Objective
The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences ...in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS.
Methods
We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model.
Results
Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p < 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p < 0.001), higher incidences of ALS‐FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p = 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p < 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p < 0.001). UNC13A was associated with lower scores on ALS‐specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p = 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p = 0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p = 0.045 and p = 0.036).
Interpretation
Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796–806
Background
The extensive heterogeneity between patients with amyotrophic lateral sclerosis (ALS) complicates the quantification of disease progression. In this study, we determine the value of ...remote, accelerometer-based monitoring of physical activity in patients with ALS.
Methods
This longitudinal cohort study was conducted in a home-based setting; all study materials were sent by mail. Patients wore the ActiGraph during waking hours for 7 days every 2–3 months and provided information regarding their daily functioning (ALSFRS-R). We defined four accelerometer-based endpoints that either reflect the average daily activity or quantify the patient’s physical capacity.
Results
A total of 42 patients participated; the total valid monitoring period was 9288 h with a 93.0% adherence rate. At baseline, patients were active 27.9% (range 11.6–52.4%) of their time; this declined by 0.64% (95% 0.43–0.86,
p
< 0.001) per month. Accelerometer-based endpoints were strongly associated with the ALSFRS-R (
r
0.78, 95% CI 0.63–0.92,
p
< 0.001), but showed less variability over time than the ALSFRS-R (coefficient of variation 0.64–0.81 vs. 1.06, respectively). Accelerometer-based endpoints could reduce sample size by 30.3% for 12-month trials and 44.6% for 18-month trials; for trials lasting less than 9 months, the ALSFRS-R resulted in smaller sample sizes.
Conclusion
Accelerometry is an objective method for quantifying disease progression, which could obtain real-world insights in the patient’s physical functioning and may personalize the delivery of care. In addition, remote monitoring provides patients with the opportunity to participate in clinical trials from home, paving the way to a patient-centric clinical trial model.
Background and purpose
RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron ...degeneration in amyotrophic lateral sclerosis (ALS).
Methods
We conducted a randomized, multicenter, placebo‐controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double‐blind period, all patients received RT001 during an open‐label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS‐R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.
Results
In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least‐squares mean difference in ALSFRS‐R total score at week 24 of treatment was 1.90 (95% confidence interval = −1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.
Conclusions
Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.
Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural ...history of lung function in SMA has, however, not been studied in much detail.
We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV
), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV
and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV
ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from - 0.1% to - 1.4% for FEV
, - 0.2% to - 1.4% for FVC, and + 0.2% to - 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV
values measured in either sitting or supine position.
Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV
or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.
Abstract
Objective
After stroke, people experience difficulties with walking that lead to restrictions in participation in daily life. The purpose of this study was to examine the effect of virtual ...reality gait training (VRT) compared to non–virtual reality gait training (non-VRT) on participation in community-living people after stroke.
Methods
In this assessor-blinded, randomized controlled trial with 2 parallel groups, people were included between 2 weeks and 6 months after stroke and randomly assigned to the VRT group or non-VRT group. Participants assigned to the VRT group received training on the Gait Real-time Analysis Interactive Lab (GRAIL), and participants assigned to the non-VRT group received treadmill training and functional gait exercises without virtual reality. Both training interventions consisted of 12 30-minute sessions during 6 weeks. The primary outcome was participation measured with the restrictions subscale of the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) 3 months postintervention. Secondary outcomes included subjective physical functioning, functional mobility, walking ability, dynamic balance, walking activity, fatigue, anxiety and depression, falls efficacy, and quality of life.
Results
Twenty-eight participants were randomly assigned to the VRT group and 27 to the non-VRT group, of whom 25 and 22 attended 75% or more of the training sessions, respectively. No significant differences between the groups were found over time for the USER-P restrictions subscale (1.23; 95% CI = −0.76 to 3.23) or secondary outcome measures. Patients’ experiences with VRT were positive, and no serious adverse events were related to the interventions.
Conclusions
The effect of VRT was not statistically different from non-VRT in improving participation in community-living people after stroke.
Impact
Although outcomes were not statistically different, treadmill-based VRT was a safe and well-tolerated intervention that was positively rated by people after stroke. VR training might, therefore, be a valuable addition to stroke rehabilitation.
Lay Summary
VRT is feasible and was positively experienced by people after stroke. However, VRT was not more effective than non-VRT for improving walking ability and participation after stroke.
The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross‐sectional cohort of patients of varying type, disease severity and ...age. Thirty‐one patients with SMA types 2 and 3 (aged 29.6 7.6‐73.9 years) and 20 healthy controls (aged 37.9 17.7‐71.6 years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded HFMSE) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = −0.56 and −0.59; both P < .001) whereas for fat fraction values are τ = −0.50 and −0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.
qMRI of thigh muscle in a cross‐sectional cohort of spinal muscular atrophy patients reveals an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls. We acknowledged the confounding effect of fatty infiltration on our data with simulations. DTI parameters FA and MD manifest stronger effects than can be accounted for by the effect of fat replacement. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction.
Objectives
Quantitative MRI (qMRI) of muscles is a promising tool to measure disease progression or to assess therapeutic effects in neuromuscular diseases. Longitudinal imaging studies are needed to ...show sensitivity of qMRI in detecting disease progression in spinal muscular atrophy (SMA). In this pilot study we therefore studied one‐year changes in quantitative MR parameters in relation to clinical scores.
Methods
We repeated quantitative 3 T MR analysis of thigh muscles and clinical testing one year after baseline in 10 treatment‐naïve patients with SMA, 5 with Type 2 (21.6 ± 7.0 years) and 5 with Type 3 (33.4 ± 11.9 years). MR protocol consisted of Dixon, T2 mapping and diffusion tensor imaging (DTI). The temporal relation of parameters was examined with a mixed model.
Results
We detected a significant increase in fat fraction (baseline, 38.2% SE 0.6; follow‐up, 39.5% SE 0.6; +1.3%, p = 0.001) in all muscles. Muscles with moderate to high fat infiltration at baseline show a larger increase over time (+1.6%, p < 0.001). We did not find any changes in DTI parameters except for low fat‐infiltration muscles (m. adductor longus and m. biceps femoris (short head)). The T2 of muscles decreased from 28.2 ms to 28.0 ms (p = 0.07). Muscle strength and motor function scores were not significantly different between follow‐up and baseline.
Conclusion
Longitudinal imaging data show slow disease progression in skeletal muscle of the thigh of (young‐) adult patients with SMA despite stable strength and motor function scores. Quantitative muscle imaging demonstrates potential as a biomarker for disease activity and monitoring of therapy response.
Quantitative 3T MRI of thigh muscle in spinal muscular atrophy patients detected a significant increase in fat fraction and decrease in T2 over the course of one year. We did not find any changes in the DTI parameters MD and FA except for low fat‐infiltration muscles (m. adductor longus and m. biceps femoris (short head)). Muscle strength and motor function scores remained stable. Quantitative muscle MRI demonstrates potential as a biomarker for disease activity and monitoring of therapy response.
Patients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients ...consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants.
An online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint.
There was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results.
The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.
Plasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint ...in clinical trials.
We used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.
A total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale-Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39-0.46), p<0.001), muscle strength (0.55 (0.51-0.58), p<0.001) and overall mortality (HR 0.88 (0.86-0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.
Plasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient's functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.
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