Huntington's Disease Gene Mutation Research Articles

The prevalence of pain in Huntington's disease in a large worldwide cohort

IntroductionPain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers. MethodsA cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons. ResultsIn the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%–35%), of painful conditions 17% (95% CI 15%–19%) and analgesic use 13% (95% CI 11%–15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%–35%] vs 42% [95% CI 39%–45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%–18%] vs 12% [95% CI 10%–14%], 15% [95% CI 13%–17%], P < 0,01]. No significant group difference was present in analgesic use. ConclusionsThe prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain.

Cognitive Screening Tests in Huntington Gene Mutation Carriers: Examining the Validity of the Mini-Mental State Examination and the Montreal Cognitive Assessment.

Due to high prevalence of cognitive impairment in Huntington's disease (HD) gene mutation carriers, even before onset of motor symptoms, cognitive screening is important for the optimal management of patients. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are widely used, but the validity for HD has only been evaluated in few studies with important limitations. To evaluate the discriminative validity of the MMSE and the MoCA for the assessment of cognitive dysfunction in HD gene mutation carriers, independently of motor manifestation and furthermore, to report estimated probabilities for cognitive impairment with different score ranges on the MMSE and the MoCA. 106 pre-motor-manifest and motor-manifest HD gene mutation carriers and 40 non-HD gene mutation carriers were administered the MMSE, the MoCA, and an extensive neuropsychological battery with operationalized criteria for cognitive impairment. The same physician and the same neuropsychologist performed all examinations; blinded to one another. The area under the receiver operating characteristic (ROC) curve was 0.70 for the MMSE and 0.82 for the MoCA. The latter correctly diagnosed 82% of the cognitively impaired and not-impaired HD gene mutation carriers and non-HD gene mutation carriers, whereas the MMSE only diagnosed 73% correctly. The MMSE and the MoCA can both be used as cognitive screening tests in HD gene mutation carriers, but both have important limitations. Our results indicate that the MoCA is a better cognitive screening test for HD than the MMSE. In addition, our study provides estimated probabilities for cognitive impairment with different score ranges, which may be used as clinical guidelines in the interpretation of results from the two tests.

Natural biological variation of white matter microstructure is accentuated in Huntington's disease.

Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG‐repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome‐wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification. We have previously shown that while white matter diffusivity patterns in the left sensorimotor network were similar in controls and HD gene‐carriers, they were more extreme in the HD group. We hypothesized that the influence of natural variation in diffusivity on effects of HD pathogenesis on white matter is not limited to the sensorimotor network but extends to cognitive, limbic, and visual networks. Using tractography, we investigated 32 bilateral pathways within HD‐related networks, including motor, cognitive, and limbic, and examined diffusivity metrics using principal components analysis. We identified three independent patterns of diffusivity common to controls and HD gene‐carriers that predicted HD status. The first pattern involved almost all tracts, the second was limited to sensorimotor tracts, and the third encompassed cognitive network tracts. Each diffusivity pattern was associated with network specific performance. The consistency in diffusivity patterns across both groups coupled with their association with disease status and task performance indicates that naturally‐occurring patterns of diffusivity can become accentuated in the presence of the HD gene mutation to influence clinical brain function.

Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls.

Huntington's disease (HD) is an inherited brain disorder characterized by progressive motor, cognitive, and behavioral dysfunctions. It is caused by abnormally large trinucleotide cytosine-adenine-guanine (CAG) repeat expansions on exon 1 of the Huntingtin gene. CAG repeat length (CAG-RL) inversely correlates with an earlier age of onset. Region-based studies have shown that HD gene mutation carrier (HDgmc) individuals (CAG-RL ≥36) present functional connectivity alterations in subcortical (SC) and default mode networks. In this analysis, we expand on previous HD studies by investigating associations between CAG-RL and connectivity in the whole brain, as well as between CAG-dependent connectivity and motor and cognitive performances. We used group-independent component analysis on resting-state functional magnetic resonance imaging scans of 261 individuals (183 HDgmc and 78 healthy controls) from the PREDICT-HD study, to obtain whole-brain resting state networks (RSNs). Regression analysis was applied within and between RSNs connectivity (functional network connectivity [FNC]) to identify CAG-RL associations. Connectivity within the putamen RSN is negatively correlated with CAG-RL. The FNC between putamen and insula decreases with increasing CAG-RL, and also shows significant associations with motor and cognitive measures. The FNC between calcarine and middle frontal gyri increased with CAG-RL. In contrast, FNC in other visual (VIS) networks declined with increasing CAG-RL. In addition to observed effects in SC areas known to be related to HD, our study identifies a strong presence of alterations in VIS regions less commonly observed in previous reports and provides a step forward in understanding FNC dysfunction in HDgmc.

Understandings of psychological difficulties in people with the Huntington's disease gene and their expectations of psychological therapy.

This study sought to investigate how people who had tested positive for the Huntington's disease (HD) gene mutation understood and experienced psychological distress and their expectations of psychological therapy. A qualitative methodology was adopted involving semi-structured interviews and interpretative phenomenological analysis (IPA). A total of nine participants (five women and four men) who had opted to engage in psychological therapy were recruited and interviewed prior to the start of this particular psychological therapeutic intervention. Interviews were transcribed verbatim and analysed using IPA whereby themes were analysed within and across transcripts and classified into superordinate themes. Three superordinate themes were developed: Attributing psychological distress to HD: 'you're blaming everything on that now'; Changes in attributions of distress over time: 'in the past you'd just get on with it'; and Approaching therapy with an open mind, commitment, and hope: 'a light at the end of the tunnel'. Understandings of psychological distress in HD included biological and psychological explanations, with both often being accepted simultaneously by the same individual but with biomedical accounts generally dominating. Individual experience seemed to reflect a dynamic process whereby people's understanding and experience of their distress changed over time. Psychological therapy was accepted as a positive alternative to medication, providing people with HD with hope that their psychological well-being could be enhanced. People with the Huntington's disease gene mutation have largely biomedical understandings of their psychological distress. This largely biomedical understanding does not, however, preclude them for being interested in the potential gains resulting from psychological therapy. The mechanisms of psychological therapy should be explained in detail before therapy and explored along with current attributions of distress.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003-13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10-10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10-8DHFR p=8·37 × 10-7 MTRNR2L2 p=2·15 × 10-9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10-4DHFR p=8·45 × 10-4MTRNR2L2 p=1·20 × 10-3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10-8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16-0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06-0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Important but not Enough - Information about HD Related Topics and Peer andProfessional Support for Young Adults from HD Families.

The number of people affected by Huntington's disease (HD) is far greater than those with manifest HD because it also includes those at risk, both HD gene mutation carriers and family members not carrying the HD mutation. Many relevant needs of young adults from HD families may not be met at present. This includes advice on important life decisions e.g. family planning and having children, psychological support and treatment of medical conditions. To survey the opinion of young adults from HD families about relevance and availability of information and support regarding several aspects of HD. An online anonymous questionnaire translated into ten languages contained questions regarding the importance and availability of information and support about HD related topics, and attitudes towards research. Answers were captured in categories or on Likert scales. Information about HD related topics and the availability of peer and professional support are very important for young adults from HD families. In addition, with the exception of general information about HD, or predictive testing, the vast majority of respondents stated that they did not receive enough information on other important topics, for instance regarding legal advice and they did not feel supported enough by healthcare professionals. HD research was considered to be of high value, though most did not participate in HD research. The results of this survey can help devise a strategy to address these unmet needs and also to facilitate research participation of more young adults from HD families.

Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre‐symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale ’99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme‐linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy‐six participants were included in this cross‐sectional multicenter international pilot study. Age‐adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = −0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age‐adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9.

Globus pallidus degeneration and clinicopathological features of Huntington disease.

Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology. Stereology was used to measure regional atrophy, neuronal loss, and soma neuronal atrophy in 3 components of the GP-the external segment (GPe), internal segment (GPi), and ventral pallidum (VP)-in 8 HD cases compared with 7 matched control cases. The findings in the HD patients were compared with HD striatal neuropathological grade, and symptom scores of motor impairment, chorea, cognition, and mood. Relative to controls, in the HD patients the GPe showed a 54% overall volume decline, 60% neuron loss, and 34% reduced soma volume. Similarly, the VP was reduced in volume by 31%, with 48% neuron loss and 64% reduced soma volume. In contrast, the GPi was less affected, with a 38% reduction in overall volume only. The extent of GP neurodegeneration correlated with increasing striatal neuropathological grade. Decreasing GPe and VP volumes were associated with poorer cognition and increasing motor impairments, but not chorea. In contrast, decreasing GPi volumes were associated with decreasing levels of irritability. The HD gene mutation produces variable degrees of GP segment degeneration, highlighting the differential vulnerability of striato-GP target projections. The relationship established between clinical symptom scores and pallidal degeneration provides a novel contribution to understanding the clinicopathological associations in HD. Ann Neurol 2016;80:185-201.

Prenatal testing in Huntington disease: after the test, choices recommence.

The objective of this study was (1) to determine the impact of prenatal diagnosis (PND) for Huntington disease (HD) on subsequent reproductive choices and family structure; and (2) to assess whether children born after PND were informed of their genetic status. Out of 354 presymptomatic carriers of HD gene mutation, aged 18-45 years, 61 couples requested 101 PNDs. Fifty-four women, 29 female carriers and 25 spouses of male carriers, accepted to be interviewed (0.6-16.3 years after the last PND, median 6.5 years) on their obstetrical history and information given to children born after PND. Women were willing to undergo two or more PNDs with a final success rate of 75%. Reproductive decisions differed depending on the outcome of the first PND. If favourable, 62% couples decided against another pregnancy and 10% chose to have an untested child. If unfavourable, 83% decided for another pregnancy (P<0.01), and the majority (87%) re-entered the PND procedure. In contrast, after a second PND, only 37% asked for a PND and 30% chose to have an untested child. Thirty-three percent had both, tested and untested children. Among children born after PND, 10 years and older, 75% were informed of their genetic status. The decision to prevent transmission of the HD mutation is made anew with each pregnancy. Couples may need more psychological support after PND and pre-counselling sessions should take into account the effect of the outcome of a first PND on subsequent reproductive choices.

Factors Associated with Low Body Mass Index in Huntington's Disease: A Spanish Multicenter Study of the European Huntington's Disease Registry.

Patients with Huntington's disease (HD) are at risk for body weight loss and increased risk for institutionalization, morbidity, and mortality. The aim of this study was to determine the factors associated with low body mass index (BMI) in patients with HD. In this national, observational, cross-sectional study of the European Huntington's Disease Network, the frequency of food consumption, calories, and nutrient intake in patients with HD was assessed using questionnaires validated for the Spanish population and were calculated using the software package Alimentación and Salud (Diet and Health), version 2.0. Nutritional status was estimated using the BMI, and disease severity was assessed using the Unified Huntington's Disease Rating Scale and a total functional capacity (TFC) score. Linear regression models were performed using BMI as the dependent variable and using energy balance (energy caloric intake - energy expenditure); the TFC score; the presence of a caregiver; dysphagia; cytosine, adenine, guanine (CAG) repeats; comorbidities; intake of supplements; pharmacologic treatments; age; gender; education; and physical activity as the independent variables. Two hundred twenty-four patients with HD were included (59% women), and their mean age was 47.41 ± 14.26 years, a median TFC score of 9 (range, 3-13), normal BMI in 124 patients (55.4%), and low BMI in 13 patients (6.7%). In the linear regression model, older age (β = 0.003; P = 0.01), male gender (β = 0.13; P = 0.003), and lower energy balance (β = -0.0001; P = 0.0003) were associated with a higher log-transformed BMI. Younger female HD patients are at risk for low BMI. To counteract the influence of the HD gene mutation on decreased BMI, an increase in kilocalories per day should be encouraged.

The cognitive burden in Huntington's disease: Pathology, phenotype, and mechanisms of compensation

Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder. The most prominent sign of HD is the presence of involuntary motor movements. However, HD is also characterized by marked cognitive decline, which often precedes the onset of motor symptoms and is generally considered to be more debilitating to the patients and their families, compared to motor symptoms. Cognitive decline is widespread across most faculties of cognition in later stages of the disease, but seems to be selective in preclinical and early stages of the disease, with deficits in the HD patients' ability to multitask, their speed of processing, and executive function. It is now well established that preceding clinical diagnosis there is a preclinical stage, during which HD gene mutation carriers are relatively symptom free, despite disease pathological onset and the presence of neurodegeneration. Evidence from functional brain imaging studies suggests the presence of neural compensation in preclinical stages of HD, whereby the brain undergoes functional reorganization in response to neurodegeneration to preserve motor and cognitive performance. In this review, we will describe the underlying HD pathology with a focus on how it links to the cognitive phenotype. We will also present evidence regarding the presence of neural compensation in HD and the possible mechanisms supporting it. Finally, we will discuss current research in the field of cognitive interventions that aim to support and enhance neural compensation in HD. These research efforts could, one day, prolong the preclinical stage and assist with symptom management of those affected with HD.

Neurochemical correlates of caudate atrophy in Huntington's disease

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy ((1)H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous (1)H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two (1)H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized (1)H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N-acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches.

Changes in cognitive control in pre-manifest Huntington's disease examined using pre-saccadic EEG potentials - a longitudinal study.

It is well-known that Huntington's disease (HD) affects saccadic processing. However, saccadic dysfunctions in HD may be seen as a result of dysfunctional processes occurring at the oculomotor level prior to the execution of saccades, i.e., at a pre-saccadic level. Virtually nothing is known about possible changes in pre-saccadic processes in HD. This study examines pre-saccadic processing in pre-manifest HD gene mutation carriers (pre-HDs) by using clinically available EEG measures. Error rates, pre-saccadic EEG potentials and saccade onset EEG potentials were measured in 14 pre-HDs and case-matched controls performing prosaccades and antisaccades in a longitudinal study over a 15-month period. The results show that pre-saccadic potentials were changed in pre-HDs, relative to controls and also revealed changes across the 15-month longitudinal period. In particular, pre-saccadic ERP in pre-HDs were characterized by lower amplitudes and longer latencies, which revealed longitudinal changes. These changes were observed for anti-saccades, but not for pro-saccades. Overt saccadic trajectories (potentials) were not different to those in controls, showing that pre-saccadic processes are sensitive to subtle changes in fronto-striatal networks in pre-HDs. Deficits in pre-saccadic processes prior the execution of an erroneous anti-saccade can be seen as an effect of dysfunctional cognitive control in HD. This may underlie saccadic abnormalities and hence a major phenotype of HD. Pre-saccadic EEG potentials preceding erroneous anti-saccades are sensitive to pre-manifest disease progression in HD.

Large genetic animal models of Huntington's Disease.

The dominant nature of the Huntington's disease gene mutation has allowed genetic models to be developed in multiple species, with the mutation causing an abnormal neurological phenotype in all animals in which it is expressed. Many different rodent models have been generated. The most widely used of these, the transgenic R6/2 mouse, carries the mutation in a fragment of the human huntingtin gene and has a rapidly progressive and fatal neurological phenotype with many relevant pathological changes. Nevertheless, their rapid decline has been frequently questioned in the context of a disease that takes years to manifest in humans, and strenuous efforts have been made to make rodent models that are genetically more 'relevant' to the human condition, including full length huntingtin gene transgenic and knock-in mice. While there is no doubt that we have learned, and continue to learn much from rodent models, their usefulness is limited by two species constraints. First, the brains of rodents differ significantly from humans in both their small size and their neuroanatomical organization. Second, rodents have much shorter lifespans than humans. Here, we review new approaches taken to these challenges in the development of models of Huntington's disease in large brained, long-lived animals. We discuss the need for such models, and how they might be used to fill specific niches in preclinical Huntington's disease research, particularly in testing gene-based therapeutics. We discuss the advantages and disadvantages of animals in which the prodromal period of disease extends over a long time span. We suggest that there is considerable 'value added' for large animal models in preclinical Huntington's disease research.

Faster Perceptual Learning through Excitotoxic Neurodegeneration

Glutamatergic neural transmission is involved in both neural plasticity and neurodegeneration. This combination of roles could result in ambivalent effects in which excitotoxic neurodegeneration augments neural plasticity in parallel. Neural plasticity can be induced by exposure-based learning (EBL) that resembles timing properties of long-term potentiation (LTP) protocols (i.e., LTP-like learning). Even though it has not been demonstrated so far in animal models that perceptual effects of such stimulation protocols are mediated by typical LTP mechanisms, it has been shown that exposure-based learning exerts strong effects on cognitive brain functioning and is modulated by glutamatergic neural transmission. We reveal that exposure-based perceptual learning is more efficient in a human model of excitotoxic neurodegeneration than in healthy participants. Premanifest Huntington's disease gene mutation carriers showed faster increases in perceptual sensitivities than controls. This in turn changed attentional processing in extrastriate visual areas objectified using electroencephalogram data. The emergence of faster learning correlated positively with genetic disease load. Our results confirm an ambivalent action of increased glutamatergic transmission, implying that the process of excitotoxic neurodegeneration is associated with enhanced perceptual learning, which can be used to improve attentional and behavioral control via the alteration of perceptual sensitivities.

Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach

Background: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e. less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. Objectives: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. Methods: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. Results: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. Conclusion: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.

Default-mode network changes in preclinical Huntington's disease

The default-mode network (DMN) refers to as a set of brain regions which are active when the brain does not engage in a cognitive task and which are deactivated with task-related cognitive effort. Altered function of the DMN has been associated with a decline of cognition in several neurodegenerative diseases and related at-risk conditions. In Huntington's disease, an autosomal dominant inherited neurodegenerative disorder, several studies so far have shown abnormal task-related brain activation patterns even in preclinical carriers of the Huntington's disease gene mutation (preHD). To date, however, the functional integrity of the DMN has not been addressed in this population. The aim of this study was to study the functional connectivity of the DMN in 18 preHD and 18 healthy controls who underwent functional magnetic resonance imaging during an attention task. A group independent component analysis identified spatiotemporally distinct patterns of two DMN subsystems. The spatial distribution of these components in preHD was similar to controls. However, preHD showed lower subsystem-specific connectivity in the anterior medial prefrontal cortex, the left inferior parietal and the posterior cingulate cortex (p<0.05, cluster-corrected). Connectivity between the two DMN subsystems was increased in preHD compared to controls. In preHD individuals lower functional connectivity of the left inferior parietal cortex was associated with shorter reaction times in the attention task. This suggests that some functionally critical regions of the DMN may have to remain active to maintain or optimise cognitive performance in preHD.

On the role of fronto-striatal neural synchronization processes for response inhibition—Evidence from ERP phase-synchronization analyses in pre-manifest Huntington's disease gene mutation carriers

Fronto-striatal loops play an important role action selection processes, especially when discordant sensory and contextual information has to be integrated to allow adequate selection of actions. Neurodegeneration weakens neural inter-connectivity, which compromises the precision of neural synchronization processes. Yet, it is widely unknown how far changes in the precision of neural synchronization processes are induced by only slight dysfunctions of striatal neural inter-connectivity and in how far such slight changes may affect action selection processes.We investigated these processes in a sample of 25 pre-HDs and case-matched controls in a modified Go/Nogo task, while assessing neural synchronization processes by means of phase-locking factors (PLFs) as derived from event-related potentials (ERPs).The results show that pre-HDs only encounter problems in response inhibition, when discordant contextual information and sensory input have to be integrated. No deficits were evident, when response inhibition can be based on more habitual stimulus–response mappings, i.e., when contextual and sensory information were congruent. While ‘habitual’ action selection is unaffected by changes in striatal structures influencing reliability of neural synchronization processes, efficient ‘controlled’ processes of action seem to be closely dependent upon highly reliable neural synchronization processes. The neurophysiological analysis suggests that especially pre-motor inhibition processes (Nogo-N2) are affected. This was most strongly reflected in a decline in the degree of phase-locking in the Nogo-N2 range. Deficits in pre-HDs seem to emerge as a consequence of phase-locking-behavioural decoupling. Of clinical interest, declines in the precision of phase-locking depended on the amount of the individual's mutant huntingtin exposure and predicted the probability of disease manifestation in the next five years. This suggests that phase-locking parameters may prove useful in future studies evaluating a possible function as a biomarker in Huntington's disease.

Magnetic resonance perfusion imaging of resting-state cerebral blood flow in preclinical Huntington's disease

Magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). The aim of this study was to investigate the sensitivity of resting-state perfusion MRI in preHD and to identify neural changes, which could serve as biomarkers for future clinical trials. Differences in regional cerebral blood flow (rCBF) in 18 preHD and 18 controls were assessed with a novel MRI method based on perfusion images obtained with continuous arterial spin labeling. High-resolution structural data were collected to test for changes of brain volume. Compared with controls, preHD individuals showed decreased rCBF in medial and lateral prefrontal regions and increased rCBF in the precuneus. PreHD near to symptom onset additionally showed decreased rCBF in the putamen and increased rCBF in the hippocampus. Network analyses revealed an abnormal lateral prefrontal pattern in preHD far and near to motor onset. These data suggest early changes of frontostriatal baseline perfusion in preHD independent of substantial reductions of gray matter volume. This study also shows the feasibility of detecting neural changes in preHD with a robust MRI technique that would be suitable for longitudinal multisite application.