Abstract:Background
The aim was to develop a prognostic index for motor diagnosis in Huntington's disease and examine its predictive performance in external observational studies.
Methods
The pre-diagnosis Neuro-biological Predictors of Huntington's Disease study (N=945 gene-positive) was used to select a Cox regression model for computing a prognostic index. Cross-validation was used for selecting a model with good internal validity performance using the research sites as natural splits of the data set. Then the ext… Show more
“…The association between baseline NfL concentration in plasma and subsequent disease onset was significant (HR 3·29 per 1·0 log pg/mL, 95% CI 1·48–7·34, p=0·0036; figure 3), and remained so after adjustment for age, CAG repeat count, and their interactions (3·03 per 1·0 log pg/mL, 1·07–8·60, p=0·0371) and for each baseline brain volume measure (appendix). 27 A receiver operating characteristic curve for risk of diagnosis within 3 years showed that mean sensitivity and specificity were highest when NfL concentration in plasma was 3·61 log pg/mL at baseline (appendix), which is close to the median value among participants with premanifest Huntington's disease at baseline of 3·69 log pg/mL.Figure 3Association between baseline NfL concentration in plasma and progression to manifest Huntington's disease in HTT mutation carriers who were premanifest at baseline(A) NfL concentration in plasma at baseline by disease progression status at 3 years. Boxes show first and third quartiles, the central band shows the median, and the whiskers show data within 1·5 IQR of the median.…”
SummaryBackgroundBlood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.MethodsWe did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.FindingsBaseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=–0·374, p<0·0001; Stroop word reading r=–0·248, p=0·0033), total functional capacity (r=–0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=–0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48–7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.
“…The association between baseline NfL concentration in plasma and subsequent disease onset was significant (HR 3·29 per 1·0 log pg/mL, 95% CI 1·48–7·34, p=0·0036; figure 3), and remained so after adjustment for age, CAG repeat count, and their interactions (3·03 per 1·0 log pg/mL, 1·07–8·60, p=0·0371) and for each baseline brain volume measure (appendix). 27 A receiver operating characteristic curve for risk of diagnosis within 3 years showed that mean sensitivity and specificity were highest when NfL concentration in plasma was 3·61 log pg/mL at baseline (appendix), which is close to the median value among participants with premanifest Huntington's disease at baseline of 3·69 log pg/mL.Figure 3Association between baseline NfL concentration in plasma and progression to manifest Huntington's disease in HTT mutation carriers who were premanifest at baseline(A) NfL concentration in plasma at baseline by disease progression status at 3 years. Boxes show first and third quartiles, the central band shows the median, and the whiskers show data within 1·5 IQR of the median.…”
SummaryBackgroundBlood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.MethodsWe did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.FindingsBaseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=–0·374, p<0·0001; Stroop word reading r=–0·248, p=0·0033), total functional capacity (r=–0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=–0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48–7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.
“…First, recent research has examined the prediction of motor diagnosis in HD using multiple baseline measures [17,18]. In comparison, the joint model adopted in this present analysis can only handle a single longitudinal measure.…”
BACKGROUND
Prediction of motor diagnosis in Huntington’s disease (HD) can be improved by incorporating other phenotypic and biological clinical measures in addition to cytosine-adenine-guanine (CAG) repeat length and age.
OBJECTIVE
The objective was to compare various clinical and biomarker trajectories for tracking HD progression and predicting motor conversion.
METHODS
Participants were from the PREDICT-HD study. We constructed a mixed-effect model to describe the change of measures while jointly modeling the process with time to HD diagnosis. The model was then used for subject-specific prediction. We employed the time-dependent receiver operating characteristic (ROC) method to assess the discriminating capability of the measures to identify high and low risk patients. The strongest predictor was used to illustrate the dynamic prediction of the disease risk and future trajectories of biomarkers for three hypothetical patients.
RESULTS
1078 individuals were included in this analysis. Five longitudinal clinical and imaging measures were compared. The putamen volume had the best discrimination performance with area under the curve (AUC) ranging from 0.74 to 0.82 over time. The total motor score showed a comparable discriminative ability with AUC ranging from 0.69 to 0.78 over time. The model showed that decreasing putamen volume was a significant predictor of motor conversion. A web-based calculator was developed for implementing the methods.
CONCLUSIONS
By jointly modeling longitudinal data with time-to-event outcomes, it is possible to construct an individualized dynamic event prediction model that renews over time with accumulating evidence. If validated, this could be a valuable tool to guide the clinician in predicting age of onset and potentially rate of progression.
“…Recently, another prognostic index for HD has been published, based on data from REGISTRY, Track-HD and the Cooperative Huntington Observational Trial. This score gives reasonable probabilities for conversion from premanifest to manifest HD, but requires the symbol-digit-modality test and a full UHDRS motor score [57]. Here, digital biomarkers may represent another modality for early detection of prodromal HD.…”
Section: Can We Deal With the Expenses For A New Therapy?mentioning
Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.
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