Risk Of ALS Research Articles

Antibiotic use might increase risk of ALS.

Antibiotic use might increase risk of ALS.

Type II diabetes mellitus and the incidence of amyotrophic lateral sclerosis.

The aim of this study was to investigate the relationship between type II diabetes mellitus (T2DM) and ALS incidence using the National Health Insurance Research Database and Serious Disabling Disease database of Taiwan. This was a population-based cohort study. The index date was the date of the first T2DM diagnosis + 365days. We included T2DM patients diagnosis between 2000 and 2013 (n = 2,135,427). These patients were matched by sex, age, urbanization, and insurance premium at a ratio of 1:1 to include patients without diabetes mellitus. Competing risk-adjusted Cox regression analysis was performed to investigate the association between T2DM and the incidence of ALS. In the patients not stratified by age, T2DM was not associated with the incidence of ALS after controlling for confounding factors. The interaction test of age subgroup (< 55 and ≥ 55years) and T2DM on ALS risk was significance (p < 0.001). Subgroup analysis showed that T2DM was negatively associated with ALS in patients whose age at the first T2DM diagnosis was ≥ 55years. Among T2DM patients, T2DM combined with hypertension was negatively associated with ALS among patients whose age at the first T2DM diagnosis was ≥ 55years. Among T2DM patients, T2DM combined with hyperlipidemia was positively associated with ALS among patients whose age at the first T2DM diagnosis was < 55years. The late-onset of T2DM may exert negative association with ALS, especially when combined with hypertension. The early-onset of T2DM may exert positive association with ALS, especially when combined with hyperlipidemia.

Is Myopia Associated with the Incidence and Progression of Diabetic Retinopathy?

We sought to determine the association of refractive error and its associated determinants (axial length [AL], anterior chamber depth, and corneal curvature) with the incidence and progression of diabetic retinopathy (DR). Population-based cohort study. A total of 1562 eyes of 840 individuals with diabetes and gradable retinal photographs (mean age [SD], 57.0 [8.3] years, 48.2% female) from the Singapore Malay and Indian Eye Studies at baseline (2004-2009) and follow-up (2011-2015) examinations were included in the analyses. Refractive error was calculated as sphere plus half negative cylinder, while AL, anterior chamber depth, and corneal curvature were assessed using optical biometry. Incident DR was defined as having no baseline DR and any DR at follow-up; incident vision-threatening DR as no baseline vision-threatening DR but present at follow-up; and DR progression as an increase in severity at follow-up from at least minimal baseline DR. Eye-specific data and generalized estimating equation models were used to account for between-eye correlation to determine the relationships between the exposures and outcomes, adjusted for traditional DR risk factors. At follow-up, 164 of 1273 (12.9%) eyes had incident DR, 17 of 1542 (1.1%) eyes had incident vision-threatening DR, and 75 of 269 (27.9%) eyes with baseline DR experienced progression. A longer AL (per millimeter increase) (risk ratio 0.58 [95% confidence interval 0.38-0.88) was associated with a lower risk of incident DR. No other associations were found. Our findings show that a longer AL is protective of incident DR.

PON1 is a disease modifier gene in amyotrophic lateral sclerosis: association of the Q192R polymorphism with bulbar onset and reduced survival.

Previous studies have associated single-nucleotide polymorphisms (SNPs) in the gene encoding the detoxifying enzyme paraoxonase 1 (PON1) to the risk of sporadic ALS. Here, we aimed to assess the role of the coding rs662 (Q192R) SNP as a modifier of ALS phenotype. We genotyped a cohort of 409 patients diagnosed with ALS at our Center between 2002 and 2009 (269 males and 140 females; mean age at onset, 58.3 ± 37.5years). We found PON1 to be a disease modifier gene in ALS, with the minor allele G associated both with bulbar onset (30.9% vs. 24.6%, p = 0.013) and independently with reduced survival (OR = 1.38, p = 0.012) under a dominant model. No association was found with gender or age at onset. As this SNP is known to modify the detoxifying activity of paraxonase 1 with respect to different substrates as well as other activities of the protein, we hypothesize that the identified association might reflect specific motor neuron vulnerability to certain exogenous toxic substances metabolized less efficiently by the 192R alloenzyme, or to detrimental endogenous pathophysiological processes such as oxidative stress. Further exploration of this possible metabolic susceptibility could deepen our knowledge of ALS pathomechanisms.

Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations.

Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.

Routine preoperative mechanical bowel preparation with additive oral antibiotics is associated with a reduced risk of anastomotic leakage in patients undergoing elective oncologic resection for colorectal cancer

BackgroundAnastomotic leakage (AL) following colorectal resection is a serious issue. AL in oncologic patients might negatively affect the overall survival. Recently, mechanical bowel preparation with additive oral antibiotics (MBP + AB) prior to surgery has been suggested as a means of reducing AL. However, it is unclear whether this positive effect is secondary to MBP alone or secondary to the additive oral antibiotic (MBP + AB). The aim of this study was to investigate the effect of mechanical bowel preparation with additive oral antibiotics (MBP + AB) and without additive oral antibiotics (MBP − AB) on the rate of AL following colorectal resection for cancer.Materials and methodsPatients undergoing surgical management for colorectal cancer with anastomosis from January 2014 till September 2017 were included for analysis. Cases undergoing MBP + AB were included in the study group. Patients undergoing MBP − AB were included in the control group. Both groups were compared with regard to the rate of AL.ResultsFour hundred and ninety-six patients: 125 undergoing MBP + AB and 371 undergoing MBP – AB were included for analysis. Significantly, more male patients were included in the MBP – AB group compared to the MBP + AB group: 60.1% vs. 45.6% respectively (p = 0.03). Both groups were similar with regard to age distribution and clinicopathological findings (p > 0.05). The rate of AL was significantly higher in the control group (MBP − AB) compared to study group (MBP + AB) (9.1% vs. 4.0%, p = 0.03).ConclusionMechanical bowel preparation with additive oral antibiotics prior to elective colorectal resection with anastomosis significantly reduces the risk of AL. Therefore, mechanical bowel preparation with additive non-absorbable oral antibiotics should be recommended in all cases prior to elective colorectal surgery.

Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.

Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.

Anastomotic Location Predicts Anastomotic Leakage After Elective Colonic Resection for Cancer

BackgroundAnastomotic leakage (AL) is a potential feared complication after colorectal resection, which is associated with an increased risk of postoperative mortality and frequently requires additional surgery. The aim of this study was to assess major independent risk factors for AL after elective colonic resection for cancer, including anastomotic location. MethodsAmong 1940 consecutive patients referred to our institution for colorectal adenocarcinoma, 1025 patients had elective colonic resection with intraperitoneal anastomosis without diverting stoma. Risk factors were assessed among preoperative, operative, and histological data. ResultsClinical AL was observed in 36 patients (3.5%) with 24 patients requiring revisional surgery (67%). In multivariate analysis, endoscopic impassable tumor and colo-colic or ileo-colic anastomosis were independent risk factors for AL. The occurrence of AL was associated with poor overall (43.1 months vs. 146.4 months; p < 0.001) and disease-free survival (40.5 months vs. 137.3 months; p = 0.003). ConclusionAnastomotic leakage occurs more frequently after colo-colic and ileo-colic anastomosis than after intraperitoneal colorectal anastomosis.The right colectomy appears to be at higher risk of AL, with a greater risk of surgical intervention than after an elective left colectomy. Ileo-colic anastomosis should be avoided in cases of suboptimal conditions.

Prediagnostic body size and risk of amyotrophic lateral sclerosis death in 10 studies

Objectives and Methods: Using pooled multivariable-adjusted rate ratios (RR), we explored relationships between prediagnostic body-mass-index (BMI), waist-to-hip-ratio (WHR), and weight-gain during adulthood, and ALS in 419,894 women and 148,166 men from 10 community-based cohorts in USA, Europe, and Australia; 428 ALS deaths were documented in women and 204 in men. Results: Higher mid-to-later adulthood BMI was associated with lower ALS mortality. For 5 kg/m2 increased BMI, the rate was 15% lower (95% confidence interval [CI]: 4–24%; p = 0.005). Although a clear linear trend was not evident for WHR at enrollment (p = 0.099) individuals in the highest cohort-specific quartile had 27% (95% CI: 0–47%; p = 0.053) lower ALS compared to those in the lowest. BMI in early adulthood did not predict ALS; fewer than 10% of participants had early adulthood BMI >25 kg/m2, limiting power. Weight-gain during adulthood was strongly associated with lower ALS; for an additional 1kg gain in weight/year, the RR = 0.43 (95% CI: 0.28–0.65; p < 0.001). Associations persisted when adjusted for diabetes at enrollment, restricted to never-smokers, and ALS deaths in the 5 years after enrollment were excluded (accounting for recent weight loss). Conclusions: These findings confirm somewhat conflicting, underpowered evidence that adiposity is inversely associated with ALS. We newly demonstrate that weight-gain during adulthood is strongly predictive of lower ALS risk.

Pre-diagnostic branched chain amino acids and the risk of ALS (P5.166)

Pre-diagnostic branched chain amino acids and the risk of ALS (P5.166)

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

ImportanceAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.ObjectivesTo examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways.Design, Setting, and ParticipantsIn this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria.Main Outcomes and MeasuresThe primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models.ResultsAmong 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; β = –0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005).Conclusions and RelevanceThis study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder.

How to Identify Young People al Risk to Change their LIfestyle

How to Identify Young People al Risk to Change their LIfestyle

How to Identify Young People al Risk to Change their LIfestyle

How to Identify Young People al Risk to Change their LIfestyle

Military service and the risk of amyotrophic lateral sclerosis: A meta-analysis

To explore the relationship between the risk of amyotrophic lateral sclerosis and exposure to overall military service, we conducted a search of articles relevant to military service and the risk of ALS that used human subjects and were published in English through 20 May 2016, using Ovid Medline and Embase databases. Studies specially investigating the risk of ALS for Gulf war veterans were excluded. Quality of the cohort and case-control studies was assessed according to the Newcastle-Ottawa Scale (NOS). Analysis of data and publication bias were performed with Review Manager 5.3. A total of 8 case-control studies and 3 cohort studies were included in the meta-analysis. Only two case-control studies were conducted in Japan, comparing to 9 studies conducted in Europe/USA. The NOS scores of all studies were ≥6/9. The risk of ALS was significantly increased in military personnel compared to non-military personnel (pooled OR=1.29, 95% CI: 1.08–1.54, by random-effects model), with a moderate heterogeneity (P=0.01, I2=55%) due to some studies with lower quality, conformed by subgroup and sensitivity analysis. The present meta-analysis supports a positive association between overall military service and the risk of ALS. Additional studies are needed to find out related factors influencing the ALS risk of veterans, especially by gender and for specific geographic regions such as Asia. That would also do some favor to explore the etiology and mechanism of ALS.

PERFORMANCE OF PRIMARY RADICAL SURGERIES IN PATIENTS WITH COLORECTAL CANCER COMPLICATED BY LOCAL PERITONITIS AND ILEUS

155 patients with cancer of proximal rectum and sigmoid colon complicated by acute ileus were included and divided into 2 groups. Postoperative complications have arisen in 5 (5.3%) patients of group I and in 11 (18.4%) patients of group II. Anastomotic leakage has arisen only in 1 patient in the basic group (1.1%) and in 7 (11.7%) patients of the compared group on the 5th-12th day after operation. We have worked out the rate score of risk factors of anastomotic leakage. А score was given for each AL factor which we had selected for elaboration of this scale. The lowest point which we received during this analysis was 7 and the highest was 32. For better analysis of the proposed scale, we have constructed comparing ROC curve between sensitivity and specificity of AL risk index. The area under this curve is 81.8%, which is a good index and it indicates that the proposed risk scale is a good method to identify patients who are at high risk of AL development (95% confidence interval of this area ranges from 73.1% to 90.5%).

Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis.

History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0-14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted. Eligible studies (N = 32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken. Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04-1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05-1.19) and for AML (OR 1.13, 95%CI 0.91-1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02-1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19-4.60). In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.

Association of fractures with the incidence of amyotrophic lateral sclerosis

Objective: Elevated bone turnover observed in ALS patients suggests poor bone health and increased fracture risk. We therefore evaluated the relationship of fracture to subsequent ALS risk.Methods: We followed 4,529,460 Swedes from 1987 to 2010 and identified ALS and fractures from the Swedish National Patient Register. We examined associations of ALS risk with all fractures, osteoporotic and non-osteoporotic fractures, and traumatic and non-traumatic fractures among individuals aged 30–80 years. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We analysed the association of ALS with time since fracture using a Poisson regression model.Results: All fractures (HR: 1.51, 95% CI 1.39–1.65) as well as osteoporotic (HR: 1.59, 95% CI 1.41–1.79), non-osteoporotic (HR: 1.46, 95% CI 1.31–1.63), traumatic (HR: 1.50, 95% CI 1.37–1.63), and non-traumatic (HR: 1.80, 95% CI 1.35–2.40) fractures were associated with a higher incidence of ALS. Increased ALS incidence was associated with fractures occurring from one (HR: 2.33, 95% CI 2.04–2.66) to 18 (HR: 1.19, 95% CI 1.01–1.43) years before ALS diagnosis.Conclusions: Poor bone health may be related to ALS. These findings may offer insight into ALS pathophysiology.

No association between soil constituents and amyotrophic lateral sclerosis relative risk in Ireland

IntroductionWe have recently mapped ALS spatial risk in Ireland using Bayesian and cluster analysis methods at electoral division (ED) and small area (SA) levels. As a number of metal elements (both minerals and toxins) have been proposed as risk factors for ALS, here we extend this analysis to include soil constituents from the Irish National Soils Database as Bayesian conditional auto-regression covariates to determine associations with small area ALS risk. MethodsData on 45 different soil parameters were obtained under license from National Soils Database (via Irish EPA). We interpolated average values of each soil constituent for each small area using ordinary kriging. All cases of ALS in Ireland from January 1995 to December 2013 were identified from the Irish ALS register and observed and age and gender standardised expected cases were calculated for each SA. Besag-York-Mollié (BYM) models were then built including each parameter from the national soils database in turn as a Bayesian covariate in the BYM model. Models were compared using the deviance information criterion (DIC) and separate models were built for ALS subtypes. Results1701 ALS patients were included – 959 (56%) were male, 938 (55%) had limb onset ALS. 315 Bayesian models were built in total. Of the 315 models built, only one resulted in a coefficient that did not overlap zero. For limb onset cases, total magnesium had a mean coefficient of 0.319 (credible interval 0.033–0.607). DiscussionWe report the first spatial analysis of potential association between ALS and soil minerals using a population-based dataset collected over 18 years. Our sole non-zero finding is likely a random finding due to the high number of models built. We did not find any evidence to support soil mineral and toxin levels as risk factors for ALS. However as soil parameters are an ecological assessment of exposure in a given area, individual level measures of exposure are required.

Th17 Cell Response in SOD1G93A Mice following Motor Nerve Injury.

An increased risk of ALS has been reported for veterans, varsity athletes, and professional football players. The mechanism underlying the increased risk in these populations has not been identified; however, it has been proposed that motor nerve injury may trigger immune responses which, in turn, can accelerate the progression of ALS. Accumulating evidence indicates that abnormal immune reactions and inflammation are involved in the pathogenesis of ALS, but the specific immune cells involved have not been clearly defined. To understand how nerve injury and immune responses may contribute to ALS development, we investigated responses of CD4+ T cell after facial motor nerve axotomy (FNA) at a presymptomatic stage in a transgenic mouse model of ALS (B6SJL SOD1G93A). SOD1G93A mice, compared with WT mice, displayed an increase in the basal activation state of CD4+ T cells and higher frequency of Th17 cells, which were further enhanced by FNA. In conclusion, SOD1G93A mice exhibit abnormal CD4+ T cell activation with increased levels of Th17 cells prior to the onset of neurological symptoms. Motor nerve injury exacerbates Th17 cell responses and may contribute to the development of ALS, especially in those who carry genetic susceptibility to this disease.

Risk of ALS and passive long-term residential exposure to pesticides: a population based study

Risk of ALS and passive long-term residential exposure to pesticides: a population based study