Variability in interval production is due to timing‐dependent deficits in Huntington's disease

In Huntington's disease (HD), increased variability is seen in performance of motor tasks that require implicit control of timing. We examined whether timing variability was also evident in an explicit interval‐timing task. Sixty subjects (21 controls, 19 manifest HD, and 20 pre‐manifest HD) performed a single‐interval production task with three target intervals (1.1 s, 2.2 s, 3.3 s). We analyzed accuracy (proportional error) and precision (standard deviation) across groups and intervals. No differences were seen in accuracy across groups or intervals. Precision was significantly lower in manifest (P = 0.0001) and pre‐manifest HD (P = 0.04) compared with controls. This was particularly true for pre‐manifest subjects close to diagnosis (based on probability of diagnosis in 5 years). Precision was correlated with proximity to diagnosis (r² = 0.3, P < 0.01). To examine the source of reduced precision, we conducted linear regression of standard deviation with interval duration. Slope of the regression was significantly higher in manifest HD (P = 0.02) and in pre‐manifest HD close to diagnosis (P = 0.04) compared with controls and pre‐manifest participants far from diagnosis. Timing precision is impaired before clinical diagnosis in Huntington's disease. Slope analysis suggests that timing variability (decreased precision) was attributable to deficits in timing‐dependent processes. Our results provide additional support for the proposal that the basal ganglia are implicated in central timekeeping functions. Because the single interval production task was sensitive to deficits in pre‐manifest HD, temporal precision may be a useful outcome measure in future clinical trials. © 2014 International Parkinson and Movement Disorder Society     

Grasping premanifest Huntington's disease – shaping new endpoints for new trials

Future clinical trials in subjects with premanifest Huntington's disease (preHD) may depend on the availability of biomarkers. It was previously shown in symptomatic HD that, the grip force variability coefficient‐of‐variation (GFV‐C) in a grasping paradigm was correlated to the Unified‐Huntington's‐Disease‐Rating‐Scale‐Total‐Motor‐Score (UHDRS‐TMS) and increased in a 3 year follow‐up study. To further elucidate its potential as a biomarker, we investigated whether GFV‐C is able to detect a motor phenotype in preHD and is correlated to the genotype assessed by a disease‐burden‐score. The ability of preHD (n = 15) and symptomatic HD subjects (n = 20) to maintain stable grip forces, while holding an object (250 g and 500 g), was measured and compared with the controls (n = 19). GFV‐C was increased in preHD at 500 g, in symptomatic subjects at both weights and was correlated to the disease‐burden‐score and UHDRS‐TMS. GFV‐C may be a useful objective and quantitative marker of motor dysfunction across genetically diagnosed premanifest and symptomatic HD subjects. © 2010 Movement Disorder Society     

Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease

The purpose of this study was to quantify gait impairments in presymptomatic and symptomatic Huntington's disease (HD) subjects, and examine sensitivity of gait measures. Our sample (n = 65) included presymptomatic mutation carriers (PMC) (n = 15), symptomatic HD subjects (SHD) (n = 30) and healthy controls (n = 20). Participants were requested to walk at their preferred speed on a computerized walkway that recorded spatiotemporal variables. We administered the Unified HD Rating Scale (UHDRS) for PMC and SHD. PMC demonstrated decreased gait velocity (P < 0.01), stride length (P < 0.008), and increased time in double support (P < 0.001); and demonstrated higher variability in stride length (P < 0.01) and step time (P < 0.004) compared with controls. These impairments worsened with increasing disease severity for SHD. Gait impairments were correlated with predicted years to onset in PMC (velocity = ?0.65; cadence = ?0.70, step time = 0.71) and demonstrated high sensitivity and specificity in distinguishing between controls and mutation carriers. In contrast, UHDRS scores did not reveal impairments in gait and balance. Gait bradykinesia and dynamic balance impairments begin in the presymptomatic stage of HD and continue to worsen in the symptomatic stages. Gait measures are sensitive in differentiating between mutation positive and negative individuals even when impairments were not detected by clinical neurological examination. © 2008 Movement Disorder Society     

Coordination of prehensile forces during precision grip in Huntington's disease

The present study examined the coordination of prehensile forces during precision grip in subjects with Huntington's disease (HD). Fingertip forces were measured in 12 subjects with HD and 12 age-matched controls during the lifting of an instrumented object whose weight and surface texture were varied. The results indicate that subjects with HD have impaired initiation and delayed transitions between movement sequences and produce excessive and variable forces. However, subjects with HD demonstrated anticipatory scaling of force development based on the object's expected physical properties (planning) and adjustment of the force to the object's actual physical properties (sensorimotor integration). The observed findings generally were unrelated to the overall disease severity. However, the variability in forces was correlated with functional capacity and motor performance suggesting that variability is a key feature of the motor deficit. These results provide insights into the impaired hand function observed in individuals with HD.     

Distinct Brain Volume Changes Correlating with Clinical Stage,Disease Progression Rate,Mutation Size,and Age at Onset Prediction as Early Biomarkers of Brain Atrophy in Huntington's Disease

Searching brain and peripheral biomarkers is a requisite to cure Huntington's disease (HD). To search for markers indicating the rate of brain neurodegenerative changes in the various disease stages, we quantified changes in brain atrophy in subjects with HD. We analyzed the cross‐sectional and longitudinal rate of brain atrophy, quantitatively measured by fully‐automated multiparametric magnetic resonance imaging, as fractional gray matter (GM, determining brain cortex volume), white matter (WM, measuring the volume of axonal fibers), and corresponding cerebral spinal fluid (CSF, a measure of global brain atrophy), in 94 gene‐positive subjects with presymptomatic to advanced HD, and age‐matched healthy controls. Each of the three brain compartments we studied (WM, GM, and CSF) had a diverse role and their time courses differed in the development of HD. GM volume decreased early in life. Its decrease was associated with decreased serum brain‐derived‐neurotrophic‐factor and started even many years before onset symptoms, then decreased slowly in a nonlinear manner during the various symptomatic HD stages. WM volume loss also began in the presymptomatic stage of HD a few years before manifest symptoms appear, rapidly decreasing near to the zone‐of‐onset. Finally, the CSF volume increase began many years before age at onset. Its volume measured in presymptomatic subjects contributed to improve the CAG‐based model of age at onset prediction. The progressive CSF increase depended on CAG mutation size and continued linearly until the last stages of HD, perhaps representing the best marker of progression rate and severity in HD (R²= 0.25, P < 0.0001).     

Functional magnetic resonance imaging of working memory in Huntington's disease: Cross‐sectional data from the IMAGE‐HD study

We used functional magnetic resonance imaging (fMRI) to investigate spatial working memory (WM) in an N–BACK task (0, 1, and 2‐BACK) in premanifest Huntington's disease (pre‐HD, n = 35), early symptomatic Huntington's disease (symp‐HD, n = 23), and control (n = 32) individuals. Overall, both WM conditions (1‐BACK and 2‐BACK) activated a large network of regions throughout the brain, common to all groups. However, voxel‐wise and time‐course analyses revealed significant functional group differences, despite no significant behavioral performance differences. During 1‐BACK, voxel‐wise blood‐oxygen‐level‐dependent (BOLD) signal activity was significantly reduced in a number of regions from the WM network (inferior frontal gyrus, anterior insula, caudate, putamen, and cerebellum) in pre‐HD and symp‐HD groups, compared with controls; however, time‐course analysis of the BOLD response in the dorsolateral prefrontal cortex (DLPFC) showed increased activation in symp‐HD, compared with pre‐HD and controls. The pattern of reduced voxel‐wise BOLD activity in pre‐HD and symp‐HD, relative to controls, became more pervasive during 2‐BACK affecting the same structures as in 1‐BACK, but also incorporated further WM regions (anterior cingulate gyrus, parietal lobe and thalamus). The DLPFC BOLD time‐course for 2‐BACK showed a reversed pattern to that observed in 1‐BACK, with a significantly diminished signal in symp‐HD, relative to pre‐HD and controls. Our findings provide support for functional brain reorganisation in cortical and subcortical regions in both pre‐HD and symp‐HD, which are modulated by task difficulty. Moreover, the lack of a robust striatal BOLD signal in pre‐HD may represent a very early signature of change observed up to 15 years prior to clinical diagnosis. Hum Brain Mapp 35:1847–1864, 2014. © 2013 Wiley Periodicals, Inc.     

Tongue force analysis assesses motor phenotype in premanifest and symptomatic Huntington's disease

Motor symptoms in Huntington's Disease (HD) are commonly assessed by the Unified Huntington's Disease Rating Scale‐Total Motor Score (UHDRS‐TMS). However, the UHDRS‐TMS is limited by interrater variability, its categorical nature, and insensitivity in premanifest subjects. More objective and quantitative measures of motor phenotype may complement the use of the UHDRS‐TMS as outcome measure and increase the power and sensitivity of clinical trials. Deficits in tongue protrusion are well acknowledged in HD and constitute a subitem of the UHDRS‐TMS. We, therefore, investigated whether objective and quantitative assessment of tongue protrusion forces (TPF) provides measures that (1) correlate to the severity of motor phenotype detected in the UHDRS‐TMS in symptomatic HD, (2) detect a motor phenotype in premanifest HD gene‐carriers, and (3) exhibit a correlation to the genotype as assessed by a disease burden score (based on CAG‐repeat length and age). Using a precalibrated force transducer, the ability of premanifest gene carriers (n = 15) and subjects with symptomatic HD (n = 20) to generate and maintain isometric TPF at three target force levels (0.25, 0.5, and 1.0 N) was assessed and compared with age‐matched controls (n = 20) in a cross‐sectional study. Measures of variability of TPF and tongue contact time distinguished controls, premanifest, and symptomatic HD groups and correlated to the UHDRS‐TMS and disease burden score, suggesting a strong genotype‐phenotype correlation. Group distinction was most reliable at the lowest target force level. We conclude that assessment of TPF may be a useful objective and quantitative marker of motor dysfunction in premanifest and symptomatic HD. © 2010 Movement Disorder Society     

What is the impact of education on Huntington's disease?

Huntington's disease (HD) is a neurodegenerative disease caused by a cytosine adenosine guanine (CAG) expansion in the huntingtin gene. The length of the triplet repeat is the most important factor in determining age of onset and the severity of the disease, but substantial variability of these parameters is attributed to other factors. To investigate the relationship between the years of education and the age at onset and the severity of the phenotype in patients with HD, we applied multiple linear regression analysis to examine the impact of education on the age at onset and the severity of the clinical scores assessed by the Unified Huntington's Disease Rating Scale (UHDRS) of 891 patients with HD from the multinational observational study “Registry” conducted by the European Huntintgton's Disease Network. The model was adjusted for CAG repeat length and age at the time of assessment. Patients with lengthier education exhibited earlier estimated age at onset but less severe clinical scores (motor = ?3.6, P = 0.006; cognitive = 27.0, P < 0.001; behavioral = ?3.0, P < 0.001; and functional capacity = 1.1 points, P < 0.001) than those with shorter education, after controlling for age and number of CAG repeats. These differences persisted throughout all quartiles of disease severity. An earlier recognition of symptoms and manifestations among the more educated patients could explain the earlier estimated age at onset in this group. The link between better clinical UHDRS scores and higher education might reflect a beneficial effect of education or its covariates on the course of HD. © 2011 Movement Disorder Society     

Motor cortex synchronization influences the rhythm of motor performance in premanifest huntington's disease

Background : In Huntington's disease there is evidence of structural damage in the motor system, but it is still unclear how to link this to the behavioral disorder of movement. One feature of choreic movement is variable timing and coordination between sequences of actions. We postulate this results from desynchronization of neural activity in cortical motor areas. Objectives : The objective of this study was to explore the ability to synchronize activity in a motor network using transcranial magnetic stimulation and to relate this to timing of motor performance. Methods : We examined synchronization in oscillatory activity of cortical motor areas in response to an external input produced by a pulse of transcranial magnetic stimulation. We combined this with EEG to compare the response of 16 presymptomatic Huntington's disease participants with 16 age‐matched healthy volunteers to test whether the strength of synchronization relates to the variability of motor performance at the following 2 tasks: a grip force task and a speeded‐tapping task. Results : Phase synchronization in response to M1 stimulation was lower in Huntington's disease than healthy volunteers (P < .01), resulting in a reduced cortical activity at global (P < .02) and local levels (P < .01). Participants who showed better timed motor performance also showed stronger oscillatory synchronization (r = ?0.356; P < .05) and higher cortical activity (r = ?0.393; P < .05). Conclusions : Our data may model the ability of the motor command to respond to more subtle, physiological inputs from other brain areas. This novel insight indicates that impairments of the timing accuracy of synchronization and desynchronization could be a physiological basis for some key clinical features of Huntington's disease. © 2018 International Parkinson and Movement Disorder Society     

Factors contributing to institutionalization in patients with Huntington's disease

The objective of this study was to determine which factors are predictive of institutionalization in Huntington's disease. Seven hundred and ninety‐nine subjects with 4313 examinations from the Baltimore Huntington's Disease Center were included in the data set; 88 of these patients with an average follow‐up time of 9.2 years went from living at home to being institutionalized while being observed in our clinic. We examined demographic, genetic, and clinical variables for a relationship with institutionalization using linear regressions, a Cox proportional hazards model, and χ² or t tests in certain cases. In our linear models, scores on the Quantified Neurologic Examination (R² = 0.203, P < .001), Huntington's disease Activities of Daily Living Scale (R² = 0.259, P < .001), and Motor Impairment Score (R² = 0.173, P < .001) were found to have the strongest correlation with time until institutionalization. In addition, CAG repeat length (R² = 0.248, P < .001) was significantly associated with disease duration at institutionalization, when controlling for age at onset. In the Cox proportional hazards model, scores on the Activities of Daily Living Scale, Mini–Mental State Examination, Quantified Neurologic Examination, and Motor Impairment Score all significantly predicted placement in long‐term care. Finally, institutionalized patients were shown to have a higher CAG number and a lower level of educational attainment than patients who avoided institutionalization for at least 15 years after disease onset. Neurologic findings, functional capacity, cognitive impairment, and CAG repeat length are all likely determinants of institutionalization. In contrast with other dementing conditions like Parkinson's and Alzheimer's, psychiatric symptoms were not shown to predict institutionalization in Huntington's disease. This may illustrate the especially debilitating nature of the movement disorder of Huntington's disease in comparison with the other dementias. © 2011 Movement Disorder Society     

Large‐scale brain network abnormalities in Huntington's disease revealed by structural covariance

Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel‐based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre‐specified motor, working memory, cognitive flexibility, and social‐affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre‐HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre‐HD were observed, but increased positive correlations were evident for mHD, relative to pre‐HD and HC. These findings could be explained by a HD‐related neuronal loss heterogeneously affecting the examined network at the pre‐HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow‐up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs. Hum Brain Mapp 37:67–80, 2016. © 2015 Wiley Periodicals, Inc.     

Altered frontostriatal coupling in pre‐manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals. Methods: Sixteen healthy controls and sixteen pre‐HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load‐dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre‐HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre‐HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre‐HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre‐HD individuals are modulated by cognitive demand.     

Natural variation in sensory‐motor white matter organization influences manifestations of Huntington's disease

While the HTT CAG‐repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age‐at‐onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory‐motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory‐motor structural MRI, tractography, resting‐state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory‐motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory‐motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory‐motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non‐CAG‐driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory‐motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non‐CAG‐driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615–4628, 2016. © 2016 Wiley Periodicals, Inc.     

Whole‐brain atrophy as a measure of progression in premanifest and early Huntington's disease

Therapeutic trials in Huntington's disease (HD) are challenging as clinical progression is slow and variable and reliable biomarkers are lacking. We used magnetic resonance imaging and the brain boundary shift integral to quantify whole‐brain atrophy rates over 1 year in early and premanifest HD subjects, and controls. Early HD subjects had statistically significantly (P = 0.007) increased (threefold higher) rates of whole‐brain atrophy compared with controls. Higher atrophy rates were associated with longer CAG repeat length. MRI‐based measures of whole‐brain atrophy may have potential as a measure of progression in HD. © 2009 Movement Disorder Society     

HD‐CAB: A cognitive assessment battery for clinical trials in Huntington's disease1,2,3

Cognitive dysfunction is central to Huntington's disease (HD) and undermines quality of life. Clinical trials are now targeting cognitive outcomes in HD; however, no cognitive battery has been optimized for HD clinical trials. We evaluated 16 cognitive tests in a 20‐site, five‐country, observational study designed to mimic aspects of a clinical trial (e.g., data collection managed by a contract research organization, repeated testing, prespecified statistical analyses). Fifty‐five early HD, 103 premanifest HD (pre‐HD), and 105 controls were tested at visit 1, visit 2 (1‐3 days later), and visit 3 (5‐7 weeks after visit 1). For inclusion in a recommended battery, tests were evaluated for sensitivity, practice effects, reliability, domain coverage, feasibility, and tolerability. Most tests differentiated controls from pre‐HD and early HD and showed excellent psychometric properties. We selected six tests to constitute the Huntington's Disease Cognitive Assessment Battery (HD‐CAB): Symbol Digit Modalities Test, Paced Tapping, One Touch Stockings of Cambridge (abbreviated), Emotion Recognition, Trail Making B, and the Hopkins Verbal Learning Test. These tests demonstrated sensitivity to disease status (Cohen's d effect sizes: early HD= ?1.38 to ?1.90 and pre‐HD= ?0.41 to ?0.78), and acceptable reliability (r's 0.73‐0.93). A composite score yielded large effect sizes (early HD = ?2.44 and pre‐HD = ?0.87) and high reliability (r = 0.95). HD‐CAB is the first cognitive battery designed specifically for use in late premanifest and early HD clinical trials. Adoption of the HD‐CAB will facilitate evaluation of treatments to improve cognition in HD. © 2014 International Parkinson and Movement Disorder Society     

DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease

Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double‐strand breaks (histone variant pγ‐H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre‐HD and HD groups showed shorter telomeres (p < 0.0001) and a significant increase of pγ‐H2AX compared to the controls (p < 0.0001). The levels of pγ‐H2AX correlated robustly with the presence of the mutated gene in pre‐HD and HD. The availability of a potentially reversible biomarker (pγ‐H2AX) in the premanifest stage of HD, negligible in HC, provides a novel tool to monitor premanifest subjects and find patient‐specific drugs. Ann Neurol 2018;00:1–6 ANN NEUROL 2019;85:296–301.     

Rate and acceleration of whole‐brain atrophy in premanifest and early Huntington's disease

Huntington's disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole‐brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole‐brain atrophy quantification encompasses the totality of mutant huntingtin's effects on brain volume and may be useful in tracking progression in trials. We studied whole‐brain atrophy in HD using a 2‐year follow‐up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2‐year scan pair, age‐ and gender‐standardized mean brain atrophy rate was greater (P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62–1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00–0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence (P= 0.048) of acceleration year‐on‐year (mean acceleration = 0.69% yr^?2; 95% confidence interval: 0.01% yr^?2 to 1.37% yr^?2), although this was not formally significantly different from that in controls (n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole‐brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials. © 2009 Movement Disorder Society     

Objective assessment of progression in Huntington's disease: a 3-year follow-up study

Objective measures to assess progression of Huntington's disease (HD) are desirable. The authors have previously found that patients with HD with higher Unified Huntington's Disease Rating Scale (UHDRS) motor scores exhibited higher variability of isometric grip forces while grasping an object. Therefore, the authors assessed grip force variability during this task in 10 HD patients with a 3-year follow-up. Grip force variability increased in all patients at the follow-up. Thus, grip force variability during grasping might be an objective and quantitative measure to assess motor deficits associated with the progression of HD.     

The structural involvement of the cingulate cortex in premanifest and early Huntington's disease

The impact of Huntington's disease neuropathology on the structure of the cingulate is uncertain, with evidence of both cortical enlargement and atrophy in this structure in early clinical disease. We sought to determine differences in cingulate volume between premanifest Huntington's disease and early Huntington's disease groups compared with controls using detailed manual measurements. Thirty controls, 30 subjects with premanifest Huntington's disease, and 30 subjects with early Huntington's disease were selected from the Vancouver site of the TRACK‐HD study. Subjects underwent 3 Tesla magnetic resonance imaging and motor, cognitive, and neuropsychiatric assessment. The cingulate was manually delineated and subdivided into rostral, caudal, and posterior segments. Group differences in volume and associations with performance on 4 tasks thought to utilize cingulate function were examined, with adjustment for appropriate covariates. Cingulate volumes were, on average, 1.7 mL smaller in early Huntington's disease (P = .001) and 0.9 mL smaller in premanifest Huntington's disease (P = .1) compared with controls. Smaller volumes in subsections of the cingulate were associated with impaired recognition of negative emotions (P = .04), heightened depression (P = .009), and worse visual working memory performance (P = .01). There was no evidence of associations between volume and ability on a performance‐monitoring task. This study disputes previous findings of enlargement of the cingulate cortex in Huntington's disease and instead suggests that the cingulate undergoes structural degeneration during early Huntington's disease with directionally consistent, nonsignificant differences seen in premanifest Huntington's disease. Cingulate atrophy may contribute to deficits in mood, emotional processing, and visual working memory in Huntington's disease. © 2011 Movement Disorder Society     

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy

TRACK‐HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3‐Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross‐sectional data from this large well‐characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene‐positive subjects (120 PreHD and 119 early HD) from the TRACK‐HD study were included. Using voxel‐based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti‐saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.