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Rodríguez-Agudelo Y, Chávez-Oliveros M, Ochoa-Morales A, Martínez-Ruano L, Camacho-Molina A, Paz-Rodríguez F. Psychological discomfort in carriers and non-carriers of the Huntington disease mutation and its relationship with disease burden. Neurologia 2025; 40:1-9. [PMID: 36058517 DOI: 10.1016/j.nrleng.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/29/2022] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Huntington's disease (HD) is a neurodegenerative and hereditary disorder. Due to the predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. Several studies have reported an increase in psychiatric symptoms in carriers of the HD gene without motor symptoms. OBJECTIVE To identify psychological distress in carriers of the mutation that causes HD, without motor symptoms, utilizing the Symptom Checklist 90 (SCL-90), and to correlate with the burden and proximity of the disease. METHOD A sample of 175 participants in a HD Predictive Diagnostic Program (PDP-HD) was divided into HEP carriers (39.4%) and NPEH non-carriers (61.6%) of the HD-causing mutation. By means of mathematical formulas, the disease burden and proximity to the manifest stage in the PEH group were obtained and it was correlated with the results of the SCL-90-R. RESULTS Comparing the results obtained in the SCL-90-R of the PEH and NPEH, the difference is observed in the positive somatic male index, where the PEH obtains higher average scores. The correlations between disease burden and psychological distress occur in the domains; obsessions and compulsions, interpersonal sensitivity, hostility, global severity index and positive somatic distress index. A low correlation is observed between the burden of disease and the scores obtained in psychological discomfort. CONCLUSIONS In general, we found that the PEH group obtained a higher score in the dimensions evaluated with the SCL-90-R, showing a relationship with the burden and differences due to the proximity of the disease. Higher scores on the SCL-90-R dimensions in carriers of the HD gene may suggest an early finding of psychological symptoms in the disease.
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Affiliation(s)
- Y Rodríguez-Agudelo
- Laboratorio de Neuropsicología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - M Chávez-Oliveros
- Laboratorio de Neuropsicología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - A Ochoa-Morales
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - L Martínez-Ruano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - A Camacho-Molina
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - F Paz-Rodríguez
- Laboratorio de Neuropsicología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México.
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Fitzgerald ES, Manousakis JE, Glikmann-Johnston Y, Rankin M, Anderson C, Stout JC, Jackson ML. Sleep fragmentation despite intact rest-activity patterns in premanifest Huntington's disease: An actigraphy study. Sleep Med 2024; 124:16-29. [PMID: 39250876 DOI: 10.1016/j.sleep.2024.08.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/23/2024] [Accepted: 08/23/2024] [Indexed: 09/11/2024]
Abstract
OBJECTIVE Sleep research in Huntington's disease (HD) has primarily focused on manifest HD, with significantly less attention given to premanifest HD (Pre-HD). Therefore, we investigated sleep and rest-activity patterns in people with Pre-HD versus healthy controls (HC). METHODS We conducted a cross-sectional study including 36 Pre-HD and 48 HC participants. Pre-HD participants were stratified into three groups according to their proximity to estimated diagnosis, using a cytosine-adenine-guanine (CAG) and current age-based predictive model: NEAR (<9 years to diagnosis), MID (9-15 years to diagnosis) and FAR (>15 years to diagnosis). Sleep and rest-activity patterns were assessed using wrist-worn actigraphy, a sleep diary, and sleep questionnaires. RESULTS NEAR and MID groups experienced higher fragmentation index than HC and FAR groups. NEAR and MID groups also exhibited greater WASO than the FAR group. NEAR and MID groups showed lower intra-daily variability (IV) than HC and FAR groups, with the NEAR group also being more active in the most active 10 h (M10). Groups did not differ on subjective sleep measures, inter-daily stability (IS), sleep regularity index, relative amplitude, or amount of activity in the least active 5 h (L5). Considering all Pre-HD participants, fewer years to diagnosis, higher CAG-age-product (CAP) scores (a measure of cumulative exposure to the HD-causing gene mutation) and larger CAG repeat lengths correlated with higher WASO, fragmentation index, L5, IS, and lower sleep efficiency and IV. Higher CAP score correlated with higher M10. CONCLUSIONS Despite intact rest-activity patterns and similar subjective sleep quality to HC, greater sleep fragmentation is a prominent and early feature in Pre-HD. Therefore, reducing sleep fragmentation may be a potential target for sleep intervention in HD. Longitudinal studies using larger samples are needed to assess sleep across the disease spectrum and its impact on clinical outcomes, like cognition.
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Affiliation(s)
- Emily S Fitzgerald
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Jessica E Manousakis
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Yifat Glikmann-Johnston
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Meg Rankin
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Clare Anderson
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia; Centre for Human Brain Health, School of Psychology, University of Birmingham, Edgbaston, UK
| | - Julie C Stout
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia.
| | - Melinda L Jackson
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
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3
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Hobbs NZ, Papoutsi M, Delva A, Kinnunen KM, Nakajima M, Van Laere K, Vandenberghe W, Herath P, Scahill RI. Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group. J Huntingtons Dis 2024; 13:163-199. [PMID: 38788082 PMCID: PMC11307036 DOI: 10.3233/jhd-240016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2024] [Indexed: 05/26/2024]
Abstract
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.
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Affiliation(s)
- Nicola Z. Hobbs
- HD Research Centre, UCL Institute of Neurology, UCL, London, UK
| | - Marina Papoutsi
- HD Research Centre, UCL Institute of Neurology, UCL, London, UK
- IXICO plc, London, UK
| | - Aline Delva
- Department of Neurosciences, KU Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Belgium
| | | | | | - Koen Van Laere
- Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, KU Leuven, Belgium
- Division of Nuclear Medicine, University Hospitals Leuven, Belgium
| | - Wim Vandenberghe
- Department of Neurosciences, KU Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Belgium
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Ashner MC, Garcia TP. Understanding the implications of a complete case analysis for regression models with a right-censored covariate. AM STAT 2023; 78:335-344. [PMID: 39070115 PMCID: PMC11281394 DOI: 10.1080/00031305.2023.2282629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 10/23/2023] [Accepted: 10/28/2023] [Indexed: 07/30/2024]
Abstract
Despite its drawbacks, the complete case analysis is commonly used in regression models with incomplete covariates. Understanding when the complete case analysis will lead to consistent parameter estimation is vital before use. Our aim here is to demonstrate when a complete case analysis is consistent for randomly right-censored covariates and to discuss the implications of its use even when consistent. Across the censored covariate literature, different assumptions are made to ensure a complete case analysis produces a consistent estimator, which leads to confusion in practice. We make several contributions to dispel this confusion. First, we summarize the language surrounding the assumptions that lead to a consistent complete case estimator. Then, we show a unidirectional hierarchical relationship between these assumptions, which leads us to one sufficient assumption to consider before using a complete case analysis. Lastly, we conduct a simulation study to illustrate the performance of a complete case analysis with a right-censored covariate under different censoring mechanism assumptions, and we demonstrate its use with a Huntington disease data example.
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Affiliation(s)
| | - Tanya P. Garcia
- Department of Biostatistics, University of North Carolina at Chapel Hill
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5
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Hu B, Younes L, Bu X, Liu CF, Ratnanather JT, Paulsen J, Georgiou-Karistianis N, Miller MI, Ross C, Faria AV. Mixed longitudinal and cross-sectional analyses of deep gray matter and white matter using diffusion weighted images in premanifest and manifest Huntington's disease. Neuroimage Clin 2023; 39:103493. [PMID: 37582307 PMCID: PMC10448214 DOI: 10.1016/j.nicl.2023.103493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/29/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
Changes in the brain of patients with Huntington's disease (HD) begin years before clinical onset, so it remains critical to identify biomarkers to track these early changes. Metrics derived from tensor modeling of diffusion-weighted MRIs (DTI), that indicate the microscopic brain structure, can add important information to regional volumetric measurements. This study uses two large-scale longitudinal, multicenter datasets, PREDICT-HD and IMAGE-HD, to trace changes in DTI of HD participants with a broad range of CAP scores (a product of CAG repeat expansion and age), including those with pre-manifest disease (i.e., prior to clinical onset). Utilizing a fully automated data-driven approach to study the whole brain divided in regions of interest, we traced changes in DTI metrics (diffusivity and fractional anisotropy) versus CAP scores, using sigmoidal and linear regression models. We identified points of inflection in the sigmoidal regression using change-point analysis. The deep gray matter showed more evident and earlier changes in DTI metrics over CAP scores, compared to the deep white matter. In the deep white matter, these changes were more evident and occurred earlier in superior and posterior areas, compared to anterior and inferior areas. The curves of mean diffusivity vs. age of HD participants within a fixed CAP score were different from those of controls, indicating that the disease has an additional effect to age on the microscopic brain structure. These results show the regional and temporal vulnerability of the white matter and deep gray matter in HD, with potential implications for experimental therapeutics.
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Affiliation(s)
- Beini Hu
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Laurent Younes
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA
| | - Xuan Bu
- Department of Radiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Chin-Fu Liu
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - J Tilak Ratnanather
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jane Paulsen
- Department of Psychiatry, Neurology, Psychological Brain Sciences, University of Iowa, USA; Department Neurology, University of Wisconsin-Madison, USA
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and Turner Institute of Brain and Mental Health, Monash University, Australia
| | - Michael I Miller
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Christopher Ross
- Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Andreia V Faria
- Department of Radiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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6
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Eisenmenger LB, Peret A, Famakin BM, Spahic A, Roberts GS, Bockholt JH, Johnson KM, Paulsen JS. Vascular contributions to Alzheimer's disease. Transl Res 2023; 254:41-53. [PMID: 36529160 PMCID: PMC10481451 DOI: 10.1016/j.trsl.2022.12.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia and is characterized by progressive neurodegeneration and cognitive decline. Understanding the pathophysiology underlying AD is paramount for the management of individuals at risk of and suffering from AD. The vascular hypothesis stipulates a relationship between cardiovascular disease and AD-related changes although the nature of this relationship remains unknown. In this review, we discuss several potential pathological pathways of vascular involvement in AD that have been described including dysregulation of neurovascular coupling, disruption of the blood brain barrier, and reduced clearance of metabolite waste such as beta-amyloid, a toxic peptide considered the hallmark of AD. We will also discuss the two-hit hypothesis which proposes a 2-step positive feedback loop in which microvascular insults precede the accumulation of Aß and are thought to be at the origin of the disease development. At neuroimaging, signs of vascular dysfunction such as chronic cerebral hypoperfusion have been demonstrated, appearing early in AD, even before cognitive decline and alteration of traditional biomarkers. Cerebral small vessel disease such as cerebral amyloid angiopathy, characterized by the aggregation of Aß in the vessel wall, is highly prevalent in vascular dementia and AD patients. Current data is unclear whether cardiovascular disease causes, precipitates, amplifies, precedes, or simply coincides with AD. Targeted imaging tools to quantitatively evaluate the intracranial vasculature and longitudinal studies in individuals at risk for or in the early stages of the AD continuum could be critical in disentangling this complex relationship between vascular disease and AD.
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Affiliation(s)
- Laura B Eisenmenger
- Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Anthony Peret
- Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Bolanle M Famakin
- Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Alma Spahic
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Grant S Roberts
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Jeremy H Bockholt
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, Georgia
| | - Kevin M Johnson
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Jane S Paulsen
- Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin.
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7
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Fitzgerald ES, Stout JC, Glikmann-Johnston Y, Anderson C, Jackson ML. Sleep, Circadian Rhythms, and Cognitive Dysfunction in Huntington's Disease. J Huntingtons Dis 2023; 12:293-304. [PMID: 37599535 DOI: 10.3233/jhd-230578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
BACKGROUND In healthy people, sleep and circadian disruption are linked to cognitive deficits. People with Huntington's disease (HD), who have compromised brain function and sleep and circadian disturbances, may be even more susceptible to these cognitive effects. OBJECTIVE To conduct a comprehensive review and synthesis of the literature in HD on the associations of cognitive dysfunction with disturbed sleep and circadian rhythms. METHODS We searched MEDLINE via OVID, CINAHL Plus, EMBASE via OVID, and PubMed in May 2023. The first author then screened by title and abstract and conducted a full review of remaining articles. RESULTS Eight studies investigating the influence of sleep and/or circadian rhythms on cognitive function in HD were found. In manifest HD, poorer sleep was associated with worse cognitive function. For behavioral 24-hour (circadian) rhythms, two studies indicated that later wake times correlated with poorer cognitive function. No reported studies in HD examined altered physiological 24-hour (circadian) rhythms and cognitive impairment. CONCLUSION Some associations exist between poor sleep and cognitive dysfunction in manifest HD, yet whether these associations are present before clinical diagnosis is unknown. Whether circadian disturbances relate to cognitive impairment in HD also remains undetermined. To inform sleep and circadian interventions aimed at improving cognitive symptoms in HD, future research should include a range of disease stages, control for external factors, and utilize robust cognitive batteries targeted to the aspects of cognitive function known to be adversely affected in HD.
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Affiliation(s)
- Emily S Fitzgerald
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Julie C Stout
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Yifat Glikmann-Johnston
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Clare Anderson
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
| | - Melinda L Jackson
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
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8
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Caligiuri M, Culbert B, Prasad N, Snell C, Hall A, Smirnova A, Churchill E, Corey-Bloom J. Graphomotor Dysfluency as a Predictor of Disease Progression in Premanifest Huntington's Disease. J Huntingtons Dis 2023; 12:283-292. [PMID: 37182891 DOI: 10.3233/jhd-230562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
BACKGROUND Prior studies have relied on conventional observer-based severity ratings such as the Unified Huntington's Disease Rating Scale (UHDRS) to identify early motor markers of decline in Huntington's disease (HD). OBJECTIVE The present study examined the predictive utility of graphomotor measures handwriting and drawing movements. METHODS Seventeen gene-positive premanifest HD subjects underwent comprehensive clinical, cognitive, motor, and graphomotor assessments at baseline and at follow-up intervals ranging from 9-36 months. Baseline graphomotor assessments were subjected to linear multiple regression procedures to identify factors associated with change on the comprehensive UHDRS index. RESULTS Subjects were followed for an average of 21.2 months. Three multivariate regression models based on graphomotor variables derived from a complex loop task, a maximum speed circle drawing task and a combined task returned adjusted R2 coefficients of 0.76, 0.71, and 0.80 respectively accounting for a significant portion of the variability in cUHDRS change score. The best-fit model based on the combined tasks indicated that greater decline on the cUHDRS was associated with increased pen movement dysfluency and stroke-stroke variability at baseline. CONCLUSION Performance on multiple measures of graphomotor dysfluency assessed during the premanifest or prodromal stage in at-risk HD individuals was associated with decline on a multidimensional index of HD morbidity preceding an HD diagnosis.
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Affiliation(s)
| | - Braden Culbert
- Department of Neurosciences, UC San Diego, La Jolla, CA, USA
| | - Nikita Prasad
- Department of Neurosciences, UC San Diego, La Jolla, CA, USA
| | - Chase Snell
- Department of Neurosciences, UC San Diego, La Jolla, CA, USA
| | - Andrew Hall
- Department of Neurosciences, UC San Diego, La Jolla, CA, USA
| | - Anna Smirnova
- Department of Neurosciences, UC San Diego, La Jolla, CA, USA
| | - Emma Churchill
- Department of Neurosciences, UC San Diego, La Jolla, CA, USA
- Department of Psychology, San Diego State University, San Diego, CA, USA
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9
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Castro E, Polosecki P, Pustina D, Wood A, Sampaio C, Cecchi GA. Predictive Modeling of Huntington's Disease Unfolds Thalamic and Caudate Atrophy Dissociation. Mov Disord 2022; 37:2407-2416. [PMID: 36173150 DOI: 10.1002/mds.29219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/16/2022] [Accepted: 07/28/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Atrophy in the striatum is a hallmark of Huntington's disease (HD), including the period before clinical motor diagnosis (before-CMD), but it extends to other subcortical structures. The study of the covariation of these structures could improve the detection of disease-related longitudinal progression before-CMD, provide mechanistic insights of the disease, and potentially be used to obtain accurate prospective estimates of atrophy before-CMD and early after-CMD. METHODS We analyzed data from 337 before-CMD individuals, 236 healthy control subjects, and 95 early after-CMD individuals from three studies, and we used nine subcortical regions volumes in two analyses. First, we discriminated before-CMD from healthy control trajectories by integrating volume changes from these regions. Second, we estimated prospective atrophy before-CMD and early after-CMD by considering the influence of a region's present volume over the future volume of another one. RESULTS Before-CMD progression was robustly detected across studies. Indeed, detection of before-CMD progression improved when multiple structures were integrated, as opposed to analyzing the striatum alone, likely because of the reduced partial correlation between caudate and thalamic volume change before-CMD. Our multivariate atrophy prediction model found a thalamus-caudate association that is consistent with this pattern, which yields an improved caudate atrophy prediction in early after-CMD. CONCLUSIONS This study is the first attempt to validate before-CMD multivariate subcortical change detection across studies and to do multivariate prospective atrophy prediction in HD. These models achieve improved performance by detecting a dissociation between caudate and thalamic atrophy trajectories, and they provide a possible mechanistic understanding of the dynamics of HD. © 2022 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Eduardo Castro
- Digital Health, IBM T.J. Watson Research Center, Yorktown Heights, New York, USA
| | - Pablo Polosecki
- Digital Health, IBM T.J. Watson Research Center, Yorktown Heights, New York, USA
| | - Dorian Pustina
- CHDI Management/CHDI Foundation, Princeton, New Jersey, USA
| | - Andrew Wood
- CHDI Management/CHDI Foundation, Princeton, New Jersey, USA
| | | | - Guillermo A Cecchi
- Digital Health, IBM T.J. Watson Research Center, Yorktown Heights, New York, USA
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Taheri M, Ebrahimzadeh K, Noroozi R. The emerging role of long non-coding RNAs, microRNAs, and an accelerated epigenetic age in Huntington’s disease. Front Aging Neurosci 2022; 14:987174. [PMID: 36185471 PMCID: PMC9520620 DOI: 10.3389/fnagi.2022.987174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease with variable clinical manifestations. Recent studies highlighted the contribution of epigenetic alterations to HD progress and onset. The potential crosstalk between different epigenetic layers and players such as aberrant expression of non-coding RNAs and methylation alterations has been found to affect the pathogenesis of HD or mediate the effects of trinucleotide expansion in its pathophysiology. Also, microRNAs have been assessed for their roles in the modulation of HD manifestations, among them are miR-124, miR-128a, hsa-miR-323b-3p, miR-432, miR-146a, miR-19a, miR-27a, miR-101, miR-9*, miR-22, miR-132, and miR-214. Moreover, long non-coding RNAs such as DNM3OS, NEAT1, Meg3, and Abhd11os are suggested to be involved in the pathogenesis of HD. An accelerated DNA methylation age is another epigenetic signature reported recently for HD. The current literature search collected recent findings of dysregulation of miRNAs or lncRNAs as well as methylation changes and epigenetic age in HD.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Ebrahimzadeh
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Kaveh Ebrahimzadeh,
| | - Rezvan Noroozi
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
- Rezvan Noroozi,
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11
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Lobanov SV, McAllister B, McDade-Kumar M, Landwehrmeyer GB, Orth M, Rosser AE, Paulsen JS, Lee JM, MacDonald ME, Gusella JF, Long JD, Ryten M, Williams NM, Holmans P, Massey TH, Jones L. Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1. NPJ Genom Med 2022; 7:53. [PMID: 36064847 PMCID: PMC9445028 DOI: 10.1038/s41525-022-00317-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 07/15/2022] [Indexed: 01/29/2023] Open
Abstract
Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington's disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington's disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1 × 10-9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.
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Affiliation(s)
- Sergey V Lobanov
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Branduff McAllister
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Mia McDade-Kumar
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | | | - Michael Orth
- Department of Old Age Psychiatry and Psychotherapy, Bern University, Bern, Switzerland
- Swiss Huntington's Disease Centre, Siloah, Gümligen, Switzerland
| | - Anne E Rosser
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
- School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK
| | - Jane S Paulsen
- Department of Neurology, University of Wisconsin, Madison, WI53705, USA
| | - Jong-Min Lee
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Marcy E MacDonald
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - James F Gusella
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Jeffrey D Long
- Departments of Psychiatry and Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Mina Ryten
- Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University, College London, London, UK
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
| | - Nigel M Williams
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Peter Holmans
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Thomas H Massey
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
| | - Lesley Jones
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
- UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK
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12
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Malestar psicológico en portadores y no portadores de la mutación causante de enfermedad de Huntington y su relación con la carga de la enfermedad. Neurologia 2022. [DOI: 10.1016/j.nrl.2022.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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13
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Tabrizi SJ, Schobel S, Gantman EC, Mansbach A, Borowsky B, Konstantinova P, Mestre TA, Panagoulias J, Ross CA, Zauderer M, Mullin AP, Romero K, Sivakumaran S, Turner EC, Long JD, Sampaio C. A biological classification of Huntington's disease: the Integrated Staging System. Lancet Neurol 2022; 21:632-644. [PMID: 35716693 DOI: 10.1016/s1474-4422(22)00120-x] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 02/11/2022] [Accepted: 03/11/2022] [Indexed: 12/24/2022]
Abstract
The current research paradigm for Huntington's disease is based on participants with overt clinical phenotypes and does not address its pathophysiology nor the biomarker changes that can precede by decades the functional decline. We have generated a new research framework to standardise clinical research and enable interventional studies earlier in the disease course. The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments. We used a formal consensus method that involved representatives from academia, industry, and non-profit organisations. The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be precisely classified into stages based on thresholds of stage-specific landmark assessments. We also demonstrated the internal validity of this system. The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.
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Affiliation(s)
- Sarah J Tabrizi
- UCL Huntington's Disease Centre, Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, UK Dementia Research Institute, University College London, UK.
| | - Scott Schobel
- Product Development Neuroscience, F Hoffmann-La Roche, Basel, Switzerland
| | | | | | | | | | - Tiago A Mestre
- Parkinson's Disease and Movement Disorders Centre, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
| | | | - Christopher A Ross
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Neurology, Neuroscience, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | | | - Klaus Romero
- Critical Path Institute, Tucson, Arizona 85718, USA
| | | | | | - Jeffrey D Long
- Department of Psychiatry, Department of Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Cristina Sampaio
- CHDI Management/CHDI Foundation, Princeton, NJ, USA; Clinical Pharmacology Laboratory, Faculdade de Medicina de Lisboa, University of Lisbon, Lisbon, Portugal.
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14
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Warner JH, Long JD, Mills JA, Langbehn DR, Ware J, Mohan A, Sampaio C. Standardizing the CAP Score in Huntington's Disease by Predicting Age-at-Onset. J Huntingtons Dis 2022; 11:153-171. [PMID: 35466943 DOI: 10.3233/jhd-210475] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Huntington's disease (HD) is an autosomal dominant, neurological disease caused by an expanded CAG repeat near the N-terminus of the huntingtin (HTT) gene. A leading theory concerning the etiology of HD is that both onset and progression are driven by cumulative exposure to the effects of mutant (or CAG expanded) huntingtin (mHTT). The CAG-Age-Product (CAP) score (i.e., the product of excess CAG length and age) is a commonly used measure of this cumulative exposure. CAP score has been widely used as a predictor of a variety of disease state variables in HD. The utility of the CAP score has been somewhat diminished, however, by a lack of agreement on its precise definition. The most commonly used forms of the CAP score are highly correlated so that, for purposes of prediction, it makes little difference which is used. However, reported values of CAP scores, based on commonly used definitions, differ substantially in magnitude when applied to the same data. This complicates the process of inter-study comparison. OBJECTIVE In this paper, we propose a standardized definition for the CAP score which will resolve this difficulty. Our standardization is chosen so that CAP = 100 at the expected age of diagnosis. METHODS Statistical methods include novel survival analysis methodology applied to the 13 disease landmarks taken from the Enroll-HD database (PDS 5) and comparisons with the existing, gold standard, onset model. RESULTS Useful by-products of our work include up-to-date, age-at-onset (AO) results and a refined AO model suitable for use in other contexts, a discussion of several useful properties of the CAP score that have not previously been noted in the literature and the introduction of the concept of a toxicity onset model. CONCLUSION We suggest that taking L = 30 and K = 6.49 provides a useful standardization of the CAP score, suitable for use in the routine modeling of clinical data in HD.
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Affiliation(s)
| | - Jeffrey D Long
- Departments of Psychiatry, Biostatistics, University of Iowa, Iowa City, IA, USA
| | - James A Mills
- Departments of Psychiatry, Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Douglas R Langbehn
- Departments of Psychiatry, Biostatistics, University of Iowa, Iowa City, IA, USA
| | | | - Amrita Mohan
- CHDI Management/CHDI Foundation, Princeton, NJ, USA
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15
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Lee JM, Huang Y, Orth M, Gillis T, Siciliano J, Hong E, Mysore JS, Lucente D, Wheeler VC, Seong IS, McLean ZL, Mills JA, McAllister B, Lobanov SV, Massey TH, Ciosi M, Landwehrmeyer GB, Paulsen JS, Dorsey ER, Shoulson I, Sampaio C, Monckton DG, Kwak S, Holmans P, Jones L, MacDonald ME, Long JD, Gusella JF. Genetic modifiers of Huntington disease differentially influence motor and cognitive domains. Am J Hum Genet 2022; 109:885-899. [PMID: 35325614 DOI: 10.1016/j.ajhg.2022.03.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/01/2022] [Indexed: 12/12/2022] Open
Abstract
Genome-wide association studies (GWASs) of Huntington disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction by using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWASs. Combined with imputation with the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified additional modifier effects at the PMS1 and PMS2 loci and implicated a potential second locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.
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16
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Zhang S, Shen L, Jiao B. Cognitive Dysfunction in Repeat Expansion Diseases: A Review. Front Aging Neurosci 2022; 14:841711. [PMID: 35478698 PMCID: PMC9036481 DOI: 10.3389/fnagi.2022.841711] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/24/2022] [Indexed: 11/16/2022] Open
Abstract
With the development of the sequencing technique, more than 40 repeat expansion diseases (REDs) have been identified during the past two decades. Moreover, the clinical features of these diseases show some commonality, and the nervous system, especially the cognitive function was affected in part by these diseases. However, the specific cognitive domains impaired in different diseases were inconsistent. Here, we survey literature on the cognitive consequences of the following disorders presenting cognitive dysfunction and summarizing the pathogenic genes, epidemiology, and different domains affected by these diseases. We found that the cognitive domains affected in neuronal intranuclear inclusion disease (NIID) were widespread including the executive function, memory, information processing speed, attention, visuospatial function, and language. Patients with C9ORF72-frontotemporal dementia (FTD) showed impairment in executive function, memory, language, and visuospatial function. While in Huntington's disease (HD), the executive function, memory, and information processing speed were affected, in the fragile X-associated tremor/ataxia syndrome (FXTAS), executive function, memory, information processing speed, and attention were impaired. Moreover, the spinocerebellar ataxias showed broad damage in almost all the cognitive domains except for the relatively intact language ability. Some other diseases with relatively rare clinical data also indicated cognitive dysfunction, such as myotonic dystrophy type 1 (DM1), progressive myoclonus epilepsy (PME), Friedreich ataxia (FRDA), Huntington disease like-2 (HDL2), and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We drew a cognitive function landscape of the related REDs that might provide an aspect for differential diagnosis through cognitive domains and effective non-specific interventions for these diseases.
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Affiliation(s)
- Sizhe Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Lu Shen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China
- Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Bin Jiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China
- Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
- *Correspondence: Bin Jiao
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17
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Rosser AE, Jones L. Huntington's Disease Gene Hunters: An Expanding Tale. Mov Disord Clin Pract 2022; 9:330-333. [PMID: 35392298 PMCID: PMC8974877 DOI: 10.1002/mdc3.13375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/25/2021] [Accepted: 11/09/2021] [Indexed: 11/08/2022] Open
Affiliation(s)
- Anne E. Rosser
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences Cardiff University School of Medicine Cardiff United Kingdom
- Cardiff Brain Repair Group Cardiff University School Biosciences Cardiff United Kingdom
- Wales Brain Research And Intracranial Neurotherapeutics (BRAIN) Unit Cardiff United Kingdom
| | - Lesley Jones
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences Cardiff University School of Medicine Cardiff United Kingdom
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18
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Benatar M, Wuu J, McHutchison C, Postuma RB, Boeve BF, Petersen R, Ross CA, Rosen H, Arias JJ, Fradette S, McDermott MP, Shefner J, Stanislaw C, Abrahams S, Cosentino S, Andersen PM, Finkel RS, Granit V, Grignon AL, Rohrer JD, McMillan CT, Grossman M, Al-Chalabi A, Turner MR. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain 2022; 145:27-44. [PMID: 34677606 PMCID: PMC8967095 DOI: 10.1093/brain/awab404] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/16/2021] [Accepted: 10/08/2021] [Indexed: 11/12/2022] Open
Abstract
Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.
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Affiliation(s)
- Michael Benatar
- Department of Neurology, University of Miami, Miami, FL, USA
| | - Joanne Wuu
- Department of Neurology, University of Miami, Miami, FL, USA
| | - Caroline McHutchison
- Human Cognitive Neuroscience, Department of Psychology, University of Edinburgh, Edinburgh, UK
- Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK
| | - Ronald B Postuma
- Department of Neurology, Montreal Neurological Institute, McGill University, Montreal, Canada
| | | | | | - Christopher A Ross
- Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Howard Rosen
- Department of Neurology, University of California San Francisco, CA, USA
| | - Jalayne J Arias
- Department of Neurology, University of California San Francisco, CA, USA
| | | | - Michael P McDermott
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Jeremy Shefner
- Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA
| | | | - Sharon Abrahams
- Human Cognitive Neuroscience, Department of Psychology, University of Edinburgh, Edinburgh, UK
- Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK
| | | | - Peter M Andersen
- Department of Clinical Science, Neurosciences, Umeå University, Sweden
| | - Richard S Finkel
- Department of Pediatric Medicine, Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Volkan Granit
- Department of Neurology, University of Miami, Miami, FL, USA
| | | | - Jonathan D Rohrer
- Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK
| | - Corey T McMillan
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Murray Grossman
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ammar Al-Chalabi
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
- Department of Neurology, King's College Hospital, London, UK
| | - Martin R Turner
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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19
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Xie S, McDonnell E, Wang Y. Conditional Gaussian graphical model for estimating personalized disease symptom networks. Stat Med 2022; 41:543-553. [PMID: 34866214 PMCID: PMC8792223 DOI: 10.1002/sim.9274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 10/13/2021] [Accepted: 11/15/2021] [Indexed: 11/10/2022]
Abstract
The co-occurrence of symptoms may result from the direct interactions between these symptoms and the symptoms can be treated as a system. In addition, subject-specific risk factors (eg, genetic variants, age) can also exert external influence on the system. In this work, we develop a covariate-dependent conditional Gaussian graphical model to obtain personalized symptom networks. The strengths of network connections are modeled as a function of covariates to capture the heterogeneity among individuals and subgroups of individuals. We assess the performance of our proposed method by simulation studies and an application to a large natural history study of Huntington's disease to investigate the networks of symptoms in multiple clinical domains (motor, cognitive, psychiatric) and identify important brain imaging biomarkers that are associated with the connections. We show that the symptoms in the same clinical domain interact more often with each other than cross domains and the psychiatric subnetwork is the densest network. We validate the findings using the subjects' symptom measurements at follow-up visits.
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Affiliation(s)
- Shanghong Xie
- School of Statistics and Center of Statistical Research, Southwestern University of Finance and Economics, Chengdu, China
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, U.S.A
| | - Erin McDonnell
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, U.S.A
| | - Yuanjia Wang
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, U.S.A
- Department of Psychiatry, Columbia University Medical Center, New York, NY, U.S.A
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20
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Kinnunen KM, Schwarz AJ, Turner EC, Pustina D, Gantman EC, Gordon MF, Joules R, Mullin AP, Scahill RI, Georgiou-Karistianis N. Volumetric MRI-Based Biomarkers in Huntington's Disease: An Evidentiary Review. Front Neurol 2021; 12:712555. [PMID: 34621236 PMCID: PMC8490802 DOI: 10.3389/fneur.2021.712555] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 08/10/2021] [Indexed: 01/02/2023] Open
Abstract
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.
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Affiliation(s)
| | - Adam J Schwarz
- Takeda Pharmaceuticals, Ltd., Cambridge, MA, United States
| | | | - Dorian Pustina
- CHDI Management/CHDI Foundation, Princeton, NJ, United States
| | - Emily C Gantman
- CHDI Management/CHDI Foundation, Princeton, NJ, United States
| | - Mark F Gordon
- Teva Pharmaceuticals, West Chester, PA, United States
| | | | - Ariana P Mullin
- Critical Path Institute, Tucson, AZ, United States.,Wave Life Sciences, Ltd., Cambridge, MA, United States
| | - Rachael I Scahill
- Huntington's Disease Research Centre, UCL Institute of Neurology, London, United Kingdom
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
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21
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Pradhan N, Singh C, Singh A. Coenzyme Q10 a mitochondrial restorer for various brain disorders. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:2197-2222. [PMID: 34596729 DOI: 10.1007/s00210-021-02161-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022]
Abstract
Coenzyme Q10 (ubiquinone or CoQ10) is a lipid molecule that acts as an electron mobile carrier of the electron transport chain and also contains antioxidant properties. Supplementation of CoQ10 has been very useful to treat mitochondrial diseases. CoQ10 along with its synthetic analogue, idebenone, is used largely to treat various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Friedreich's ataxia and additional brain disease condition like autism, multiple sclerosis, epilepsy, depression, and bipolar disorder, which are related to mitochondrial impairment. In this article, we have reviewed numerous physiological functions of CoQ10 and the rationale for its use in clinical practice in different brain disorders.
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Affiliation(s)
- Nilima Pradhan
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, 144603, Punjab, India
| | - Charan Singh
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, 144603, Punjab, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, 144603, Punjab, India.
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22
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Gusella JF, Lee JM, MacDonald ME. Huntington's disease: nearly four decades of human molecular genetics. Hum Mol Genet 2021; 30:R254-R263. [PMID: 34169318 PMCID: PMC8490011 DOI: 10.1093/hmg/ddab170] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 11/13/2022] Open
Abstract
Huntington's disease (HD) is a devastating neurogenetic disorder whose familial nature and progressive course were first described in the 19th century but for which no disease-modifying treatment is yet available. Through the active participation of HD families, this disorder has acted as a flagship for the application of human molecular genetic strategies to identify disease genes, understand pathogenesis and identify rational targets for development of therapies.
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Affiliation(s)
- James F Gusella
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Medical and Population Genetics Program, The Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Jong-Min Lee
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Medical and Population Genetics Program, The Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA
- Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
| | - Marcy E MacDonald
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Medical and Population Genetics Program, The Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA
- Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
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23
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Perceptions about Research Participation among Individuals at Risk and Individuals with Premanifest Huntington's Disease: A Survey Conducted by the European Huntington Association. J Pers Med 2021; 11:jpm11080815. [PMID: 34442459 PMCID: PMC8400079 DOI: 10.3390/jpm11080815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/23/2022] Open
Abstract
There has been great progress in Huntington's disease (HD) research. Yet, effective treatments to halt disease before the onset of disabling symptoms are still unavailable. Scientific breakthroughs require an active and lasting commitment from families. However, they are traditionally less involved and heard in studies. Accordingly, the European Huntington Association (EHA) surveyed individuals at risk (HDRisk) and with premanifest HD (PreHD) to determine which factors affect their willingness to participate in research. Questions assessed research experience and knowledge, information sources, reasons for involvement and noninvolvement, and factors preventing and facilitating participation. The survey included 525 individuals, of which 68.8% never participated in studies and 38.6% reported limited research knowledge. Furthermore, 52% trusted patient organizations to get research information. Reasons for involvement were altruistic and more important than reasons for noninvolvement, which were related to negative emotions. Obstacles included time/financial constraints and invasive procedures, while professional support was seen as a facilitator. PreHD individuals reported less obstacles to research participation than HDRisk individuals. Overall, a high motivation to participate in research was noted, despite limited experience and literacy. This motivation is influenced by subjective and objective factors and, importantly, by HD status. Patient organizations have a key role in fostering motivation through education and support.
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Grosso Jasutkar H, Yamamoto A. Do Changes in Synaptic Autophagy Underlie the Cognitive Impairments in Huntington's Disease? J Huntingtons Dis 2021; 10:227-238. [PMID: 33780373 PMCID: PMC8293641 DOI: 10.3233/jhd-200466] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Although Huntington's disease (HD) is classically considered from the perspective of the motor syndrome, the cognitive changes in HD are prominent and often an early manifestation of disease. As such, investigating the underlying pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. In this review, we first discuss evidence from both HD patients and animal models that cognitive changes correlate with early pathological changes at the synapse, an observation that is similarly made in other neurodegenerative conditions that primarily affect cognition. We then describe how autophagy plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease.
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Affiliation(s)
| | - Ai Yamamoto
- Department of Neurology, Columbia University, New York, NY, USA.,Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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25
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Abeyasinghe PM, Long JD, Razi A, Pustina D, Paulsen JS, Tabrizi SJ, Poudel GR, Georgiou-Karistianis N. Tracking Huntington's Disease Progression Using Motor, Functional, Cognitive, and Imaging Markers. Mov Disord 2021; 36:2282-2292. [PMID: 34014005 DOI: 10.1002/mds.28650] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 04/25/2021] [Accepted: 04/27/2021] [Indexed: 12/21/2022] Open
Abstract
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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Affiliation(s)
- Pubu M Abeyasinghe
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia
| | - Jeffrey D Long
- Department of Psychiatry, Carver Collage of Medicine, The University of Iowa, Iowa City, Iowa, USA.,Department of Biostatistics, College of Public Health, The University of Iowa, Iowa City, Iowa, USA
| | - Adeel Razi
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia.,Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia.,Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom
| | - Dorian Pustina
- CHDI Management/CHDI Foundation, Princeton, New Jersey, USA
| | - Jane S Paulsen
- Department of Neurology, University of Wisconsin, Madison, Wisconsin, USA
| | - Sarah J Tabrizi
- UCL Department of Neurodegenerative Disease and Huntington's Disease Centre, UCL Queen Square Institute of Neurology, Dementia Research Institute at UCL, London, United Kingdom
| | - Govinda R Poudel
- Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia
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26
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Abstract
The biomarker networks measured by different modalities of data (e.g., structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI)) may share the same true underlying biological model. In this work, we propose a node-wise biomarker graphical model to leverage the shared mechanism between multi-modality data to provide a more reliable estimation of the target modality network and account for the heterogeneity in networks due to differences between subjects and networks of external modality. Latent variables are introduced to represent the shared unobserved biological network and the information from the external modality is incorporated to model the distribution of the underlying biological network. We propose an efficient approximation to the posterior expectation of the latent variables that reduces computational cost by at least 50%. The performance of the proposed method is demonstrated by extensive simulation studies and an application to construct gray matter brain atrophy network of Huntington's disease by using sMRI data and DTI data. The identified network connections are more consistent with clinical literature and better improve prediction in follow-up clinical outcomes and separate subjects into clinically meaningful subgroups with different prognosis than alternative methods.
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Affiliation(s)
- Shanghong Xie
- Department of Biostatistics, Mailman School of Public Health, Columbia University
| | - Donglin Zeng
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
| | - Yuanjia Wang
- Department of Biostatistics, Mailman School of Public Health, Columbia University
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27
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Hong EP, MacDonald ME, Wheeler VC, Jones L, Holmans P, Orth M, Monckton DG, Long JD, Kwak S, Gusella JF, Lee JM. Huntington's Disease Pathogenesis: Two Sequential Components. J Huntingtons Dis 2021; 10:35-51. [PMID: 33579862 PMCID: PMC7990433 DOI: 10.3233/jhd-200427] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Historically, Huntington's disease (HD; OMIM #143100) has played an important role in the enormous advances in human genetics seen over the past four decades. This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was the first autosomal disease for which the genetic defect was assigned to a position on the human chromosomes using only genetic linkage analysis with common DNA polymorphisms. This discovery set off a multitude of similar studies in other diseases, while the HD gene, later renamed HTT, and its vicinity in chromosome 4p16.3 then acted as a proving ground for development of technologies to clone and sequence genes based upon their genomic location, with the growing momentum of such advances fueling the Human Genome Project. The identification of the HD gene has not yet led to an effective treatment, but continued human genetic analysis of genotype-phenotype relationships in large HD subject populations, first at the HTT locus and subsequently genome-wide, has provided insights into pathogenesis that divide the course of the disease into two sequential, mechanistically distinct components.
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Affiliation(s)
- Eun Pyo Hong
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Neurology, Harvard Medical School, Boston, MA, USA.,Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA
| | - Marcy E MacDonald
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Neurology, Harvard Medical School, Boston, MA, USA.,Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA
| | - Vanessa C Wheeler
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Neurology, Harvard Medical School, Boston, MA, USA
| | - Lesley Jones
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Peter Holmans
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michael Orth
- Department of Neurology, University of Ulm, Germany
| | - Darren G Monckton
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Jeffrey D Long
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA
| | - Seung Kwak
- CHDI Management/CHDI Foundation, Princeton, NJ, USA
| | - James F Gusella
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.,Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA.,Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Jong-Min Lee
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Neurology, Harvard Medical School, Boston, MA, USA.,Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA
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28
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Donaldson J, Powell S, Rickards N, Holmans P, Jones L. What is the Pathogenic CAG Expansion Length in Huntington's Disease? J Huntingtons Dis 2021; 10:175-202. [PMID: 33579866 PMCID: PMC7990448 DOI: 10.3233/jhd-200445] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Huntington's disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds- the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70- 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60- 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments.
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Affiliation(s)
- Jasmine Donaldson
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - Sophie Powell
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - Nadia Rickards
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - Peter Holmans
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - Lesley Jones
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
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29
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Tan B, Shishegar R, Poudel GR, Fornito A, Georgiou-Karistianis N. Cortical morphometry and neural dysfunction in Huntington's disease: a review. Eur J Neurol 2020; 28:1406-1419. [PMID: 33210786 DOI: 10.1111/ene.14648] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/22/2020] [Accepted: 11/12/2020] [Indexed: 01/09/2023]
Abstract
Numerous neuroimaging techniques have been used to identify biomarkers of disease progression in Huntington's disease (HD). To date, the earliest and most sensitive of these is caudate volume; however, it is becoming increasingly evident that numerous changes to cortical structures, and their interconnected networks, occur throughout the course of the disease. The mechanisms by which atrophy spreads from the caudate to these cortical regions remains unknown. In this review, the neuroimaging literature specific to T1-weighted and diffusion-weighted magnetic resonance imaging is summarized and new strategies for the investigation of cortical morphometry and the network spread of degeneration in HD are proposed. This new avenue of research may enable further characterization of disease pathology and could add to a suite of biomarker/s of disease progression for patient stratification that will help guide future clinical trials.
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Affiliation(s)
- Brendan Tan
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
| | - Rosita Shishegar
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia.,Australian e-Health Research Centre, CSIRO, Melbourne, VIC, Australia.,Monash Biomedical Imaging, Melbourne, VIC, Australia
| | - Govinda R Poudel
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia.,Sydney Imaging, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.,Australian Catholic University, Melbourne, VIC, Australia
| | - Alex Fornito
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia.,Monash Biomedical Imaging, Melbourne, VIC, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
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30
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Lee CYD, Wang N, Shen K, Stricos M, Langfelder P, Cheon KH, Cortés EP, Vinters HV, Vonsattel JP, Wexler NS, Damoiseaux R, Frydman J, Yang XW. Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients. Sci Rep 2020; 10:20295. [PMID: 33219289 PMCID: PMC7679413 DOI: 10.1038/s41598-020-77164-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/28/2020] [Indexed: 11/09/2022] Open
Abstract
In Huntington's disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.
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Affiliation(s)
- C Y Daniel Lee
- Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Nan Wang
- Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Koning Shen
- Department of Biology and BioX Program, Stanford University, Stanford, CA, USA
- Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA
| | - Matthew Stricos
- Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Peter Langfelder
- Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kristina H Cheon
- Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Etty P Cortés
- Division of Aging and Dementia, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Harry V Vinters
- Department of Pathology and Laboratory Medicine, Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jean Paul Vonsattel
- Division of Aging and Dementia, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Nancy S Wexler
- Departments of Neurology and Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Hereditary Disease Foundation, New York, NY, USA
| | - Robert Damoiseaux
- California NanoSystems Institute, University of California, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Judith Frydman
- Department of Biology and BioX Program, Stanford University, Stanford, CA, USA
| | - X William Yang
- Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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31
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Mitchell CT, Krier I, Arjomand J, Borowsky B, Tabrizi SJ, Leavitt BR, Luthi-Carter R. Longitudinal expression changes are weak correlates of disease progression in Huntington's disease. Brain Commun 2020; 2:fcaa172. [PMID: 33305259 PMCID: PMC7713990 DOI: 10.1093/braincomms/fcaa172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 08/31/2020] [Accepted: 09/16/2020] [Indexed: 11/15/2022] Open
Abstract
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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Affiliation(s)
- Christopher T Mitchell
- University of Leicester, University Road, Leicester LE1 7RH, UK
- School of Medicine, King's College London, London, UK
| | - Irina Krier
- École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | | | | | - Sarah J Tabrizi
- UCL Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Dementia Research Institute at UCL, Huntington's Disease Centre, London WC1N 3BG, UK
| | - Blair R Leavitt
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada 75Z 4H4
| | - Ruth Luthi-Carter
- University of Leicester, University Road, Leicester LE1 7RH, UK
- School of Medicine, King's College London, London, UK
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32
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Carlozzi NE, Goodnight S, Kratz AL, Stout JC, McCormack MK, Paulsen JS, Boileau NR, Cella D, Ready RE. Validation of Neuro-QoL and PROMIS Mental Health Patient Reported Outcome Measures in Persons with Huntington Disease. J Huntingtons Dis 2020; 8:467-482. [PMID: 31424415 DOI: 10.3233/jhd-190364] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Patient-reported outcomes (PROs) for mental health are important for persons with Huntington disease (HD) who commonly experience symptoms of depression, anxiety, irritability, anger, aggression, and apathy. Given this, there is a need for reliable and valid patient-reported outcomes measures of mental health for use as patient-centered outcomes in clinical trials. OBJECTIVE Thus, the purpose of this study was to establish the psychometric properties (i.e., reliability and validity) of six Neuro-QoL and PROMIS mental health measures to support their clinical utility in persons with HD. METHODS 294 individuals with premanifest (n = 102) or manifest HD (n = 131 early HD; n = 61 late HD) completed Neuro-QoL/PROMIS measures of Emotional and Behavioral Dyscontrol, Positive Affect and Well-Being, Stigma, Anger, Anxiety, and Depression, legacy measures of self-reported mental health, and clinician-rated assessments of functioning. RESULTS Convergent validity and discriminant validity for the Neuro-QoL and PROMIS measures of Emotional and Behavioral Dyscontrol, Positive Affect and Well-Being, Stigma, Anger, Anxiety, and Depression, were supported in persons with HD. Neuro-QoL measures of Anxiety and Depression also demonstrated moderate sensitivity and specificity (i.e., they were able to distinguish between individuals with and without clinically significant anxiety and depression). CONCLUSIONS Findings provide psychometric support for the clinical utility of the Neuro-QoL/PROMIS measures of mental health measures in persons with HD. As such, these measures should be considered for the standardized assessment of health-related quality of life in persons with HD.
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Affiliation(s)
- Noelle E Carlozzi
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA
| | - Siera Goodnight
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA
| | - Anna L Kratz
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA
| | - Julie C Stout
- Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Michael K McCormack
- Department of Psychiatry, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, USA.,Department of Pathology, Rowan-School of Medicine, Stratford, NJ, USA
| | - Jane S Paulsen
- Departments of Psychiatry, Neurology, and Psychology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
| | - Nicholas R Boileau
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA
| | - David Cella
- Departments of Medical Social Sciences and Preventative Medicine, Northwestern University, Chicago, IL, USA
| | - Rebecca E Ready
- Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, USA
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33
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Porciuncula F, Wasserman P, Marder KS, Rao AK. Quantifying Postural Control in Premanifest and Manifest Huntington Disease Using Wearable Sensors. Neurorehabil Neural Repair 2020; 34:771-783. [PMID: 32672492 DOI: 10.1177/1545968320939560] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background. Impairments in postural control in Huntington disease (HD) have important consequences for daily functioning. This observational study systematically examined baseline postural control and the effect of sensory attenuation and sensory enhancement on postural control across the spectrum of HD. Methods. Participants (n = 39) included healthy controls and individuals in premanifest (pHD) and manifest stages (mHD) of HD. Using wearable sensors, postural control was assessed according to (1) postural set (sit vs stand), (2) sensory attenuation using clinical test of sensory integration, and (3) sensory enhancement with gaze fixation. Outcomes included sway smoothness, amplitude, and frequency. Results. Based on postural set, pHD reduced postural sway in sitting relative to standing, whereas mHD had pronounced sway in standing and sitting, highlighting a baseline postural deficit. During sensory attenuation, postural control in pHD deteriorated relative to controls when proprioceptive demands were high (eyes closed on foam), whereas mHD had significant deterioration of postural control when proprioception was attenuated (eyes open and closed on foam). Finally, gaze fixation improved sway smoothness, amplitude, and frequency in pHD; however, no benefit was observed in mHD. Conclusions. Systematic examination of postural control revealed a fundamental postural deficit in mHD, which further deteriorates when proprioception is challenged. Meanwhile, postural deficits in pHD are detectable when proprioceptive challenge is high. Sensory enhancing strategies using gaze fixation to benefit posture may be useful when introduced well before motor diagnosis. These findings encourage further examination of wearable sensors as part of routine clinical assessments in HD.
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Affiliation(s)
- Franchino Porciuncula
- Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA
| | - Paula Wasserman
- G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Karen S Marder
- G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.,Department of Neurology, Psychiatry, G.H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain; Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Ashwini K Rao
- G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.,Department of Rehabilitation and Regenerative Medicine (Program in Physical Therapy), G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
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34
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Li F, Li K, Li C, Luo S. Predicting the Risk of Huntington's Disease with Multiple Longitudinal Biomarkers. J Huntingtons Dis 2020; 8:323-332. [PMID: 31256145 DOI: 10.3233/jhd-190345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Huntington's disease (HD) has gradually become a public health threat, and there is a growing interest in developing prognostic models to predict the time for HD diagnosis. OBJECTIVE This study aims to develop a novel prognostic model that leverages multiple longitudinal biomarkers to inform the risk of HD. METHODS The multivariate functional principal component analysis was used to summarize the essential information from multiple longitudinal markers and to obtain a set of prognostic scores. The prognostic scores were used as predictors in a Cox model to predict the right-censored time to diagnosis. We used cross-validation to determine the best model in PREDICT-HD (n = 1,039) and ENROLL-HD (n = 1,776); external validation was carried out in ENROLL-HD. RESULTS We considered six commonly measured longitudinal biomarkers in PREDICT-HD and ENROLL-HD (Total Motor Score, Symbol Digit Modalities Test, Stroop Word Test, Stroop Color Test, Stroop Interference Test, and Total Functional Capacity). The prognostic model utilizing these longitudinal biomarkers significantly improved the predictive performance over the model with baseline biomarker information. A new prognostic index was computed using the proposed model, and can be dynamically updated over time as new biomarker measurements become available. CONCLUSION Longitudinal measurements of commonly measured clinical biomarkers substantially improve the risk prediction of Huntington's disease diagnosis. Calculation of the prognostic index informs the patient's risk category and facilitates patient selection in future clinical trials.
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Affiliation(s)
- Fan Li
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.,Duke Clinical Research Institute, Durham, NC, USA
| | - Kan Li
- Merck Research Lab, Merck & Co, North Wales, PA, USA
| | - Cai Li
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA
| | - Sheng Luo
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.,Duke Clinical Research Institute, Durham, NC, USA
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Paulsen JS, Coffey CS. Antisense oligonucleotides might change the therapeutic landscape for Huntington's disease. Lancet Neurol 2020; 18:911-912. [PMID: 31526747 DOI: 10.1016/s1474-4422(19)30329-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 08/16/2019] [Indexed: 10/26/2022]
Affiliation(s)
- Jane S Paulsen
- Department of Neurology, Psychiatry, Psychological and Brain Sciences, University of Iowa, Iowa City, IA 52242, USA; University of Iowa, Iowa City, IA 52242, USA.
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36
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Psychometric properties and responsiveness of Neuro-QoL Cognitive Function in persons with Huntington disease (HD). Qual Life Res 2019; 29:1393-1403. [PMID: 31853881 DOI: 10.1007/s11136-019-02391-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2019] [Indexed: 10/25/2022]
Abstract
PURPOSE Individuals with Huntington disease (HD) experience progressive cognitive decline that may appear years before motor manifestations of the disease. These declines have a profound effect on health-related quality of life (HRQOL) over the disease course, and thus it is important that self-report measures of cognitive function are validated for use in longitudinal studies. METHODS 359 individuals with premanifest or manifest HD completed baseline and at least one follow-up (12- and 24-month) assessment. Neuro-QoL™ Cognitive Function was administered at each time-point. Participants completed a self-reported global rating of cognitive change, as well as performance-based cognitive changes (using the Symbol Digit Modalities Test). Standardized response means (SRMs) and general linear models evaluated whether Neuro-QoL™ Cognitive Function was responsive to change over time with respect to self-reported and performance-based anchors. Test-retest reliability and known-group validity were also examined. RESULTS Responsiveness was supported by effect sizes that were small in magnitude, but in the expected direction relative to self-reported and performance-based change. General linear models generally supported 12- and 24-month responsiveness relative to self-reported cognitive change and 12-month responsiveness relative to performance-based change. Test-retest reliability was excellent, and the measure exhibited known-group validity. CONCLUSION Longitudinal analyses generally indicate that the Neuro-QoL™ Cognitive Function measure is sensitive to change over time in individuals with HD. Neuro-QoL Cognitive Function changes reflect self-reported cognitive change at 12 and 24 months and performance-based change at 12 months. This measure may be useful in clinical trials or longitudinal observation studies.
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Ringkøbing SP, Larsen IU, Jørgensen K, Vinther-Jensen T, Vogel A. Cognitive Screening Tests in Huntington Gene Mutation Carriers: Examining the Validity of the Mini-Mental State Examination and the Montreal Cognitive Assessment. J Huntingtons Dis 2019; 9:59-68. [PMID: 31658065 DOI: 10.3233/jhd-190350] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Due to high prevalence of cognitive impairment in Huntington's disease (HD) gene mutation carriers, even before onset of motor symptoms, cognitive screening is important for the optimal management of patients. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are widely used, but the validity for HD has only been evaluated in few studies with important limitations. OBJECTIVE To evaluate the discriminative validity of the MMSE and the MoCA for the assessment of cognitive dysfunction in HD gene mutation carriers, independently of motor manifestation and furthermore, to report estimated probabilities for cognitive impairment with different score ranges on the MMSE and the MoCA. METHODS 106 pre-motor-manifest and motor-manifest HD gene mutation carriers and 40 non-HD gene mutation carriers were administered the MMSE, the MoCA, and an extensive neuropsychological battery with operationalized criteria for cognitive impairment. The same physician and the same neuropsychologist performed all examinations; blinded to one another. RESULTS The area under the receiver operating characteristic (ROC) curve was 0.70 for the MMSE and 0.82 for the MoCA. The latter correctly diagnosed 82% of the cognitively impaired and not-impaired HD gene mutation carriers and non-HD gene mutation carriers, whereas the MMSE only diagnosed 73% correctly. CONCLUSIONS The MMSE and the MoCA can both be used as cognitive screening tests in HD gene mutation carriers, but both have important limitations. Our results indicate that the MoCA is a better cognitive screening test for HD than the MMSE. In addition, our study provides estimated probabilities for cognitive impairment with different score ranges, which may be used as clinical guidelines in the interpretation of results from the two tests.
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Affiliation(s)
- Signe Pertou Ringkøbing
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark
| | - Ida Unmack Larsen
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark
| | - Kasper Jørgensen
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark
| | - Tua Vinther-Jensen
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark
| | - Asmus Vogel
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.,Department of Psychology, University of Copenhagen, Denmark
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Silajdžić E, Björkqvist M. A Critical Evaluation of Wet Biomarkers for Huntington's Disease: Current Status and Ways Forward. J Huntingtons Dis 2019; 7:109-135. [PMID: 29614689 PMCID: PMC6004896 DOI: 10.3233/jhd-170273] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
There is an unmet clinical need for objective biomarkers to monitor disease progression and treatment response in Huntington's disease (HD). The aim of this review is, therefore, to provide practical advice for biomarker discovery and to summarise studies on biofluid markers for HD. A PubMed search was performed to review literature with regard to candidate saliva, urine, blood and cerebrospinal fluid biomarkers for HD. Information has been organised into tables to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations for future studies. Many of the markers published converge on metabolic and inflammatory pathways, although changes in other analytes representing antioxidant and growth factor pathways have also been found. The most promising markers reflect neuronal and glial degeneration, particularly neurofilament light chain. International collaboration to standardise assays and study protocols, as well as to recruit sufficiently large cohorts, will facilitate future biomarker discovery and development.
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Affiliation(s)
- Edina Silajdžić
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Maria Björkqvist
- Department of Experimental Medical Science, Brain Disease Biomarker Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
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Carlozzi NE, Schilling SG, Boileau NR, Chou KL, Perlmutter JS, Frank S, McCormack MK, Stout JC, Paulsen JS, Lai JS, Dayalu P. How different aspects of motor dysfunction influence day-to-day function in huntington's disease. Mov Disord 2019; 34:1910-1914. [PMID: 31609508 DOI: 10.1002/mds.27866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/24/2019] [Accepted: 08/13/2019] [Indexed: 11/07/2022] Open
Abstract
PURPOSE This study examined the relationships between different aspects of motor dysfunction (chorea, dystonia, rigidity, incoordination, oculomotor dysfunction, dysarthria, and gait difficulties) and functional status in persons with Huntington's disease. METHODS A total of 527 persons with Huntington's disease completed the Unified Huntington's Disease Rating Scale motor, total functional capacity, and functional assessments. RESULTS Confirmatory factor analysis indicated that a 4-factor model provided a better model fit than the existing 5-factor model. Exploratory factor analysis identified the following 4 factors from the motor scale: dystonia, chorea, rigidity, and a general motor factor. Regression indicated that dystonia (β = -0.47 and -0.79) and rigidity (β = -0.28 and -0.59) had strong associations with function, whereas chorea had modest correlations (β = -0.16 and -0.15). CONCLUSIONS Dystonia and rigidity have stronger relationships with functional status than chorea in persons with Huntington's disease. The findings underscore the need for further research regarding the effects of dystonia and rigidity on functioning. © 2019 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Noelle E Carlozzi
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan, USA
| | - Stephen G Schilling
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan, USA
- Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA
| | - Nicholas R Boileau
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan, USA
| | - Kelvin L Chou
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Joel S Perlmutter
- Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Samuel Frank
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Michael K McCormack
- Department of Psychiatry, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
- Department of Pathology, Rowan-SOM (School of Medicine), Stratford, New Jersey, USA
| | - Julie C Stout
- School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Jane S Paulsen
- Department of Psychiatry, Neurology, and Psychological and Brain Sciences, The University of Iowa, Iowa City, Iowa, USA
| | - Jin-Shei Lai
- Department of Medical Social Sciences, Northwestern University, Chicago, Illinois, USA
| | - Praveen Dayalu
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
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40
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Byrne LM, Rodrigues FB, Johnson EB, Wijeratne PA, De Vita E, Alexander DC, Palermo G, Czech C, Schobel S, Scahill RI, Heslegrave A, Zetterberg H, Wild EJ. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease. Sci Transl Med 2019; 10:10/458/eaat7108. [PMID: 30209243 DOI: 10.1126/scitranslmed.aat7108] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 08/23/2018] [Indexed: 11/02/2022]
Abstract
Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.
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Affiliation(s)
- Lauren M Byrne
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK.
| | - Filipe B Rodrigues
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK
| | - Eileanor B Johnson
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK
| | - Peter A Wijeratne
- Centre for Medical Image Computing, Department of Computer Science, UCL, London WC1E 6EA, UK
| | - Enrico De Vita
- Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.,Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London SE1 7EH, UK
| | - Daniel C Alexander
- Centre for Medical Image Computing, Department of Computer Science, UCL, London WC1E 6EA, UK.,Clinical Imaging Research Centre, National University of Singapore, Singapore 117599, Singapore
| | - Giuseppe Palermo
- Neuroscience, Ophthalmology, and Rare Diseases, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., 4070 Basel, Switzerland
| | - Christian Czech
- Neuroscience, Ophthalmology, and Rare Diseases, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., 4070 Basel, Switzerland
| | - Scott Schobel
- Neuroscience, Ophthalmology, and Rare Diseases, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., 4070 Basel, Switzerland
| | - Rachael I Scahill
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK
| | - Amanda Heslegrave
- Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Henrik Zetterberg
- Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.,UK Dementia Research Institute at UCL, London WC1E 6BT, UK.,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, 405 30 Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, 413 45 Gothenburg, Sweden
| | - Edward J Wild
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK.
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Wesson M, Boileau NR, Perlmutter JS, Paulsen JS, Barton SK, McCormack MK, Carlozzi NE. Suicidal Ideation Assessment in Individuals with Premanifest and Manifest Huntington Disease. J Huntingtons Dis 2019; 7:239-249. [PMID: 30056431 DOI: 10.3233/jhd-180299] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Huntington disease (HD) is associated with increased risk of suicide. OBJECTIVE This study compares suicide ideation in HD to the general population, assesses factors associated with increased prevalence of suicidal thoughts, and compares clinician-rated to self-reported assessments of suicidal ideation. METHODS We examined 496 participants with premanifest or manifest HD. Clinician-rated suicidal ideation was measured using the Problem Behaviors Assessment - short form. Self-reported ideation was measured using two items from the HDQLIFE Concern with Death and Dying item bank. Independent sample t-tests were conducted to compare the prevalence of suicidal thoughts between our HD sample and the U.S. POPULATION Logistic regression analyses were used to determine characteristics associated with higher odds of clinically significant suicidal ideation. Kappa agreement coefficients were calculated to evaluate concurrence between clinician-rated and self-reported assessments. RESULTS Our sample had a significantly higher occurrence of suicidal ideation (19.76%) and suicidal plans (2.1%) than the general population (p < 0.0001). Odds of clinically significant suicidal ideation were 6.8 times higher in females (p = 0.04) on the clinician measure, and Hispanic/Latinos had 10.9 times higher odds than non-Hispanics (p = 0.025) on the self-report measure. Clinician-rated assessment had fair agreement (k = 0.2-0.4) with self-reported assessments, except in early stage HD where there was no overlap in the identification of participants with clinically significant suicidal ideation. DISCUSSION Assessment for suicidal ideation and clinically significant suicidal thoughts in HD with a multimodal approach that includes clinician-rated and self-report measures is critical at all stages of the disease.
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Affiliation(s)
- Melissa Wesson
- Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA
| | - Nicholas R Boileau
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA
| | - Joel S Perlmutter
- Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.,Radiology, Neuroscience, Physical Therapy, Occupational Therapy, Washington University in St. Louis, St. Louis, MO, USA
| | - Jane S Paulsen
- Neurology, Psychiatry, Psychological and Brain Sciences, University of Iowa, Iowa City, IA, USA
| | - Stacey K Barton
- Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
| | - Michael K McCormack
- Department of Pathology, Rowan University School of Medicine, Glassboro, NJ, USA.,Department of Psychiatry, Rutgers-RWJMS, Piscataway Township, NJ, USA
| | - Noelle E Carlozzi
- Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA
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The prevalence and the burden of pain in patients with Huntington disease: a systematic review and meta-analysis. Pain 2019; 160:773-783. [PMID: 30889051 DOI: 10.1097/j.pain.0000000000001472] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
It is remarkable that studies focusing on the prevalence and the burden of pain in patients with Huntington disease (HD) are scarce. This may lead to inadequate recognition of pain and hence lack of treatment, eventually affecting the quality of life. The aim of this review is to investigate the prevalence of pain and its burden in HD by performing a systematic literature search. In February 2018, a systematic search was performed in the electronic databases of Pubmed, Embase, Cinahl, Cochrane, and PsycINFO. Studies focusing on patients with juvenile HD were excluded. All other types of study were included without language restrictions. In total, 2234 articles were identified, 15 of which met the inclusion criteria and provided information on 2578 patients with HD. The sample-weighted prevalence of pain was 41.3% (95% confidence interval: 36%-46%). The pain burden, which was measured with the SF-36, is significantly less compared with that in the general population. The sample-weighted mean score on the SF-36 was 84 (95% confidence interval: 81-86), where a score of 100 represents the lowest symptom burden. The results demonstrate that pain could be an important nonmotor symptom in patients with HD, and there are indications that the pain burden could be diminished because of HD. Larger and high-quality prospective cohort and clinical studies are required to confirm these findings. In the meantime, awareness about pain and its burden in patients with HD is warranted in clinical practice.
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Zeun P, Scahill RI, Tabrizi SJ, Wild EJ. Fluid and imaging biomarkers for Huntington's disease. Mol Cell Neurosci 2019; 97:67-80. [PMID: 30807825 DOI: 10.1016/j.mcn.2019.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/25/2019] [Accepted: 02/12/2019] [Indexed: 01/18/2023] Open
Abstract
Huntington's disease is a chronic progressive neurodegenerative condition for which there is no disease-modifying treatment. The known genetic cause of Huntington's disease makes it possible to identify individuals destined to develop the disease and instigate treatments before the onset of symptoms. Multiple trials are already underway that target the cause of HD, yet clinical measures are often insensitive to change over typical clinical trial duration. Robust biomarkers of drug target engagement, disease severity and progression are required to evaluate the efficacy of treatments and concerted efforts are underway to achieve this. Biofluid biomarkers have potential advantages of direct quantification of biological processes at the molecular level, whilst imaging biomarkers can quantify related changes at a structural level in the brain. The most robust biofluid and imaging biomarkers can offer complementary information, providing a more comprehensive evaluation of disease stage and progression to inform clinical trial design and endpoints.
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Affiliation(s)
- Paul Zeun
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
| | - Rachael I Scahill
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
| | - Sarah J Tabrizi
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
| | - Edward J Wild
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
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Júlio F, Ribeiro MJ, Patrício M, Malhão A, Pedrosa F, Gonçalves H, Simões M, van Asselen M, Simões MR, Castelo-Branco M, Januário C. A Novel Ecological Approach Reveals Early Executive Function Impairments in Huntington's Disease. Front Psychol 2019; 10:585. [PMID: 30967810 PMCID: PMC6438896 DOI: 10.3389/fpsyg.2019.00585] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/01/2019] [Indexed: 11/13/2022] Open
Abstract
Introduction: Impairments in executive functions are common in neurogenetic disorders such as Huntington's disease (HD) and are thought to significantly influence the patient's functional status. Reliable tools with higher ecological validity that can assess and predict the impact of executive dysfunction in daily-life performance are needed. This study aimed to develop and validate a novel non-immersive virtual reality task ("EcoKitchen") created with the purpose of capturing cognitive and functional changes shown by HD carriers without clinical manifestations of the disease (Premanifest HD), in a more realistic setting. Materials and Methods: We designed a virtual reality task with three blocks of increasing executive load. The performance of three groups (Controls, CTRL; Premanifest HD individuals, HP; Early Manifest HD patients, HD) was compared in four main components of the study protocol: the EcoKitchen; a subjective (self-report) measure - "The Adults and Older Adults Functional Assessment Inventory (IAFAI)"; the "Behavioural Assessment of Dysexecutive Syndrome battery (BADS)"; and a conventional neuropsychological test battery. We also examined statistical associations between EcoKitchen and the other executive, functional and clinical measures used. Results: The HD group showed deficits in all the assessment methods used. In contrast, the HP group was only found to be impaired in the EcoKitchen task, particularly in the most cognitively demanding blocks, where they showed a higher number of errors compared to the CTRL group. Statistically significant correlations were identified between the EcoKitchen, measures of the other assessment tools, and HD clinical features. Discussion: The EcoKitchen task, developed as an ecological executive function assessment tool, was found to be sensitive to early deficits in this domain. Critically, in premanifest HD individuals, it identifies dysfunction prior to symptom onset. Further it adds a potential tool for diagnosis and management of the patients' real-life problems.
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Affiliation(s)
- Filipa Júlio
- Faculty of Psychology and Education Sciences, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Maria J. Ribeiro
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Miguel Patrício
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Alexandre Malhão
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Fábio Pedrosa
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Hélio Gonçalves
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Marco Simões
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Marieke van Asselen
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Mário R. Simões
- Faculty of Psychology and Education Sciences, University of Coimbra, Coimbra, Portugal
- Center for Research in Neuropsychology and Cognitive Behavioral Intervention, Faculty of Psychology and Education Sciences, University of Coimbra, Coimbra, Portugal
| | - Miguel Castelo-Branco
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
- Institute of Nuclear Sciences Applied to Health, University of Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Cristina Januário
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra University Hospital, Coimbra, Portugal
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Petrella LI, Castelhano JM, Ribeiro M, Sereno JV, Gonçalves SI, Laço MN, Hayden MR, Rego AC, Castelo-Branco M. A whole brain longitudinal study in the YAC128 mouse model of Huntington's disease shows distinct trajectories of neurochemical, structural connectivity and volumetric changes. Hum Mol Genet 2019; 27:2125-2137. [PMID: 29668904 DOI: 10.1093/hmg/ddy119] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/26/2018] [Indexed: 12/20/2022] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disorder causing cognitive and motor impairments, evolving to death within 15-20 years after symptom onset. We previously established a mouse model with the entire human HD gene containing 128 CAG repeats (YAC128) which accurately recapitulates the natural history of the human disease. Defined time points in this natural history enable the understanding of longitudinal trajectories from the neurochemical and structural points of view using non-invasive high-resolution multi-modal imaging. Accordingly, we designed a longitudinal structural imaging (MRI and DTI) and spectroscopy (1H-MRS) study in YAC128, at 3, 6, 9 and 12 months of age, at 9.4 T. Structural analysis (MRI/DTI), confirmed that the striatum is the earliest affected brain region, but other regions were also identified through connectivity analysis (pre-frontal cortex, hippocampus, globus pallidus and thalamus), suggesting a striking homology with the human disease. Importantly, we found for the first time, a negative correlation between striatal and hippocampal changes only in YAC128. In fact, the striatum showed accelerated volumetric decay in HD, as opposed to the hippocampus. Neurochemical analysis of the HD striatum suggested early neurometabolic alterations in neurotransmission and metabolism, with a significant increase in striatal GABA levels, and specifically anticorrelated levels of N-acetyl aspartate and taurine, suggesting that the later is homeostatically adjusted for neuroprotection, as neural loss, indicated by the former, is progressing. These results provide novel insights into the natural history of HD and prove a valuable role for longitudinal multi-modal panels of structural and metabolite/neurotransmission in the YAC128 model.
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Affiliation(s)
- Lorena I Petrella
- Institute of Nuclear Science Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal.,Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal
| | - João M Castelhano
- Institute of Nuclear Science Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal.,Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Mario Ribeiro
- Institute of Nuclear Science Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal.,Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal
| | - José V Sereno
- Institute of Nuclear Science Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal.,Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Sónia I Gonçalves
- Institute of Nuclear Science Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal.,Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal.,Neuroplasticity and Neural Activity Laboratory, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal
| | - Mário N Laço
- Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Michael R Hayden
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
| | - A Cristina Rego
- Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Miguel Castelo-Branco
- Institute of Nuclear Science Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal.,Center for Neuroscience and Cell Biology-Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, 3000-548 Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
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46
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Rodrigues FB, Byrne LM, De Vita E, Johnson EB, Hobbs NZ, Thornton JS, Scahill RI, Wild EJ. Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI. Eur J Neurosci 2019; 49:1632-1639. [PMID: 30687961 PMCID: PMC6618296 DOI: 10.1111/ejn.14356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/11/2019] [Accepted: 01/22/2019] [Indexed: 11/27/2022]
Abstract
Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross-sectional study comparing people with early stage Huntington's disease with age- and gender-matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub-arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter-group differences with Wilcoxon rank-sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics - that is, one that would justify dose-adjustments of intrathecal drugs - is unlikely to exist in Huntington's disease.
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Affiliation(s)
- Filipe B Rodrigues
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Lauren M Byrne
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Enrico De Vita
- Neuroradiological Academic Unit, UCL Queen Square Institute of Neurology, University College London, London, UK.,Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
| | - Eileanoir B Johnson
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | | | - John S Thornton
- Neuroradiological Academic Unit, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Rachael I Scahill
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Edward J Wild
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
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47
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Paulsen JS, Lourens S, Kieburtz K, Zhang Y. Sample enrichment for clinical trials to show delay of onset in huntington disease. Mov Disord 2019; 34:274-280. [PMID: 30644132 DOI: 10.1002/mds.27595] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 10/19/2018] [Accepted: 11/26/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Disease-modifying clinical trials in persons without symptoms are often limited in methods to assess the impact associated with experimental therapeutics. This study suggests sample enrichment approaches to facilitate preventive trials to delay disease onset in individuals with the dominant gene for Huntington disease. METHODS Using published onset prediction indexes, we conducted the receiver operating curve analysis for diagnosis within a 3-year clinical trial time frame. We determined optimal cut points on the indexes for participant recruitment and then conducted sample size and power calculations to detect varying effect sizes for treatment efficacy in reducing 3-year rates of disease onset (or diagnosis). RESULTS Area under the curve for 3 onset prediction indexes all demonstrated excellent value in sample enrichment methodology, with the best-performing index being the multivariate risk score (MRS). CONCLUSIONS This study showed that conducting an intervention trial in premanifest and prodromal individuals with the gene expansion for Huntington disease is highly feasible using sample enrichment recruitment methods. Ongoing natural history studies are highly likely to indicate additional markers of disease prior to diagnosis. Statistical modeling of identified markers can facilitate participant enrichment to increase the likelihood of detecting a difference between treatment arms in a cost-effective and efficient manner. Such variations may expedite translation of emerging therapies to persons in an earlier phase of the disease. TRIAL REGISTRATION PREDICT-HD is registered with www.clinicaltrials.gov, number NCT00051324. © 2019 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Jane S Paulsen
- Departments of Neurology, Psychiatry, and Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA
| | - Spencer Lourens
- Department of Biostatistics, Indiana University Fairbanks School of Public Health and School of Medicine, Indianapolis, Indiana, USA
| | - Karl Kieburtz
- Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA
| | - Ying Zhang
- Department of Biostatistics, Indiana University Fairbanks School of Public Health and School of Medicine, Indianapolis, Indiana, USA
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48
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Long JD, Mills JA. Joint modeling of multivariate longitudinal data and survival data in several observational studies of Huntington's disease. BMC Med Res Methodol 2018; 18:138. [PMID: 30445915 PMCID: PMC6240282 DOI: 10.1186/s12874-018-0592-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/29/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Joint modeling is appropriate when one wants to predict the time to an event with covariates that are measured longitudinally and are related to the event. An underlying random effects structure links the survival and longitudinal submodels and allows for individual-specific predictions. Multiple time-varying and time-invariant covariates can be included to potentially increase prediction accuracy. The goal of this study was to estimate a multivariate joint model on several longitudinal observational studies of Huntington's disease, examine external validity performance, and compute individual-specific predictions for characterizing disease progression. Emphasis was on the survival submodel for predicting the hazard of motor diagnosis. METHODS Data from four observational studies was analyzed: Enroll-HD, PREDICT-HD, REGISTRY, and Track-HD. A Bayesian approach to estimation was adopted, and external validation was performed using a time-varying AUC measure. Individual-specific cumulative hazard predictions were computed based on a simulation approach. The cumulative hazard was used for computing predicted age of motor onset and also for a deviance residual indicating the discrepancy between observed diagnosis status and model-based status. RESULTS The joint model trained in a single study had very good performance in discriminating among diagnosed and pre-diagnosed participants in the remaining test studies, with the 5-year mean AUC = .83 (range .77-.90), and the 10-year mean AUC = .86 (range .82-.92). Graphical analysis of the predicted age of motor diagnosis showed an expected strong relationship with the trinucleotide expansion that causes Huntington's disease. Graphical analysis of the deviance-type residual revealed there were individuals who converted to a diagnosis despite having relatively low model-based risk, others who had not yet converted despite having relatively high risk, and the majority falling between the two extremes. CONCLUSIONS Joint modeling is an improvement over traditional survival modeling because it considers all the longitudinal observations of covariates that are predictive of an event. Predictions from joint models can have greater accuracy because they are tailored to account for individual variability. These predictions can provide relatively accurate characterizations of individual disease progression, which might be important in the timing of interventions, determining the qualification for appropriate clinical trials, and general genotypic analysis.
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Affiliation(s)
- Jeffrey D. Long
- Department of Psychiatry, Carver College of Medicine, University of Iowa, 500 Newton Road, Iowa City, IA 52242-1000 USA
- Department of Biostatistics, Department of Public Health, University of Iowa, 145 N. Riverside Drive, Iowa City, IA 52242-1000 USA
| | - James A. Mills
- Department of Psychiatry, Carver College of Medicine, University of Iowa, 500 Newton Road, Iowa City, IA 52242-1000 USA
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49
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Molecular Imaging in Huntington's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 142:289-333. [PMID: 30409256 DOI: 10.1016/bs.irn.2018.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Huntington's disease (HD) is a rare monogenic neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the huntingtin gene resulting in the formation of intranuclear inclusions of mutated huntingtin. The accumulation of mutated huntingtin leads to loss of GABAergic medium spiny neurons (MSNs); subsequently resulting in the development of chorea, cognitive dysfunction and psychiatric symptoms. Premanifest HD gene expansion carriers, provide a unique cohort to examine very early molecular changes, occurring before the development of overt symptoms, to elucidate disease pathophysiology and identify reliable biomarkers of HD progression. Positron emission tomography (PET) is a non-invasive molecular imaging technique allowing the evaluation of specific molecular targets in vivo. Selective PET radioligands provide invaluable tools to investigate the role of the dopaminergic system, brain metabolism, microglial activation, phosphodiesterase 10A, and cannabinoid, GABA, adenosine and opioid receptors in HD. PET has been employed to monitor disease progression aiming to identify a reliable biomarker to predict phenoconversion from premanifest to manifest HD.
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50
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Tang X, Ross CA, Johnson H, Paulsen JS, Younes L, Albin RL, Ratnanather JT, Miller MI. Regional subcortical shape analysis in premanifest Huntington's disease. Hum Brain Mapp 2018; 40:1419-1433. [PMID: 30376191 DOI: 10.1002/hbm.24456] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 10/18/2018] [Accepted: 10/23/2018] [Indexed: 11/11/2022] Open
Abstract
Huntington's disease (HD) involves preferential and progressive degeneration of striatum and other subcortical regions as well as regional cortical atrophy. It is caused by a CAG repeat expansion in the Huntingtin gene, and the longer the expansion the earlier the age of onset. Atrophy begins prior to manifest clinical signs and symptoms, and brain atrophy in premanifest expansion carriers can be studied. We employed a diffeomorphometric pipeline to contrast subcortical structures' morphological properties in a control group with three disease groups representing different phases of premanifest HD (far, intermediate, and near to onset) as defined by the length of the CAG expansion and the participant's age (CAG-Age-Product). A total of 1,428 magnetic resonance image scans from 694 participants from the PREDICT-HD cohort were used. We found significant region-specific atrophies in all subcortical structures studied, with the estimated abnormality onset time varying from structure to structure. Heterogeneous shape abnormalities of caudate nuclei were present in premanifest HD participants estimated furthest from onset and putaminal shape abnormalities were present in participants intermediate to onset. Thalamic, hippocampal, and amygdalar shape abnormalities were present in participants nearest to onset. We assessed whether the estimated progression of subcortical pathology in premanifest HD tracked specific pathways. This is plausible for changes in basal ganglia circuits but probably not for changes in hippocampus and amygdala. The regional shape analyses conducted in this study provide useful insights into the effects of HD pathology in subcortical structures.
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Affiliation(s)
- Xiaoying Tang
- Department of Electrical and Electronic Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Christopher A Ross
- Division of Neurobiology, Departments of Psychiatry, Neurology, Neuroscience and Pharmacology, and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hans Johnson
- Departments of Neurology and Psychiatry, The University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Jane S Paulsen
- Departments of Neurology and Psychiatry, The University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Laurent Younes
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, Maryland.,Center for Imaging Science, Johns Hopkins University, Baltimore, Maryland.,Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Roger L Albin
- Neurology Service and GRECC, VAAAHS, Ann Arbor, Michigan.,Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan
| | - J Tilak Ratnanather
- Center for Imaging Science, Johns Hopkins University, Baltimore, Maryland.,Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.,Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Michael I Miller
- Center for Imaging Science, Johns Hopkins University, Baltimore, Maryland.,Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.,Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
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