G-protein-coupled receptor (GPCR) that has been linked to various psychiatric disorders. However, no extensive description of its localization has been provided so far. Here, we investigate the spatiotemporal expression of the GPR88 in prenatal and postnatal rat tissues by using in situ hybridization and immunohistochemistry.
View Article and Find Full Text PDFWe tested the hypothesis that epigenetic mechanisms in the brain and the immune system are associated with chronic pain. Genome-wide DNA methylation assessed in 9 months post nerve-injury (SNI) and Sham rats, in the prefrontal cortex (PFC) as well as in T cells revealed a vast difference in the DNA methylation landscape in the brain between the groups and a remarkable overlap (72%) between differentially methylated probes in T cells and prefrontal cortex. DNA methylation states in the PFC showed robust correlation with pain score of animals in several genes involved in pain.
View Article and Find Full Text PDFBorderline Personal Disord Emot Dysregul
September 2015
Background: Research has demonstrated an association between exposure to early life stress and an increased risk of psychiatric disorders in later life, in particular depression. However, the mechanism through which early life stress contributes to disease development remains unclear. Previous studies have reported an association between early life stress and altered methylation of the serotonin transporter gene (SLC6A4), a key candidate gene for several psychiatric disorders.
View Article and Find Full Text PDFPrenatal maternal stress (PNMS) in animals and humans predicts obesity and metabolic dysfunction in the offspring. Epigenetic modification of gene function is considered one possible mechanism by which PNMS results in poor outcomes in offspring. Our goal was to determine the role of maternal objective exposure and subjective distress on child BMI and central adiposity at 13½ years of age, and to test the hypothesis that DNA methylation mediates the effect of PNMS on growth.
View Article and Find Full Text PDFOne of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown.
View Article and Find Full Text PDFTraumatic brain injury (TBI), including mild TBI (mTBI), is importantly associated with vigilance and sleep complaints. Because sleep is required for learning, plasticity and recovery, we here evaluated the bidirectional relationship between mTBI and sleep with two specific objectives: (1) Test that mTBI rapidly impairs sleep-wake architecture and the dynamics of the electrophysiological marker of sleep homeostasis (i.e.
View Article and Find Full Text PDFBackground: Prenatal maternal stress (PNMS) predicts a wide variety of behavioral and physical outcomes in the offspring. Although epigenetic processes may be responsible for PNMS effects, human research is hampered by the lack of experimental methods that parallel controlled animal studies. Disasters, however, provide natural experiments that can provide models of prenatal stress.
View Article and Find Full Text PDFEarly-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by "epigenetic" mechanisms.
View Article and Find Full Text PDFPhilos Trans R Soc Lond B Biol Sci
September 2012
The monoamine hypothesis of depression has dominated our understanding of both the pathophysiology of depression and the action of pharmacological treatments for the last decades, and it has led to the production of several generations of antidepressant agents. However, there are serious limitations to the current monoamine theory, and additional mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, as well as neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. Moreover, new data have recently indicated that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways leading to depression-like behaviours in animal models.
View Article and Find Full Text PDFTranscriptome analyses were performed in the anterior raphe area of mutant mice deficient in the serotonin transporter (5-HTT KO) or overexpressing this protein (5-HTT TG), which exhibit opposite changes in anxiety-related behavior. Among genes with altered expression, the gene encoding the neuropeptide urocortin 1 was down-regulated in 5-HTT KO and up-regulated in 5-HTT TG mice. Expression of the gene encoding cocaine-and-amphetamine-related-peptide, which colocalizes with urocortin 1, was also increased in 5-HTT TG mutants.
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