Lipids, Apolipoproteins, Statins, and Intracerebral Hemorrhage: A Mendelian Randomization Study.

OBJECTIVE: To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease. METHODS: Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH. RESULTS: Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH. INTERPRETATION: Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022;92:390-399.

Mutation-specific metabolic profiles in presymptomatic amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Growing evidence shows that ALS patients feature a disturbed energy metabolism. However, these features have rarely been investigated in the presymptomatic stage. METHODS: A total of 60 presymptomatic ALS mutation carriers and 70 age- and gender-matched controls (non-mutation carriers from the same families) were recruited. All subjects underwent assessments of their metabolic profiles under fasting conditions at enrollment, including body mass index (BMI), blood pressure and serum levels of blood glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein. RESULTS: All mutations combined, no differences between presymptomatic ALS gene carriers and controls were found. From a cardiovascular point of view, presymptomatic chromosome 9 open reading frame 72 (C9ORF72) gene carriers showed lower cardiovascular risk profiles compared to healthy controls, including lower BMI (median 22.9, interquartile range [IQR] 20.6-26.1 kg/m2 vs. 24.9, IQR 22.7-30.5 kg/m2 ; p = 0.007), lower systolic blood pressure (120, IQR 110-130 mmHg vs. 128, IQR 120-140 mmHg; p = 0.02), lower fasting serum glucose (89.0, IQR 85.0-97.0 mg/dl vs. 96.0, IQR 89.3-102.0 mg/dl; p = 0.005) and higher HDL (1.6, IQR 1.3-1.8 mmol/l vs. 1.2, IQR 1.0-1.4 mmol/l; p = 0.04). However, presymptomatic superoxide dismutase 1 (SOD1) gene mutation carriers showed higher cardiovascular risk profiles compared to healthy controls, including higher BMI (28.0, IQR 26.1-31.5 kg/m2 vs. 24.9, IQR 22.7-30.5 kg/m2 ; p = 0.02), higher fasting serum glucose (100.0, IQR 94.0-117.0 mg/dl vs. 96.0, IQR 89.3-102.0 mg/dl; p = 0.04) and lower HDL (1.2, IQR 1.0-1.4 mmol/l vs. 1.4, IQR 1.2-1.7 mmol/l; p = 0.01). These features were most prominent in patients carrying SOD1 gene mutations associated with slow disease progression. CONCLUSIONS: This study identified distinct metabolic profiles in presymptomatic ALS gene carriers, which might be associated with disease progression in the symptomatic phase.

Lipids and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.

OBJECTIVE: Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis. METHODS: Using genome-wide association study summary-level data for total cholesterol (TC) (n = 188,578), high-density lipoprotein cholesterol (HDL-C) (n = 403,943), low-density lipoprotein cholesterol (LDL-C) (n = 440,546), apolipoprotein A1 (ApoA1) (n = 391,193), apolipoprotein B (ApoB) (n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL-C is a potential mediator on the pathway from traits of LDL-C-related polyunsaturated fatty acids (PUFAs) to ALS risk. RESULTS: We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL-C had the most potent effect (OR 1.028, 95% CI 1.008-1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL-C-modifying lifestyles and ALS. The mediation analysis revealed that LDL-C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009. CONCLUSIONS: We provided high-level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL-C in the pathway from PUFAs to ALS.

Trends in the clinical features of amyotrophic lateral sclerosis: A 14-year Chinese cohort study.

BACKGROUND AND PURPOSE: The aim was to determine the transitional patterns in the clinical characteristics, treatments and comorbidities in amyotrophic lateral sclerosis (ALS) patients over the past 14 years using data from a large clinical cohort in mainland China. METHODS: Sporadic ALS patients who visited the Peking University Third Hospital from January 2005 to December 2018 were included in this study. The 14 years were divided into three periods, and changes in the baseline characteristics of the participants were analyzed at 5-year intervals. RESULTS: In total, 3410 patients with sporadic ALS were recruited: 2181 were men and 1229 were women. The proportion of patients with bulbar-onset ALS increased from 13.0% in 2005-2009 to 19.5% in 2015-2018 (p < 0.001). The mean (standard deviation) age at onset increased from 49.5 (11.4) years in 2005-2009 to 53.0 (11.0) years in 2015-2018 (p < 0.001). ALS patients with diabetes or hypertension showed a delay in ALS onset, and the delay was even more apparent when the patients had both comorbidities. The proportion of riluzole users in 2015-2018 was approximately 2.5-fold of that in 2005-2009 (p < 0.001). CONCLUSIONS: In the context of a lack of clinical data on ALS in mainland China, this study evaluated a large cohort of patients diagnosed over a 14-year period. The age at onset and percentage of patients who used riluzole both increased over the study period. Additionally, it was found that patients with comorbidities such as diabetes and hypertension had a delayed age of ALS onset.

Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease.

Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease.

Essential Nutrients and White Matter Hyperintensities: A Two-Sample Mendelian Randomization Study.

Stroke and dementia have been linked to the appearance of white matter hyperintensities (WMHs). Meanwhile, diffusion tensor imaging (DTI) might capture the microstructural change in white matter early. Specific dietary interventions may help to reduce the risk of WMHs. However, research on the relationship between specific nutrients and white matter changes is still lacking. We aimed to investigate the causal effects of essential nutrients (amino acids, fatty acids, mineral elements, and vitamins) on WMHs and DTI measures, including fraction anisotropy (FA) and mean diffusivity (MD), by a Mendelian randomization analysis. We selected single nucleotide polymorphisms (SNPs) associated with each nutrient as instrumental variables to assess the causal effects of nutrient-related exposures on WMHs, FA, and MD. The outcome was from a recently published large-scale European Genome Wide Association Studies pooled dataset, including WMHs (N = 18,381), FA (N = 17,663), and MD (N = 17,467) data. We used the inverse variance weighting (IVW) method as the primary method, and sensitivity analyses were conducted using the simple median, weighted median, and MR-Egger methods. Genetically predicted serum calcium level was positively associated with WMHs risk, with an 8.1% increase in WMHs risk per standard deviation unit increase in calcium concentration (OR = 1.081, 95% CI = 1.006-1.161, p = 0.035). The plasma linoleic acid level was negatively associated with FA (OR = 0.776, 95% CI = 0.616-0.978, p = 0.032). Our study demonstrated that genetically predicted calcium was a potential risk factor for WMHs, and linoleic acid may be negatively associated with FA, providing evidence for interventions from the perspective of gene-environment interactions.

Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects.

BACKGROUND: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. METHODS: Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. RESULTS: Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013-1.141, p = 0.017; after removing: OR = 1.036, 95% CI = 0.949-1.131, p = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823-1.296, p = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991-1.005, p = 0.538) had no association with ALS. CONCLUSIONS: Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention.

Systematic Screening of Associations between Medication Use and Risk of Neurodegenerative Diseases Using a Mendelian Randomization Approach.

BACKGROUND: Systematically assessing the causal associations between medications and neurodegenerative diseases is significant in identifying disease etiology and novel therapies. Here, we investigated the putative causal associations between 23 existing medication categories and major neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS: A two-sample mendelian randomization (MR) approach was conducted. Estimates were calculated using the inverse-variance weighted (IVW) method as the main model. A sensitivity analysis and a pleiotropy analysis were performed to identify potential violations. RESULTS: Genetically predisposition to antihypertensives (OR = 0.809, 95% CI = 0.668-0.981, p = 0.031), thyroid preparations (OR = 0.948, 95% CI = 0.909-0.988, p = 0.011), and immunosuppressants (OR = 0.879, 95% CI = 0.789-0.979, p = 0.018) was associated with a decreased risk of AD. Genetic proxies for thyroid preparations (OR = 0.934, 95% CI = 0.884-0.988, p = 0.017), immunosuppressants (OR = 0.825, 95% CI = 0.699-0.973, p = 0.022), and glucocorticoids (OR = 0.862, 95% CI = 0.756-0.983, p = 0.027) were causally associated with a decreased risk of PD. Genetically determined antithrombotic agents (OR = 1.234, 95% CI = 1.042-1.461, p = 0.015), HMG CoA reductase inhibitors (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005), and salicylic acid and derivatives (OR = 1.294, 95% CI = 1.078-1.553, p = 0.006) were associated with an increased risk of ALS. CONCLUSIONS: We presented a systematic view concerning the causal associations between medications and NDs, which will promote the etiology discovery, drug repositioning and patient management for NDs.

Unlocking the Medicinal Mysteries: Preventing Lacunar Stroke with Drug Repurposing.

Currently, only the general control of the risk factors is known to prevent lacunar cerebral infarction, but it is unknown which type of medication for controlling the risk factors has a causal relationship with reducing the risk of lacunar infarction. To unlock this medical mystery, drug-target Mendelian randomization analysis was applied to estimate the effect of common antihypertensive agents, hypolipidemic agents, and hypoglycemic agents on lacunar stroke. Lacunar stroke data for the transethnic analysis were derived from meta-analyses comprising 7338 cases and 254,798 controls. We have confirmed that genetic variants mimicking calcium channel blockers were found to most stably prevent lacunar stroke. The genetic variants at or near HMGCR, NPC1L1, and APOC3 were predicted to decrease lacunar stroke incidence in drug-target MR analysis. These variants mimic the effects of statins, ezetimibe, and antisense anti-apoC3 agents, respectively. Genetically proxied GLP1R agonism had a marginal effect on lacunar stroke, while a genetically proxied improvement in overall glycemic control was associated with reduced lacunar stroke risk. Here, we show that certain categories of drugs currently used in clinical practice can more effectively reduce the risk of stroke. Repurposing several drugs with well-established safety and low costs for lacunar stroke prevention should be given high priority when doctors are making decisions in clinical practice. This may contribute to healthier brain aging.

Essential nutrients and cerebral small vessel diseases: a two-sample Mendelian randomization study.

Background: Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed. Object: We intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis. Method: We obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR-Egger method were adopted for sensitivity analyses. Results: For ICH or SVS, increased levels of phenylalanine (OR = 1.188, p < 0.001) and dihomo-gamma-linolenic acid (DGLA) (OR = 1.153, p = 0.001) showed risk effects, while docosapentaenoic acid (DPA) (OR = 0.501, p < 0.001), zinc (OR = 0.919, p < 0.001), and arachidonic acid (OR = 0.966, p = 0.007) showed protective effects. For lobar hemorrhage or SVS, AA (OR = 0.978, p < 0.001), zinc (OR = 0.918, p < 0.001), and retinol (OR = 0.753, p < 0.001) showed risk effects; DPA (OR = 0.682, p = 0.022), gamma-linolenic acid (OR = 0.120, p = 0.033) and 25(OH)D (OR = 0.874, p = 0.040) showed protective effects. For nonlobar hemorrhage or SVS, DGLA (OR = 1.088, p < 0.001) and phenylalanine (OR = 1.175, p = 0.001) showed risk effects. Conclusion: Our study analyzed the effect of nutrients on CSVD risk from a genetic perspective, with implications for CSVD prevention through nutrient supplementation.

Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). It remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertensive drugs (AHDs), ALS, and their corresponding genome-wide association study (GWAS) summary datasets were obtained from the most recent studies with the largest sample sizes. The inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods were used for sensitivity analyses. To exclude the interference between SBP and DBP, a multivariable MR approach was used. RESULTS: We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960-0.996, P = 0.017) and that increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003-1.025, P = 0.015), which is supported by sensitivity analyses. The use of calcium channel blocker (CCB) showed a causal relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused changes in BP. CONCLUSIONS: This study provides genetic support for a causal effect of BP and ALS that increased DBP has a protective effect on ALS, and increased SBP is a risk factor for ALS, which may be related to sympathetic excitability. Blood pressure management is essential in ALS, and CCB may be a promising candidate.

Dietary-Derived Essential Nutrients and Amyotrophic Lateral Sclerosis: A Two-Sample Mendelian Randomization Study.

Previous studies have suggested a close but inconsistent relationship between essential nutrients and the risk of amyotrophic lateral sclerosis (ALS), and whether this association is causal remains unknown. We aimed to investigate the potential causal relation between essential nutrients (essential amino acids, essential fatty acids, essential minerals, and essential vitamins) and the risk of ALS using Mendelian randomization (MR) analysis. Large-scale European-based genome-wide association studies' (GWASs) summary data related to ALS (assembling 27,205 ALS patients and 110,881 controls) and essential nutrient concentrations were separately obtained. MR analysis was performed using the inverse variance-weighted (IVW) method, and sensitivity analysis was conducted by the weighted median method, simple median method, MR-Egger method and MR-PRESSO method. We found a causal association between genetically predicted linoleic acid (LA) and the risk of ALS (OR: 1.066; 95% CI: 1.011-1.125; p = 0.019). An inverse association with ALS risk was noted for vitamin D (OR: 0.899; 95% CI: 0.819-0.987; p = 0.025) and for vitamin E (OR: 0.461; 95% CI: 0.340-0.626; p = 6.25 × 10-7). The sensitivity analyses illustrated similar trends. No causal effect was observed between essential amino acids and minerals on ALS. Our study profiled the effects of diet-derived circulating nutrients on the risk of ALS and demonstrated that vitamin D and vitamin E are protective against the risk of ALS, and LA is a suggested risk factor for ALS.

Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, whether this association is causal remains unclear. In this study, we aimed to explore the causal relationship between leukocyte telomere length (LTL) and ALS by a two-sample Mendelian randomization (MR) approach. Single-nucleotide polymorphisms (SNPs) for LTL were identified through high-quality genome-wide association studies (GWASs). The ALS GWAS summary data (20,806 cases; 59,804 controls) with largest sample size to date was obtained. We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR-PRESSO method to perform sensitivity analyses. RESULTS: We found that genetically determined increased LTL was inversely associated with the risk of ALS (odds ratio (OR) = 0.846, 95% confidence interval (CI): 0.744-0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. The results were further confirmed by sensitivity analysis with the MR Egger method (OR = 0.647, 95% CI = 0.447-0.936, P = 0.050). Analyses by the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935, P = 0.535) also showed a similar trend. The MR Egger analysis did not suggest directional pleiotropy, with an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. CONCLUSIONS: Our results suggest that genetically predicted increased LTL has a causal relationship with a lower risk of ALS. Protecting against telomere loss may be of great importance in the prevention and treatment of ALS.

Daytime sleepiness might increase the risk of ALS: a 2-sample Mendelian randomization study.

BACKGROUND: Observational studies have indicated that there is a high prevalence of habitual sleep disturbances in amyotrophic lateral sclerosis (ALS). However, the actual relationship between these symptoms and ALS remains unclear. METHODS: We used 2-sample Mendelian randomization to determine whether the sleep disturbances associated with ALS are also related to the risk of ALS. The summary statistics we used were from recent, large genome-wide association studies on daytime sleepiness and other night sleep traits (n = 85,670-452,071) and ALS (n = 20,806 cases, n = 59,804 controls). The inverse variance-weighted (IVW) method was used as the main method for assessing causality. RESULTS: Daytime sleepiness might increase the risk of ALS (IVW odds ratio = 2.45, 95% confidence interval: 1.15-5.21; P = 0.020). ALS was not associated with sleep efficiency, number of sleep episodes or sleep duration. CONCLUSIONS: Our results provide novel evidence that daytime sleepiness increases the risk of ALS and points out the importance of daytime sleepiness that often goes unnoticed in ALS.

Physical activity and amyotrophic lateral sclerosis: a Mendelian randomization study.

Physical activity (PA) participation has been noted as a potential risk factor for amyotrophic lateral sclerosis (ALS) for decades. However, current studies have been unable to pinpoint the exact relationship between them. Here, we used 2-sample Mendelian randomization (MR), a novel method to systematically investigate causal relationships between PA and ALS. Summary-level data for accelerometer-based and self-reported PA phenotypes were obtained from 2 large genome-wide association studies (GWASs; n = 91,105-377,234), and the ALS summary statistics were from a GWAS of 20,806 cases and 59,804 healthy participants. The present MR study affords no support for causality between 5 included activity habits and ALS. We conclude that PA in the general population is unlikely to affect ALS incidence.

Education, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study.

OBJECTIVE: To systematically investigate causal relationships between educational attainment, cognitive-related phenotypes, and amyotrophic lateral sclerosis (ALS). METHODS: Summary statistics from genome-wide association studies for educational attainment, math ability, highest math class taken, cognitive performance, intelligence, and ALS were used. A two-sample Mendelian randomization (MR) design was applied to explore the potential causal associations between them. RESULTS: Genetically predisposition to longer educational attainment and harder math class taken were associated with significantly lower statistical odds ratio of ALS. For per year increase in education completed there was a 21% lower (95% confidence interval [CI] = 27-14%) in risk for ALS. For per 1-SD increase in the highest math class taken obtained there was a 19% lower (95% CI = 9-28%) in risk for ALS. Genetically predisposition to math ability, cognitive performance, and intelligence did not decrease the risk of ALS. INTERPRETATION: This study provides genetic support for a causal association between higher educational attainment and a lower risk of ALS. The genes related to these phenotypes are involved in almost all aspects of neuron-to-neuron communication. ALS patients are occasionally accompanied by varying degrees of cognitive impairment. People with greater cognitive reserve may be better able to offset damages of degenerative brain changes associated with dementia or other brain diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or ALS.

Increased Interleukin-6 Levels in the Astrocyte-Derived Exosomes of Sporadic Amyotrophic Lateral Sclerosis Patients.

Neuroinflammation plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. However, it is difficult to evaluate inflammation of the central nervous system (CNS) or the relationship between neuroinflammation and disease progression in ALS patients. Recent advances in the field of exosomes and CNS-derived exosomes extraction technology provide the possibility of measuring the inflammatory status in the CNS without brain biopsy. In this pilot study, we extracted astrocyte-derived exosomes from the plasma of sporadic ALS patients and age-, sex-matched healthy controls and determined Interleukin-6 (IL-6) levels by an enzyme-linked immunosorbent assay (ELISA). The IL-6 levels in astrocyte-derived exosomes were increased in sALS patients and positively associated with the rate of disease progression. However, the association between IL-6 levels and disease progression rate was limited to patients whose disease duration were less than 12 months. These data suggest an increased inflammatory cascade in the CNS of sALS patients. Our pilot study demonstrates that CNS-derived exosomes could be useful to reveal neuroinflammation of the CNS in ALS patients.