scholarly journals Recommendations to Optimize the Use of Volumetric MRI in Huntington's Disease Clinical Trials

2021 ◽  
Vol 12 ◽  
Author(s):  
Kirsi M. Kinnunen ◽  
Ariana P. Mullin ◽  
Dorian Pustina ◽  
Emily C. Turner ◽  
Jackson Burton ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Atrophy ◽  
Staging System ◽  
Brain Structures ◽  
Regulatory Science ◽  
Volumetric Mri ◽  
Disease Staging ◽  
Definition Of ◽  
Derived Data

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.

scholarly journals Huntington’s Disease Integrated Staging System (HD-ISS): A Novel Evidence-Based Classification System For Staging

2021 ◽  
Author(s):  
Sarah J. Tabrizi ◽  
Scott Schobel ◽  
Emily C. Gantman ◽  
Alexandra Mansbach ◽  
Beth Borowsky ◽  
...  
Keyword(s):  
Clinical Research ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Critical Path ◽  
Functional Decline ◽  
Signs And Symptoms ◽  
Staging System ◽  
Regulatory Science ◽  
Cross Sectional ◽  
Evidenced Based

ABSTRACTBackgroundDespite the monogenic autosomal dominant nature of Huntington’s disease (HD), the current research paradigm is still based on overt clinical phenotypes and does not address disease pathobiology and biomarkers that are evident decades before functional decline. A new research framework is needed to standardize clinical research and enable interventional studies earlier in the course of HD.MethodsThe HD Regulatory Science Consortium (HD-RSC), a precompetitive Critical Path Institute initiative that includes 37 member organizations, created the Regulatory Science Forum working group (RSF), which includes industry and academic representatives. To generate a new evidenced-based HD Integrated Staging System (HD-ISS) using a formal consensus methodology, the RSF considered prognostic biomarkers, signs, and symptoms of HD, and performed empirical data analysis. We used observational data to calculate healthy-control-based landmark variable cut-offs for Stage classification and to internally validate the framework.FindingsThe HD-ISS starts with Stage 0, which comprises individuals with ≥ 40 cytosine-adenine-guanine repeats (CAG) in the huntingtin gene (HTT), before detectable indications of disease. We concluded that detectable HD progression is verified with measurable indicators of underlying pathophysiology (Stage 1), proceeds to a detectable clinical phenotype (Stage 2), and continues to a decline in function (Stage 3). Operationally, individuals can be unambiguously classified into Stages 1-3 based on CAG-independent thresholds of landmark assessments. Both cross-sectional status and longitudinal HD-ISS Stage progress align with HD natural history, and Stage transitions accelerate as CAG increase.InterpretationThe HD-ISS encompasses the full course of HD starting at birth, defined by the presence of the genetic expansion. This new framework aims to standardize language for clinical research and its immediate use will enable further validation. The HD-ISS provides structure to harmonize clinical study populations and facilitates the clinical assessment of interventions earlier in HD to prevent or slow disease progression.FundingCHDI Foundation Inc.

Reduction in brain atrophy associated with Ethyl-Eicosapentaenoic Acid in Patients with Huntington's disease

2008 ◽  
Vol 23 ◽  
pp. S196 ◽  
Author(s):  
B.K. Puri ◽  
G.M. Bydder ◽  
A. Clarke ◽  
M.S. Manku ◽  
C.F. Beckmann
Keyword(s):  
Eicosapentaenoic Acid ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Atrophy

Brain atrophy in Huntington's disease

1989 ◽  
Vol 31 (2) ◽  
pp. 156-159 ◽  
Author(s):  
S. E. Starkstein ◽  
S. E. Folstein ◽  
J. Brandt ◽  
G. D. Pearlson ◽  
A. McDonnell ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Atrophy

Abnormal resting-state connectivity of motor and cognitive networks in early manifest Huntington's disease

2014 ◽  
Vol 44 (15) ◽  
pp. 3341-3356 ◽  
Author(s):  
R. C. Wolf ◽  
F. Sambataro ◽  
N. Vasic ◽  
M. S. Depping ◽  
P. A. Thomann ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Function ◽  
Neural Activity ◽  
Resting State ◽  
Brain Atrophy ◽  
Clinical Symptoms ◽  
Resting State Fmri ◽  
Cognitive Networks ◽  
The Impact

Background.Functional magnetic resonance imaging (fMRI) of multiple neural networks during the brain's ‘resting state’ could facilitate biomarker development in patients with Huntington's disease (HD) and may provide new insights into the relationship between neural dysfunction and clinical symptoms. To date, however, very few studies have examined the functional integrity of multiple resting state networks (RSNs) in manifest HD, and even less is known about whether concomitant brain atrophy affects neural activity in patients.Method.Using MRI, we investigated brain structure and RSN function in patients with early HD (n = 20) and healthy controls (n = 20). For resting-state fMRI data a group-independent component analysis identified spatiotemporally distinct patterns of motor and prefrontal RSNs of interest. We used voxel-based morphometry to assess regional brain atrophy, and ‘biological parametric mapping’ analyses to investigate the impact of atrophy on neural activity.Results.Compared with controls, patients showed connectivity changes within distinct neural systems including lateral prefrontal, supplementary motor, thalamic, cingulate, temporal and parietal regions. In patients, supplementary motor area and cingulate cortex connectivity indices were associated with measures of motor function, whereas lateral prefrontal connectivity was associated with cognition.Conclusions.This study provides evidence for aberrant connectivity of RSNs associated with motor function and cognition in early manifest HD when controlling for brain atrophy. This suggests clinically relevant changes of RSN activity in the presence of HD-associated cortical and subcortical structural abnormalities.

Correction of Brain Atrophy in Metabolic Imaging of Presymptomatic Huntington’s Disease: A Combined FDG PET and MRI Study

2008 ◽  
Vol 5 (2) ◽  
pp. 366-367 ◽  
Author(s):  
Y MA ◽  
A FEIGIN ◽  
S PENG ◽  
P KINGSLEY ◽  
V DHAWAN ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Atrophy ◽  
Fdg Pet ◽  
Metabolic Imaging ◽  
Mri Study
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