Publications by authors named "Sarah J Tabrizi"

258 Publications

Tracking Huntington's Disease Progression Using Motor, Functional, Cognitive, and Imaging Markers.

Mov Disord 2021 May 20. Epub 2021 May 20.

School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia.

Background: Potential therapeutic targets and clinical trials for Huntington's disease have grown immensely in the last decade. However, to improve clinical trial outcomes, there is a need to better characterize profiles of signs and symptoms across different epochs of the disease to improve selection of participants.

Objective: The objective of the present study was to best distinguish longitudinal trajectories across different Huntington's disease progression groups.

Methods: Clinical and morphometric imaging data from 1082 participants across IMAGE-HD, TRACK-HD, and PREDICT-HD studies were combined, with longitudinal times ranging between 1 and 10 years. Participants were classified into 4 groups using CAG and age product. Using multivariate linear mixed modeling, 63 combinations of markers were tested for their sensitivity in differentiating CAG and age product groups. Next, multivariate linear mixed modeling was applied to define the best combination of markers to track progression across individual CAG and age product groups.

Results: Putamen and caudate volumes, individually and/or combined, were identified as the best variables to both differentiate CAG and age product groups and track progression within them. The model using only caudate volume best described advanced disease progression in the combined data set. Contrary to expectations, combining clinical markers and volumetric measures did not improve tracking longitudinal progression.

Conclusions: Monitoring volumetric changes throughout a trial (alongside primary and secondary clinical end points) may provide a more comprehensive understanding of improvements in functional outcomes and help to improve the design of clinical trials. Alternatively, our results suggest that imaging deserves consideration as an end point in clinical trials because of the prospect of greater sensitivity. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28650DOI Listing
May 2021

Expanding the Spectrum of Movement Disorders Associated With Hexanucleotide Expansions.

Neurol Genet 2021 Apr 12;7(2):e575. Epub 2021 Mar 12.

Department of Neurodegenerative Diseases (C.E.-F., D.H.M., S.J.T.), Department of Clinical and Movement Neurosciences (A.L, F.M., E.M., G.D.L., M.M., K.P.B.), and Department of Neuromuscular Disorders (H.H.), UCL Queen Square Institute of Neurology, United Kingdom; Department of Neurosciences, Biomedicine and Movement Sciences (F.M.), University of Verona, Italy; St George's University of London (D.H.M.), United Kingdom; Department of Systems Medicine (G.D.L.), University of Rome Tor Vergata, Italy; and Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health (M.M.), University of British Columbia, Vancouver, Canada.

Objective: Hexanucleotide repeat expansions (HREs) in are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in through a retrospective review of patients' medical records.

Methods: We retrospectively reviewed the clinical records of patients carrying a HRE in the pathogenic range and compared the characteristics of patients with and without MD.

Results: Seventeen of 40 patients with a HRE had a documented MD. In 6 of 17, MD were the presenting symptom, and in 2 of 17, MD were the sole manifestation of the disease. FTD was present in 13 of 17 patients, ALS in 5 of 17 patients, and 2 of 17 patients did not develop FTD or ALS. Thirteen of 17 patients had more than one MD. The most common MD were parkinsonism and tremor (resembling essential tremor syndrome), each one present in 11 of 17 patients. Distal, stimulus-sensitive upper limbs myoclonus was present in 6 of 17 patients and cervical dystonia in 5 of 17 patients. Chorea was present in 5 of 17 patients, 4 of whom showed marked orofacial dyskinesias. The most frequent MD combination was tremor and parkinsonism, observed in 8 of 17 patients, 5 of whom also had myoclonus. patients without MD had shorter follow-up times and higher proportion of ALS, although these results did not survive the correction for multiple comparisons.

Conclusions: MD are frequent in . They may precede signs of ALS or FTD, or even be present in isolation. Parkinsonism, tremor, and myoclonus are most commonly observed.
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http://dx.doi.org/10.1212/NXG.0000000000000575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105892PMC
April 2021

Altered nuclear architecture in blood cells from Huntington's disease patients.

Neurol Sci 2021 May 11. Epub 2021 May 11.

CompuMAINE Lab, Department of Chemical and Biomedical Engineering, University of Maine, Orono, ME, 04469, USA.

Background: Cell nuclear architecture has been explored in cancer and laminopathies but not in neurodegenerative disorders. Huntington's disease (HD) is a neurodegenerative disorder that leads to neuronal death. Chromosome-wide changes in gene expression have been reported in HD, not only in the brain but also in peripheral blood cells, but whether this translates into nuclear and chromosome architecture alterations has not yet been studied.

Methods: We investigate nuclear structure and chromosome organization in HD blood cells using fluorescence in situ hybridization in ultrathin cryosections (cryoFISH), coupled with machine learning image analysis to evaluate size, distribution, and morphology of nuclei and chromosomes. Four chromosomes were analyzed based on up- or downregulation of gene expression in HD.

Results: We show that blood cells from HD patients display increased nuclear size and filamentary shape, increased size of gene-rich chromosome 19, decreased filamentary shape of gene-rich chromosome 22, and a more radially centralized position for chromosome 19, whereas chromosomes 4 and 5 do not show detectable differences.

Conclusions: We identify gross changes in nuclear architecture and chromosome organization associated with HD in blood. This adds a new layer of information onto disrupting mechanisms in HD and increases the potential of using blood to survey HD.
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http://dx.doi.org/10.1007/s10072-021-05289-wDOI Listing
May 2021

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

Front Neurol 2021 14;12:616272. Epub 2021 Apr 14.

Department of Neurodegenerative Disease, Huntington's Disease Centre, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom.

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. Using a cohort of early Huntington's disease (HD) patients ( = 46) and controls ( = 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. 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 ( < 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. 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.
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http://dx.doi.org/10.3389/fneur.2021.616272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079754PMC
April 2021

Human Huntington's disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species.

J Neuroinflammation 2021 Apr 19;18(1):94. Epub 2021 Apr 19.

Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK.

Background: Neuroinflammation may contribute to the pathogenesis of Huntington's disease, given evidence of activated microglia and elevated levels of inflammatory molecules in disease gene carriers, even those many years from symptom onset. We have shown previously that monocytes from Huntington's disease patients are hyper-reactive to stimulation in a manner dependent on their autonomous expression of the disease-causing mutant HTT protein. To date, however, whether human microglia are similarly hyper-responsive in a cell-autonomous manner has not been determined.

Methods: Microglial-like cells were derived from human pluripotent stem cells (PSCs) expressing mutant HTT containing varying polyglutamine lengths. These included lines that are otherwise isogenic, such that any observed differences can be attributed with certainty to the disease mutation itself. Analyses by quantitative PCR and immunofluorescence microscopy respectively of key genes and protein markers were undertaken to determine whether Huntington's disease PSCs differentiated normally to a microglial fate. The resultant cultures and their supernatants were then assessed by various biochemical assays and multiplex ELISAs for viability and responses to stimulation, including the release of pro-inflammatory cytokines and reactive oxygen species. Conditioned media were applied to PSC-derived striatal neurons, and vice versa, to determine the effects that the secretomes of each cell type might have on the other.

Results: Human PSCs generated microglia successfully irrespective of the expression of mutant HTT. These cells, however, were hyper-reactive to stimulation in the production of pro-inflammatory cytokines such as IL-6 and TNFα. They also released elevated levels of reactive oxygen species that have neurotoxic potential. Accompanying such phenotypes, human Huntington's disease PSC-derived microglia showed increased levels of apoptosis and were more susceptible to exogenous stress. Such stress appeared to be induced by supernatants from human PSC-derived striatal neurons expressing mutant HTT with a long polyglutamine tract.

Conclusions: These studies show, for the first time, that human Huntington's disease PSC-derived microglia are hyper-reactive due to their autonomous expression of mutant HTT. This provides a cellular basis for the contribution that neuroinflammation might make to Huntington's disease pathogenesis.
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http://dx.doi.org/10.1186/s12974-021-02147-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054367PMC
April 2021

Disease Onset in Huntington's Disease: When Is the Conversion?

Mov Disord Clin Pract 2021 Apr 31;8(3):352-360. Epub 2021 Jan 31.

Department of Neurology Leiden University Medical Center Leiden The Netherlands.

Background: Determination of disease onset in Huntington's disease is made by clinical experience. The diagnostic confidence level is an assessment regarding the certainty about the clinical diagnosis based on motor signs. A level of 4 means the rater has ≥99% confidence motor abnormalities are unequivocal signs of disease. However, it does not state which motor abnormalities are signs of disease and how many must be present.

Objective: Our aim is to explore how accurate the diagnostic confidence level is in estimating disease onset using the Enroll-HD data set. For clinical disease onset we use a cut-off total motor score >5 of the Unified Huntington's Disease Rating Scale. This score is used in the TRACK-HD study, with ≤5 indicating no substantial motor signs in premanifests.

Methods: At baseline premanifest participants who converted to manifest (converters) and non-converters were compared for clinical symptoms and diagnostic confidence level. Clinical symptoms and diagnostic confidence levels were longitudinally displayed in converters.

Results: Of 3731 eligible participants, 455 were converters and 3276 non-converters. Baseline diagnostic confidence levels were significantly higher in converters compared to non-converters ( < 0.001). 232 (51%) converters displayed a baseline motor score >5 (mean = 6.7). Converters had significantly more baseline clinical symptoms, and higher disease burden compared to non-converters ( < 0.001). Diagnostic confidence level before disease onset ranged between 1 and 3 in converters.

Conclusions: According to this data the diagnostic confidence level is not an accurate instrument to determine phenoconversion. With trials evaluating disease modifying therapies it is important to develop more reliable diagnostic criteria.
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http://dx.doi.org/10.1002/mdc3.13148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015887PMC
April 2021

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

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jan 11. Epub 2021 Jan 11.

Huntington's Disease Centre, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom; Wellcome Centre for Human Neuroimaging, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bpsc.2020.12.015DOI Listing
January 2021

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.

EBioMedicine 2021 Mar 9;65:103266. Epub 2021 Mar 9.

Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; Dementia Research Institute at University College London, London, UK.

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.
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http://dx.doi.org/10.1016/j.ebiom.2021.103266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960938PMC
March 2021

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

Biol Psychiatry 2021 04 18;89(8):807-816. Epub 2020 Nov 18.

Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986936PMC
April 2021

Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease.

Mov Disord 2021 05 20;36(5):1259-1264. Epub 2021 Jan 20.

Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

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.
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http://dx.doi.org/10.1002/mds.28489DOI Listing
May 2021

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

Sci Transl Med 2020 12;12(574)

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1B 5EH, UK.

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.
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http://dx.doi.org/10.1126/scitranslmed.abc2888DOI Listing
December 2020

Longitudinal expression changes are weak correlates of disease progression in Huntington's disease.

Brain Commun 2020 17;2(2):fcaa172. Epub 2020 Oct 17.

University of Leicester, University Road, Leicester LE1 7RH, UK.

Huntington's disease is a severe but slowly progressive hereditary illness for which only symptomatic treatments are presently available. Clinical measures of disease progression are somewhat subjective and may require years to detect significant change. There is a clear need to identify more sensitive, objective and consistent measures to detect disease progression in Huntington's disease clinical trials. Whereas Huntington's disease demonstrates a robust and consistent gene expression signature in the brain, previous studies of blood cell RNAs have lacked concordance with clinical disease stage. Here we utilized longitudinally collected samples from a well-characterized cohort of control, Huntington's disease-at-risk and Huntington's disease subjects to evaluate the possible correlation of gene expression and disease status within individuals. We interrogated these data in both cross-sectional and longitudinal analyses. A number of changes in gene expression showed consistency within this study and as compared to previous reports in the literature. The magnitude of the mean disease effect over 2 years' time was small, however, and did not track closely with motor symptom progression over the same time period. We therefore conclude that while blood-derived gene expression indicators can be of value in understanding Huntington's disease pathogenesis, they are insufficiently sensitive to be of use as state biomarkers.
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http://dx.doi.org/10.1093/braincomms/fcaa172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713990PMC
October 2020

Genetic testing in dementia - utility and clinical strategies.

Nat Rev Neurol 2021 Jan 9;17(1):23-36. Epub 2020 Nov 9.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK.

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information.
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http://dx.doi.org/10.1038/s41582-020-00416-1DOI Listing
January 2021

Reply to 'Topographical layer imaging as a tool to track neurodegenerative disease spread in M1'.

Nat Rev Neurosci 2021 01;22(1):69

Wellcome Centre for Human Neuroimaging, UCL Institute of Neurology, University College London, London, UK.

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http://dx.doi.org/10.1038/s41583-020-00405-9DOI Listing
January 2021

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

J Neurol Neurosurg Psychiatry 2021 02 31;92(2):143-149. Epub 2020 Oct 31.

Department of Psychiatry, University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1136/jnnp-2020-324104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841479PMC
February 2021

Wild-type huntingtin regulates human macrophage function.

Sci Rep 2020 10 14;10(1):17269. Epub 2020 Oct 14.

UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.

The huntingtin (HTT) protein in its mutant form is the cause of the inherited neurodegenerative disorder, Huntington's disease. Beyond its effects in the central nervous system, disease-associated mutant HTT causes aberrant phenotypes in myeloid-lineage innate immune system cells, namely monocytes and macrophages. Whether the wild-type form of the protein, however, has a role in normal human macrophage function has not been determined. Here, the effects of lowering the expression of wild-type (wt)HTT on the function of primary monocyte-derived macrophages from healthy, non-disease human subjects were examined. This demonstrated a previously undescribed role for wtHTT in maintaining normal macrophage health and function. Lowered wtHTT expression was associated, for instance, with a diminished release of induced cytokines, elevated phagocytosis and increased vulnerability to cellular stress. These may well occur by mechanisms different to that associated with the mutant form of the protein, given an absence of any effect on the intracellular signalling pathway predominantly associated with macrophage dysfunction in Huntington's disease.
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http://dx.doi.org/10.1038/s41598-020-74042-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560844PMC
October 2020

Diffusion imaging in Huntington's disease: comprehensive review.

J Neurol Neurosurg Psychiatry 2020 Oct 8. Epub 2020 Oct 8.

Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK

Huntington's disease (HD) is a monogenic disorder with 100% penetrance. With the advent of genetic testing in adults, disease-related, structural brain changes can be investigated from the earliest, premorbid stages of HD. While examining macrostructural change characterises global neuronal damage, investigating microstructural alterations provides information regarding brain organisation and its underlying biological properties. Diffusion MRI can be used to track the progression of microstructural anomalies in HD decades prior to clinical disease onset, providing a greater understanding of neurodegeneration. Multiple approaches, including voxelwise, region of interest and tractography, have been used in HD cohorts, showing a centrifugal pattern of white matter (WM) degeneration starting from deep brain areas, which is consistent with neuropathological studies. The corpus callosum, longer WM tracts and areas that are more densely connected, in particular the sensorimotor network, also tend to be affected early during premanifest stages. Recent evidence supports the routine inclusion of diffusion analyses within clinical trials principally as an additional measure to improve understanding of treatment effects, while the advent of novel techniques such as multitissue compartment models and connectomics can help characterise the underpinnings of progressive functional decline in HD.
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http://dx.doi.org/10.1136/jnnp-2020-324377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803908PMC
October 2020

Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington'S Disease Model.

Brain Commun 2020 3;2(2):fcaa066. Epub 2020 Aug 3.

Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL, Queen Square, WC1N 3BG, UK.

Huntington's disease is caused by the expansion of a CAG repeat within exon 1 of the gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington's disease, that were known to abrogate somatic instability in Huntington's disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 with 90 CAGs, a mutation that causes juvenile Huntington's disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington's disease patient's blood, but which has been detected in post-mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG) mice and that this correlated with the onset of transcriptional dysregulation. Whereas in R6/2(CAG) mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG) brains have different properties to those in the R6/2(CAG) mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilized by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG) brains polymerize into larger structures that appear as inclusion bodies. These data emphasize that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.
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http://dx.doi.org/10.1093/braincomms/fcaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425396PMC
August 2020

Activity or connectivity? A randomized controlled feasibility study evaluating neurofeedback training in Huntington's disease.

Brain Commun 2020 23;2(1):fcaa049. Epub 2020 Apr 23.

UCL Huntington's Disease Centre, Queen Square Institute of Neurology, University College London, London WC1B 5EH, UK.

Non-invasive methods, such as neurofeedback training, could support cognitive symptom management in Huntington's disease by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of neurofeedback training in Huntington's disease by examining two different methods, activity and connectivity real-time functional MRI neurofeedback training. Thirty-two Huntington's disease gene-carriers completed 16 runs of neurofeedback training, using an optimized real-time functional MRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the supplementary motor area, and another receiving neurofeedback based on the correlation of supplementary motor area and left striatum activity (connectivity neurofeedback training), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during neurofeedback training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants' ability to upregulate neurofeedback training target levels without feedback (near transfer), as well as by examining change in objective, a priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher neurofeedback training target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two neurofeedback training methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and learning success. We conclude that although there is evidence that neurofeedback training can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust.
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http://dx.doi.org/10.1093/braincomms/fcaa049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425518PMC
April 2020

A new family with GLRB-related hyperekplexia showing chorea in homo- and heterozygous variant carriers.

Parkinsonism Relat Disord 2020 Aug 18;79:97-99. Epub 2020 Aug 18.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2020.08.016DOI Listing
August 2020

Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities.

Nat Rev Neurol 2020 Oct 14;16(10):529-546. Epub 2020 Aug 14.

Huntington's Disease Centre, University College London, London, UK.

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.
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http://dx.doi.org/10.1038/s41582-020-0389-4DOI Listing
October 2020

Therapeutic strategies for Huntington's disease.

Curr Opin Neurol 2020 08;33(4):508-518

University College London (UCL), Huntington's Disease Centre.

Purpose Of Review: Huntington's disease is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HTT gene, and current therapies focus on symptomatic treatment. This review explores therapeutic approaches that directly target the pathogenic mutation, disrupt HTT mRNA or its translation.

Recent Findings: Zinc-finger transcription repressors and CRISPR-Cas9 therapies target HTT DNA, thereby preventing all downstream pathogenic mechanisms. These therapies, together with RNA interference (RNAi), require intraparenchymal delivery to the brain in viral vectors, with only a single delivery potentially required, though they may carry the risk of irreversible side-effects.Along with RNAi, antisense oligonucleotides (ASOs) target mRNA, but are delivered periodically and intrathecally. ASOs have safely decreased mutant huntingtin protein (mHTT) levels in the central nervous system of patients, and a phase 3 clinical trial is currently underway.Finally, orally available small molecules, acting on splicing or posttranslational modification, have recently been shown to decrease mHTT in animal models.

Summary: Huntingtin-lowering approaches act upstream of pathogenic mechanisms and therefore have a high a priori likelihood of modifying disease course. ASOs are already in late-stage clinical development, whereas other strategies are progressing rapidly toward human studies.
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http://dx.doi.org/10.1097/WCO.0000000000000835DOI Listing
August 2020

The human motor cortex microcircuit: insights for neurodegenerative disease.

Nat Rev Neurosci 2020 08 18;21(8):401-415. Epub 2020 Jun 18.

Wellcome Centre for Human Neuroimaging, UCL Institute of Neurology, University College London, London, UK.

The human motor cortex comprises a microcircuit of five interconnected layers with different cell types. In this Review, we use a layer-specific and cell-specific approach to integrate physiological accounts of this motor cortex microcircuit with the pathophysiology of neurodegenerative diseases affecting motor functions. In doing so we can begin to link motor microcircuit pathology to specific disease stages and clinical phenotypes. Based on microcircuit physiology, we can make future predictions of axonal loss and microcircuit dysfunction. With recent advances in high-resolution neuroimaging we can then test these predictions in humans in vivo, providing mechanistic insights into neurodegenerative disease.
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http://dx.doi.org/10.1038/s41583-020-0315-1DOI Listing
August 2020

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.

Lancet Neurol 2020 06 26;19(6):502-512. Epub 2020 May 26.

Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; Dementia Research Institute at University College London, London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/S1474-4422(20)30143-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254065PMC
June 2020

Longitudinal Structural MRI in Neurologically Healthy Adults.

J Magn Reson Imaging 2020 11 29;52(5):1385-1399. Epub 2020 May 29.

Department of Neurology, Ulm University Hospital, Ulm, Germany.

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.
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http://dx.doi.org/10.1002/jmri.27203DOI Listing
November 2020

Expression of mutant exon 1 huntingtin fragments in human neural stem cells and neurons causes inclusion formation and mitochondrial dysfunction.

FASEB J 2020 06 23;34(6):8139-8154. Epub 2020 Apr 23.

Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.

Robust cellular models are key in determining pathological mechanisms that lead to neurotoxicity in Huntington's disease (HD) and for high throughput pre-clinical screening of potential therapeutic compounds. Such models exist but mostly comprise non-human or non-neuronal cells that may not recapitulate the correct biochemical milieu involved in pathology. We have developed a new human neuronal cell model of HD, using neural stem cells (ReNcell VM NSCs) stably transduced to express exon 1 huntingtin (HTT) fragments with variable length polyglutamine (polyQ) tracts. Using a system with matched expression levels of exon 1 HTT fragments, we investigated the effect of increasing polyQ repeat length on HTT inclusion formation, location, neuronal survival, and mitochondrial function with a view to creating an in vitro screening platform for therapeutic screening. We found that expression of exon 1 HTT fragments with longer polyQ tracts led to the formation of intra-nuclear inclusions in a polyQ length-dependent manner during neurogenesis. There was no overt effect on neuronal viability, but defects of mitochondrial function were found in the pathogenic lines. Thus, we have a human neuronal cell model of HD that may recapitulate some of the earliest stages of HD pathogenesis, namely inclusion formation and mitochondrial dysfunction.
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http://dx.doi.org/10.1096/fj.201902277RRDOI Listing
June 2020

The Dementias Platform UK (DPUK) Data Portal.

Eur J Epidemiol 2020 Jun 23;35(6):601-611. Epub 2020 Apr 23.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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http://dx.doi.org/10.1007/s10654-020-00633-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320955PMC
June 2020

Antisense oligonucleotides for neurodegeneration.

Science 2020 Mar;367(6485):1428-1429

Huntington's Disease Centre, Department of Neurodegenerative Disease, and UK Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, University College London, London, UK.

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http://dx.doi.org/10.1126/science.aba4624DOI Listing
March 2020

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

Ann Neurol 2020 05 14;87(5):751-762. Epub 2020 Mar 14.

Center for Medical Image Computing, Department of Computer Science, University College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1002/ana.25709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187160PMC
May 2020