Amyotrophic lateral sclerosis & frontotemporal degeneration最新文献

Clinical onset and exacerbation of autosomal dominant SPG9A hereditary spastic paraplegia, including reversible wasting, has been described during pregnancy. SPG9A is due to ALDH18A1 mutations resulting in proline and ornithine deficiency. We present the case of a 29 year old primagravida at 32 weeks who presented with six months of upper limb amyotrophic wasting on a background unrecognized progressive spasticity due to SPG9A. The wasting reversed significantly following delivery. Our report highlights the unusual clinical features including cataract and joint laxity which may suggest SPG9A, echoes the existing descriptions of pregnancy-related provocation of amyotrophy in this condition and documents the outcome of two subsequent pregnancies following dietary intervention.

Objective: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients.

Methods: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients.

Results and conclusions: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.

Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.

Objective: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia.

Methods: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories.

Results: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p < 0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners.

Conclusions: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by neuronal degeneration of the spinal cord and brain and believed to be related to the immune system. In this study, our aim is to use Mendelian randomization (MR) to search for immune markers related to ALS. A total of 731 immune cell traits were included in this study. MR analysis was used to identify the causality between 731 immune cell traits (with 3,757 Europeans) and ALS (with 138,086 Europeans). Colocalization analysis was used to verify the found causality, protein-protein interaction prediction was used to look for the interacting proteins that are known to be involved in ALS. We found low expression levels of CD3 on central memory CD8+ T cell is risk factor for ALS (OR = 0.90, 95% CI: 0.86-0.95, P = 0.0000303). CD3 can interact with three ALS-related proteins: VCP, HLA-DRA and HLA-DRB5, which are associated with adaptive immune response. Our study reported for the first time that low-level CD3 is a risk factor for ALS and the possible mechanism, which could provide a potential strategy for ALS diagnosis and therapy.

The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.

Objective: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs).

Methods: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson's correlation, with p < 0.05 considered significant. Cohen's d was reported to compare the standardized mean difference (SMD) of QSM.

Results: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = -0.845), right CN (SMD = -0.851), whole CN (SMD = -1.016), and left subthalamic nucleus (STN) (SMD = -1.000). Susceptibility in the left putamen (SMD = -0.857), left thalamus (SMD = -1.081), and whole thalamus (SMD = -0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration.

Conclusions: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.

Objective: To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH).

Method: CSF levels of NfL, NfM, and pNfH were analyzed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Center in Stockholm, Sweden. NfM levels were analyzed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations.

Result: Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls. Similarly, higher NfM levels were found in fast compared with slow progressing patients for baseline and longitudinal progression when evaluating both total and subscores of ALSFRS-R. These findings were consistent with the results observed for NfL and pNfH. All three proteins, used individually as well as in combination, showed comparable performance when classifying fast vs slow progressing patients (AUCs 0.78-0.85). For all neurofilaments, higher survival probability was observed for patients with low CSF levels.

Conclusion: Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. Additional investigations with independent cohorts and longitudinal studies are needed to further assess the potential added value of NfM.

Objectives: We investigated the relationship between occupational lead exposure and amyotrophic lateral sclerosis (ALS) survival in Denmark.

Methods: We identified 2,161 ALS cases diagnosed from 1982 to 2013 with at least 5 years of employment history before ALS diagnosis, via the Danish National Patient Registry. Cases were followed until March 2017. We defined lead exposure as never employed in a lead job, ever employed in a lead job, and ever employed in a lead job by exposure probability (<50% vs. ≥50%), excluding jobs held in the 5 years before diagnosis in main analyses. Survival was evaluated using Cox proportional hazards models and stratified by sex and age of diagnosis.

Results: Median age of diagnosis was 63.5 years, and individuals in lead-exposed jobs were diagnosed at a younger age. Adjusted hazard ratios (aHR) were slightly decreased for men ever lead-exposed (aHR:0.92, 95%CI: 0.80, 1.05) and more so among those diagnosed at age 60-69 (lead ≥ 50% aHR: 0.66, 95%CI: 0.45, 0.98), but reversed for men diagnosed at age 70 and later (aHR: 2.03, 95%CI: 1.13, 3.64). No apparent pattern was observed among women.

Conclusions: Occupational lead exposure contributed to shorter survival among men diagnosed at older ages. The inverse associations observed for men diagnosed earlier could relate to possible healthy worker hire effect or health advantages of working in lead-exposed jobs. Our results are consistent with an adverse impact of lead exposure on ALS survival at older ages, with the age at which lead's effects on survival worsen later on among those in lead-exposed jobs.