Background: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS. Methods: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles. Results: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05). Conclusions: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.

GGC repeat expansions in the 5’ untranslated region (5’UTR) of the Notch Homolog 2 N-terminal-like C gene (NOTCH2NLC) have been reported to be the genetic cause of neuronal intranuclear inclusion disease (NIID). However, whether they exist in other neurodegenerative disorders remains unclear. To determine whether there is a medium-length amplification of NOTCH2NLC in patients with amyotrophic lateral sclerosis (ALS), we screened 476 ALS patients and 210 healthy controls for the presence of a GGC repeat expansion in NOTCH2NLC by using repeat-primed polymerase chain reaction (RP-PCR) and fragment analysis. The repeat number in ALS patients was 16.11 ± 5.7 (range 7–46), whereas the repeat number in control subjects was 16.19 ± 3.79 (range 10–29). An intermediate-length GGC repeat expansion was observed in two ALS patients (numbers of repeats: 45, 46; normal repeat number ≤ 40) but not in the control group. The results suggested that the intermediate NOTCH2NLC GGC repeat expansion was associated with Chinese ALS patients, and further functional studies for intermediate-length variation are required to identify the mechanism.

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.

Previous studies have found that migraine patients are associated with white matter lesions (WMLs), but the causal relationship between the two remains unclear. We intend to explore the bidirectional causal relationship between migraine and WMLs using a two-sample mendelian randomization (MR) method. We employed summary-level data from a recent large-scale genome-wide association study (GWAS) that characterized three white matter (WM) phenotypes: white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467), as well as migraine (N = 589,356). The inverse variance-weighted (IVW) method was used as the main approach for analyzing causality. Weighted median analysis, simple median analysis, and MR-Egger regression served as complementary methods. The bidirectional MR study affords no support for causality between WMLs and migraine. In all MR methods, there was no obvious causal evidence between them. In our bidirectional MR study, we didn't reach this conclusion that WMLs can cause migraine, migraine wouldn’t increase the risk of WMLs, either.

Migraine is a common clinical primary headache with unclear aetiology. In recent years, studies have shown that migraine is related to right-to-left shunts (RLS), and some patients with migraine have white matter lesions. However, the relationship among the three is unclear. To explore the characteristics of white matter lesions (WMLs) in migraine patients with right-to-left shunts and to predict the presence of right-to-left shunts through magnetic resonance imaging (MRI) characteristics in patients with migraine, we conducted a retrospective study. We enrolled 214 patients who were diagnosed with migraines in an outpatient clinic from January 2019 to December 2021. All of them had completed contrast transcranial Doppler ultrasound (cTCD) and magnetic resonance imaging (MRI) examination. Through the inclusion and exclusion criteria, 201 patients were finally included. The patients were grouped according to the presence of WMLs and were compared by age, sex, hypertension, diabetes, RLS, and other characteristic data. We observed the MRI fluid attenuation inversion recovery sequence (FLAIR) image and compared the differences in WMLs between the RLS-positive group and the RLS-negative group. There were 71 cases and 130 cases of migraine with and without WMLs, respectively. A statistically significant difference in near-cortical WMLs with RLS in migraine patients was observed (p = 0.007). Logistic regression analysis was adjusted by age, sex, duration of migraine, and severity. Migraine with aura and family history identified the RLS status as the sole determinant for the presence of near-cortical WMLs (OR = 2.69; 95%CI 1.386–5.219; p = 0.003). Near-cortical white matter lesions in migraine patients are related to RLS, especially in the blood supply area of the anterior cerebral artery. This small demyelination of the near-cortical WMLs may be a potential marker for the right-to-left shunt of the heart. Transcranial Doppler ultrasonography may help finding more RLS in migraineurs with near-cortical WMLs.

Background Migraine is a common clinical primary headache with unclear aetiology. In recent years, studies have shown that migraine is related to patent foramen ovale, and some patients with migraine have white matter lesions. However, the relationship among the three is unclear. Objective To explore the characteristics of white matter lesions (WMLs) in migraine patients with patent foramen ovale and to predict the occurrence of patent foramen ovale through magnetic resonance imaging (MRI) characteristics in patients with migraine. Methods Seventy-seven patients clinically diagnosed with migraine were examined by transcranial Doppler ultrasound (cTCD) and MRI. The patients were grouped according to the presence of WMLs, with matching by age, sex, hypertension, diabetes, PFO and other characteristic data. We observed the MRI fluid attenuation inversion recovery sequence (FLAIR) image and compared and analysed the difference in WMLs between the PFO-positive group and the PFO-negative group. Results There were 42 cases and 35 cases of migraine with and without WMLs, respectively. A statistically significant difference in near-cortical WMLs with PFO in migraine patients was observed (P=0.001). Logistic regression analysis adjusted by age, sex, hypertension and diabetes identified PFO status as the sole determinant for the presence of near-cortical WMLs (OR = 0.14; 95%CI 0.045–0.421; p < 0.001) Conclusion Near-cortical white matter lesions in migraine patients are related to PFO. Transcranial Doppler ultrasonography may reveal more PFO in patients with migraine and near-cortical WMLs.

卵圆孔未闭(patent foramen ovale, PFO)是成人最为常见的先天性心脏疾病, 偏头痛是一种严重影响生活质量的慢性头痛,通常临床上很难把PFO与偏头痛联系在一起,但近年来越来越多的研究发现偏头痛的患者合并PFO的患病率高于常规人群,两者之间存在密切的联系:部分PFO 存在右向左分流的患者会出现偏头痛症状, 且患者在接受封堵术治疗后,偏头痛症状有所缓解,但另外一部分患者术后效果不佳. 由于目前偏头痛发作与PFO之间的病理生理机制未明,本文将主要描述偏头痛与PFO之间的相关研究进展,希望能为临床工作提供有价值的参考.