Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease.

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington's disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington's disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington's disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington's disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington's disease and their effect on brain structure.

Longitudinal evaluation of proton magnetic resonance spectroscopy metabolites as biomarkers in Huntington's disease.

Proton magnetic resonance spectroscopy is a non-invasive method of exploring cerebral metabolism. In Huntington's disease, altered proton magnetic resonance spectroscopy-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies are lacking. Proton magnetic resonance spectroscopy metabolites may represent a source of biomarkers, thus their relationship with established markers of disease progression require further exploration to assess prognostic value and elucidate pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardized collection of CSF, blood, phenotypic and volumetric imaging data, we used 3 T proton magnetic resonance spectroscopy in conjunction with the linear combination of model spectra method to quantify seven metabolites (total n-acetylaspartate, total creatine, total choline, myo-inositol, GABA, glutamate and glutathione) in the putamen of 59 participants at baseline (15 healthy controls, 15 premanifest and 29 manifest Huntington's disease gene expansion carriers) and 48 participants at 2-year follow-up (12 healthy controls, 13 premanifest and 23 manifest Huntington's disease gene expansion carriers). Intergroup differences in concentration and associations with CSF and plasma biomarkers; including neurofilament light chain and mutant Huntingtin, volumetric imaging markers; namely whole brain, caudate, grey matter and white matter volume, measures of disease progression and cognitive decline, were assessed cross-sectionally using generalized linear models and partial correlation. We report no significant groupwise differences in metabolite concentration at baseline but found total creatine and total n-acetylaspartate to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, total creatine and myo-inositol displayed significant associations with reduced caudate volume across both time points in gene expansion carriers. Although relationships were observed between proton magnetic resonance spectroscopy metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value, we examined whether baseline proton magnetic resonance spectroscopy values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed-effects models revealed glutamine + glutamate to display a slow linear decrease over time in gene expansion carriers. Altogether, our findings show some evidence of reduced total n-acetylaspartate and total creatine as the disease progresses and cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of consistent group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change suggests that proton magnetic resonance spectroscopy metabolites have limited potential as Huntington's disease biomarkers.

Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.

Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.

Timing of selective basal ganglia white matter loss in premanifest Huntington's disease.

OBJECTIVES: To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington's disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. METHODS: We performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. RESULTS: We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington's disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. CONCLUSIONS: Our findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.

Revealing the Timeline of Structural MRI Changes in Premanifest to Manifest Huntington Disease.

BACKGROUND AND OBJECTIVES: Longitudinal measurements of brain atrophy using structural MRI (sMRI) can provide powerful markers for tracking disease progression in neurodegenerative diseases. In this study, we use a disease progression model to learn individual-level disease times and hence reveal a new timeline of sMRI changes in Huntington disease (HD). METHODS: We use data from the 2 largest cohort imaging studies in HD-284 participants from TRACK-HD (100 control, 104 premanifest, and 80 manifest) and 159 participants from PREDICT-HD (36 control and 128 premanifest)-to train and test the model. We longitudinally register T1-weighted sMRI scans from 3 consecutive time points to reduce intraindividual variability and calculate regional brain volumes using an automated segmentation tool with rigorous manual quality control. RESULTS: Our model reveals, for the first time, the relative magnitude and timescale of subcortical and cortical atrophy changes in HD. We find that the largest (∼20% average change in magnitude) and earliest (∼2 years before average abnormality) changes occur in the subcortex (pallidum, putamen, and caudate), followed by a cascade of changes across other subcortical and cortical regions over a period of ∼11 years. We also show that sMRI, when combined with our disease progression model, provides improved prediction of onset over the current best method (root mean square error = 4.5 years and maximum error = 7.9 years vs root mean square error = 6.6 years and maximum error = 18.2 years). DISCUSSION: Our findings support the use of disease progression modeling to reveal new information from sMRI, which can potentially inform imaging marker selection for clinical trials.

A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington's Disease.

Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington's disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington's disease, influencing the choice of biomarkers and the recruitment of participants.

Validating Automated Segmentation Tools in the Assessment of Caudate Atrophy in Huntington's Disease.

Background: Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials. Methods: Using a cohort of early Huntington's disease (HD) patients (n = 46) and controls (n = 35), we compared the performance of four automated segmentation tools (FIRST, FreeSurfer, STEPS, MALP-EM) with manual delineation for generating cross-sectional caudate volume, a region known to be vulnerable in HD. We then examined the effect of each of these baseline regions on the ability to detect change over 15 months using the established longitudinal Caudate Boundary Shift Integral (cBSI) method, an automated longitudinal pipeline requiring a baseline caudate region as an input. Results: All tools, except Freesurfer, generated significantly smaller caudate volumes than the manually derived regions. Jaccard indices showed poorer levels of overlap between each automated segmentation and manual delineation in the HD patients compared with controls. Nevertheless, each method was able to demonstrate significant group differences in volume (p < 0.001). STEPS performed best qualitatively as well as quantitively in the baseline analysis. Caudate atrophy measures generated by the cBSI using automated baseline regions were largely consistent with those derived from a manually segmented baseline, with STEPS providing the most robust cBSI values across both control and HD groups. Conclusions: Atrophy measures from the cBSI were relatively robust to differences in baseline segmentation technique, suggesting that fully automated pipelines could be used to generate outcome measures for clinical trials.

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites-tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid-in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.

Aberrant Striatal Value Representation in Huntington's Disease Gene Carriers 25 Years Before Onset.

BACKGROUND: In this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task with gain and loss domains could be one of the earliest functional imaging features associated with carrying the Huntington's disease (HD) gene. Based on previous work, we hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning. METHODS: We recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data. RESULTS: In comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes. CONCLUSIONS: Behaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.

Altered iron and myelin in premanifest Huntington's Disease more than 20 years before clinical onset: Evidence from the cross-sectional HD Young Adult Study.

BACKGROUND: Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. METHODS: 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. FINDINGS: We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. INTERPRETATION: Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease.

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.

Dynamics of Cortical Degeneration Over a Decade in Huntington's Disease.

BACKGROUND: Characterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well established that Huntington's disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. METHODS: Capitalizing on a unique longitudinal dataset with a minimum of 3 and maximum of 7 brain scans from 49 HD gene carriers and 49 age-matched control subjects, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over 10 years. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. RESULTS: We show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, the occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. CONCLUSIONS: HD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.

Fronto-striatal circuits for cognitive flexibility in far from onset Huntington's disease: evidence from the Young Adult Study.

OBJECTIVES: Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington's disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit. METHODS: In the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage. RESULTS: Our results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants. CONCLUSION: We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

Longitudinal Structural MRI in Neurologically Healthy Adults.

BACKGROUND: Structural brain MRI measures are frequently examined in both healthy and clinical groups, so an understanding of how these measures vary over time is desirable. PURPOSE: To test the stability of structural brain MRI measures over time. POPULATION: In all, 112 healthy volunteers across four sites. STUDY TYPE: Retrospective analysis of prospectively acquired data. FIELD STRENGTH/SEQUENCE: 3 T, magnetization prepared - rapid gradient echo, and single-shell diffusion sequence. ASSESSMENT: Diffusion, cortical thickness, and volume data from the sensorimotor network were assessed for stability over time across 3 years. Two sites used a Siemens MRI scanner, two sites a Philips scanner. STATISTICAL TESTS: The stability of structural measures across timepoints was assessed using intraclass correlation coefficients (ICC) for absolute agreement, cutoff ≥0.80, indicating high reliability. Mixed-factorial analysis of variance (ANOVA) was used to examine between-site and between-scanner type differences in individuals over time. RESULTS: All cortical thickness and gray matter volume measures in the sensorimotor network, plus all diffusivity measures (fractional anisotropy plus mean, axial and radial diffusivities) for primary and premotor cortices, primary somatosensory thalamic connections, and the cortico-spinal tract met ICC. The majority of measures differed significantly between scanners, with a trend for sites using Siemens scanners to produce larger values for connectivity, cortical thickness, and volume measures than sites using Philips scanners. DATA CONCLUSION: Levels of reliability over time for all tested structural MRI measures were generally high, indicating that any differences between measurements over time likely reflect underlying biological differences rather than inherent methodological variability. LEVEL OF EVIDENCE: 4. TECHNICAL EFFICACY STAGE: 1.

Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

BACKGROUND: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. METHODS: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0·05 deemed a significant result. FINDINGS: Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29·0 years (SD 5·6) and 29·1 years (5·7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23·6 years (SD 5·8) from predicted onset (FDR 0·22-0·87 for cognitive measures, 0·31-0·91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0·03), but this did not appear to be closely related to predicted years to onset (FDR=0·54). There were no group differences in other brain imaging measures (FDR >0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001). INTERPRETATION: We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact. FUNDING: Wellcome Trust, CHDI Foundation.

Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease.

OBJECTIVE: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD. METHODS: We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers. RESULTS: We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers. INTERPRETATION: Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762.

Multimodal characterization of the visual network in Huntington's disease gene carriers.

OBJECTIVE: A sensorimotor network structural phenotype predicted motor task performance in a previous study in Huntington's disease (HD) gene carriers. We investigated in the visual network whether structure - function - behaviour relationship patterns, and the effects of the HD mutation, extended beyond the sensorimotor network. METHODS: We used multimodal visual network MRI structural measures (cortical thickness and white matter connectivity), plus visual evoked potentials and task performance (Map Search; Symbol Digit Modalities Test) in healthy controls and HD gene carriers. RESULTS: Using principal component (PC) analysis, we identified a structure - function relationship common to both groups. PC scores differed between groups indicating white matter disorganization (higher RD, lower FA) and slower, and more disperse, VEP signal transmission (higher VEP P100 latency and lower VEP P100 amplitude) in HD than controls while task performance was similar. CONCLUSIONS: HD may be associated with reduced white matter organization and efficient visual network function but normal task performance. SIGNIFICANCE: These findings indicate that structure - function relationships in the visual network, and the effects of the HD mutation, share some commonalities with those in the sensorimotor network. However, implications for task performance differ between the two networks suggesting the influence of network specific factors.

Huntington's disease: Brain imaging in Huntington's disease.

Huntington's disease (HD) gene-carriers show prominent neuronal loss by end-stage disease, and the use of magnetic resonance imaging (MRI) has been increasingly used to quantify brain changes during earlier stages of the disease. MRI offers an in vivo method of measuring structural and functional brain change. The images collected via MRI are processed to measure different anatomical features, such as brain volume, macro- and microstructural changes within white matter and functional brain activity. Structural imaging has demonstrated significant volume loss across multiple white and gray matter regions in HD, particularly within subcortical structures. There also appears to be increasing disorganization of white matter tracts and between-region connectivity with increasing disease progression. Finally, functional changes are thought to represent changes in brain activity underlying compensatory mechanisms in HD. This chapter will provide an overview of the principles of MRI and practicalities associated with using MRI in HD studies, and summarize findings from MRI studies investigating brain structure and function in HD.

Automated Segmentation of Cortical Grey Matter from T1-Weighted MRI Images.

Within neuroimaging research, a number of recent studies have discussed the impact of between-study differences in volumetric findings that are thought to result from the use of different segmentation tools to generate brain volumes. Here, processing pipelines for seven automated tools that can be used to segment grey matter within the brain are presented. The protocol provides an initial step for researchers aiming to find the most accurate method for generating grey matter volumes from T1-weighted MRI scans. Steps to undertake detailed visual quality control are also included in the manuscript. This protocol covers a range of potential segmentation tools and encourages users to compare the performance of these tools within a subset of their data before selecting one to apply to a full cohort. Furthermore, the protocol may be further generalized to the segmentation of other brain regions.