Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease.

Background: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD. Methods: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD. Results: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD. Conclusions: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia.

BACKGROUND: There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS: We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS: MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10-5) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10-5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10-94), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10-5), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10-6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10-13; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10-09)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10-36) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10-5)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10-07; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10-07)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10-06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10-05) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS: Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

Expanding causal genes for Parkinson's disease via multi-omics analysis.

Genome­wide association studies (GWASs) have revealed numerous loci associated with Parkinson's disease (PD). However, some potential causal/risk genes were still not revealed and no etiological therapies are available. To find potential causal genes and explore genetically supported drug targets for PD is urgent. By integrating the expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets from multiple tissues (blood, cerebrospinal fluid (CSF) and brain) and PD GWAS summary statistics, a pipeline combing Mendelian randomization (MR), Steiger filtering analysis, Bayesian colocalization, fine mapping, Protein-protein network and enrichment analysis were applied to identify potential causal genes for PD. As a result, GPNMB displayed a robust causal role for PD at the protein level in the blood, CSF and brain, and transcriptional level in the brain, while the protective role of CD38 (in brain pQTL and eQTL) was also identified. We also found inconsistent roles of DGKQ on PD between protein and mRNA levels. Another 9 proteins (CTSB, ARSA, SEC23IP, CD84, ENTPD1, FCGR2B, BAG3, SNCA, FCGR2A) were associated with the risk for PD based on only a single pQTL after multiple corrections. We also identified some proteins' interactions with known PD causative genes and therapeutic targets. In conclusion, this study suggested GPNMB, CD38, and DGKQ may act in the pathogenesis of PD, but whether the other proteins involved in PD needs more evidence. These findings would help to uncover the genes underlying PD and prioritize targets for future therapeutic interventions.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for AD and analyse their pathophysiological mechanisms and potential side effects. METHODS: A two-sample MR integrating the identified druggable genes was performed to estimate the causal effects of blood and brain druggable expression quantitative trait loci (eQTLs) on AD. A repeat study was conducted using different blood and brain eQTL data sources to validate the identified genes. Using AD markers with available genome-wide association studies data, we evaluated the causal relationship between established AD markers to explore possible mechanisms. Finally, the potential side effects of the druggable genes for AD treatment were assessed using a phenome-wide MR. RESULTS: Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset. Among them, three prior druggable genes (epoxide hydrolase 2 (EPHX2), SERPINB1 and SIGLEC11) reached significant levels in both blood and brain tissues. EPHX2 may mediate the pathogenesis of AD by affecting the entire hippocampal volume. Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2, SERPINB1 or SIGLEC11. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritising AD drug development.

Low serum uric acid levels may be a potential biomarker of poor sleep quality in patients with Parkinson's disease.

BACKGROUND: Sleep disorders are common non-motor symptoms in patients with Parkinson's disease (PD). However, the pathogenesis of sleep disorders in PD patients remains unclear. Previous studies have implicated oxidative stress in sleep disorders associated with PD. Considering uric acid (UA) acts as a natural antioxidant, in this study, we aimed to assess the use of serum UA as a potential biomarker of sleep disorder in PD patients. METHODS: This study recruited 149 PD patients and 84 Age- and sex-matched individuals. According to the Pittsburgh Sleep Quality Index (PSQI) score, PD patients were divided into three groups, good (≤5), intermediate (6-10), and poor (>10). Multivariate logistic regression and receiver operating characteristic (ROC) curve analyses were also performed to identify clinical features and serum UA levels that help establish an accurate diagnostic model for poor sleep quality in PD patients. RESULTS: PD patients who experienced poor sleep quality had lower serum UA levels. PSQI scores have significant negative relationships with serum UA levels and significant positive relationships with Hamilton Depression Scale (HAMD) scores in PD. Poor sleep quality was independently associated with serum UA levels and HAMD scores. A serum UA level of 328.7 µmol/L and HAMD scores of 19.5 could distinguish PD patients with poor or intermediate sleep to a certain extent, sensitivity of 79.4% and specificity of 76.6%. CONCLUSIONS: Low serum UA levels may correlate with the severity of sleep disorder in PD patients and may serve as a biomarker for poor sleep quality in PD.

Cortical atrophy is associated with cognitive impairment in Parkinson's disease: a combined analysis of cortical thickness and functional connectivity.

We aimed to perform a combined analysis of cortical thickness and functional connectivity to explore their association with cognitive impairment in Parkinson's disease (PD). A total of 53 PD and 15 healthy control subjects were enrolled. PD patients were divided into PD with normal cognition (PD-NC, n = 25), PD with mild cognitive impairment (PD-MCI, n = 11), and PD with dementia (PDD, n = 17). In some analyses, the PD-MCI and PDD groups were aggregated to represent "PD patients with cognitive impairment". Cognitive status was assessed with the Mini-Mental State Examination (MMSE). Anatomical magnetic resonance imaging and resting-state functional connectivity analysis were performed in all subjects. First, surface-based morphometry measurements of cortical thickness and voxels with cortical thickness reduction were detected. Then, regions showing reduced thickness were analyzed for changes in resting-state functional connectivity in PD involving cognitive impairment. Our results showed that, compared with PD-NC, patients with cognitive impairment showed decreased cortical thickness in the left superior temporal, left lingual, right insula, and right fusiform regions. PD-MCI patients showed these alterations in the right lingual region. Widespread cortical thinning was detected in PDD subjects, including the left superior temporal, left fusiform, right insula, and right fusiform areas. We found that cortical thinning in the left superior temporal, left fusiform, and right temporal pole regions positively correlated with MMSE score. In the resting-state functional connectivity analysis, we found a decrease in functional connectivity between the cortical atrophic brain areas mentioned above and cognition-related brain networks, as well as an increase in functional connectivity between those region and the cerebellum. Alterations in cortical thickness may result in a dysfunction of resting-state functional connectivity, contributing to cognitive decline in patients with PD. However, it is more probable that the relation between structure and FC would be bidirectional,and needs more research to explore in PD cognitve decline.

Plasma neurofilament light chain levels are associated with depressive and anxiety symptoms in Parkinson's disease.

The present study aimed to explore the association of plasma neurofilament light chain (NfL) levels with depression and anxiety in Parkinson's disease (PD). This prospective study enrolled 116 patients with PD and 38 healthy controls, and found plasma NfL levels were higher in patients with depression or anxiety than in those without these symptoms. Binary logistic regression identified NfL concentration as an independent predictor of depression and anxiety in PD. In conclusion, elevated plasma NfL may be associated with severity of depression and anxiety in PD patients and may serve as a diagnostic biomarker of PD with moderate to severe depression or anxiety.

REM sleep behavioral disorder may be an independent risk factor for orthostatic hypotension in Parkinson's disease.

PURPOSE: The purpose of this study was to evaluate the association between clinically possible rapid eye movement (REM) sleep behavioral disorder (pRBD) and orthostatic hypotension (OH) in PD patients, as well as to explore the mechanisms underlying the association. METHODS: PD patients (n = 116) were assigned to a group with OH (PD-OH) or without OH (PD-NOH). General demographic and clinical data were collected. A series of scales were used to assess the clinical symptoms in the two groups. RESULTS: A total of 27 patients (23.3%) had OH. The PD-OH group showed significantly higher H-Y staging score and significantly higher frequencies of pRBD, anxiety, depression, and cognitive impairment than the PD-NOH group. Binary logistic regression analysis identified the following factors as independently associated with PD-OH: H-Y staging [odds ratio (OR) 2.565, 95% confidence interval (CI) 1.160-5.673; P = 0.020], RBD (OR 7.680, 95% CI 1.944-30.346; P = 0.004), UPDRS II (OR 1.021, 95% CI 0.980-1.063; P = 0.020), depression (OR 7.601, 95% CI 1.492-38.718; P = 0.015), and cognitive impairment (OR 0.824, 95% CI 0.696-0.976; P = 0.025). CONCLUSIONS: Our results suggest that pRBD is an independent risk factor for OH in patients with PD. We speculate that there may be a close relationship between RBD and OH, which requires attention. Early diagnosis of RBD may help predict the appearance of OH in PD patients.

Association between plasma neurofilament light chain levels and cognitive function in patients with Parkinson's disease.

This study investigated the potential association between levels of plasma neurofilament light chain (NfL) and cognitive function in patients suffering from Parkinson's disease (PD) in P.R. China.We collected a total of 168 participants (130 PD patients and 38 healthy controls),and evaluated the relationship of plasma NfL levels with cognitive dysfunction in PD patients. Our results shown that plasma NfL levels increased with an increase in cognitive impairment across the three groups of PD patients: PD with normal cognition (PD-NC), 17.9 ± 8.9 pg/ml; PD with mild cognitive impairment (PD-MCI),21.9 ± 10.3 pg/ml; and PD dementia (PDD), 35.7 ± 21.7 pg/ml. Higher MMSE scores were associated with lower plasma NfL levels (r = -0.49, 95% CI -0.61 to -0.34, p < 0.0001). Our results associating plasma NfL levels with cognitive dysfunction in PD are consistent with previous studies carried out in several countries/district, based on our meta-analysis.

Resting-state functional magnetic resonance imaging of the cerebellar vermis in patients with Parkinson's disease and visuospatial disorder.

PURPOSE: Visuospatial disorders (VSDs) are common in Parkinson's disease (PD). VSDs may involve cerebellar vermis, but evidence from functional connectivity (FC) studies is lacking. Here we compared FC between cerebellar vermis and the entire brain between PD patients with or without VSD, and between patients and healthy controls. METHODS: Resting-state 3.0-T functional magnetic resonance imaging was performed on 19 controls, 31 PD patients with VSD and 12 PD patients without VSD. Correlations in brain network were calculated between eight regions of interest in the cerebellar vermis (I-VIII) and other voxels in the brain, and voxel-based FC was analyzed. Patients were assessed in terms of cognitive function as well as motor and non-motor symptoms. RESULTS: In both types of patients, cerebellar vermis VIII, IX and X showed positive FC with the default-mode network (DMN), executive control network and sensorimotor network. Cerebellar vermis I and II showed positive FC with the visual network and DMN in controls, but negative FC in PD patients without VSD. Cerebellar vermis X showed negative FC with lobules VIII and IX of the left cerebellar hemisphere in controls, but positive FC in PD patients with VSD. CONCLUSION: Positive FC connecting the cerebellar vermis VIII and X with associated brain networks in PD patients with VSD may be compensatory activation. PD may involve disruption of functional coupling between the cerebellar vermis and cerebral cortex.