Premanifest Huntington's Disease Research Articles

Assessment of Perivascular Space Morphometry Across the White Matter in Huntington's Disease Using MRI.

Perivascular spaces (PVS) are fluid-filled cavities surrounding small cerebral blood vessels. There are limited reports of enlarged PVS across the grey matter in manifest Huntington's disease (HD). Little is known about how PVS morphometry in the white matter may contribute to HD. Enlarged PVS have the potential to both contribute to HD pathology and affect the distribution and success of intraparenchymal and intrathecally administered huntingtin-lowering therapies. To investigate PVS morphometry in the global white matter across the spectrum of HD. Relationships between PVS morphometry and disease burden and severity measures were examined. White matter PVS were segmented on 3T T2 W MRI brain scans of 33 healthy controls, 30 premanifest HD (pre-HD), and 32 early manifest HD (early-HD) participants from the Vancouver site of the TRACK-HD study. PVS count and total PVS volume were measured. PVS total count slightly increased in pre-HD (p = 0.004), and early-HD groups (p = 0.005), compared to healthy controls. PVS volume, as a percentage of white matter volume, increased subtly in pre-HD compared to healthy controls (p = 0.044), but not in early-HD. No associations between PVS measures and HD disease burden or severity were found. This study reveals relatively preserved PVS morphometry across the global white matter of pre-HD and early-HD. Subtle morphometric abnormalities are implied but require confirmation in a larger cohort. However, in conjunction with previous publications, further investigation of PVS in HD and its potential impact on future treatments, with a focus on subcortical grey matter, is warranted.

High Levels of Mutant Huntingtin Protein in Tear Fluid From Huntington's Disease Gene Expansion Carriers.

Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects middle-aged adults. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which, to our knowledge, has never been measured before. We recruited 20 manifest and 13 premanifest HD gene expansion carriers, and 20 age-matched controls. All patients underwent detailed assessments, including the Unified Huntington's Disease Rating Scale (UHDRS) total motor score (TMS) and total functional capacity (TFC) score. Tear fluid was collected using paper Schirmer's strips. The level of tear mHTT was determined using single-molecule counting SMCxPRO technology. The average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than those in controls (1,622 ± 2,179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, "estimated years to diagnosis," disease burden score and UHDRS TMS and TFC. The receiver operating curve demonstrated an almost perfect score (area under the curve [AUC] = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cutoff value for distinguishing between controls and manifest patients was 4,544 fM, whereas it was 6,596 fM for distinguishing between controls and premanifest patients. Tear mHTT has potential for early and noninvasive detection of alterations in HD patients and could be integrated into both clinical trials and clinical diagnostics.

Associations between Sleep Quality and Serum Levels of Neurofilament Light in Individuals with Premanifest Huntington Disease

Abstract Objectives To evaluate the associations between sleep quality and serum levels of neurofilament light (NfL) protein in individuals with premanifest Huntington disease (HD). Materials and Methods We recruited 28 individuals with premanifest HD from a pre-existing database (of the Huntington's Environmental Research Optimisation Scheme, HEROs). The participants filled out the Pittsburgh Sleep Quality Index (PSQI), a subjective measure of sleep quality, and blood was collected via routine venepuncture to measure peripheral NfL levels. Results The PSQI scores (median: 5.0; interquartile range: 4.0–7.5) indicated poor sleep quality. General linear modelling revealed no significant (p = 0.242) association between PSQI scores and NfL levels. No significant differences were found between individuals with good and poor sleep quality for any demographic variable collected. Discussion Contrary to studies on other neurological conditions, there was no association between sleep quality and NfL levels in individuals with premanifest HD. This was unexpected, given the influence of environmental factors (such as social network size) on neurodegeneration in individuals with premanifest HD.

Altered Iron and Microstructure in Huntington's Disease Subcortical Nuclei: Insight From 7T MRI.

Pathophysiological changes of Huntington's disease (HD) can precede symptom onset by decades. Robust imaging biomarkers are needed to monitor HD progression, especially before the clinical onset. To investigate iron dysregulation and microstructure alterations in subcortical regions as HD imaging biomarkers, and to associate such alterations with motor and cognitive impairments. Prospective. Fourteen individuals with premanifest HD (38.0 ± 11.0 years, 9 females; far-from-onset N = 6, near-onset N = 8), 21 manifest HD patients (49.1 ± 12.1 years, 11 females), and 33 age-matched healthy controls (43.9 ± 12.2 years, 17 females). 7 T, T1 -weighted imaging, quantitative susceptibility mapping, and diffusion tensor imaging. Volume, susceptibility, fractional anisotropy (FA), and mean diffusivity (MD) within subcortical brain structures were compared across groups, used to establish HD classification models, and correlated to clinical measures and cognitive assessments. Generalized linear model, multivariate logistic regression, receiver operating characteristics with the area under the curve (AUC), and likelihood ratio test comparing a volumetric model to one that also includes susceptibility and diffusion metrics, Wilcoxon paired signed-rank test, and Pearson's correlation. A P-value <0.05 after Benjamini-Hochberg correction was considered statistically significant. Significantly higher striatal susceptibility and FA were found in premanifest and manifest HD preceding atrophy, even in far-from-onset premanifest HD compared to controls (putamen susceptibility: 0.027 ± 0.022 vs. 0.018 ± 0.013 ppm; FA: 0.358 ± 0.048 vs. 0.313 ± 0.039). The model with additional susceptibility, FA, and MD features showed higher AUC compared to volume features alone when differentiating premanifest HD from HC (0.83 vs. 0.66), and manifest from premanifest HD (0.94 vs. 0.83). Higher striatal susceptibility significantly correlated with cognitive deterioration in HD (executive function: r = -0.600; socioemotional function: r = -0.486). 7 T MRI revealed iron dysregulation and microstructure alterations with HD progression, which could precede volume loss, provide added value to HD differentiation, and might be associated with cognitive changes. 2 TECHNICAL EFFICACY: Stage 2.

54 Sleep and Circadian Rhythms in Premanifest Huntington’s disease: Relationship with Cognition

Objective:Huntington’s disease (HD) is a neurodegenerative disease characterised by motor, psychiatric and cognitive decline. Currently, no treatments have been identified in HD for slowing down cognitive decline or improving cognitive function. We are interested in identifying potentially modifiable factors in HD that can be targeted to improve or maintain cognitive function. Sleep and circadian disruption stand out as possible modifiable targets because sleep and circadian symptoms are common in HD, and such disruptions are known to impact cognition in the general population. Despite some emerging evidence that sleep quality correlates with cognition in manifest HD, whether these same relationships exist in the premanifest period is unknown. Further, whether circadian rhythms relate to cognition in premanifest HD remains open. Therefore, we aimed to determine whether sleep and circadian parameters relate to cognitive performance in premanifest HD.Participants and Methods:To date, we have recruited 27 premanifest HD participants to a two-week remote sleep study. During the study, participants wore an Actiwatch-2 and completed a sleep diary for 14 consecutive days to assess their sleep and rest-activity patterns. Participants also completed online sleep and mood questionnaires and a cognitive assessment using videoconference. We calculated Pearson correlations to examine whether cognitive performance relates to subjective sleep quality, objective sleep parameters and circadian rest-activity rhythms. Thus far, we have analysed data from 15 female participants with premanifest HD (Mage = 43.20, SD = 11.58).Results:Preliminary results indicate that measures of subjective sleep quality, insomnia severity, daytime sleepiness, and fatigue severity in premanifest HD do not correlate with cognitive performance. Increases in objectively measured sleep efficiency, however, strongly correlated with better performance on the Hopkins-Verbal Learning Test-Revised (HVLT-R) immediate (r = 0.562, p &lt; 0.05) and delayed recall trials (r = 0.597, p &lt; 0.05) and the Trail Making Test Part B (TMT-B; r = 0.550, p &lt; 0.05). More time spent awake (i.e., wake after sleep onset) was strongly linked to reduced performance on the TMT-B (r = -0.542, p &lt; 0.05) and Symbol Digit Modalities Test (r = -0.556, p &lt; 0.05). Further, increases in total sleep time were associated with better performance on the HVLT-R immediate (r = 0.682, p &lt; 0.05) and delayed recall trial (r = 0.616, p &lt; 0.05). For our circadian parameters, less fragmented day-today rest-activity rhythms (i.e., higher intra-daily variability) strongly correlated with higher scores on the HVLT-R immediate (r = 0.768, p &lt; 0.001) delayed recall trials (r = 0.7276, p &lt; 0.05) and TMT-B (r = 0.516, p &lt; 0.05), whereas consistent and stable day-to-day rest-activity rhythms (i.e., higher inter-daily stability) was associated with poorer performance on ERT (r = -0.587, p &lt; 0.05).Conclusions:Preliminary results suggest that fragmented sleep, sleep inefficiency, reduced total sleep time, rest-activity rhythm stability and fragmentation relate to poorer cognitive performance in people with premanifest HD. Should analysis of our whole sample confirm these preliminary findings, targeting sleep in HD (e.g., through sleep hygiene and/or psychoeducation) may be a useful strategy to improve or maintain cognition.

Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Huntington’s disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden.In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain’s resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.

Graphomotor Dysfluency as a Predictor of Disease Progression in Premanifest Huntington's Disease.

Prior studies have relied on conventional observer-based severity ratings such as the Unified Huntington's Disease Rating Scale (UHDRS) to identify early motor markers of decline in Huntington's disease (HD). The present study examined the predictive utility of graphomotor measures handwriting and drawing movements. Seventeen gene-positive premanifest HD subjects underwent comprehensive clinical, cognitive, motor, and graphomotor assessments at baseline and at follow-up intervals ranging from 9-36 months. Baseline graphomotor assessments were subjected to linear multiple regression procedures to identify factors associated with change on the comprehensive UHDRS index. Subjects were followed for an average of 21.2 months. Three multivariate regression models based on graphomotor variables derived from a complex loop task, a maximum speed circle drawing task and a combined task returned adjusted R2 coefficients of 0.76, 0.71, and 0.80 respectively accounting for a significant portion of the variability in cUHDRS change score. The best-fit model based on the combined tasks indicated that greater decline on the cUHDRS was associated with increased pen movement dysfluency and stroke-stroke variability at baseline. Performance on multiple measures of graphomotor dysfluency assessed during the premanifest or prodromal stage in at-risk HD individuals was associated with decline on a multidimensional index on HD morbidity preceding an HD diagnosis.

The shape of things to come. Mapping spatiotemporal progression of striatal morphology in Huntington disease: The IMAGE-HD study

Mapping the spatiotemporal progression of neuroanatomical change in Huntington's Disease (HD) is fundamental to the development of bio-measures for prognostication. Statistical shape analysis to measure the striatum has been performed in HD, however there have been a limited number of longitudinal studies. To address these limitations, we utilised the Spherical Harmonic Point Distribution Method (SPHARM-PDM) to generate point distribution models of the striatum in individuals, and used linear mixed models to test for localised shape change over time in pre-manifest HD (pre-HD), symp-HD (symp-HD) and control individuals. Longitudinal MRI scans from the IMAGE-HD study were used (baseline, 18 and 30 months). We found significant differences in the shape of the striatum between groups. Significant group-by-time interaction was observed for the putamen bilaterally, but not for caudate. A differential rate of shape change between groups over time was observed, with more significant deflation in the symp-HD group in comparison with the pre-HD and control groups. CAG repeats were correlated with bilateral striatal shape in pre-HD and symp-HD. Robust statistical analysis of the correlates of striatal shape change in HD has confirmed the suitability of striatal morphology as a potential biomarker correlated with CAG-repeat length, and potentially, an endophenotype.

Spatiotemporal gait parameters in adults with premanifest and manifest Huntington's Disease: A systematic review.

To systematically review and critically evaluate literature on spatiotemporal gait deviations in individuals with premanifest and manifest Huntington's Disease (HD) in comparison with healthy cohorts. We conducted a systematic review, guided by the Joanna Briggs Institute's Manual for Evidence Synthesis and pre-registered with the International Prospective Register of Systematic Reviews. Eight electronic databases were searched. Studies comparing spatiotemporal footstep parameters in adults with premanifest and manifest HD to healthy controls were screened, included and critically appraised by independent reviewers. Data on spatiotemporal gait changes and variability were extracted and synthesised. Meta-analysis was performed on gait speed, cadence, stride length and stride length variability measures. We screened 2721 studies, identified 1245 studies and included 25 studies (total 1,088 participants). Sample sizes ranged from 14 to 96. Overall, the quality of the studies was assessed as good, but reporting of confounding factors was often unclear. Meta-analysis found spatiotemporal gait deviations in participants with HD compared to healthy controls, commencing in the premanifest stage. Individuals with premanifest HD walk significantly slower (-0.17m/s; 95% confidence interval (CI) [-0.22,-0.13]), with reduced cadence (-6.63 steps/min; 95%CI [-10.62, -2.65]) and stride length (-0.09m; 95%CI [-0.13, -0.05]). Stride length variability was also increased in premanifest cohorts by 2.18% (95% CI [0.69, 3.68]), with these changes exacerbated in participants with manifest disease. Findings suggest individuals with premanifest and manifest HD display significant spatiotemporal footstep deviations. Clinicians could monitor individuals in the premanifest stage of disease for gait changes to identify the onset of Huntington's symptoms.

Measuring cognitive impairment and monitoring cognitive decline in Huntington’s disease: a comparison of assessment instruments

BackgroundProgressive cognitive decline is an inevitable feature of Huntington’s disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment.MethodsWe collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another.ResultsThe PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories.ConclusionThe PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia.

Using the LASSI-L to Detect Robust Interference Effects in Premanifest Huntington Disease.

Diagnosis of manifest Huntington disease (HD) is based primarily on motor symptoms, but premanifest HD (preHD) is often associated with subtle cognitive decline. The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is a validated verbal learning test that can be used to detect early cognitive decline. To determine the utility of the LASSI-L for detecting early cognitive decline in individuals with preHD and to compare the results of the LASSI-L with those of commonly used neuropsychological tests in HD. We administered the LASSI-L to 13 individuals with preHD and 13 healthy controls matched for age, sex, and education as part of a longitudinal study of disease progression. For comparison purposes, we administered the Mini-Mental State Examination; Stroop Color and Word Test; Symbol Digit Modalities Test; Trail-Making Test, Parts A and B; and category fluency (animals) task. Five of the seven sections on the LASSI-L captured group differences: Proactive Semantic Interference (PSI; P < 0.001), Failure to Recover From PSI (P = 0.038), Retroactive Semantic interference (RSI; P = 0.013), Delayed Recall (P < 0.001), and B1 Cued Recall Intrusions (P = 0.036). Using a false discovery rate of <0.05, PSI, RSI, and Delayed Recall remained significant. The LASSI-L is a sensitive instrument for detecting early interference effects in individuals with preHD that outperforms commonly used neuropsychological tests. The LASSI-L could be a useful addition to clinical and research protocols involving individuals with preHD.

Application Value of Serum Neurofilament Light Protein for Disease Staging in Huntington's Disease.

Neurofilament light protein (NfL) has been proven to be a sensitive biomarker for Huntington's disease (HD). However, these studies did not include HD patients at advanced stages or with larger CAG repeats (>50), leading to a knowledge gap of the characteristics of NfL. Serum NfL (sNfL) levels were quantified using an ultrasensitive immunoassay. Participants were assessed by clinical scales and 7.0 T magnetic resonance imaging. Longitudinal samples and clinical data were obtained. Baseline samples were available from 110 controls, 90 premanifest HD (pre-HD) and 137 HD individuals. We found levels of sNfL significantly increased in HD compared to pre-HD and controls (both P < 0.0001). The increase rates of sNfL were differed by CAG repeat lengths. However, there was no difference in sNfL levels in manifest HD from early to late stages. In addition, sNfL levels were associated with cognitive measures in pre-HD and manifest HD group, respectively. The increased levels of sNfL were also closely related to microstructural changes in white matter. In the longitudinal analysis, baseline sNfL did not correlate with subsequent clinical function decline. Random forest analysis revealed that sNfL had good power for predicting disease onset. Although sNfL levels are independent of disease stages in manifest HD, it is still an optimal indicator for predicting disease onset and has potential use as a surrogate biomarker of treatment effect in clinical trials. © 2023 International Parkinson and Movement Disorder Society.

Prevalence of Neurocognitive Disorder in a Pre-manifest Huntington’s disease Cohort (P1-11.014)

<h3>Objective:</h3> To determine the prevalence of mild and major neurocognitive disorder in premanifest HD patients using DSM-5 criteria. <h3>Background:</h3> Huntington’s disease (HD) is a neurological disorder characterized by progressive dysfunction across three domains: movement, cognition, and behavior. The diagnosis of manifest HD is based primarily on motor dysfunction, however cognitive decline typically begins in the pre-manifest (preHD) phase and often exerts an understated functional impact. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has established criteria for both mild and major neurocognitive disorder (NCD), however, these are not routinely applied in HD. <h3>Design/Methods:</h3> The following cognitive battery was administered to both preHD (CAG repeat &gt; 36) and control participants: Stroop Color and Word Test (SCWT), Symbol Digit Modalities Test (SDMT), and Verbal fluency (Category). DSM-5 criteria for NCD were then applied to these test results to determine diagnostic prevalence of NCD. <h3>Results:</h3> 23 preHD participants and 26 Healthy Controls (HC) were enrolled. PreHD participants’ age was (40.7±11.5) (mean±SD), years of education (15.7±2.7), CAG repeat length (42.1±2.7). The UHDRSTM total motor score was (2.0±2.2). HC age was (37.1 ± 12.0), and education of (16.6 ± 2.1). Group differences in age and education were not statistically significant, however, group differences were observed for Verbal Fluency (p = 0.03) and Word Reading (p = 0.004). Using DSM-5 criteria, the prevalence of NCD-mild was 35% in preHD vs. 3% in HC, NCD-major was 13% in preHD versus 0% in HC. <h3>Conclusions:</h3> The prevalence of NCD in preHD is surprisingly elevated. Establishing a clinical diagnosis of NCD prior to motor manifestation can be critical for access to services, anticipating longitudinal care, expanding recruitment for disease-modifying trials, and validating patient concerns when appropriate. Consideration should be given to incorporating NCD criteria into clinical practice. <b>Disclosure:</b> Mr. Sierra has nothing to disclose. Miss Ullman has nothing to disclose. Ms. Baselga-Garriga has nothing to disclose. Miss Hildebrand has nothing to disclose. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sage Therapeutics. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for uniQure. The institution of Dr. Frank has received research support from Huntington’s Disease Society of America. The institution of Dr. Frank has received research support from Roche/Genentech. The institution of Dr. Frank has received research support from CHDI Foundation. The institution of Dr. Frank has received research support from Huntington Study Group. The institution of Dr. Frank has received research support from Triplet Therapeutics. Dr. Laganiere has received research support from HDSA.

Ganglioside-focused Glycan Array Reveals Abnormal Anti-GD1b Auto-antibody in Plasma of Preclinical Huntington’s Disease

Huntington's disease (HD) is a progressive and devastating neurodegenerative disease marked by inheritable CAG nucleotide expansion. For offspring of HD patients carrying abnormal CAG expansion, biomarkers that predict disease onset are crucially important but still lacking. Alteration of brain ganglioside patterns has been observed in the pathology of patients carrying HD. Here, by using a novel and sensitive ganglioside-focused glycan array, we examined the potential of anti-glycan auto-antibodies for HD. In this study, we collected plasma from 97 participants including 42 control (NC), 16 pre-manifest HD (pre-HD), and 39 HD cases and measured the anti-glycan auto-antibodies by a novel ganglioside-focused glycan array. The association between plasma anti-glycan auto-antibodies and disease progression was analyzed using univariate and multivariate logistic regression. The disease-predictive capacity of anti-glycan auto-antibodies was further investigated by receiver operating characteristic (ROC) analysis. We found that anti-glycan auto-antibodies were generally higher in the pre-HD group when compared to the NC and HD groups. Specifically, anti-GD1b auto-antibody demonstrated the potential for distinguishing between pre-HD and control groups. Moreover, in combination with age and the number of CAG repeat, the level of anti-GD1b antibody showed excellent predictability with an area under the ROC curve (AUC) of 0.95 to discriminate between pre-HD carriers and HD patients. With glycan array technology, this study demonstrated abnormal auto-antibody responses that showed temporal changes from pre-HD to HD.

"Ten euros now" temporal discounting in Huntington disease.

When making decisions, one often faces a trade-off between immediate and long-term rewards. In these situations, people may prefer immediate over later rewards, even if immediate rewards are smaller than later ones; a phenomenon known as temporal discounting. In this study, we, for the first time, assessed temporal discounting in three populations: participants with manifest Huntington disease (HD), participants with premanifest HD, and control participants. Using the temporal discounting task, we invited participants to choose between small immediate amount of money vs. delayed, but larger amount of money (e.g., "Which do you prefer: you get 10 euros right now or 50 euros in a month?"). We also measured inhibition in order to test if it impacts discounting performance. Analysis demonstrated higher temporal discounting (i.e., a preference for the immediate rewards) in participants with manifest HD compared to those with premanifest HD or control participants, but no significant differences were observed in participants with premanifest HD and control participants. Analysis also demonstrated significant correlations between temporal discounting and scores on an inhibition test in participants with manifest HD, but not in those with premanifest HD or in control participants. We suggest that, when making decisions, patients with manifest HD may have difficulties with suppressing the temptation of smaller, but immediate, rewards.

Peripheral Biomarkers in Manifest and Premanifest Huntington's Disease.

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.

Speech biomarkers in Huntington's disease: A cross-sectional study in pre-symptomatic, prodromal and early manifest stages.

Motor speech alterations are a prominent feature of clinically manifest Huntington's disease (HD). Objective acoustic analysis of speech can quantify speech alterations. It is currently unknown, however, at what stage of HD speech alterations can be reliably detected. We aimed to explore the patterns and extent of speech alterations using objective acoustic analysis in HD and to assess correlations with both rater-assessed phenotypical features and biological determinants of HD. Speech samples were acquired from 44 premanifest (29 pre-symptomatic and 15 prodromal) and 25 manifest HD gene expansion carriers, and 25 matched healthy controls. A quantitative automated acoustic analysis of 10 speech dimensions was performed. Automated speech analysis allowed us to differentiate between participants with HD and controls, with areas under the curve of 0.74 for pre-symptomatic, 0.92 for prodromal, and 0.97 for manifest stages. In addition to irregular alternating motion rates and prolonged pauses seen only in manifest HD, both prodromal and manifest HD displayed slowed articulation rate, slowed alternating motion rates, increased loudness variability, and unstable steady-state position of articulators. In participants with premanifest HD, speech alteration severity was associated with cognitive slowing (r=-0.52, p < 0.001) and the extent of bradykinesia (r=0.43, p=0.004). Speech alterations correlated with a measure of exposure to mutant gene products (CAG-age-product score; r=0.60, p < 0.001). Speech abnormalities in HD are associated with other motor and cognitive deficits and are measurable already in premanifest stages of HD. Therefore, automated speech analysis might represent a quantitative HD biomarker with potential for assessing disease progression.

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.

Local synchronicity in dopamine-rich caudate nucleus influences Huntington's disease motor phenotype.

Structural grey and white matter changes precede the manifestation of clinical signs of Huntington's disease by many years. Conversion to clinically manifest disease therefore likely reflects not merely atrophy but a more widespread breakdown of brain function. Here, we investigated the structure-function relationship close to and after clinical onset, in important regional brain hubs, particularly caudate nucleus and putamen, which are central to maintaining normal motor behaviour. In two independent cohorts of patients with premanifest Huntington's disease close to onset and very early manifest Huntington's disease (total n = 84; n = 88 matched controls), we used structural and resting state functional MRI. We show that measures of functional activity and local synchronicity within cortical and subcortical regions remain normal in the premanifest Huntington's disease phase despite clear evidence of brain atrophy. In manifest Huntington's disease, homeostasis of synchronicity was disrupted in subcortical hub regions such as caudate nucleus and putamen, but also in cortical hub regions, for instance the parietal lobe. Cross-modal spatial correlations of functional MRI data with receptor/neurotransmitter distribution maps showed that Huntington's disease-specific alterations co-localize with dopamine receptors D1 and D2, as well as dopamine and serotonin transporters. Caudate nucleus synchronicity significantly improved models predicting the severity of the motor phenotype or predicting the classification into premanifest Huntington's disease or motor manifest Huntington's disease. Our data suggest that the functional integrity of the dopamine receptor-rich caudate nucleus is key to maintaining network function. The loss of caudate nucleus functional integrity affects network function to a degree that causes a clinical phenotype. These insights into what happens in Huntington's disease could serve as a model for what might be a more general relationship between brain structure and function in neurodegenerative diseases in which other brain regions are vulnerable.

Are you angry? Neural basis of impaired facial expression recognition in pre-manifest Huntington's

IntroductionEarly non-motor symptoms in Huntington's disease (HD), including visual perceptual difficulties, can have profound negative impacts on quality of life. In particular, deficits in emotion recognition may contribute to misinterpretation of social cues, and may adversely affect interpersonal relationships, work relationships and/or general well-being. This may be particularly salient during the pre-manifest period, a period prior to the onset of motor symptoms. We sought to evaluate impairments in emotion recognition in gene-positive individuals who did not meet criterial for a diagnosis of HD; we also sought to determine associations between emotion recognition processing and altered cortico-striatal circuitry. MethodsWe used a standardized battery to evaluate performance on a facial expression recognition task in a cohort of motor pre-manifest HD (Pre-HD) individuals (N = 21). Functional MRI (fMRI) was then used to assess the face processing network in a subset (N = 15). ResultsWe found significantly decreased response accuracy to certain facial expressions, particularly of negative emotions (p < 0.001) in Pre-HDs. When Pre-HDs viewed faces with different emotions, activation within the Superior Temporal Sulcus (fSTS) was reduced compared to controls; in contrast, the level of evoked response within other face-selective cortical regions was comparable. ConclusionEarly deficits in emotion recognition in Pre-HD appear to be associated with alterations in the fSTS response, a distinctly different pathway from that involved in face perception and provide support for early cognitive and behavioral interventions.