Huntington's Disease Gene Carriers Research Articles

Auditory mismatch negativity in pre-manifest and manifest Huntington’s disease

AimThe aim of this study was to investigate the characteristics of the electrophysiological brain response elicited in a passive acoustic oddball paradigm, i.e. mismatch negativity (MMN), in patients with Huntington’s disease (HD) in the premanifest (pHD) and manifest (mHD) phases. In this regard, we correlated the results of event-related potentials (ERP) with disease characteristics. MethodsThis was an observational cross-sectional MMN study. In addition to the MMN recording of the passive oddball task, all subjects with first-degree inheritance for HD underwent genetic testing for mutant HTT, the Huntington’s Disease Rating Scale, the Total Functional Capacity Scale, the Problem Behaviors Assessment short form, and the Mini-Mental State Examination. ResultsWe found that global field power (GFP) was reduced in the MMN time window in mHD patients compared to pHD and normal controls (NC). In the pHD group, MMN amplitude was only slightly and not significantly increased compared to mHD, while pHD patients showed increased theta coherence between trials compared to mHD. In the entire sample of HD gene carriers, the main MMN traits were not correlated with motor performance, cognitive impairment and functional disability. ConclusionThese results suggest an initial and subtle deterioration of pre-attentive mechanisms in the presymptomatic phase of HD, with an increasing phase shift in the MMN time frame. This result could indicate initial functional changes with a possible compensatory effect. SignificanceAn initial and slight decrease in MMN associated with increased phase coherence in the corresponding EEG frequencies could indicate an early functional involvement of pre-attentive resources that could precede the clinical expression of HD.

The pathobiology of depression in Huntington's disease: an unresolved puzzle.

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic-pituitary-adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

Melatonin for Huntington Disease (HD) Gene Carriers with HD-Related Sleep Disturbance - a Pilot Study (P1-11.013)

<h3>Objective:</h3> To evaluate the efficacy of exogenous melatonin in improving sleep quality in Huntington disease (HD) gene carriers. <h3>Background:</h3> Various sleep disorders have been identified in HD. Low melatonin levels might explain disrupted circadian behavior in HD [1]. There is evidence of improvement in sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI) in individuals receiving melatonin [2]. This is the first study evaluating the efficacy of melatonin in HD. <h3>Design/Methods:</h3> Randomized, double-blind, placebo-controlled, crossover, proof of concept study. HD gene carriers with a PSQI ≥5 and stable medications for the past 2 months were recruited from the UTHealth, Houston HDSA Center of Excellence. The PSQI, HD Sleep Questionnaire, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale (HADS), Clinical Global Impression (CGI) scale, and UHDRSc were administered. Wilcoxon signed-rank test was used to analyze the data. <h3>Results:</h3> We enrolled 15 patients (mean age 47.5 years, 46% female), 73% white, 13% African American, and 13% Hispanic. As expected, both melatonin and placebo groups showed significant differences in the PSQI-6 since they were taking medications for sleep. Interestingly, compared to baseline the melatonin group had significantly improved scores in the HD Sleep Questionnaire, and increased scores in the improvement component of the CGI. No differences were noted in the HADS or ESS. <h3>Conclusions:</h3> This pilot study in HD gene carriers demonstrates a potential benefit of melatonin for sleep disturbances. Consistent with previous data in other neurodegenerative diseases, melatonin can positively impact sleep quality. Analysis of other variables including changes in BMI, subcomponents of the UHDRS, and measures of quality of life will be forthcoming. Future studies that use objective assessments such as polysomnogram or actigraphy, a larger sample size, and differentiating between disease stages might provide valuable information regarding the utility of melatonin in HD. <b>Disclosure:</b> Dr. Patino Murillas has nothing to disclose. Dr. Zadegan has nothing to disclose. Natalia Pessoa Rocha has nothing to disclose. An immediate family member of Dr. Karagas has received personal compensation for serving as an employee of Thirty Madison. An immediate family member of Dr. Karagas has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Thirty Madison. An immediate family member of Dr. Karagas has stock in Thirty Madison. Mr. Tanigaki has nothing to disclose. Mrs. Duncan has nothing to disclose. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Michael J. Fox Foundation. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. The institution of Dr. Furr-Stimming has received research support from Cures within Reach. The institution of Dr. Furr-Stimming has received research support from Huntington’s Disease Society of America. The institution of Dr. Furr-Stimming has received research support from Roche/Genetech. The institution of Dr. Furr-Stimming has received research support from Uniqure. The institution of Dr. Furr-Stimming has received research support from CHDI. The institution of Dr. Furr-Stimming has received research support from Huntington Study Group/Neurocrine. The institution of Dr. Furr-Stimming has received research support from NIH/University of Iowa. The institution of Dr. Furr-Stimming has received research support from Sage Therapeutics. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

RWD87 Association Between Functional Endpoints and Quality-of-Life Outcomes in Huntington's Disease Gene Carriers: Results From a Real-World Data Analysis of the Enroll-HD Global Registry

Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder that leads to progressive loss of functional capacity. This retrospective, registry-based study assessed the associations between HD functional endpoints measured by the Unified HD Rating Scale (UHDRS) Total Functional Score (TFC) and other scales (Total Motor Score [TMS] , Verbal Fluency Test [VFT], Problem Behavior Assessment [PBA]-Apathy), and quality-of-life outcomes (QoL) measured by Short-Form Survey 12 (SF-12) and other QoL scales (Euro-QoL-5D [EQ-5D], Work Productivity and Activity Impairment-Overall Work Impairment due to HD [WPAI-OWIHD]) in HD gene carriers.

Cerebral blood flow is associated with markers of neurodegeneration in Huntington’s disease

IntroductionThe ultimate cause of neuronal death in Huntington's disease (HD) is still uncertain. Apart from impairment in systems handling abnormal proteins, other mechanisms might contribute to neurodegeneration and progression of HD. Decreased cerebral blood flow (CBF) has been described in other neurodegenerative disorders and may play a role in HD. ObjectivesTo investigate CBF changes in HD gene carriers. MethodsA group of 39 HD gene carriers (18 premanifest and 21 manifest HD) and 16 controls underwent a comprehensive clinical evaluation and a brain magnetic resonance imaging protocol that included pseudo-continuous arterial spin labeling to quantify CBF. Regions of interest (ROI) analyses were performed to compare CBF in controls vs premanifest HD vs manifest HD. Correlation analyses were performed to ascertain the relationship between CBF and clinical and biomarkers data. ResultsWe found a decrease in CBF in bilateral caudate and putamen of patients with manifest HD in comparison with controls. CBF of premanifest HD carriers in the same ROIs was midway between controls and the HD patients, with differences not reaching statistical significance. Lower CBF in caudate and putamen was associated with worse motor symptoms, functionality, and cognitive performance. CBF was also associated with markers of neurodegeneration: higher CBF in caudate and putamen significantly correlated to higher volumes in the same ROI and to lower levels of neurofilament light chain. ConclusionAs CBF changes in caudate and putamen nuclei were associated with markers of neurodegeneration and with clinical outcomes, decreased CBF and oxygen supply could emerge as a relevant mechanism contributing to degeneration in HD.

Clinical Correlates of Depression and Suicidality in Huntington Disease: An Analysis of the Enroll-HD Observational Study.

Depression and suicidality are commonly experienced by Huntington disease (HD) gene carriers. Research on these behavioral symptoms is imperative, not only to increase our understanding of the symptoms and how they relate to HD, but also to contribute to improving patients' care and quality of life. To identify clinical variables associated with a history of depression and suicidality in HD gene carriers. We conducted a cross-sectional study of HD gene carriers from the Enroll-HD database PDS4 (periodic data set 4; N = 11,582). Data from baseline visits were obtained, and binary logistic regression models were used to ascertain the effects of clinical variables on the likelihood that HD gene carriers would have previous depression and suicidal ideation/attempts. Approximately 65% (n = 7526) of the HD gene carriers had a history of depression, and ~27% (n = 3152) had previous suicidal ideation/attempts. Female sex; diagnosis of manifest HD; history of perseverative/obsessive behavior, apathy, and psychosis; and previous suicidal ideation/attempts were significantly associated with a history of depression in the HD gene carriers. Medical history of apathy, psychosis, and depression, as well as worse scores on the Total Functional Capacity and Irritability Scales, were significantly associated with previous suicidal ideation/attempts in the HD gene carriers. The prevalence of depression and suicidality is high among HD gene carriers. An improved understanding of the risk factors for depression and suicide in HD gene carriers can assist providers in recognizing at-risk individuals and allow providers to implement therapeutic strategies.

Lower Prevalence of Chronic Pain in Manifest Huntington's Disease: A Pilot Observational Study.

Pain is a minor problem compared with other Huntington Disease (HD) symptoms. Nevertheless, in HD it is poorly recognized and underestimated. So far, no study evaluated the presence of chronic pain in HD. The aim of this pilot study was to evaluate the presence and features of chronic pain in a cohort of HD gene carriers. An observational cross-sectional study was conducted in a cohort of HD gene carriers compared to not gene carriers (n.134 HD subjects, n.74 not gene mutation carriers). A specific pain interview, alongside a neurological, cognitive and behavioural examination, was performed in order to classify the type of pain, subjective intensity. A significant prevalence of “no Pain” in HD was found, which tended to increase with HD progression and a reduced frequency of pain in the last 3 months. A clear difference was found between manifest and premanifest HD in terms of intensity of pain, which did not change significantly with HD progression; however, a tendency emerges to a progressive reduction. No significant group difference was present in analgesic use, type and the site of pain. These findings could support a lower prevalence of chronic pain in manifest HD. Prevalence and intensity of chronic pain seem directly influenced by the process of neurodegeneration rather than by an incorrect cognitive and emotional functioning.

Editors' Note: Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease

Dr. McAllister and colleagues retrospectively analyzed the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers in 6,316 individuals in the European HD Network (REGISTRY). They found that psychiatric and cognitive symptoms were common and functionally debilitating in HD gene carriers, with 42.4% of patients with HD reporting at least 1 psychiatric or cognitive symptom before motor symptoms, most commonly depression. However, the initial manifestation of HD was increasingly likely to be motor and less likely to be psychiatric as the age at presentation increased. The authors concluded that nonmotor symptoms should not be used to make a clinical diagnosis of HD because it was impossible to distinguish confidently between nonmotor symptoms arising from HD vs primary psychiatric disorders, particularly in younger premanifest patients. In response, Dr. Bird et al. argue that such a conclusion is too broad and negative, while agreeing that caution is needed and depression should not be used as a diagnostic factor. They argue that psychiatric, behavioral, and cognitive symptoms can be diagnostically meaningful in the setting of a positive genetic test, noting examples like the onset of auditory hallucinations, paranoid delusions, a sustained personality change, or decreased work performance with impaired cognition. They note that such symptoms are part of the diagnostic process for genetic forms of behavioral frontotemporal dementia, which is phenotypically similar to HD, and that earlier diagnosis can help connect patients and families to critical services. Responding to these comments, the authors note that clinical onset of HD is typically diagnosed using the emergence of specific extrapyramidal motor features. They agree that certain neuropsychiatric symptoms like apathy and increased aggression are more strongly suggestive of HD pathology. However, they caution that other commonly reported symptoms may reflect environmental sequelae or those related to the knowledge of their genetic status and should not be used on their own to make an HD diagnosis. This exchange highlights the clinical challenges of defining the onset of a complex neuropsychiatric disease like HD when one already knows the patient's genetic status. Nonetheless, the early diagnosis of HD in the appropriate clinical and genetic setting may allow for deployment of important patient resources. Dr. McAllister and colleagues retrospectively analyzed the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers in 6,316 individuals in the European HD Network (REGISTRY). They found that psychiatric and cognitive symptoms were common and functionally debilitating in HD gene carriers, with 42.4% of patients with HD reporting at least 1 psychiatric or cognitive symptom before motor symptoms, most commonly depression. However, the initial manifestation of HD was increasingly likely to be motor and less likely to be psychiatric as the age at presentation increased. The authors concluded that nonmotor symptoms should not be used to make a clinical diagnosis of HD because it was impossible to distinguish confidently between nonmotor symptoms arising from HD vs primary psychiatric disorders, particularly in younger premanifest patients. In response, Dr. Bird et al. argue that such a conclusion is too broad and negative, while agreeing that caution is needed and depression should not be used as a diagnostic factor. They argue that psychiatric, behavioral, and cognitive symptoms can be diagnostically meaningful in the setting of a positive genetic test, noting examples like the onset of auditory hallucinations, paranoid delusions, a sustained personality change, or decreased work performance with impaired cognition. They note that such symptoms are part of the diagnostic process for genetic forms of behavioral frontotemporal dementia, which is phenotypically similar to HD, and that earlier diagnosis can help connect patients and families to critical services. Responding to these comments, the authors note that clinical onset of HD is typically diagnosed using the emergence of specific extrapyramidal motor features. They agree that certain neuropsychiatric symptoms like apathy and increased aggression are more strongly suggestive of HD pathology. However, they caution that other commonly reported symptoms may reflect environmental sequelae or those related to the knowledge of their genetic status and should not be used on their own to make an HD diagnosis. This exchange highlights the clinical challenges of defining the onset of a complex neuropsychiatric disease like HD when one already knows the patient's genetic status. Nonetheless, the early diagnosis of HD in the appropriate clinical and genetic setting may allow for deployment of important patient resources.

Huntington's Disease Gene Hunters: An Expanding Tale.

Huntington's Disease Gene Hunters: An Expanding Tale.

Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem.

Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of 11C-UCB-J small-animal PET imaging in the central nervous system of mice with HD. Methods: Dynamic 11C-UCB-J small-animal PET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 mo) in the heterozygous knock-in Q175DN mouse model of HD and wild-type littermates (16-18 mice per genotype and time point). Cerebral 11C-UCB-J analyses were performed to assess genotypic differences during presymptomatic (3 mo) and symptomatic (7-16 mo) disease stages. 11C-UCB-J binding in the spinal cord was quantified at 16 mo. 3H-UCB-J autoradiography and SV2A immunofluorescence were performed postmortem in mouse and human brain tissues. Results:11C-UCB-J binding was lower in symptomatic heterozygous mice than in wild-type littermates in parallel with disease progression (7 and 10 mo: P < 0.01; 16 mo: P < 0.0001). Specific 11C-UCB-J binding was detectable in the spinal cord, with symptomatic heterozygous mice displaying a significant reduction (P < 0.0001). 3H-UCB-J autoradiography and SV2A immunofluorescence corroborated the invivo measurements demonstrating lower SV2A in heterozygous mice (P < 0.05). Finally, preliminary analysis of SV2A in the human brain postmortem suggested lower SV2A in HD gene carriers than in controls without dementia. Conclusion:11C-UCB-J PET detected SV2A deficits during symptomatic disease in heterozygous mice in both the brain and the spinal cord and therefore may be suitable as a novel marker of synaptic integrity widely distributed in the central nervous system. On clinical application, 11C-UCB-J PET imaging may have promise for SV2A measurement in patients with HD during disease progression and after disease-modifying therapeutic strategies.

Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology.

ObjectiveTo define the role played by microglia in different stages of Huntington disease (HD), we used the TSPO radioligand [11C]-ER176 and PET to evaluate microglial activation in relation to neurodegeneration and in relation to the clinical features seen at premanifest and manifest stages of the disease.MethodsThis is a cross-sectional study in which 18 subjects (6 controls, 6 premanifest, and 6 manifest HD gene carriers) underwent a [11C]-ER176 PET scan and an MRI for anatomic localization. Segmentation of regions of interest (ROIs) was performed, and group differences in [11C]-ER176 binding (used to evaluate the extent of microglial activation) were assessed by the standardized uptake value ratio (SUVR). Microglial activation was correlated with ROIs volumes, disease burden, and the scores obtained in the clinical scales. As an exploratory aim, we evaluated the dynamic functions of microglia in vitro, by using induced microglia-like (iMG) cells from peripheral blood monocytes.ResultsIndividuals with manifest HD present higher [11C]-ER176 SUVR in both globi pallidi and putamina in comparison with controls. No differences were observed when we compared premanifest HD with controls or with manifest HD. We also found a significant correlation between increased microglial activation and cumulative disease burden, and with reduced volumes. iMG from controls, premanifest HD, and manifest HD patients showed similar phagocytic capacity.ConclusionsAltogether, our data demonstrate that microglial activation is involved in HD pathophysiology and is associated with disease progression.

Sex Differences in Huntington's Disease: Evaluating the Enroll-HD Database.

Identifying sex-related differences is critical for enhancing our understanding of factors that may impact prognosis and advance treatments in Huntington's disease (HD). To investigate if sex-related differences exist in clinical HD. Longitudinal study of the Enroll-HD database. Manifest HD patients were included in the analysis (N = 8401). Linear mixed models were used to assess motor, behavioral, and cognitive functioning over a series of four annual visits, and compared male and female HD gene carriers. HD patients showed significant sex-dependent differences in motor, cognitive, and behavioral symptoms. Both sexes had worsened motor symptoms over the course of four visits, but there was a significant disparity between sexes, with females consistently presenting with more symptoms than males. For behavioral symptoms, specifically depressive symptoms, females had significantly more depressive symptoms, although self-reported symptoms in both sexes became less severe throughout time. Our analyses suggest that women have worse symptoms than men during the course of HD.

Aberrant Striatal Value Representation in Huntington's Disease Gene Carriers 25 Years Before Onset

BackgroundIn this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task with gain and loss domains could be one of the earliest functional imaging features associated with carrying the Huntington's disease (HD) gene. Based on previous work, we hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning. MethodsWe recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data. ResultsIn comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes. ConclusionsBehaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.

Central Cognitive Processing Speed Is an Early Marker of Huntington's Disease Onset.

Several studies have suggested that cognitive processing speed may be useful for assessing early cognitive change in premanifest Huntington's disease (HD); however, current measures lack the ability to control for the effects of motor dysfunction commonly found in HD. The Computerized Test of Information Processing (CTiP) is a rapidly administered computerized tool that allows for the examination of central cognitive processing speed by using motor-corrected scores to account for motor dysfunction. To examine central cognitive processing speed as an early marker of HD onset using the CTiP. The CTiP and other measures were administered to 102 HD gene carriers and 55 healthy adults (HA). Gene carriers included presymptomatic HD (pre-HD; n = 33), prodromal HD (pro-HD; ie, individuals close to disease onset; n = 23), and mild-moderate HD (HD; n = 46). The HD group performed significantly slower than all other groups (HA, pre-HD, and pro-HD) on most subtests (Ps < .05). Moreover, the pro-HD group performed significantly slower than the HA group on both motor-corrected subtests (Ps < 0.05). Effect sizes associated with significant group differences between the pro-HD and HA groups on motor-corrected CTiP subtests (d = 0.73 and 0.84) were similar to effect sizes associated with group differences on the Symbol Digit Modalities Test (d = .82) and other traditional cognitive assessments (Montreal Cognitive Assessment, d = .75; Mini-Mental State Examination, d = .84). The CTiP may be a useful marker of deficits in central cognitive processing speed in individuals close to manifest onset of HD.

Peripheral Levels of Renin-Angiotensin System Components Are Associated With Cognitive Performance in Huntington's Disease.

The renin-angiotensin system (RAS) has proven to be involved in the pathophysiology of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), serving as a potential therapeutic target and a disease burden marker. Studies have associated negative clinical outcomes with the activation of the classical RAS arm composed of the angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, while suggested positive outcomes with the activation of the counter-regulatory RAS arm involving ACE2 and Ang-(1–7). Huntington’s disease (HD) shares many pathological and clinical outcomes with AD and PD, but the evidence of direct involvement of RAS components in the pathophysiology of HD is still limited and needs further investigation. Herein, we investigated peripheral levels of the RAS components Ang II, Ang-(1–7), ACE, and ACE2 in controls, premanifest, and manifest HD gene carriers and their relationship with clinical outcomes. Peripheral blood samples were collected via phlebotomy, and plasma concentrations of RAS components were measured by Enzyme-Linked Immunosorbent Assay. Clinical evaluation included a questionnaire about socio-demographic characteristics, motor, and cognitive assessments. Results showed (1) no significant group differences in plasma concentrations of RAS components; (2) positive correlations between ACE2 and Verbal Fluency Test (VFT) scores; and (3) negative correlations between Ang II and Mini–Mental State Examination scores. These results corroborate the proposed balance between the classical (ACE/Ang II) and the counter-regulatory [ACE2/Ang-(1–7)] arms of the RAS, with the former associated with negative clinical outcomes and the latter with positive effects in HD.

Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease

BackgroundCharacterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well established that Huntington’s disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. MethodsCapitalizing on a unique longitudinal dataset with a minimum of 3 and maximum of 7 brain scans from 49 HD gene carriers and 49 age-matched control subjects, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over 10 years. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. ResultsWe show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, the occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. ConclusionsHD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.

Gene Expression Profiling in Huntington's Disease: Does Comorbidity with Depressive Symptoms Matter?

Huntington’s disease (HD) is an inherited neurodegenerative disease. Besides the well-characterized motor symptoms, HD is marked by cognitive impairment and behavioral changes. In this study, we analyzed the blood of HD gene carries using RNA-sequencing techniques. We evaluated samples from HD gene carriers with (n = 8) and without clinically meaningful depressive symptoms (n = 8) compared with healthy controls (n = 8). Groups were age- and sex-matched. Preprocessing of data and between-group comparisons were calculated using DESeq2. The Wald test was used to generate p-values and log2 fold changes. We found 60 genes differently expressed in HD and healthy controls, of which 21 were upregulated and 39 downregulated. Within HD group, nineteen genes were differently expressed between patients with and without depression, being 6 upregulated and 13 downregulated. Several of the top differentially expressed genes are involved in nervous system development. Although preliminary, our findings corroborate the emerging view that in addition to neurodegenerative mechanisms, HD has a neurodevelopmental component. Importantly, the emergence of depression in HD might be related to these mechanisms.

Irritability in Huntington's Disease.

Huntington’s disease (HD) is a heritable and fatal neurodegenerative disease characterized by a triad of motor, cognitive and neuropsychiatric symptoms. A common and particularly detrimental neuropsychiatric alteration in HD gene carriers is irritability, which frequently manifests as abrupt and unpredictable outbursts of anger. This symptom increases the burden of HD in multiple ways, such as jeopardizing employment and straining familial or caregiver support. Although irritability in HD is diagnosed by the administration of standardized rating scales and clinical expertise, measurement of severity and progression is complicated by several factors. Currently, individuals with HD who present with irritability may be managed with a variety of psychotropic medications, primarily antidepressants and antipsychotics. While these therapies offer relief to individuals suffering from irritability in HD, they are often not sufficient. Here, we review irritability in the context of HD and emphasize the need for treatments that are better tailored to mitigate this troublesome symptom. An expeditious strategy in pursuit of this goal involves evaluating the efficacy of approved medications that are used to treat similar neuropsychiatric symptoms.

Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

SummaryBackgroundDisease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset.MethodsWe did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0·05 deemed a significant result.FindingsData were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29·0 years (SD 5·6) and 29·1 years (5·7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23·6 years (SD 5·8) from predicted onset (FDR 0·22–0·87 for cognitive measures, 0·31–0·91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0·03), but this did not appear to be closely related to predicted years to onset (FDR=0·54). There were no group differences in other brain imaging measures (FDR >0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001).InterpretationWe report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact.FundingWellcome Trust, CHDI Foundation.