Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice.
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ABSTRACT:
SUBMITTER: Pfalzer AC
PROVIDER: S-EPMC7773276 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Global untargeted metabolomics studies performed in the striatum tissue, the brain region most sensitive to neurodegeneration in Huntington’s Disease, to investigate global Mn-dependent and Mn-responsive biology following various Mn exposures in a mouse model of HD.
2020-03-27 | ST001333 | MetabolomicsWorkbench
Project description:BACKGROUND:The expression of the HTT CAG repeat expansion mutation causes neurodegeneration in Huntington's disease (HD). OBJECTIVES:In light of the - mainly in-vitro - evidence suggesting an additional role of huntingtin in neurodevelopment we used 3T MRI to test the hypothesis that in CAG-expanded individuals without clinical signs of HD (preHD) there is evidence for neurodevelopmental abnormalities. METHODS:We specifically investigated the complexity of cortical folding, a measure of cortical neurodevelopment, employing a novel method to quantify local fractal dimension (FD) measures that uses spherical harmonic reconstructions. RESULTS:The complexity of cortical folding differed at a group level between preHD (n = 57) and healthy volunteers (n = 57) in areas of the motor and visual system as well as temporal cortical areas. However, there was no association between the complexity of cortical folding and the loss in putamen volume that was clearly evident in preHD. CONCLUSIONS:Our results suggest that HTT CAG repeat length may have an influence on cortical folding without evidence that this leads to developmental pathology or was clinically meaningful. This suggests that the HTT CAG-repeat expansion mutation may influence the processes governing cortical neurodevelopment; however, that influence seems independent of the events that lead to neurodegeneration.
| S-EPMC6627026 | biostudies-literature
Project description:Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be "pre-manifest." Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids, and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon, and amylin were also observed. Total cholesterol, HDL-C, and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development.
| S-EPMC4066441 | biostudies-literature
Project description:Motivation is characterized by a willingness to overcome both cognitive and physical effort costs. Impairments in motivation are common in striatal disorders, such as Huntington's disease (HD), but whether these impairments are isolated to particular domains of behavior is controversial. We ask whether HD differentially affects the willingness of individuals to overcome cognitive versus physical effort. We tested 20 individuals with pre-manifest HD and compared their behavior to 20 controls. Across separate trials, participants made choices about how much cognitive or physical effort they were willing to invest for reward. Our key results were that individuals with pre-manifest HD were less willing than controls to invest cognitive effort but were no different in their overall preference for physical effort. These results cannot be explained by group differences in neuropsychological or psychiatric profiles. This dissociation of cognitive- and physical-effort-based decisions provides important evidence for separable, domain-specific mechanisms of motivation.
| S-EPMC7762769 | biostudies-literature
Project description:Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.
| S-EPMC3326253 | biostudies-literature
Project description:There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington's Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within n = 21,045 participants, we identified n = 1901 premanifest and n = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. n = 841 premanifest and n = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all p < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all p < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all p < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all p < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects.
| S-EPMC9219784 | biostudies-literature
Project description:Huntington's disease (HD) is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain. In particular, cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals' mental state may emerge many years before the motor symptoms. This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose: 1) the impairment of emotion recognition in HD is moderated by the emotions' valence, and 2) inhibitory control is impaired in HD. Forty manifest and 20 pre-manifest HD patients and their age- and gender-matched controls completed both the traditional "Stroop Color and Word Test" (SCWT) and the newly created "Stroop Emotion Recognition under Word Interference Task" (SERWIT), which consist in 120 photographs of sad, calm, or happy faces with either congruent or incongruent word interference. On the SERWIT, impaired emotion recognition in manifest HD was moderated by emotion type, with deficits being larger in recognizing sadness and calmness than in recognizing happiness, but it was not moderated by stimulus congruency. On the SCWT, six different interference scores yielded as many different patterns of group effects. Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions' valence, but do not provide evidence for the hypothesis that inhibitory control is impaired in HD. Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD, and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD. Looking beyond this study, the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders. The research was approved by the Ethics Committee of the "Istituto Leonarda Vaccari", Rome on January 24, 2018.
| S-EPMC7059581 | biostudies-literature
Project description:Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and non-synaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month-old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2- and 10-month-old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 mm glucose and 15 mm pyruvate. In the medium with 2.5 mm glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared with cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O2 consumption, CO2 release, physical activity, food consumption and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared with WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis.
| S-EPMC4527489 | biostudies-literature
Project description:Background and objectivesCognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets.MethodsLASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy.ResultsPreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test-retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume.DiscussionThe LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD.
| S-EPMC10393264 | biostudies-literature
Project description:Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.
| S-EPMC10094222 | biostudies-literature