Symptomatic Huntington's Disease Research Articles

The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort

PurposeTo determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD). MethodsWe screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range. ResultsParticipants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range. ConclusionOur findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.

Gray matter alterations in Huntington's disease: A meta-analysis of VBM neuroimaging studies.

Increasing neuroimaging studies have attempted to identify biomarkers of Huntington's disease (HD) progression. Here, we conducted voxel-based meta-analyses of voxel-based morphometry (VBM) studies on HD to investigate the evolution of gray matter volume (GMV) alterations and explore the effects of genetic and clinical features on GMV changes. A systematic review was performed to identify the relevant studies. Meta-analyses of whole-brain VBM studies were performed to assess the regional GMV changes in all HD mutation carriers, in presymptomatic HD (pre-HD), and in symptomatic HD (sym-HD). A quantitative comparison was performed between pre-HD and sym-HD. Meta-regression analyses were used to explore the effects of genetic and clinical features on GMV changes. Twenty-eight studies were included, comparing a total of 1811 HD mutation carriers [including 1150 pre-HD and 560 sym-HD] and 969 healthy controls (HCs). Pre-HD showed decreased GMV in the bilateral caudate nuclei, putamen, insula, anterior cingulate/paracingulate gyri, middle temporal gyri, and left dorsolateral superior frontal gyrus compared with HCs. Compared with pre-HD, GMV decrease in sym-HD extended to the bilateral median cingulate/paracingulate gyri, Rolandic operculum and middle occipital gyri, left amygdala, and superior temporal gyrus. Meta-regression analyses found that age, mean lengths of CAG repeats, and disease burden were negatively associated with GMV atrophy of the bilateral caudate and right insula in all HD mutation carriers. This meta-analysis revealed the pattern of GMV changes from pre-HD to sym-HD, prompting the understanding of HD progression. The pattern of GMV changes may be biomarkers for disease progression in HD.

Neurochemical changes in the progression of Huntington's disease: A meta-analysis of in vivo1H-MRS studies

Proton magnetic resonance spectroscopy (1H-MRS) allows measuring specific brain metabolic alterations in Huntington's disease (HD), and these metabolite profiles may serve as non-invasive biomarkers associated with disease progression. Despite this potential, previous findings are inconsistent. Accordingly, we performed a meta-analysis on available in vivo1H-MRS studies in premanifest (Pre-HD) and symptomatic HD stages (Symp-HD), and quantified neurometabolic changes relative to controls in 9 Pre-HD studies (227 controls and 188 mutation carriers) and 14 Symp-HD studies (326 controls and 306 patients). Our results indicated decreased N-acetylaspartate and creatine in the basal ganglia in both Pre-HD and Symp-HD. The overall level of myo-inositol was decreased in Pre-HD while increased in Symp-HD. Besides, Symp-HD patients showed more severe metabolism disruption than Pre-HD patients. Taken together, 1H-MRS is important for elucidating progressive metabolite changes from Pre-HD to clinical conversion; N-acetylaspartate and creatine in the basal ganglia are already sensitive at the preclinical stage and are promising biomarkers for tracking disease progression; overall myo-inositol is a possible characteristic metabolite for distinguishing HD stages.

Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

Reflexive and voluntary saccadic eye movements as biomarker of Huntington's Disease.

Subtle abnormalities in the preclinical stage of Huntington's Disease (HD) can be detected using saccadic eye movement assessment reflecting disease progression. This study was aimed to evaluate abnormalities in saccade parameters in asymptomatic carriers and symptomatic HD patients at various stages of HD. The study enrolled 104 participants, including 14 asymptomatic carriers of HTT mutations, 44 symptomatic HD patients, and 46 control subjects. HD severity was measured using the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) and Total Functional Capacity Scale (TFC). The evaluation of rapid eye movements (reflexive saccades, anti-saccades, memory-guided saccades) was carried out using 'Saccadometer Research'. Measures of reflexive and volitional saccades did not differ between the asymptomatic carriers and controls. Significant latency prolongation and increased physiological variability of latency times, as well as higher error rates among HD patients, were found in all saccade tasks (p < 0.001) compared to the controls. Abnormalities in saccade parameters were more pronounced in the advanced stages of the disease. Latency of saccades and error rate of volitional saccades correlated with the UHDRS-TMS and TFC scores. The saccade parameters in asymptomatic HD carriers with a long time to disease development were similar to those in the control group. Saccade abnormalities appeared in symptomatic patients at the beginning of the disease, and correlated with HD severity.

Impaired saccadic adaptation as a biomarker for disease status in pre- and early symptomatic Huntington's disease

Impaired saccadic adaptation as a biomarker for disease status in pre- and early symptomatic Huntington's disease

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

P.018 Oculomotor learning as a biomarker in Huntington’s Disease (HD) patients

Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder associated with cognitive, psychiatric, and motor dysfunction. As a potential behavioural biomarker, experimental tasks assessing motor learning may thus provide a reasonable assay of HD onset and progression. The saccadic adaptation paradigm is a non-invasive, accessible method of assessing rapid learning in the oculomotor system. Evidence demonstrates that the thalamus and basal ganglia are important loci for saccadic adaptation, also known to exhibit neurodegenerative pathology before the onset of clinically observable symptoms in HD. Methods: 26 early symptomatic HD patients (Total Functional Capacity Score ≥ 10/13) and sex/age-matched controls were tested on a standard saccadic adaptation task. Eye movements were measured using infrared oculography. Learning dynamics of how quickly the participants adapted their saccade metrics were analysed using state learning models. Results: Initial findings demonstrate that the learning dynamics of HD patients are slower and more variable with respect to saccade amplitude compared to controls. Conclusions: These results demonstrate that motor learning dynamics as captured by a saccadic adaptation task reveal early motor dysfunction in HD, thus providing a discriminating tool to detect early pathological changes in HD patients. Further work is needed regarding applications as a biomarker for disease progression.

Randomized Trial of Telegenetic Counseling for Gene Testing in Huntington’s Disease (P1-11.011)

<h3>Objective:</h3> To determine the feasibility and patient satisfaction of telegenetic counseling for Huntington’s Disease (HD). <h3>Background:</h3> Genetic counseling is necessary for pre-symptomatic or symptomatic HD genetic testing, but the lack of access to counseling due to geography or expense is a critical gap for many patients. The hypothesis of this study was that there would be no difference in patient satisfaction between telegenetic counseling (teleGC) or in-person counseling (in-personGC) for HD testing. <h3>Design/Methods:</h3> This was a prospective, randomized, unblinded study of either teleGC or in-personGC for HD gene testing. Participants had standardized genetic counseling from a certified genetic counselor in the clinic or via HIPPA appropriate telemedicine platform first, then crossed over. A study coordinator interviewed the participant using a telehealth survey after each encounter. <h3>Results:</h3> 19 in-personGC and 15 teleGC participants were included: 68% women, 41±15 yrs, 80% white, 10% Hispanic, and +CAG=45±4.4 (n=15) (P&gt;0.1). All participants were satisfied with their initial counseling experience when asked to rate on a scale of 1–10 (median 10/10, p=0.94). The majority of symptomatic HD participants (5/7) preferred in-person GC. The main advantage of teleGC was reduction in travel time for the in-personGC first (n=16) and teleGC first (n=11) groups. Technical challenges were reported (n=11) and the counseling slide deck was difficult to see (n=4) with teleGC. Visually seeing the genetic counselor improved understanding for both in-personGC (n=10) and teleGC (n=8) participants. Participants felt they were able to pick up on emotional cues (n=33) and were comfortable asking questions (n=34). <h3>Conclusions:</h3> Telegenetic counseling is a feasible option for HD gene testing, if patients are able to overcome technical issues. Having a video visit, rather than a phone call, should be considered when using telegenetic counseling for HD gene testing. In-person counseling may be preferred to increase understanding of the material in some patients, such as motor manifest HD. <b>Disclosure:</b> Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson’s Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Biohaven. The institution of Dr. Hall has received research support from Neurocrine. The institution of Dr. Hall has received research support from Uniqure. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as a Study section with NIH. Dr. Rosenbaum has nothing to disclose. Jacob Hawkins has nothing to disclose. Bichum Ouyang has nothing to disclose. Christa Suzanne Cooper, PA has nothing to disclose. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott Laboratories. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie Pharmaceuticals. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva Pharmaceuticals.

Integrated Bioinformatics Analysis of Shared Genes, miRNA, Biological Pathways and Their Potential Role as Therapeutic Targets in Huntington's Disease Stages.

Huntington's Disease (HD) is a progressive neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT). The HTT gene was the first disease-associated gene mapped to a chromosome, but the pathophysiological mechanisms, genes, proteins or miRNAs involved in HD remain poorly understood. Systems bioinformatics approaches can divulge the synergistic relationships of multiple omics data and their integration, and thus provide a holistic approach to understanding diseases. The purpose of this study was to identify the differentially expressed genes (DEGs), HD-related gene targets, pathways and miRNAs in HD and, more specifically, between the pre-symptomatic and symptomatic HD stages. Three publicly available HD datasets were analysed to obtain DEGs for each HD stage from each dataset. In addition, three databases were used to obtain HD-related gene targets. The shared gene targets between the three public databases were compared, and clustering analysis was performed on the common shared genes. Enrichment analysis was performed on (i) DEGs identified for each HD stage in each dataset, (ii) gene targets from the public databases and (iii) the clustering analysis results. Furthermore, the hub genes shared between the public databases and the HD DEGs were identified, and topological network parameters were applied. Identification of HD-related miRNAs and their gene targets was obtained, and a miRNA-gene network was constructed. Enriched pathways identified for the 128 common genes revealed pathways linked to multiple neurodegeneration diseases (HD, Parkinson's disease, Spinocerebellar ataxia), MAPK and HIF-1 signalling pathways. Eighteen HD-related hub genes were identified based on network topological analysis of MCC, degree and closeness. The highest-ranked genes were FoxO3 and CASP3, CASP3 and MAP2 were found for betweenness and eccentricity and CREBBP and PPARGC1A were identified for the clustering coefficient. The miRNA-gene network identified eleven miRNAs (mir-19a-3p, mir-34b-3p, mir-128-5p, mir-196a-5p, mir-34a-5p, mir-338-3p, mir-23a-3p and mir-214-3p) and eight genes (ITPR1, CASP3, GRIN2A, FoxO3, TGM2, CREBBP, MTHFR and PPARGC1A). Our work revealed that various biological pathways seem to be involved in HD either during the pre-symptomatic or symptomatic stages of HD. This may offer some clues for the molecular mechanisms, pathways and cellular components underlying HD and how these may act as potential therapeutic targets for HD.

Investigating the Dietary Intake Using the CyFFQ Semi-Quantitative Food Frequency Questionnaire in Cypriot Huntington's Disease Patients.

Huntington's disease (HD) is a rare progressive neurodegenerative disease characterised by autosomal dominant inheritance. The past decade saw a growing interest in the associations between the Mediterranean Diet (MD) and HD risk and outcomes. The aim of this case-control study was to assess the dietary intake and habits of Cypriot HD patients, comparing them to gender and age-matched controls, using the Cyprus Food Frequency Questionnaire (CyFFQ) and to assess adherence to the MD by disease outcomes. The method relied on the validated CyFFQ semi-quantitative questionnaire to assess energy, macro- and micronutrient intake over the past year in n = 36 cases and n = 37 controls. The MedDiet Score and the MEDAS score were used to assess adherence to the MD. Patients were grouped based on symptomatology such as movement and cognitive and behavioral impairment. The two-sample Wilcoxon rank-sum (Mann-Whitney) test was used to compare cases vs. controls. Statistically significant results were obtained for energy intake (kcal/day) (median (IQR): 4592 (3376) vs. 2488 (1917); p = 0.002) from cases and controls. Energy intake (kcal/day) (median (IQR): 3751 (1894) vs. 2488 (1917); p = 0.044) was also found to be significantly different between asymptomatic HD patients and controls. Symptomatic patients were also different from controls in terms of energy intake (kcal/day) (median (IQR): 5571 (2907) vs. 2488 (1917); p = 0.001); % energy monounsaturated fatty acids (median (IQR): 13.4 (5.2) vs. 15.5 (5.7); p = 0.0261) and several micronutrients. A significant difference between asymptomatic and symptomatic HD patients was seen in the MedDiet score (median (IQR): 31.1 (6.1) vs. 33.1 (8.1); p = 0.024) and a significant difference was observed between asymptomatic HD patient and controls (median (IQR): 5.5 (3.0) vs. 8.2 (2.0); p = 0.014) in the MEDAS score. This study confirmed previous findings that HD cases have a significantly higher energy intake than controls, revealing differences in macro and micronutrients and adherence to the MD by both patients and controls and by HD symptom severity. These findings are important as they are an effort to guide nutritional education within this population group and further understand diet-disease associations.

Structural and metabolic brain correlates of arithmetic word-problem solving in Huntington's disease.

Individuals with pre-manifest and early symptomatic Huntington's disease (HD) have shown deficits in solving arithmetic word-problems. However, the neural correlates of these deficits in HD are poorly understood. We explored the structural (gray-matter volume; GMV) and metabolic (18F-FDG PET; SUVr) brain correlates of arithmetic performance using the recently developed HD-word problem arithmetic task (HD-WPA) in seventeen preHD and sixteen HD individuals. Symptomatic participants showed significantly lower scores in the HD-WPA than preHD participants. Lower performance in the HD-WPA was associated with reduced GMV in subcortical, medial frontal, and several posterior-cortical clusters in HD participants. No significant GMV loss was found in preHD participants. 18F-FDG data revealed a widespread pattern of hypometabolism in association with lower arithmetic performance in all participants. In preHD participants, this pattern was restricted to the ventrolateral and orbital prefrontal cortex, the insula, and the precentral gyrus. In HD participants, the pattern extended to several parietal-temporal regions. Word-problem solving arithmetic deficits in HD is subserved by a pattern of asynchronous metabolic and structural compromise across the cerebral cortex as a function of disease stage. In preHD individuals, arithmetic deficits were associated with prefrontal alterations, whereas in symptomatic HD patients, more severe arithmetic deficits are associated with the compromise of several frontal-subcortical and temporo-parietal regions. Our results support the hypothesis that cognitive deficits in HD are not exclusively dominated by frontal-striatal dysfunctions but also involve fronto-temporal and parieto-occipital damage.

Predicting Severity of Huntington's Disease With Wearable Sensors.

The Unified Huntington's Disease Rating Scale (UHDRS) is the primary clinical assessment tool for rating motor function in patients with Huntington's disease (HD). However, the UHDRS and similar rating scales (e.g., UPDRS) are both subjective and limited to in-office assessments that must be administered by a trained and experienced rater. An objective, automated method of quantifying disease severity would facilitate superior patient care and could be used to better track severity over time. We conducted the present study to evaluate the feasibility of using wearable sensors, coupled with machine learning algorithms, to rate motor function in patients with HD. Fourteen participants with symptomatic HD and 14 healthy controls participated in the study. Each participant wore five adhesive biometric sensors applied to the trunk and each limb while completing brief walking, sitting, and standing tasks during a single office visit. A two-stage machine learning method was employed to classify participants by HD status and to predict UHDRS motor subscores. Linear discriminant analysis correctly classified all participants' HD status except for one control subject with abnormal gait (96.4% accuracy, 92.9% sensitivity, and 100% specificity in leave-one-out cross-validation). Two regression models accurately predicted individual UHDRS subscores for gait, and dystonia within a 10% margin of error. Our regression models also predicted a composite UHDRS score–a sum of left and right arm rigidity, total chorea, total dystonia, bradykinesia, gait, and tandem gait subscores–with an average error below 15%. Machine learning classifiers trained on brief in-office datasets discriminated between controls and participants with HD, and could accurately predict selected motor UHDRS subscores. Our results could enable the future use of biosensors for objective HD assessment in the clinic or remotely and could inform future studies for the use of this technology as a potential endpoint in clinical trials.

Quantitative Phosphoproteomics Reveals Extensive Protein Phosphorylation Dysregulation in the Cerebral Cortex of Huntington's Disease Mice Prior to Onset of Symptoms.

Protein phosphorylation plays a role in many important cellular functions such as cellular plasticity, gene expression, and intracellular trafficking. All of these are dysregulated in Huntington's disease (HD), a devastating neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene. However, no studies have yet found protein phosphorylation differences in preclinical HD mouse models. Our current study investigated changes occurring in the cortical phosphoproteome of 8-week-old (prior to motor deficits) and 20-week-old (fully symptomatic) R6/1 transgenic HD mice. When comparing 8-week-old HD mice with their wild-type (WT) littermates, we found 660 peptides differentially phosphorylated, which were mapped to 227 phosphoproteins. These proteins were mainly involved in synaptogenesis, cytoskeleton organization, axon development, and nervous system development. Tau protein, found hyperphosphorylated at multiple sites in early symptomatic HD mice, also appeared as a main upstream regulator for the changes observed. Surprisingly, we found fewer changes in the phosphorylation profile of HD mice at the fully symptomatic stage, with 29 peptides differentially phosphorylated compared to WT mice, mapped to 25 phosphoproteins. These proteins were involved in cAMP signaling, dendrite development, and microtubule binding. Furthermore, huntingtin protein appeared as an upstream regulator for the changes observed at the fully symptomatic stage, suggesting impacts on kinases and phosphatases that extend beyond the mutated polyglutamine tract. In summary, our findings show that the most extensive changes in the phosphorylation machinery appear at an early presymptomatic stage in HD pathogenesis and might constitute a new target for the development of treatments.

Dysregulation of the Basal Ganglia Indirect Pathway in Early Symptomatic Q175 Huntington's Disease Mice.

The debilitating psychomotor symptoms of Huntington's disease (HD) are linked partly to degeneration of the basal ganglia indirect pathway. At early symptomatic stages, before major cell loss, indirect pathway neurons exhibit numerous cellular and synaptic changes in HD and its models. However, the impact of these alterations on circuit activity remains poorly understood. To address this gap, optogenetic- and reporter-guided electrophysiological interrogation was used in early symptomatic male and female Q175 HD mice. D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs) were hypoactive during synchronous cortical slow-wave activity, consistent with known reductions in dendritic excitability and cortical input strength. Downstream prototypic parvalbumin-expressing external globus pallidus (PV+ GPe) neurons discharged at 2-3 times their normal rate, even during periods of D2-SPN inactivity, arguing that defective striatopallidal inhibition was not the only cause of their hyperactivity. Indeed, PV+ GPe neurons also exhibited abnormally elevated autonomous firing ex vivo Optogenetic inhibition of PV+ GPe neurons in vivo partially and fully ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative PV- GPe neurons, respectively. In contrast to STN neurons whose autonomous firing is impaired in HD mice, putative PV- GPe neuron activity was unaffected ex vivo, implying that excessive inhibition was responsible for their hypoactivity in vivo Together with previous studies, these data demonstrate that (1) indirect pathway nuclei are dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic cellular and synaptic properties; and (2) prototypic PV+ GPe neuron hyperactivity and excessive target inhibition are prominent features of early HD pathophysiology.SIGNIFICANCE STATEMENT The early symptoms of Huntington's disease (HD) are linked to degenerative changes in the action-suppressing indirect pathway of the basal ganglia. Consistent with this linkage, the intrinsic properties of cells in this pathway exhibit complex alterations in HD and its models. However, the impact of these changes on activity is poorly understood. Using electrophysiological and optogenetic approaches, we demonstrate that the indirect pathway is highly dysregulated in early symptomatic HD mice through changes in upstream activity and/or intrinsic properties. Furthermore, we reveal that hyperactivity of external globus pallidus neurons and excessive inhibition of their targets are key features of early HD pathophysiology. Together, these findings could help to inform the development and targeting of viral-based, gene therapeutic approaches for HD.

Structure and Dynamics of Large-Scale Cognitive Networks in Huntington's Disease.

Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large-scale brain cognitive networks have not yet been established. We aimed to profile changes in large-scale cognitive networks in premanifest and symptomatic patients with Huntington's disease. We prospectively recruited premanifest and symptomatic Huntington's disease mutation carriers as well as healthy controls. Clinical and sociodemographic data were obtained from all participants, and resting-state functional connectivity data, using both time-averaged and dynamic functional connectivity, was acquired from whole-brain and cognitively oriented brain parcellations. A total of 64 gene mutation carriers and 23 healthy controls were included; 21 patients with Huntington's disease were classified as premanifest and 43 as symptomatic Huntington's disease. Compared with healthy controls, patients with Huntington's disease showed decreased network connectivity within the posterior hubs of the default-mode network and the medial prefrontal cortex, changes that correlated with cognitive (t=2.25, P=0.01) and disease burden scores (t=-2.42, P=0.009). The salience network showed decreased functional connectivity between insular and supramarginal cortices and also correlated with cognitive (t=2.11, P=0.02) and disease burden scores (t=-2.35, P=0.01). Dynamic analyses showed that network variability was decreased for default-central executive networks, a feature already present in premanifest mutation carriers (dynamic factor 8, P=0.02). Huntington's disease shows an early and widespread disruption of large-scale cognitive networks. Importantly, these changes are related to cognitive and disease burden scores, and novel dynamic functional analyses uncovered subtler network changes even in the premanifest stages.

Multimodal Imaging and Visual Evoked Potentials Reveal Key Structural and Functional Features That Distinguish Symptomatic From Presymptomatic Huntington's Disease Brain.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric abnormalities. Currently, matched analyses of structural and functional differences in the brain from the same study cohort and, specifically, in HD patients from an ethnically diverse Indian population are lacking. Such findings aid in identifying noninvasive and sensitive imaging biomarkers. The aim of the study was to understand the structural and functional differences between HD and control brain, and presymptomatic and symptomatic HD brain in the Indian population. Seventeen HD (11 symptomatic HD [S-HD] and six presymptomatic HD [P-HD], with comparable CAG repeats), and 12 healthy controls were examined. Macrostructural (volume), microstructural (diffusivity), and functional (neurochemical levels and glucose metabolism) imaging of the brain was done along with the determination of visual latencies. HD brain showed increased intercaudate distance; significant subcortical volumetric loss; reduced fractional anisotropy; increased mean, axial, and radial diffusivity; lower levels of total N-acetyl aspartate; elevated total choline levels; and reduced glucose metabolism compared with control brain. Interestingly, compared with P-HD, S-HD patients demonstrated a strong inverse correlation between age at onset and CAG repeat length, and prolonged P100 latency. In addition, caudate and putamen in S-HD brain showed significant volumetric loss and increased diffusivity compared with P-HD brain. HD brain showed distinct macrostructural, microstructural, and functional differences compared with control brain in the Indian population. Interestingly, patients with S-HD had a significant volumetric loss, increased diffusivity, altered neurochemical profile, and delayed P100 latency compared with P-HD patients. Examining these alterations clinically could aid in monitoring the progression of HD.

Impaired Cerebrovascular Reactivity in Huntington's Disease.

There is increasing evidence that impairments of cerebrovascular function and/or abnormalities of the cerebral vasculature might contribute to early neuronal cell loss in Huntington’s disease (HD). Studies in both healthy individuals as well as in patients with other neurodegenerative disorders have used an exogenous carbon dioxide (CO2) challenge in conjunction with functional magnetic resonance imaging (fMRI) to assess regional cerebrovascular reactivity (CVR). In this study, we explored potential impairments of CVR in HD. Twelve gene expanded HD individuals, including both pre-symptomatic and early symptomatic HD and eleven healthy controls were administered a gas mixture targeting a 4–8 mmHg increase in CO2 relative to the end-tidal partial pressure of CO2 (PETCO2) at rest. A Hilbert Transform analysis was used to compute the cross-correlation between the time series of regional BOLD signal changes (ΔBOLD) and increased PETCO2, and to estimate the response delay of ΔBOLD relative to PETCO2. After correcting for age, we found that the cross-correlation between the time series for regional ΔBOLD and for PETCO2 was weaker in HD subjects than in controls in several subcortical white matter regions, including the corpus callosum, subcortical white matter adjacent to rostral and caudal anterior cingulate, rostral and caudal middle frontal, insular, middle temporal, and posterior cingulate areas. In addition, greater volume of dilated perivascular space (PVS) was observed to overlap, primarily along the periphery, with the areas that showed greater ΔBOLD response delay. Our preliminary findings support that alterations in cerebrovascular function occur in HD and may be an important, not as yet considered, contributor to early neuropathology in HD.

Genomic architecture differences at the HTT locus associated with symptomatic and pre-symptomatic cases of Huntington’s disease in a pilot study

Huntington’s Disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide Cytosine-Adenine-Guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this presymptomatic phase. Using peripheral blood samples from HD patients and healthy controls we used EpiSwitch®, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of the HTT gene. We evaluated chromatin conformations at 20 sites across 225 kb of the HTT locus in a small cohort of healthy controls, verified symptomatic HD patients (CAG, n&gt;39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD. Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. 85% (6 out of 7) of the patients in the symptomatic HD cohort demonstrated at least one of the specific chromosome conformations associated with symptomatic HD. Our results provide the first evidence that chromatin architecture at the HTT locus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of Chromosome Conformation Signatures (CCS) warrant further study as a prognostic tool in HD.

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range

PurposeIn some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI’s effect on AOO. MethodsWe developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. ResultsMean onset for LOI carriers (n=49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36–39 CAGs). ConclusionThe LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36–39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.