scholarly journals A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington’s Disease

2021 ◽  
Vol 4 ◽  
Author(s):  
Peter A. Wijeratne ◽  
Eileanoir B. Johnson ◽  
Sarah Gregory ◽  
Nellie Georgiou-Karistianis ◽  
Jane S. Paulsen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Stage ◽  
Drug Efficacy ◽  
Repeat Length ◽  
Cag Repeat ◽  
Event Based ◽  
Genetic Burden ◽  
The Impact

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

scholarly journals The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington’s Disease

2020 ◽  
Vol 10 (9) ◽  
pp. 575 ◽  
Author(s):  
Jordan L. Schultz ◽  
Amelia D. Moser ◽  
Peg C. Nopoulos
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Linear Regression Models ◽  
Juvenile Onset ◽  
Additional Information ◽  
Using Data ◽  
The Relationship

There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

scholarly journals Linking SNPs to CAG repeat length in Huntington's disease patients

2008 ◽  
Vol 5 (11) ◽  
pp. 951-953 ◽  
Author(s):  
Wanzhao Liu ◽  
Lori A Kennington ◽  
H Diana Rosas ◽  
Steven Hersch ◽  
Jang-Ho Cha ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Length ◽  
Cag Repeat

scholarly journals Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Tianle Chen ◽  
Yuanjia Wang ◽  
Yanyuan Ma ◽  
Karen Marder ◽  
Douglas R. Langbehn
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Family Member ◽  
Disease Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Observational Research ◽  
Accurate Estimation ◽  
Combined Data

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

Normal CAG repeat length in the Huntington's disease gene in senile chorea

Neurology ◽  
1994 ◽  
Vol 44 (11) ◽  
pp. 2183-2183 ◽  
Author(s):  
H. Shinotoh ◽  
D. B. Calne ◽  
B. Snow ◽  
M. Hayward ◽  
B. Kremer ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Gene ◽  
Repeat Length ◽  
Cag Repeat

Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum

Neuroscience ◽  
1998 ◽  
Vol 87 (1) ◽  
pp. 49-53 ◽  
Author(s):  
N.J Butterworth ◽  
L Williams ◽  
J.Y Bullock ◽  
D.R Love ◽  
R.L.M Faull ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Dna Fragmentation ◽  
Repeat Length ◽  
Cag Repeat

Transglutaminase activity is related to CAG repeat length in patients with Huntington's disease

1996 ◽  
Vol 98 (6) ◽  
pp. 633-635 ◽  
Author(s):  
L. Cariello ◽  
T. de Cristofaro ◽  
Laura Zanetti ◽  
Teresa Cuomo ◽  
Luigi Di Maio ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Length ◽  
Cag Repeat ◽  
Transglutaminase Activity
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