Early Stage Huntington's Disease Research Articles

Evaluating multicenter DTI data in Huntington's disease on site specific effects: An ex post facto approach

PurposeAssessment of the feasibility to average diffusion tensor imaging (DTI) metrics of MRI data acquired in the course of a multicenter study.Materials and methodsSixty-one early stage Huntington's disease patients and forty healthy controls were studied using four different MR scanners at four European sites with acquisition protocols as close as possible to a given standard protocol. The potential and feasibility of averaging data acquired at different sites was evaluated quantitatively by region-of-interest (ROI) based statistical comparisons of coefficients of variation (CV) across centers, as well as by testing for significant group-by-center differences on averaged fractional anisotropy (FA) values between patients and controls. In addition, a whole-brain based statistical between-group comparison was performed using FA maps.ResultsThe ex post facto statistical evaluation of CV and FA-values in a priori defined ROIs showed no differences between sites above chance indicating that data were not systematically biased by center specific factors.ConclusionAveraging FA-maps from DTI data acquired at different study sites and different MR scanner types does not appear to be systematically biased. A suitable recipe for testing on the possibility to pool multicenter DTI data is provided to permit averaging of DTI-derived metrics to differentiate patients from healthy controls at a larger scale.

Decreased Metabolism in the Cerebral Cortex in Early-Stage Huntington's Disease: A Possible Biomarker of Disease Progression?

Background and PurposeHuntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder. Genetic analysis of abnormal CAG expansion in the IT15 gene allows disease confirmation even in the preclinical stage. However, because there is no treatment to cure or delay the progression of this disease, monitoring of biological markers that predict progression is warranted.MethodsFDG-PET was applied to 13 patients with genetically confirmed HD in the early stage of the disease. We recorded the initial and follow-up statuses of patients using the Independence Scale (IS) of the Unified Huntington's Disease Rating Scale. The progression rate (PR) was calculated as the annual change in the IS. The patients were divided into two groups with faster and slower progression, using the median value of the PR as the cut-off. FDG-PET data were analyzed using regions of interest, and compared among the two patient groups and 11 age- and sex-matched controls.ResultsThe mean CAG repeat size in patients was 44.7. The CAG repeat length was inversely correlated with the age at onset as reported previously, but was not correlated with the clinical PR. Compared with normal controls, hypometabolism was observed even at very early stages of the disease in the bilateral frontal, temporal, and parietal cortices on FDG-PET. The decreases in metabolism in the bilateral frontal, parietal, and right temporal cortices were much greater in the faster-progression group than in the slower-progression group.ConclusionsA decrease in cortical glucose metabolism is suggested as a predictor for identifying a more rapid form of progression in patients with early-stage HD.

Is non-recognition of choreic movements in Huntington disease always pathological?

Clinical experience and prior studies suggest that Huntington disease (HD) patients have low insight into their motor disturbances and poor real-time awareness (concurrent awareness) of chorea. This has been attributed to sensory deficits but, until now, concurrent awareness of choreic movements has not been compared to the degree of insight that presymptomatic carriers of the HD gene and healthy control subjects have into non-pathological involuntary movements. To further investigate loss of insight into motor dysfunction in HD patients, we administered a video-recorded interview and 4experimental tasks to 68 subjects from the TRACK-HD cohort, including 28 high-functioning patients in early stages of HD, 28 premanifest mutation carriers and 12 controls. All underwent full neurological and neuropsychological evaluations and 3T MRI examinations. Subjects were asked to assess the presence, body location, frequency, practical consequences and probable causes of motor impairments, as well as the presence and body location of involuntary movements during 4experimental tasks. The accuracy of their judgments, assessed by comparison with objective criteria, was used as a measure of their insight into motor disturbances and of their concurrent awareness of involuntary movements.Insight was poor in early HD patients: motor symptoms were nearly always underestimated. In contrast, concurrent awareness of involuntary movements, although also poor, was essentially indistinguishable across the 3groups of subjects: non-pathological involuntary movements were as difficult to perceive by controls and premanifest carriers as was chorea for early HD patients. GLM analysis suggested that both concurrent awareness and perception of practical consequences of movement disorder had a positive effect on intellectual insight, and that mental flexibility is involved in concurrent awareness.Our results suggest that low insight into motor dysfunction in early HD, although marginally modulated by cognitive factors, is mainly non-pathological, and parallels a general tendency, shared by healthy subjects, to neglect self-generated involuntary movements in real time. This tendency, combined with the paucity of functional consequences of incipient chorea, could explain the difficulty of its discovery by the patients.

Speech acoustic markers of early stage and prodromal Huntington's disease: A marker of disease onset?

Speech disturbances (e.g., altered prosody) have been described in symptomatic Huntington's Disease (HD) individuals, however, the extent to which speech changes in gene positive pre-manifest (PreHD) individuals is largely unknown. The speech of individuals carrying the mutant HTT gene is a behavioural/motor/cognitive marker demonstrating some potential as an objective indicator of early HD onset and disease progression. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. There was a clear effect of group across most acoustic measures, so that speech performance differed in-line with disease progression. Comparisons across groups revealed significant differences between the control and the early stage HD group on measures of timing (e.g., speech rate). Participants carrying the mutant HTT gene presented with slower rates of speech, took longer to say words and produced greater silences between and within words compared to healthy controls. Importantly, speech rate showed a significant correlation to burden of disease scores. The speech of early stage HD differed significantly from controls. The speech of PreHD, although not reaching significance, tended to lie between the performance of controls and early stage HD. This suggests that changes in speech production appear to be developing prior to diagnosis.

J06 A comparison of the Mini Mental State Exam to the Montreal Cognitive Assessment in early stages of Huntington's disease

<h3>Introduction</h3> Cognitive dysfunction is present in the prodromal phase of Huntington Disease (HD) before motor diagnosis is given. In order to obtain an evaluation of the patients9 global cognitive function, complex batteries of exams are needed. For this purpose, the Mini Mental State Exam (MMSE) is the screening test most frequently used. On the other hand, the Montreal Cognitive Assessment (MoCA) is a recent screening test with higher sensitivity for mild cognitive impairment. It has bean applied for the detection of the earliest cognitive impairments in patients with HD. <h3>Objective</h3> To compare the MMSE with the MoCA in identifying cognitive deficits in prodromal and early stages of HD. <h3>Methods</h3> The MMSE and the MoCA were performed in 37 patients with genetic diagnosis of HD regularly evaluated in the Neurogenetic Consultation of the Coimbra9s University Hospital; as well as in 40 control subjects with no neurodegenerative pathology, using age, gender and education as comparison factors in the selection criteria. <h3>Results</h3> Both groups (subjects with HD and control subjects) showed no differences in the distribution of the demographic characteristics. The MMSE and MoCA9s total scores showed lower values in the HD group (p=0.002 and p=0.003 respectively). Samples9 description according to educational level showed differences between the two groups in the MMSE scores only, for an education lower or equal to 11 years. With the cut-offs determined to the Portuguese population, the MoCA presented a superior sensitivity to detect cognitive decline among HD patients in comparison to the MMSE (64, 9% vs 21, 6%; p&lt;0.001). Receiver Operating Characteristics curves analysis registered significant statistic results only in the MoCA, concerning Visual-Spacial, Language and Executive Function/Attention areas (p=0.01, p=0.039 and p=0.018, respectively). <h3>Conclusions</h3> According to the cut-offs established for the Portuguese population, the MoCA is a brief screening test with higher sensitivity in the detection of cognitive impairments related to Huntington9s Disease, when in comparison to the MMSE, requiring tasks inherent to cerebral areas characteristically affected in this disease. Due to the fact that it evaluates certain cerebral domains, such as the Executive/Attention Function, it reveals itself more appropriate for the detection of the mild cognitive impairment in Huntington9s disease patients, and should therefore be used instead of the MMSE.

G13 Abnormal responses to visual cortex activation in early stage Huntington disease patients using 31P-NMR spectroscopy

Objective To test the hypothesis that brain energy metabolism is abnormal in patients at an early stage of Huntington disease (HD). Background Energy metabolism has been a major focus of HD research for many years due to several observations in both patients and models of the disease. However, there are currently no in vivo biomarkers of brain energy metabolism in HD. Methods We coupled noninvasive 31P-NMR spectroscopy with activation of the occipital cortex in order to measure the levels of ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) before, during and after a visual stimulus. We studied 15 HD patients at an early stage of the disease (mean motor UHDRS =18±9) and 15 age- and sex-matched controls. Results In controls, we observed an 11% increase in Pi/PCr ratio (p=0.024) and a 13% increase in Pi/ATP ratio (p=0.016) during brain activation, reflecting increased ATP synthesis and ADP levels. Subsequently, controls had a return to baseline levels during recovery (p=0.012 et 0.022 respectively). In HD patients, both Pi/PCr and Pi/ATP ratios were unchanged during and after visual stimulation, reflecting altered mitochondrial bioenergetics. In addition, in HD patients the ratio of Pi/ATP correlated with the UHDRS score during the activation (p=0.014) and recovery periods (p=0.009), while Pi/PCr ratio correlated with the UHDRS score during recovery (p=0.016), reflecting a correlation between brain energy metabolism and disease severity in HD. Conclusions 31Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease.

Q14 Sub maximal exercise testing in people with early stage Huntington's disease

BackgroundExercise is suggested to be of benefit to people with Huntington's disease (HD), however little is known about how they respond to exercise. This study investigated sub-maximal exercise testing in...

J03 The potential of a composite cognitive score for tracking progression in Huntington's disease

Background: Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. Objective: We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntington’s disease (HD) from natural decline in healthy controls. Methods: Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. Results: In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. Conclusions: Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.

Q20 A multidisciplinary intensive rehabilitation programme for persons with Huntington's disease: results after 1 year

BackgroundPersons with Huntington's disease (HD) may benefit from intensive rehabilitation.AimTo assess effects of an intensive, multidisciplinary rehabilitation programme in subjects with early to mid-stage HD.Methods37 subjects completed a 1-year rehabilitation...

I03 Evaluation of life time physical activity levels in Huntington's disease

Background Environmental factors may influence the onset and progression of neurodegenerative disorders, either directly or by interacting with genetic risk factors. Trembath and colleagues interviewed individuals with a formal clinical diagnosis of Huntington's disease (HD) and found that those who led a more passive lifestyle had an earlier age of onset than those who were less passive.1 Aims To establish the feasibility of using self-completion questionnaires to gather life time physical activity levels in a group of early stage and premanifest HD individuals from the TRACK-HD cohort so that this data could be compared to clinical outcomes in TRACK-HD study. Methods A self-report questionnaire was developed based on the Leisure Time Exercise Questionnaire by Godin et al.2 Activity levels were calculated across activities undertaken at home, at work and during recreation and for life stages from the teenage years, across each decade to the current age or age of disease onset. Life-time activity was categorised as strenuous, moderate or light, and activity scores were calculated from the frequency and duration of each activity. Results Retrospective data were collected from 277 participants (89 controls, 109 premanifest gene carriers, 79 HD Stage I/II) and the data used to distinguish the most and least physically active individuals. Modes of activity were also investigated. Conclusions Although retrospective data may be limited by recall bias, our data suggests that it is possible to use a general measure of life time physical activity levels. Such a life course perspective on physical activity may be a useful adjunct to the assessment of physical activity with more direct quantitative measures.

Q01 SIRT 1 mediated modulation of circulating cytokines in huntington's disease- pharmacodynamics results from phase 1B study of selisistat—A SIRT 1 inhibitor

BackgroundEvidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington's disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly...

Brain metabolite alterations and cognitive dysfunction in early Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by early cognitive decline that progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aimed to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high-field-strength magnetic resonance spectroscopy (MRS) at 7 Tesla. Twelve individuals with the HD mutation in premanifest or early-stage disease versus 12 healthy controls underwent (1)H magnetic resonance spectroscopy (7.2 mL voxel in the posterior cingulate cortex) at 7 Tesla, and also T1-weighted structural magnetic resonance imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (-9.6%, P = .02) and glutamate (-10.1%, P = .02) levels than did controls. In contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r(2) = 0.50, P = .01) and glutamate (NAA) (r(2) = 0.64, P = .002) in HD subjects. Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in the early stages of HD. N-acetylaspartate and glutamate magnetic resonance spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor.

Implicit Contextual Learning in Prodromal and Early Stage Huntington's Disease Patients

Huntington's disease (HD) is a genetic neurodegenerative disorder affecting the basal ganglia. These subcortical structures are particularly important for motor functions, response selection and implicit learning. In the current study, we have assessed prodromal and symptomatic HD participants with an implicit contextual learning task that is not based on motor learning, but on a purely visual implicit learning mechanism. We used an implicit contextual learning task in which subjects need to locate a target among several distractors. In half of the trials, the positions of the distractors and target stimuli were repeated. By memorizing this contextual information, attention can be guided faster to the target stimulus. Nine symptomatic HD participants, 16 prodromal HD participants and 22 control subjects were included. We found that the responses of the control subjects were faster for the repeated trials than for the new trials, indicating that their visual search was facilitated when repeated contextual information was present. In contrast, no difference in response times between the repeated and new trials was found for the symptomatic and prodromal HD participants. The results of the current study indicate that both prodromal and symptomatic HD participants are impaired on an implicit contextual learning task.

Abnormal Responses to Visual Cortex Activation in Early Stage Huntington Disease Patients Using 31P-NMR Spectroscopy (P06.033)

Objective: To test the hypothesis that brain energy metabolism is abnormal in patients at an early stage of Huntington disease (HD). Background HD is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the HTT gene. Energy metabolism has been a major focus of HD research for many years due to several observations in both patients and models of the disease. However, there are currently no in vivo biomarkers of brain energy metabolism in HD. Design/Methods: We coupled noninvasive 31P-nuclear magnetic resonance spectroscopy (NMRS) with activation of the occipital cortex in order to measure the levels of ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) before, during and after a visual stimulus. We studied 15 HD patients at an early stage of the disease (mean motor UHDRS= 18 ±9) and 15 age- and sex-matched controls. Results: In controls, we observed an 11% increase in Pi/PCr ratio (p=0.012) and a 13% increase in Pi/ATP ratio (p=0.008) during brain activation, reflecting increased ATP synthesis and ADP levels. Subsequently, controls had a return to baseline levels during recovery (p=0.006 et 0.011 respectively). In HD patients, both Pi/PCr and Pi/ATP ratios were unchanged during and after visual stimulation, reflecting altered mitochondrial bioenergetics. In addition, in HD patients the ratio of Pi/ATP correlated with the UHDRS score during the activation (p=0.014) and recovery periods (p=0.009), while Pi/PCr ratio correlated with the UHDRS score during recovery (p=0.016), reflecting a correlation between brain energy metabolism and disease severity in HD. Conclusions: We have identified noninvasive functional biomarkers of brain energy deficit to assess therapeutic efficacy in HD. We are now extending our 31P-NMRS studies to presymptomatic individuals. Disclosure: Dr. Mochel has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Deelchand has nothing to disclose. Dr. Rinaldi has nothing to disclose. Dr. Valabregue has nothing to disclose. Dr. Wary has nothing to disclose. Dr. Carlier has nothing to disclose. Dr. Durr has nothing to disclose. Dr. Henry has nothing to disclose.

Abnormal response to cortical activation in early stages of Huntington disease

We wished to identify noninvasive in vivo biomarkers of brain energy deficit in Huntington disease. We studied 15 early affected patients (mean motor United Huntington Disease Rating Scale, 18 ± 9) and 15 age- and sex-matched controls. We coupled (31)phosphorus nuclear magnetic resonance spectroscopy with activation of the occipital cortex in order to measure the relative concentrations of adenosine triphosphate, phosphocreatine, and inorganic phosphate before, during, and after visual stimulation. In controls, we observed an 11% increase in the inorganic phosphate/phosphocreatine ratio (P = .024) and a 13% increase in the inorganic phosphate/adenosine triphosphate ratio (P = .016) during brain activation, reflecting increased adenosine diphosphate concentrations. Subsequently, controls had a return to baseline levels during recovery (P = .012 and .022, respectively). In contrast, both ratios were unchanged in patients during and after visual stimulation. (31)Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease.

Longitudinal Evaluation of Neuropsychiatric Symptoms in Huntington's Disease

A group of 111 patients with Huntington's disease (HD) underwent a minimum of three annual neuropsychiatric assessments, using the Problem Behaviors Assessment for Huntington's Disease (PBA-HD). Longitudinal prevalence of neuropsychiatric symptoms was notably higher than baseline prevalence, suggesting that previous studies may have underestimated the extent of this clinical problem. Moreover, apathy, irritability, and depression were each associated with distinct longitudinal profiles. Apathy progressed over time and across disease stages. Irritability also increased significantly, but only in early stages of HD. Depression did not increase significantly at any stage of disease. The neuropsychiatric syndrome of apathy appears to be intrinsic to the evolution and progression of HD.

Scanning Patterns of Faces do not Explain Impaired Emotion Recognition in Huntington Disease: Evidence for a High Level Mechanism

In the current study, we aimed to investigate the emotion recognition impairment in Huntington’s disease (HD) patients and define whether this deficit is caused by impaired scanning patterns of the face. To achieve this goal, we recorded eye movements during a two-alternative forced-choice emotion recognition task. HD patients in pre-symptomatic (n = 16) and symptomatic (n = 9) disease stages were tested and their performance was compared to a control group (n = 22). In our emotion recognition task, participants had to indicate whether a face reflected one of six basic emotions. In addition, and in order to define whether emotion recognition was altered when the participants were forced to look at a specific component of the face, we used a second task where only limited facial information was provided (eyes/mouth in partially masked faces). Behavioral results showed no differences in the ability to recognize emotions between pre-symptomatic gene carriers and controls. However, an emotion recognition deficit was found for all six basic emotion categories in early stage HD. Analysis of eye movement patterns showed that patient and controls used similar scanning strategies. Patterns of deficits were similar regardless of whether parts of the faces were masked or not, thereby confirming that selective attention to particular face parts is not underlying the deficits. These results suggest that the emotion recognition deficits in symptomatic HD patients cannot be explained by impaired scanning patterns of faces. Furthermore, no selective deficit for recognition of disgust was found in pre-symptomatic HD patients.

Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease.

Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington's disease (HD), a congenital neurodegenerative disorder resulting from mutation in the huntingtin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome-associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of the lamp-2 gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.

Microcirculation response to local cooling in patients with Huntington’s disease

Altered autonomic nervous system (ANS) functioning in early stages of Huntington's disease (HD) has been suggested, presumably due to distorted high-order autonomic control. ANS functioning in the early stages of HD was further investigated. Laser-Doppler (LD) flux in the skin of the fingertips, heart rate (HR), HR variability, systolic and diastolic blood pressure were measured during rest and during a 6 min cooling of one hand at 15°C. Data of 15 presymptomatic gene mutation carriers (PHD), 15 early symptomatic HD patients (EHD), and two groups of 15 age- and sex-matched controls were compared. The area under the low frequency (LF) and high frequency (HF) bands of the HR variability spectrum were calculated. An augmented reduction of cutaneous LD flux was found in response to the direct cooling in the PHD group (37.5 ± 8.5% of resting value) compared to the PHD controls (67.27 ± 8.4%) (p < 0.05). In addition, the PHD group had higher (LF/(LF + HF) index of primary sympathetic modulation of the HR at rest (53.6 ± 3.3) compared to the EHD patients (39.7 ± 4.2) (p < 0.05). In the EHD group, a significantly smaller change of HR during cooling (100.26 ± 1.2%) was found compared to the EHD controls (95.9 ± 1.0%) (p < 0.05). The results are in line with the hypothesis that ANS dysfunction occurs even in PHD subjects. Further, they support the hypothesis that dysfunction of the high-order autonomic centres are involved in HD.

Depression in the early stages of Huntington disease.

Huntington disease (HD) has traditionally been considered a movement disorder, but cognitive and psychiatric symptoms also prominently factor into its clinical presentation. Depression is one of the most common psychiatric disturbances in HD, with its prevalence highest in manifest disease during stage 2, but it is also present during the illness prodrome (the period before manifestation of motor symptoms). Identification and treatment of depression in individuals with the HD mutation is an essential part of clinical management in this population, especially owing to the high risk of suicide. This article summarizes what is currently known about the presentation and treatment of depression in the early stages of HD and provides advice to clinicians treating this population.