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Background: Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntington's disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of regional atrophy in premanifest and early HD compared with controls.Methods: Nine controls, 17 premanifest and 21 early HD subjects underwent volumetric MRI at baseline and 2 years. Premanifest subjects were on average 18.1 years before predicted motor onset. Non-linear registration was used to model within-subject change over the scanning interval, and statistical parametric mapping was used to examine group differences and associations with clinical variables.Results: In early HD, increased grey-matter (GM) atrophy rates were evident throughout the subcortical GM and over selective cortical regions compared with controls. This group also demonstrated strikingly widespread increases in white-matter (WM) atrophy rates. The authors observed no significant differences between premanifest HD and controls. Longer CAG was associated with higher atrophy rates over large WM areas including brainstem and internal capsule and over small GM regions including thalamus and occipital cortex. Worse baseline motor score was associated with regionally increased rates in the thalamus, internal capsule and occipital lobe. Sample-size calculations indicate that 19 and 24 early HD subjects per treatment arm would need to complete a 2-year trial in order to detect a 50% reduction in WM and GM atrophy rates respectively.Conclusions: Degeneration of structural connectivity may play an important role in early HD symptoms. Assessment of WM and GM changes will be important in understanding the complexity of HD and its treatment. [ABSTRACT FROM AUTHOR]

To be diagnostically useful, structural MRI must reliably distinguish Alzheimer's disease (AD) from normal aging in individual scans. Recent advances in statistical learning theory have led to the application of support vector machines to MRI for detection of a variety of disease states. The aims of this study were to assess how successfully support vector machines assigned individual diagnoses and to determine whether data-sets combined from multiple scanners and different centres could be used to obtain effective classification of scans. We used linear support vector machines to classify the grey matter segment of T1-weighted MR scans from pathologically proven AD patients and cognitively normal elderly individuals obtained from two centres with different scanning equipment. Because the clinical diagnosis of mild AD is difficult we also tested the ability of support vector machines to differentiate control scans from patients without post-mortem confirmation. Finally we sought to use these methods to differentiate scans between patients suffering from AD from those with frontotemporal lobar degeneration. Up to 96% of pathologically verified AD patients were correctly classified using whole brain images. Data from different centres were successfully combined achieving comparable results from the separate analyses. Importantly, data from one centre could be used to train a support vector machine to accurately differentiate AD and normal ageing scans obtained from another centre with different subjects and different scanner equipment. Patients with mild, clinically probable AD and age/sex matched controls were correctly separated in 89% of cases which is compatible with published diagnosis rates in the best clinical centres. This method correctly assigned 89% of patients with post-mortem confirmed diagnosis of either AD or frontotemporal lobar degeneration to their respective group. Our study leads to three conclusions: Firstly, support vector machines successfully separate patients with AD from healthy aging subjects. Secondly, they perform well in the differential diagnosis of two different forms of dementia. Thirdly, the method is robust and can be generalized across different centres. This suggests an important role for computer based diagnostic image analysis for clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To determine whether Alzheimer's disease (AD) is associated with preferential atrophy of either the left or right hippocampus. Methods: We examined right-left asymmetry in hippocampal volume and atrophy rates in 32 subjects with probable AD and 50 age-matched controls. Hippocampi were measured on two serial volumetric MRI scans using a technique that minimizes laterality bias. Results: We found a non-significant trend for right > left (R > L) asymmetry in controls at both time points (R > L: 1.7%; CI: -0.3-3.7%; p = 0.1). AD subjects showed a similar non-significant trend for R > L asymmetry at baseline (R > L: 1.8%; CI: -1.9-5.5%; p = 0.32), but not at repeat (p = 0.739). Change in R/L ratio between visits in AD patients was significant (p = 0.02). The AD group had significantly higher variance in these ratios than the controls at baseline (p = 0.02), but not repeat (p = 0.06). AD patients had higher atrophy rates than controls (p < 0.001). Mean (CI) annualized atrophy rates for left and right hippocampi were 1.2% (0.5-1.8%) and 1.1% (0.5-1.8%) for the controls, and 4.6% (3.3-6.0%) and 6.3% (4.9-7.8%) for AD subjects. There was no significant asymmetry in atrophy rates in controls (p = 0.9), but borderline significantly higher atrophy rates in the right hippocampus of the AD group (p = 0.05) compared to the left. Presence of an APOEE4 allele had no significant effect on the size, asymmetry or atrophy rates in AD (p > 0.20). Conclusions: We report minor R > L asymmetry in hippocampal volumes in controls and present some evidence to suggest that there is a change in the natural R > L asymmetry during the progression of AD. [ABSTRACT FROM AUTHOR]

Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.

Background: The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy., Objective: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS., Methods: Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis., Results: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes., Conclusions: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.

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

Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Timelines of events, such as symptom appearance or a change in biomarker value, provide powerful signatures that characterise progressive diseases. Understanding and predicting the timing of events is important for clinical trials targeting individuals early in the disease course when putative treatments are likely to have the strongest effect. However, previous models of disease progression cannot estimate the time between events and provide only an ordering in which they change. Here, we introduce the temporal event-based model (TEBM), a new probabilistic model for inferring timelines of biomarker events from sparse and irregularly sampled datasets. We demonstrate the power of the TEBM in two neurodegenerative conditions: Alzheimer's disease (AD) and Huntington's disease (HD). In both diseases, the TEBM not only recapitulates current understanding of event orderings but also provides unique new ranges of timescales between consecutive events. We reproduce and validate these findings using external datasets in both diseases. We also demonstrate that the TEBM improves over current models; provides unique stratification capabilities; and enriches simulated clinical trials to achieve a power of 80 % with less than half the cohort size compared with random selection. The application of the TEBM naturally extends to a wide range of progressive conditions., Competing Interests: The authors declare no competing financial or non-financial interests., (© 2023 Massachusetts Institute of Technology. Published under a Creative Commons CC BY-NC 4.0 license.)

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene ( HTT ), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus., Competing Interests: Funding for the study was provided by the NIH under a license agreement between AnatomyWorks LLC and the Johns Hopkins University. Dr. Michael I. Miller and the University are entitled to royalty distributions related to technology described in the study. Dr. Miller is a founder of and holds equity in AnatomyWorks LLC. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no relevant conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD)., Methods: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS)., Results: HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers., Conclusion: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Variability in neurodegenerative disease progression poses great challenges for the evaluation of potential treatments. Identifying the persons who will experience significant progression in the short term is key for the implementation of trials with smaller sample sizes. We apply here disease course mapping to forecast biomarker progression for individual carriers of the pathological CAG repeat expansions responsible for Huntington disease. We used data from two longitudinal studies (TRACK-HD and TRACK-ON) to synchronize temporal progression of 15 clinical and imaging biomarkers from 290 participants with Huntington disease. We used then the resulting HD COURSE MAP to forecast clinical endpoints from the baseline data of 11,510 participants from ENROLL-HD, an external validation cohort. We used such forecasts to select participants at risk for progression and compute the power of trials for such an enriched population. HD COURSE MAP forecasts biomarkers 5 years after the baseline measures with a maximum mean absolute error of 10 points for the total motor score and 2.15 for the total functional capacity. This allowed reducing sample sizes in trial up to 50% including participants with a higher risk for progression ensuring a more homogeneous group of participants., (© 2022. The Author(s).)

Lumbar puncture (LP) has become increasingly common for people with Huntington's disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community., (© 2022. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future., Competing Interests: Declaration of interests SJT receives research grant funding from the CHDI Foundation, Vertex Pharmaceuticals, the UK Medical Research Council, the Wellcome Trust (200181/Z/15/Z), and the UK Dementia Research Institute, which receives its funding from the UK Dementia Research Institute. The UK Dementia Research Institute is funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. SJT has undertaken consultancy services for Annexon, Alphasights, Alnylam Pharmaceuticals, Atalanta Therapeutics, Roche, Genentech, Guidepoint, Horama, Locanobio, LoQus23 Therapeutics, Novartis Pharma, PTC Therapeutics, Sanofi, Spark Therapeutics, Takeda Pharmaceuticals, Triplet Therapeutics, University College Irvine, Vertex Pharmaceuticals, and Wave Life Sciences. All honoraria for these consultancies were paid through the offices of University College London (UCL) Consultants, a wholly owned subsidiary of UCL. SJT is on the scientific advisory boards of Atalanta Therapeutics, LoQus 23 Therapeutics, and Triplet Therapeutics. SJT has a patent application number 2105484.6 on the FAN1-MLH1 interaction and structural analogues licensed to Adrestia Therapeutics. WRM is employed by the Leids Universitair Medisch Centrum (LUMC), which has patents on exon skipping approaches for neurological disorders, some of which have been licensed to ProQR and Amylon. Remunerations are paid to LUMC. WMCvR-M is an ad hoc consultant for Bridge Bio, has received project funding from Amylon and ProQR, and has received funding for contract research from UniQure. WMCvR-M is project leader in a project to develop an ASO therapy for SCA1 together with Vico Therapeutics. EJW reports grants from the CHDI Foundation, and Roche. EJW has undertaken consultancy work and advisory board work with Roche, Triplet Therapeutics, PTC Therapeutics, Takeda, Vico Therapeutics, Voyager, Huntington Study Group, Teitur Trophics, EcoR1 Capital, PTC Therapeutics, Annexon Biosciences, and Remix Therapeutics. All honoraria for these consultancies were paid through the offices of UCL Consultants. EJW holds a stock option for Triplet Therapeutics in part compensation for advisory board membership. AER is chair of the executive committee of the European Huntington Disease Network, which is funded by CHDI Foundation, with remuneration paid to Cardiff University. AER is also European co-principal investigator for the PROOF-HD trial, with remuneration paid to Cardiff University. AER also serves on the scientific advisory boards of Roche, Wave Pharma, Prilenia, and Triplet Therapeutics. AER has obtained research grants from the UK Medical Research Council, Health and Care Research Wales, EU Horizon 2020, Jacques and Gloria Gossweiler foundation, and is a chair of the Guarantors of Brain charity. BRL is on the scientific advisory board of sRNAlytics (GateHouse Bio), for which he received stock options, and reports scientific consultancy fees from Teva, Roche, Takeda, Triplet, UniQure, Novartis, Spark, Scintetica, LifeEdit, Design, Remix Therapeutics, and PTC Therapeutics. BRL's laboratory has obtained previous and current research grants from the Canadian Institutes of Health Research, Health Sciences Centre, Nanomedicines Innovation Network, CHDI Foundation, Teva, ProMIS, and uniQure. BRL is a founding co-editor-in-chief for the Journal of Huntington's Disease, former co-chair of the Huntington Study Group, and is co-founder and CEO of Incisive Genetics, in which he has stock and stock options (Incisive Genetics is an early-stage pre-clinical biotechnology company that was founded to develop in vivo lipid nanoparticle delivery of clustered regularly interspaced short palindromic repeats-Cas9 genome editing. This is not a therapeutic approach that is currently in clinical testing for Huntington's disease, nor is this approach in late pre-clinical stages. The company has no products to endorse, does not have an investigational new drug for Huntington's disease, and does not have any commercial efforts currently underway). CS serves as chief medical officer for CHDI Management and IM-S serves as vice president of Translational Biology for CHDI Management. CHDI Management is an advisor to CHDI Foundation. CHDI Foundation provided financial and scientific support to the Huntington's disease drug discovery programme developed by Ionis Pharmaceuticals through a development collaboration with Ionis Pharmaceuticals. Over time, CHDI Foundation was reimbursed for its financial support of the programme developed by Ionis Pharmaceuticals out of milestone payments received by Ionis Pharmaceuticals from Roche for progress in Roche's tominersen programme. CS received consultancy honoraria (unrelated to Huntington's disease programmes) from the following companies: Kyowa Kirin, Neuraly, the US Food and Drug Administration (New Drug Application), Neuroderm, Pinteon Pharmaceuticals, and vTv Therapeutics. CE-F receives support from a Wellcome Trust Collaborative Award (200181/Z/15/Z). Within the past 36 months MDF has received grant funding towards his research from the CHDI Foundation, the UK Dementia Research Institute, and the Rosetrees Trust. RIS reports no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development., Competing Interests: KMK is a full-time employee of IXICO. APM is a full-time employee of Wave Life Sciences, Ltd. DP, ECG, and SN are employed by CHDI Management to provide advisory services to CHDI Foundation. MFG is a full-time employee of Teva Pharmaceuticals. RIS provides consultancy for IXICO. AJS is a full-time employee and shareholder of Takeda Pharmaceuticals, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kinnunen, Mullin, Pustina, Turner, Burton, Gordon, Scahill, Gantman, Noble, Romero, Georgiou-Karistianis and Schwarz.)

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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community-biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations-to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration., Competing Interests: KMK and RJ are full-time employees of IXICO. AJS is a full-time employee and shareholder of Takeda Pharmaceuticals, Ltd. DP and ECG are employed by CHDI Management to provide advisory services to CHDI Foundation. MFG is a full-time employee of Teva Pharmaceuticals. APM is a full-time employee of Wave Life Sciences, Ltd. RIS provides consultancy for IXICO. The remaining authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kinnunen, Schwarz, Turner, Pustina, Gantman, Gordon, Joules, Mullin, Scahill, Georgiou-Karistianis and The Huntington's Disease Regulatory Science Consortium (HD-RSC).)

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., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wijeratne, Johnson, Gregory, Georgiou-Karistianis, Paulsen, Scahill, Tabrizi and Alexander.)

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., (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease-modifying huntingtin-lowering therapies., Objective: Evaluating volumetric and structural connectivity correlates of the cUHDRS., Methods: One hundred and nineteen premanifest and 119 early-HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross-sectionally and longitudinally using voxel-based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract-based spatial statistics., Results: Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito-parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline., Conclusion: The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

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., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: ER was employed by UCL during the period of data collection and image processing. She now works for IXICO plc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mansoor, Vanniyasingam, Malone, Hobbs, Rees, Durr, Roos, Landwehrmeyer, Tabrizi, Johnson and Scahill.)

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., Competing Interests: Declaration of Competing Interest SJT reports grants from Wellcome Trust, grants from UK Dementia Research Institute, during the conduct of the study; other from F. Hoffmann La Roche Ltd, personal fees from F. Hoffmann La Roche Ltd, personal fees from Annexon, personal fees from PTC Therapeutics, personal fees from Takeda Pharmaceuticals Ltd, personal fees from Vertex Pharmaceuticals Incorporated., personal fees from UCB Pharma S.A, personal fees from Alnylam Pharmaceuticals Inc, personal fees from Decision Resources Group, personal fees from Genentech, personal fees from DDF Discovery Ltd, personal fees from Triplet Theraputics, personal fees from Novartis, outside the submitted work. GR reports grants from Wellcome Trust during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: Competing interests: CL, SG, KOC, CO’C, PZ, JL, EBJ, MP, RS, GR and SJT have no competing interests. TWR and BJS consult for Cambridge Cognition., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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., (© 2020 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Biomarkers are often organized into networks, in which the strengths of network connections vary across subjects depending on subject-specific covariates (eg, genetic variants). Variation of network connections, as subject-specific feature variables, has been found to predict disease clinical outcome. In this work, we develop a two-stage method to estimate biomarker networks that account for heterogeneity among subjects and evaluate network's association with disease clinical outcome. In the first stage, we propose a conditional Gaussian graphical model with mean and precision matrix depending on covariates to obtain covariate-dependent networks with connection strengths varying across subjects while assuming homogeneous network structure. In the second stage, we evaluate clinical utility of network measures (connection strengths) estimated from the first stage. The second-stage analysis provides the relative predictive power of between-region network measures on clinical impairment in the context of regional biomarkers and existing disease risk factors. We assess the performance of proposed method by extensive simulation studies and application to a Huntington's disease (HD) study to investigate the effect of HD causal gene on the rate of change in motor symptom through affecting brain subcortical and cortical gray matter atrophy connections. We show that cortical network connections and subcortical volumes, but not subcortical connections are identified to be predictive of clinical motor function deterioration. We validate these findings in an independent HD study. Lastly, highly similar patterns seen in the gray matter connections and a previous white matter connectivity study suggest a shared biological mechanism for HD and support the hypothesis that white matter loss is a direct result of neuronal loss as opposed to the loss of myelin or dysmyelination., (© 2019 The International Biometric Society.)

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: Investigating early white matter (WM) change in Huntington's disease (HD) can improve our understanding of the way in which disease spreads from the striatum., Objectives: We provide a detailed characterization of pathology-related WM change in HD. We first examined WM microstructure using diffusion-weighted imaging and then investigated both underlying biological properties of WM and products of WM damage including iron, myelin plus neurofilament light, a biofluid marker of axonal degeneration-in parallel with the mutant huntingtin protein., Methods: We examined WM change in HD gene carriers from the HD-CSFcohort, baseline visit. We used standard-diffusion magnetic resonance imaging to measure metrics including fractional anisotropy, a marker of WM integrity, and diffusivity; a novel diffusion model (neurite orientation dispersion and density imaging) to measure axonal density and organization; T1-weighted and T2-weighted structural magnetic resonance imaging images to derive proxy iron content and myelin-contrast measures; and biofluid concentrations of neurofilament light (in cerebrospinal fluid (CSF) and plasma) and mutant huntingtin protein (in CSF)., Results: HD gene carriers displayed reduced fractional anisotropy and increased diffusivity when compared with controls, both of which were also associated with disease progression, CSF, and mutant huntingtin protein levels. HD gene carriers also displayed proxy measures of reduced myelin contrast and iron in the striatum., Conclusion: Collectively, these findings present a more complete characterization of HD-related microstructural brain changes. The correlation between reduced fractional anisotropy, increased axonal orientation, and biofluid markers suggest that axonal breakdown is associated with increased WM degeneration, whereas higher quantitative T2 signal and lower myelin-contrast may indicate a process of demyelination limited to the striatum., (© 2019 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Importance: In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing., Objective: To succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length., Design, Setting, and Participants: Prospective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019., Main Outcomes and Measures: The outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length., Results: We analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length-dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 items (total motor score, Symbol Digit Modalities Test, and Stroop word reading) from the Unified Huntington's Disease Rating Scale. For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity., Conclusions and Relevance: Results of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length-dependent association between changes in the brain and clinical manifestations of HD.