Amyotrophic lateral sclerosis & frontotemporal degeneration最新文献

Objective: The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a commonly used outcome measure in clinical trials for motor neuron disease (MND) therapies. As such, understanding how differences in scores relate to patient perception of their disease status is important when interpreting ALSFRS-R data. Our study sought to estimate the minimal important difference (MID) for the ALSFRS-R, the smallest difference in scores at which patients perceive a change in their quality of life. Methods: Data were collected as part of a longitudinal, observational saliva management study, ProSec3. These included both the ALSFRS-R and a global rating of change question (GRoC), which asked participants to rate how their disease had progressed since the previous visit. Anchor-based and distribution-based methods have been used to estimate the MID of the ALSFRS-R. The MID was estimated using two methods of calculating the total ALSFRS-R score, the original summation scale method and the recently proposed interval scale method. Results: A total of 145 people with MND had longitudinal ALSFRS-R and GRoC data. Different methods estimated the ALSFRS-R MID to be in the range of 2.02-5.43 for the summation scale and 1.23-3.31 for the interval scale method over a 3-month period, the time between study visits. Using anchor-based methods our MID estimates for the ALSFRS-R are 3.8 points and 2 points, respectively. Conclusions: The results of this study can guide clinicians and researchers in the interpretation of ALSFRS-R data. However, further studies are required to more precisely estimate the ALSFRS-R MID.

Objective: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9_pos). Further, we compared C9_pos and C9_neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status.

Methods: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients.

Results: The study enrolled 500 ALS patients, 8.8% of whom were C9_pos, with half being sporadic ALS cases. The proportion of C9_pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9_pos patients had non-Finnish European descent and were not closely related. C9_pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9_neg patients.

Conclusion: C9_pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9_pos patients has proven to be challenging. Half of C9_pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.

Evidence from neuroimaging studies suggests that the cardinal clinical manifestations of ALS stem from the dysfunction of specific neural networks. The majority of cortico-cortical and cortico-basal networks are physiologically relayed by deep cerebral and cerebellar grey matter nuclei which have been increasingly implicated in the pathophysiology of ALS. A series of recent human imaging papers revealed volume reductions, shape deformations, metabolic alterations and more recently, susceptibility changes in hippocampal subfields, thalamic, striatal, amygdalar and cerebellar nuclei. Thalamic changes have been identified in presymptomatic mutation carriers long before symptom onset and longitudinal studies have consistently confirmed progressive subcortical degeneration during the symptomatic phase of the disease. The dysfunction of circuits relayed by specific subcortical nuclei has been associated with apathy, amnestic deficits, limbic symptoms, extrapyramidal manifestations, sensory disturbances, pseudobulbar affect and cerebellar deficits. In light of emerging imaging data, the clinical heterogeneity of ALS is probably best approached from a network integrity perspective. Accordingly, the comprehensive assessment of subcortical grey matter nuclei seems imperative to untangle complex clinical phenomena in ALS.

Objective: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS).

Methods: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP).

Results: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r = 0.50, p < 0.001) and isRDP (r = 0.53, p < 0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period.

Conclusions: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.

Objective: Amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS.

Methods: Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. "Habituation" and "lack of habituation" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups.

Results: Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p = 0.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p = 0.239) which indicated lack of habituation.

Conclusions: Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.

Objective: To apply the multistep model of pathogenesis in amyotrophic lateral sclerosis (ALS) to data from a multiethnic Malaysian registry.

Methods: Clinical data, including age at symptom onset, was collected from 289 patients who presented to our multidisciplinary clinic from 2016 until 2024. A least squares linear regression model was constructed from the logarithm of approximated incidence and the logarithm of age. Population incidence was approximated by adjusting the absolute numbers of patients in 5 year groups by the size of the general population in the respective age group.

Results: A linear relationship between log of incidence versus log of age was observed, with a slope of 4.57 (95% CI, 3.3-5.8) and an r² value of 0.93, suggesting a 6-step process.

Conclusion: Progression toward symptom onset in Malaysian ALS patients appears consistent with a multistep model of disease as observed in other cohorts.

Background: The rate of disease progression, measured by the decline of ALS Functional Rating Scale-Revised (ALSFRS-R) from symptom onset to diagnosis (ΔFS) is a well-established prognostic biomarker for predicting survival. Objectives: This study aims to categorize a large patient cohort based on the initial ΔFS and subsequently investigate survival deviations from the expected prognosis defined by ΔFS.

Methods: 1056 ALS patients were stratified into three progression categories based on their ΔFS: slow progressors (below 25th percentile), intermediate progressors (between 25th and 75th percentiles), and fast progressors (above 75th percentile). Survival outcomes were classified as short survivors (<2 years), average survivors (2-5 years), and long survivors (>5 years). Clinical and demographic characteristics within each subgroup were then analyzed.

Results: ΔFS stratification yielded cutoff values of <0.29, 0.29-1.03, and >1.03 points/month. Long survivors comprised 26% and 21% were short survivors. Six percent of the fast progressors had a life expectancy of more than 5 years, and none of the clinical and demographic characteristics analyzed could fully explain this discrepancy. Conversely, 13% of intermediate progressors lived less than 2 years, according to a short-diagnostic delay in these patients.

Discussion: Our study reaffirms ΔFS as a prognostic biomarker for ALS. We disclosed outliers defying anticipated patterns. The observed shift in progression categories underscores the non-linear nature of disease progression. Genetic and unknown biological reasons may explain these deviations. Further research is needed to fully understand modulation of ALS survival.

Objective: A high glycemic index and high glycemic load diet has been associated with slower progression of amyotrophic lateral sclerosis (ALS), suggesting a benefit from high blood glucose levels. We examined the association between average blood glucose level and ALS progression in two independent cohorts.

Methods: Sporadic ALS patients enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS) who completed a 3-month follow-up visit and had available blood samples were included. Hemoglobin A1c (HbA1c) was measured from whole blood collected at the 3-month follow-up. From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we included ALS patients with one or more HbA1c measurements at enrollment and available death information. Associations between HbA1c with revised ALS functional rating scale (ALSFRS-R)/ALSFRS total score change, and tracheostomy-free survival/survival were examined in these cohorts using linear regression, linear mixed-effects models, and Cox proportional hazard models, adjusted for covariates.

Results: In the ALS COSMOS cohort (n = 193), HbA1c level was not significantly associated with the change in the ALSFRS-R total score from baseline to the 3-month follow-up (p = 0.8) nor baseline to the 6-month follow-up (p = 0.4). No significant association was found between HbA1c level and tracheostomy-free survival (p = 0.8). In the PRO-ACT cohort (n = 928), no significant association was found between HbA1c level and the rate of ALSFRS decline in the first 200 days (p = 0.81 for interaction) nor between HbA1c level and survival (p = 0.45).

Interpretation: We did not find convincing evidence that mean blood glucose level is associated with disease progression among ALS patients.