Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study.

Background: There is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it is currently unclear whether these associations reflect causal relationships. Objective: To elucidate the causal relationship between immune cells and neurodegenerative diseases, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and methods: The exposure and outcome GWAS data used in this study were obtained from an open-access database (https://gwas.mrcieu.ac.uk/), the study employed two-sample MR analysis to assess the causal relationship between 731 immune cell features and four neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). All immune cell data was obtained from Multiple MR methods were used to minimize bias and obtain reliable estimates of the causal relationship between the variables of interest and the outcomes. Instrumental variable selection criteria were restricted to ensure the accuracy and effectiveness of the causal relationship between species of immune cells and the risk of these neurodegenerative diseases. Results: The study identified potential causal relationships between various immune cells and different neurodegenerative diseases. Specifically, we found that 8 different types of immune cells have potential causal relationships with AD, 1 type of immune cells has potential causal relationships with PD, 6 different types of immune cells have potential causal relationships with ALS, and 6 different types of immune cells have potential causal relationships with MS. Conclusion: Our study, through genetic means, demonstrates close causal associations between the specific types of immune cells and AD, PD, ALS and MS, providing useful guidance for future clinical researches.

Hypertension linked to Alzheimer's disease via stroke: Mendelian randomization.

This study aimed to investigate the relationship between hypertension and Alzheimer's disease (AD) and demonstrate the key role of stroke in this relationship using mediating Mendelian randomization. AD, a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral abnormalities, severely affects the quality of life of patients. Hypertension is an important risk factor for AD. However, the precise mechanism underlying this relationship is unclear. To investigate the relationship between hypertension and AD, we used a mediated Mendelian randomization method and screened for mediating variables between hypertension and AD by setting instrumental variables. The results of the mediated analysis showed that stroke, as a mediating variable, plays an important role in the causal relationship between hypertension and AD. Specifically, the mediated indirect effect value for stroke obtained using multivariate mediated MR analysis was 54.9%. This implies that approximately 55% of the risk of AD owing to hypertension can be attributed to stroke. The results suggest that the increased risk of AD owing to hypertension is mediated through stroke. The finding not only sheds light on the relationship between hypertension and AD but also indicates novel methods for the prevention and treatment of AD. By identifying the critical role of stroke in the link between hypertension and AD, this study provides insights into potential interventions that could mitigate the impact of hypertension on AD. This could help develop personalized treatments and help improve the quality of life of patients with AD who suffer from hypertension.

Amyotrophic lateral sclerosis with primary progressive aphasia: a case report and literature review.

The association between amyotrophic lateral sclerosis (ALS) and primary progressive aphasia (PPA) is rarely seen in patients. A case of ALS-PPA with a possible reticulon 2 (RTN2) mutation was reported in this study. Moreover, we systematically reviewed the previous reports of 28 ALS cases with progressive non-fluent aphasia (PNFA) and semantic dementia (SD) to identified the unique pathologic features and strong heritability of ALS-PPA. There is a different heritability among the ALS-SD, ALS-PNFA, and the ALS-unclassified PPA groups (p=0.003). Males are more prone to have ALS-PPA than females in all the three groups (p=0.028). PPA-ALS usually starts with cognitive impairment, and the onset most often involves the bulbar. In addition, chromosome 9 open reading frame 72(C9ORF72) and TANK-binding kinase 1 (TBK1) are important pathogenic genes of PPA-ALS. Overall, heritability is of high certainty in ALS-SD, ALS-PNFA, and the ALS-unclassified PPA groups. TAR (Trans-Activator Regulatory) DNA-binding Protein 43 (TDP43) is a 100% predictive pathologic protein of ALS-PPA. C9ORF72 and TBK1 are important pathogenic genes of PPA-ALS.

Clinical Profile and Treatment Outcome in MOGAD: A Single-Center Case-Series Study in Guiyang, China.

Background: The clinical spectrum of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is expanding over time. However, the long-term management and prognosis of this disorder are still controversial. Therefore, this study aimed to report the clinical profiles and treatment outcomes of MOGAD in our center. Methods: This was a single-center case-series study. Clinical and para-clinical data, along with treatment outcomes of patients with MOGAD were analyzed. Results: A total of 27 patients were identified, of which 19 (70%) patients were women, and the median age at disease onset was 40 years (range 20-67). A total of 47 episodes were observed, with optic neuritis (53%) being the most frequent presentation and 60% of them were unilateral. Other presentations included rhombencephalitis (RE) (17%), limbic encephalitis (9%), simultaneous optic neuritis and myelitis (9%), acute disseminated encephalomyelitis (ADEM)-like presentation (6%), myelitis (4%), and ADEM (2%). One patient presenting with RE also met the diagnostic criteria of area postrema syndrome (APS). Another patient with RE presented with imaging characteristics of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). A total of 29 lumbar punctures were recorded, among which an elevated protein level was found in 34% of the samples, pleocytosis was found in 14% of the samples, and positive intrathecal oligoclonal bands were found in 19% of the patients. One patient was found to have anti-N-methyl-D-aspartate receptor antibodies both in his serum and cerebrospinal fluid. Intravenous methylprednisolone (IVMP) was administrated for 85% of the attacks while both IVMP and intravenous immunoglobulin were for 6% of the attacks. Moreover, nine patients received maintenance therapy. Among them, six patients were treated with mycophenolate mofetil, three patients were treated with prednisone, rituximab, and teriflunomide, respectively. The median follow-up period was 20 months (range 6-127). At follow-up, twelve (44%) patients experienced a relapsing course, and the median time to the first relapse was 9.5 months (range 2-120). The median Expanded Disability Status Scale score at nadir was 3.5 (range 2-8) and was 0 (range 0-3) at the last follow-up. Conclusion: The clinical spectrum of MOGAD is heterogenous, wherein APS and CLIPPERS-form can occur. The long-term outcome of MOGAD seems benign. Further studies are warranted to determine the risk factors of relapse and identify the optimal steroid-sparing agents.

Coexisting amyotrophic lateral sclerosis and chorea: A case report and literature review.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) coexisting with chorea is very rare. CASE REPORT: We present the case of a 48-year-old man with ALS and chorea; the diagnostic certainty was high based on clinical examination results. Combining the data from literature, we analyzed the characteristics of patients with ALS and chorea. We found that ALS coexisting with chorea is very rare, but is often hereditary with a genetic mutation. Most patients with ALS and chorea are caused by abnormal amplification of a CAG sequence in the HTT gene, and these patients have a mild course of disease. The FUS, VCP, and SETX genes also have low mutation frequencies in patients with ALS and chorea. CONCLUSION: The abnormal amplification of a CAG sequence in the HTT gene in ALS with chorea has an obvious familial genetic tendency, and most patients have a mild disease course.

A Chinese CADASIL family with p.R578C mutation at exon 11 of the NOTCH3 gene.

OBJECTIVE: To analyze one clinical case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), and to perform analysis of the related gene mutation for the proband and her family. METHODS: Analysis of clinical data from the patient diagnosed with CADASIL, including clinical manifestations, blood test results and brain imaging results, followed by high-throughput sequencing of blood samples. Pathogenicity assessment of the gene mutation, and first generation verification were performed on some family members according to genetic variation interpretation standards and guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: Onset of the proband occurred younger than 50-years-old with recurrent migraine attacks and positive family history of migraine and stroke, but without risk factors for cerebrovascular diseases. The craniocerebral magnetic resonance imaging (MRI) results showed diffusive white matter lesions and thus clinically met criteria for CADASIL diagnosis. NOTCH3 gene analysis showed a p.R578C mutation (1732 C > T) at the11th exon on chromosome 19 of the proband and some family members. CONCLUSIONS: NOTCH3 mutation is related to CADASIL. In this study, we observed a rather rare familial NOTCH3 mutation in China. This report further support the mutation site is pathogenic.

Atmospheric Chemistry of Enols: The Formation Mechanisms of Formic and Peroxyformic Acids in Ozonolysis of Vinyl Alcohol.

Vinyl alcohol (VA), for a long time, is thought to be a missing source of formic acid (FA) in the atmospheric models. However, a recent study has shown that FA is just a byproduct in the OH-initiated oxidation of VA, which stimulates investigation on the other sinks of VA in the atmosphere. In this study, the detailed ozonolysis mechanism of VA was investigated theoretically for the first time. The results show that two primary ozonides (syn- and anti-POZ) can be formed in the ozonolysis of VA and that FA coupled with the simplest Criegee intermediate (CH2OO) can be produced as the main nascent products. Thus, the ozonolysis of VA is predicted to be a more efficient process to produce FA in the atmosphere compared with its OH-initiated oxidation. Moreover, it is found that the syn-POZ can directly decompose to peroxyformic acid plus formaldehyde, breaking the known "Criegee mechanism" to form carbonyl oxide with carbonyl compound. This special mechanism by providing a new source of peroxy acids in the atmosphere enriches the atmospheric chemistry of enols. The atmospheric lifetime of VA by ozonolysis is predicted to be 30 h, comparable with its prevalent reaction with the OH radical. Therefore, the obtained theoretical results can be usefully incorporated into a future modeling study of enols.

Atmospheric Chemistry of Enols: Vinyl Alcohol + OH + O2 Reaction Revisited.

The OH-initiated oxidation of vinyl alcohol (VA) produced by phototautomerization of acetaldehyde is thought to be a source of formic acid (FA) in the atmosphere. A recent theoretical study predicted that the VA + OH + O2 reaction 1 proceeds by OH addition at α-C (66%) and ß-C (33%) of VA and that FA is a main product of reaction 1. However, the metastable reactant ( anti-VA, ∼18% at 298 K, 1.42 kcal mol-1 higher than syn in energy) used in that study inspired us to reinvestigate reaction 1. Using the state-of-the-art quantum-chemical and kinetic calculations, we first found that a conformer of VA has a significant influence on the rate coefficient and branching ratio of reaction 1. Upon derivation, it is found that ∼84% of reaction 1 takes place through the ß-C-addition channel and ∼16% of reaction 1 happens by the α-C-addition channel. The calculated total initial rate coefficient at 298 K is 1.48 × 10-11 cm3 molecule-1 s-1, which is in reasonable agreement with the experimental values of similar systems (vinyl ethers + OH reactions). The predicted main products of reaction 1 are glycolaldehyde and the HO2 radical, whereas FA is just a byproduct.