Amyotrophic lateral sclerosis & frontotemporal degeneration最新文献

Objective: The Latin American Epidemiologic study of ALS (LAENALS) aims to gather data on ALS epidemiology, phenotype, and risk factors in Cuba, Chile, and Uruguay, to understand the impact of genetic and environmental factors on ALS.

Methods: A harmonized data collection protocol was generated, and a Latin-American Spanish language Register was constructed. Patient data were collected in Uruguay in 2018, in Chile from 2017 to 2019, and in Cuba between 2017 and 2018. Statistical analysis was performed using SPSS 25.0.0 software. Crude cumulative incidence, standardized incidence, and prevalence were calculated in the population aged 15 years and older.

Results: During 2017-2019, 90 people with ALS from Uruguay (55.6% men), 219 from Chile (54.6% men), and 49 from Cuba (55.1% men) were included. The cumulative crude incidence in 2018 was 1.73/100,000 persons in Uruguay, 1.08 in Chile and 0.195 in Cuba. Crude prevalence in 2018 was 2.19 per 100,000 persons in Uruguay, 1.39 in Chile and 0.55 in Cuba. Mean age at onset was 61.8 ± 11.96 SD years in Uruguay, 61.9 ± 10.4 SD years in Chile, and 60.21 ± 12.45 SD years in Cuba (p = 0.75). Median survival from onset was 32.43 months (21.93 - 42.36) in Uruguay, 24 months (13.5 - 33.5) in Chile, and 29 months (15 - 42.5) in Cuba (p = 0.006).

Conclusions: These preliminary data from LAENALS confirm the lower incidence and prevalence of ALS in counties with admixed populations. The LAENALS database is now open to other Latin American countries for harmonized prospective data collection.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by progressive muscle weakness, atrophy, and paralysis. The FUS mutation-associated ALS has been classified as ALS6. We reported a case of ALS6 with de novo mutation and investigated retrospectively the characteristics of cases with FUS mutation.

Methods: We reported a male patient with a new heterozygous variant of the FUS gene and comprehensively reviewed 173 ALS cases with FUS mutation. The literature was reviewed from the PubMed MEDLINE electronic database (https://www.ncbi.nlm.nih.gov/pubmed) using "Amyotrophic Lateral Sclerosis and Fus mutation" or "Fus mutation" as key words from 1 January 2009 to 1 January 2022.

Results: We report a case of ALS6 with a new mutation point (c.1225-1227delGGA) and comprehensively review 173 ALS cases with FUS mutation. Though ALS6 is all with FUS mutation, it is still a highly heterogenous subtype. The average onset age of ALS6 is 35.2 ± 1.3 years, which is much lower than the average onset age of ALS (60 years old). Juvenile FUS mutations have an aggressive progression of disease, with an average time from onset to death or tracheostomy of 18.2 ± 0.5 months. FUS gene has the characteristics of early onset, faster progress, and shorter survival, especially in deletion mutation p.G504Wfs *12 and missense mutation of p.P525L.

Conclusions: ALS6 is a highly heterogenous subtype. Our study could allow clinicians to better understand the non-ALS typical symptoms, phenotypes, and pathophysiology of ALS6.

Objective: To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature.

Methods: Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family.

Results: We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant (C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant.

Conclusions: The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.

Background: Caregivers of Amyotrophic Lateral Sclerosis (ALS) patients experience varying psychological responses following the patient's death, including sadness, loneliness, guilt, and a loss of purpose.

Objectives: This research aims to investigate the caregiver journey experienced from the time of diagnosis to the loss of a care recipient, with a specific focus on understanding the factors that contribute to improved coping with bereavement.

Methods: The present study used the Interpretative Phenomenological Approach (IPA) to qualitatively explore the accounts of 41 Italian bereaved caregivers of people affected by ALS (Mean Age = 59.78; Female: 60.98%; Male: 39.02%).

Results: Results revealed 5 overarching themes representing 5 macro areas that emerged from the analysis of the interviews ("Caregiver's perception of his/her life", "Caregiver's feelings", "Caregiver's life after patient's death", "Caregiver's disease description", "Caregiver's help resources"), these were further defined based on 12 main themes, which were, in turn, articulated into 30 subthemes. The transition from life before ALS ("a peaceful landscape") to caregiver life (compared to the color "black") was a "shock", during which caregivers had to change their needs. However, life after the person living with ALS' death was both characterized by a sense of "re-birth" and "emptiness", and a general need for "psychological assistance" and "social support".

Conclusions: Results emphasize the need to improve the psychological support offered to caregivers of person living with ALS after the patient's death, tailoring it to the specificity of the condition, to meet their emotional needs, reduce isolation and help them cope with practical challenges and plans.

Objective: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.

Methods: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.

Results: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.

Conclusions: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

Objective: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with profound unmet need. In patients carrying genetic mutations, elevations in neurofilament light (NfL) have been shown to precede symptom onset, however, the natural history of NfL in general ALS patients is less characterized.

Methods: We performed a secondary analysis of the UK Biobank Pharma Proteomics Project (UKB-PPP), a subset of the UK Biobank, a population-based cohort study in the United Kingdom, to examine plasma NfL levels in 237 participants subsequently diagnosed with ALS. We applied logistic and Cox proportional hazards regression to compare cases to 42,752 population-based and 948 age and sex-matched controls. Genetic information was obtained from exome and genotype array data.Results and Conclusions: We observed that NfL was 1.42-fold higher in cases vs population-based controls. At two to three years pre-diagnosis, NfL levels in patients exceeded the 95^th percentile of age and sex-matched controls. A time-to-diagnosis analysis showed that a 2-fold increase in NfL levels was associated with a 3.4-fold risk of diagnosis per year, with NfL being most predictive of case status at two years (AUC = 0.96). Participants with genetic variation that might put them at risk for familial disease (N = 46) did not show a different pattern of association than those without (N = 191).

Discussion: Our findings show that NfL is elevated and discriminative of future ALS diagnosis up to two years prior to diagnosis in patients with and without genetic risk variants.

Objective: While motor symptoms are well-known in ALS, non-motor symptoms are often under-reported and may have a significant impact on quality of life. In this study, we aimed to examine the nature and extent of non-motor symptoms in ALS.

Methods: A 20-item questionnaire was developed covering the domains of autonomic function, sleep, pain, gastrointestinal disturbance, and emotional lability, posted online and shared on social media platforms to target people with ALS and controls.

Results: A total of 1018 responses were received, of which 927 were complete from 506 people with ALS and 421 unaffected individuals. Cold limbs (p 1.66 × 10^-36), painful limbs (p 6.14 × 10^-28), and urinary urgency (p 4.70 × 10^-23) were associated with ALS. People with ALS were more likely to report autonomic symptoms, pain, and psychiatric symptoms than controls (autonomic symptoms B = 0.043, p 6.10 × 10^-5, pain domain B = 0.18, p 3.72 × 10^-11 and psychiatric domain B = 0.173, p 1.32 × 10^-4).

Conclusions: Non-motor symptoms in ALS are common. The identification and management of non-motor symptoms should be integrated into routine clinical care for people with ALS. Further research is warranted to investigate the relationship between non-motor symptoms and disease progression, as well as to develop targeted interventions to improve the quality of life for people with ALS.

Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Prognostication remains sub-optimally defined. We aimed to assess clinical determinants of disease progression rates in Indian patients with ALS and to assess the role of vascular endothelial growth factor (VEGF) in disease progression.

Methods: In this cross-sectional study, consecutive patients with clinically definite/probable ALS according to the revised El Escorial criteria and controls were included. Patients were classified into fast or slow progressors based on disease progression rate (DPR). Serum and CSF VEGF level was assessed for patients and controls.

Results: Of 142 patients recruited, 93 (65.5%) were male. Mean age at enrollment was 49.37 ± 12.65 years. Mean duration of symptoms was 20.53 ± 20.88 months. Mean DPR was 1.14 ± 0.94. Based on DPR, 81 (57%) patients were slow progressors and 61 (43%) were fast progressors. Univariate analysis demonstrated a statistically significant association of DPR with age at onset, symptom duration, time to spread, wasting of small muscles of the hand, frontal release signs, and neurophysiologic bulbar abnormalities. On multivariate analysis, age at onset and symptom duration had a significant association with disease progression. The CSF VEGF levels of ALS patients (46.18 ± 27.8) were significantly elevated compared to controls (25.95 ± 25.64 pg/ml) (p = 0.001), but not serum VEGF.

Conclusion: Age at symptom onset and duration of disease had a significant impact on disease progression in Indian patients with ALS. CSF VEGF levels were significantly elevated in ALS compared to controls, indicating the role of CSF VEGF as a potential biomarker.

Objective: Outcomes for amyotrophic lateral sclerosis (ALS) patients are improved with prompt diagnosis, earlier initiation of disease-modifying treatments, and participation in a multidisciplinary clinic. We studied diagnostic delay and disease severity at time of clinic presentation between Black and non-Hispanic Caucasian ALS patients.

Methods: We performed a retrospective analysis of non-Hispanic Caucasian and Black ALS patients seen in the Virginia Commonwealth University Health System multidisciplinary ALS clinic between 2017 and 2023. Diagnostic delay, ALS Functional Rating Scale-Revised (ALSFRS-R) and upright forced vital capacity (FVC) scores at baseline appointment were collected. Patient's distance from clinic and affluency of residential neighborhood were evaluated.

Results: We analyzed 172 non-Hispanic Caucasian and 33 Black ALS patients. Black patients had a 64% increase in diagnostic delay compared to non-Hispanic Caucasian patients. Black patients had a lower performance on ALSFRS-R (5.3 points, p < 0.001) and FVC (17.9 percentage points p < 0.001) at time of first clinic visit. Black patients lived closer to clinic, with higher proportion living in the city of Richmond, but in less affluent areas with lower median house income ($55,300 ± 22,600 vs $69,900 ± 23,700).

Discussion: Our findings demonstrate a large racial difference in ALS diagnostic delay, and greater disease severity and lower respiratory function at time of diagnosis for Black ALS patients. Delay in diagnosis prolongs access to disease-modifying therapies, multidisciplinary care, durable medical equipment, and respiratory and nutritional support. Potential sources of these racial disparities include providers' implicit bias and structural racism.