Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis.

OBJECTIVE: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. METHODS: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. RESULTS: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. INTERPRETATION: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024.

High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis.

BACKGROUND: Uric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients. METHODS: We enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007-2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT). RESULTS: Out of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (µmol/L; ALS-INT, 289.7 ± 75.5 µmol/L; ALS-FTD, 271.8 ± 74.9 µmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01-1.43; p = 0.038) in binary logistic regression. CONCLUSIONS: We found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.

Mycotoxins and Amyotrophic Lateral Sclerosis: food exposure, nutritional implications and dietary solutions.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder determined by a combination of both genetic and environmental factors. Despite wide investigations, the role of chronic exposure to environmental pollutants is still rather unknown. Among natural toxins, the mycotoxins have received major attention only in the last few years, due to both technical and scientific achievements that allowed to disentangle many important features of the complex fungal biology. Whereas the effects of acute and high-dose mycotoxin exposure are well known, the potential effects of chronic and low-dose exposure on neurodegeneration have not been broadly elucidated. In this review, we have summarized all the studies concerning environmental exposure to unknown substances that caused ALS outbreaks all over the world, reinterpreting in light of the new scientific acquisitions and highlighting the potential and neglected role of mycotoxins. Then, we focused on recent papers about food exposure to mycotoxin, mycobiome and fungal infections in ALS and other neurodegenerative diseases. We analyzed the gaps of current literature that lead to an undervaluation of mycotoxins as detrimental molecules. By listing all the most important mycotoxins and analyzing all the biological pathways that they can affect, we explained the reasons why they need to be considered in the next epidemiological studies on ALS and other neurodegenerative and neuroinflammatory diseases. In conclusion, after suggesting some possible solutions to mitigate mycotoxin exposure risk, we affirm that future collaborations between scientists and policymakers are important to develop sustainable interventions and promote health through dietary diversity.

Exposure to electromagnetic fields does not modify neither the age of onset nor the disease progression in ALS patients.

Being exposed to electromagnetic fields has been suggested to increase the risk of developing Amyotrophic Lateral Sclerosis (ALS). Here, we investigated the effect of exposure to electromagnetic fields on ALS onset age and progression rate (ΔALSFRS-r). A large cohort of ALS patients (n = 1098) was geolocalized at the time of their diagnosis. Concomitantly, data on the distribution of power lines and repeater antennas (extremely low frequency electromagnetic fields) during the same period were retrieved. Exposure to each repeater antenna was calculated as the sum of 1/(distance from each antenna)^2. Exposure to power lines was calculated assuming each patient's address as the center of several circles of variable radius (100, 250, 500, 1000, and 2000 m). For each radius, the exposure was calculated as the length of the power lines included in the circle. Finally, patients were divided into low- and high-exposed based on the median of the exposure and compared using the Mann-Whitney test. A regression model (one for each radius) was also performed. Neither the onset age nor the ΔALSFRS-r differed among patients' low- and high-exposed to electromagnetic fields. Similarly, we could not find any significant relationship using the regression models. Our findings suggest that electromagnetic fields do not modify the ALS phenotype or progression.

Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease's complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell's physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification. METHODS: We analyzed plasma-derived EVs of ALS patients (n = 106) and controls (n = 96), and SOD1G93A and TDP-43Q331K mouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis. RESULTS: Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs. CONCLUSIONS: Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis.