Cerebral small vessel disease increases risk for epilepsy: a Mendelian randomization study.

BACKGROUND: Despite previous research suggesting a potential association between cerebral small vessel disease (CSVD) and epilepsy, the precise causality and directionality between cerebral small vessel disease (CSVD) and epilepsy remain incompletely understood. We aimed to investigate the causal link between CSVD and epilepsy. METHOD: A bidirectional two-sample Mendelian randomization (MR) analysis was performed to evaluate the causal relationship between CSVD and epilepsy. The analysis included five dimensions of CSVD, namely small vessel ischemic stroke (SVS), intracerebral hemorrhage (ICH), white matter damage (including white matter hyperintensity [WMH], fractional anisotropy, and mean diffusivity), lacunar stroke, and cerebral microbleeds. We also incorporated epilepsy encompassing both focal epilepsy and generalized epilepsy. Inverse variance weighted (IVW) was used as the primary estimate while other four MR techniques were used to validate the results. Pleiotropic effects were controlled by adjusting vascular risk factors through multivariable MR. RESULT: The study found a significant association between SVS (odds ratio [OR] 1.117, PFDR = 0.022), fractional anisotropy (OR 0.961, PFDR = 0.005), mean diffusivity (OR 1.036, PFDR = 0.004), and lacunar stroke (OR 1.127, PFDR = 0.007) with an increased risk of epilepsy. The aforementioned correlations primarily occurred in focal epilepsy rather than generalized epilepsy on subgroup analysis and retained their significance in the multivariable MR analysis. CONCLUSION: Our study demonstrated that genetic susceptibility to CSVD independently elevates the risk of epilepsy, especially focal epilepsy. Diffusion tensor imaging may help screen patients at high risk for epilepsy in CSVD. Improved management of CSVD may be a significant approach in reducing the overall prevalence of epilepsy.

Assessment of bidirectional relationships between multiple sclerosis and epilepsy: A two-sample Mendelian randomization study.

BACKGROUND AND OBJECTIVE: Epidemiological studies indicate that multiple sclerosis (MS) is associated with epilepsy. However, the causality and directionality of this association remain under-elucidated. This study aimed to reveal the causality between MS and epilepsy. METHODS: A two-sample Mendelian randomization (MR) analysis was performed by using summarized statistics derived from large genome-wide association studies of MS and epilepsy. We used the inverse variance weighted method as the primary approach, and then four other MR methods to bidirectionally evaluate the causality of the association between MS and epilepsy. Additional sensitivity analyses were performed to measure the robustness of the findings. RESULTS: Genetically predicted MS was positively correlated with developing all epilepsy [odds ratio (OR) = 1.027 (1.003-1.051), P  =  0.028] and generalized epilepsy [OR = 1.050 (1.008-1.094), P = 0.019]. In the reverse MR analysis, all epilepsy [OR = 1.310 (1.112-1.543), P = 0.001], generalized epilepsy [OR = 1.173 (1.010-1.363), P = 0.037], and focal epilepsy [OR = 1.264 (1.069-1.494), P  =  0.006] elevated the risk of developing MS. The result remained robust and congruous across all sensitivity analyses conducted. CONCLUSIONS: MS is potentially associated with a higher risk of developing epilepsy. Furthermore, epilepsy may be a causal determinant of MS risk. These findings may further the understanding of the interaction of the two conditions.

Mendelian randomization analysis reveals the impact of physical and occupational activities on the risk of gastroesophageal reflux disease and Barrett's esophagus.

BACKGROUND: Recent studies have indicated that participating in physical activity may provide a safeguard against gastroesophageal reflux disease (GERD). Nevertheless, the precise links between physical and occupational activity and the occurrence of GERD and Barrett's esophagus (BE) are still uncertain. METHODS: Conducting univariate and multivariate Mendelian randomization investigations to examine the causal relationship between exposures and outcomes. Genetic variation simulation was used in randomized experiments. Data on physical and occupational activity were obtained from the UK Biobank and GWAS catalog. In the meantime, data on GERD and BE were extracted from a high quality meta-analysis. RESULTS: The results of univariate Mendelian randomization analysis using multiple methods suggest a causal relationship between strenuous sports or other forms of exercise (as a protective factor) and GERD/BE. At the same time, three types of occupational related physical activities, including heavy manual or physical work, shift work and walking or standing work, are risk factors for GERD/BE and have a causal relationship with them. These results were reconfirmed through multivariate Mendelian randomization analysis, which excluding the influence of other potential confounding factors. CONCLUSIONS: The findings indicated that strenuous sports or other forms of exercise could lower the likelihood of GERD/BE, while excessive physical strain in the workplace, prolonged periods of standing or walking, and shift work could raise the risk of GERD/BE. Acknowledging this risk and implementing suitable measures can contribute to the prevention of GERD and BE, thus mitigating the associated health burden.

Altered connectivity in the cognitive control-related prefrontal cortex in Parkinson's disease with rapid eye movement sleep behavior disorder.

Rapid eye movement sleep behavior disorder (RBD) frequently occurs in Parkinson's disease (PD), however, the exact pathophysiological mechanism is not clear. The prefrontal cortex (PFC), especially ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), and inferior frontal gyrus (IFG) which may play roles by regulating cognitive control processes. The purpose of this study was to investigate whether there is abnormal functional connectivity (FC) maps and volume changes in PD with RBD(PD-RBD). We recruited 20 PD-RBD, 20 PD without RBD (PD-nRBD), and 20 normal controls (NC). We utilized resting-state functional Magnetic Resonance Imaging (rs-MRI) to explore FC changes based on regions of interest (VLPFC, DLPFC, and IFG), and used voxel-based morphology technology to analyze whole-brain volumes by 3D-T1 structural MRI. Except the REM sleep behavioral disorders questionnaire (RBDSQ), the PD-RBD showed lower visuospatial/executive and attention scores than the NC group. The RBDSQ scores were significantly positively correlated with zFC of right DLPFC to bilateral posterior cingulate cortex (PCC) (P = 0.0362, R = 0.4708, AlphaSim corrected) and also significantly positively correlated with zFC of left VLPFC to right inferior temporal (P = 0.0157, R = 0.5323, AlphaSim corrected) in PD-RBD group. Furthermore, abnormal correlations with zFC values were also found in some cognitive subdomains in PD-RBD group. The study may suggest that in PD-RBD patients, the presence of RBD may be related to the abnormal FC of VLPFC and DLPFC, meanwhile, the abnormal FC of DLPFC and IFG may be related to the mechanisms of cognitive impairment.

Antihypertensive drugs may not delay the symptom progression of Parkinson's disease: A 2-year follow-up study.

Background: Parkinson's disease (PD) is one of the most common neurodegenerative disease, and half of PD patients have hypertension as well. The effect of antihypertensive drugs on the progression of PD has been less studied. The focus of this study was on the changes in dopamine transporter (DAT) levels to assess the effect of antihypertensive drugs on the progression of PD. Methods: Data from 321 drug-naïve patients from the Parkinson's Disease Progression Marker Initiative (PPMI) were collected over a 2-year period. Patients were divided into the PD with arterial hypertension (AH) group (102 cases) with antihypertensive drugs, the PD with other cardiovascular risk factors (CVRFs) group (60 cases) with antidiabetic and/or lipid-lowering drugs, and the pure PD group (159 cases) without CVRFs. The Movement Disorder Society Sponsored Revision Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Hoehn-Yahr (H&Y) stage were used to assess progression. DAT semiquantitative values were used to evaluate damage to dopaminergic neurons in the substantia nigra, including the contralateral and ipsilateral count density ratio and asymmetry index. Results: There were no significant differences among the three groups in MDS-UPDRS score and H&Y stage. Changes in DAT levels among the three groups were without distinct differences in the first year and second year. In each group, DAT decreased more in the first year than in the second year. There was no decrease in DAT uptake in the PD with AH group compared with the other groups during the follow-up period. Conclusions: There is no evidence that antihypertensive drugs can delay PD progression within 2 years.

Cerebrospinal fluid GFAP is a predictive biomarker for conversion to dementia and Alzheimer's disease-associated biomarkers alterations among de novo Parkinson's disease patients: a prospective cohort study.

BACKGROUND: Dementia is a prevalent non-motor manifestation among individuals with advanced Parkinson's disease (PD). Glial fibrillary acidic protein (GFAP) is an inflammatory marker derived from astrocytes. Research has demonstrated the potential of plasma GFAP to forecast the progression to dementia in PD patients with mild cognitive impairment (PD-MCI). However, the predictive role of cerebrospinal fluid (CSF) GFAP on future cognitive transformation and alterations in Alzheimer's disease (AD)-associated CSF biomarkers in newly diagnosed PD patients has not been investigated. METHODS: 210 de novo PD patients from the Parkinson's Progression Markers Initiative were recruited. Cognitive progression in PD participants was evaluated using Cox regression. Cross-sectional and longitudinal associations between baseline CSF GFAP and cognitive function and AD-related CSF biomarkers were evaluated using multiple linear regression and generalized linear mixed model. RESULTS: At baseline, the mean age of PD participants was 60.85 ± 9.78 years, including 142 patients with normal cognition (PD-NC) and 68 PD-MCI patients. The average follow-up time was 6.42 ± 1.69 years. A positive correlation was observed between baseline CSF GFAP and age (ß = 0.918, p < 0.001). There was no statistically significant difference in baseline CSF GFAP levels between PD-NC and PD-MCI groups. Higher baseline CSF GFAP predicted greater global cognitive decline over time in early PD patients (Montreal Cognitive Assessment, ß = - 0.013, p = 0.014). Furthermore, Cox regression showed that high baseline CSF GFAP levels were associated with a high risk of developing dementia over an 8-year period in the PD-NC group (adjusted HR = 3.070, 95% CI 1.119-8.418, p = 0.029). In addition, the baseline CSF GFAP was positively correlated with the longitudinal changes of not only CSF α-synuclein (ß = 0.313, p < 0.001), but also CSF biomarkers associated with AD, namely, amyloid-ß 42 (ß = 0.147, p = 0.034), total tau (ß = 0.337, p < 0.001) and phosphorylated tau (ß = 0.408, p < 0.001). CONCLUSIONS: CSF GFAP may be a valuable prognostic tool that can predict the severity and progression of cognitive deterioration, accompanied with longitudinal changes in AD-associated pathological markers in early PD.

White matter hyperintensities burden in the frontal regions is positively correlated to the freezing of gait in Parkinson's disease.

Objective: Previous studies have reported that white matter hyperintensities (WMHs) are associated with freezing of gait (FOG), but it is not clear whether their distribution areas have correlations with FOG in Parkinson's disease (PD) and the potential influencing factors about WMHs. Methods: Two hundred and forty-six patients with PD who underwent brain MRI were included. Participants were divided into PD with FOG (n = 111) and PD without FOG (n = 135) groups. Scheltens score was used to assess the WMHs burden in the areas of deep white matter hyperintensities (DWMHs), periventricular hyperintensities (PVHs), basal ganglia hyperintensities (BGHs), and infratentorial foci of hyperintensities (ITF). Whole brain WMHs volume was evaluated by automatic segmentation. Binary logistic regression was used to evaluate relationships between WMHs and FOG. The common cerebrovascular risk factors that may affect WMHs were evaluated by mediation analysis. Results: There were no statistical differences between PD with and without FOG groups in whole brain WMHs volume, total Scheltens score, BGHs, and ITF. Binary logistic regression showed that the total scores of DWMHs (OR = 1.094; 95% CI, 1.001, 1.195; p = 0.047), sum scores of PVHs and DWMHs (OR = 1.080; 95% CI, 1.003, 1.164; p = 0.042), especially the DWMHs in frontal (OR = 1.263; 95% CI, 1.060, 1.505 p = 0.009), and PVHs in frontal caps (OR = 2.699; 95% CI, 1.337, 5.450; p = 0.006) were associated with FOG. Age, hypertension, and serum alkaline phosphatase (ALP) are positively correlated with scores of DWMHs in frontal and PVHs in frontal caps. Conclusion: These results indicate that WMHs distribution areas especially in the frontal of DWMHs and PVHs play a role in PD patients with FOG.

Parkinson's disease patients with freezing of gait have more severe voice impairment than non-freezers during "ON state".

BACKGROUND: Speech disorders and freezing of gait (FOG) in Parkinson's disease (PD) may have some common pathological mechanisms. The purpose of this study was to compare the acoustic parameters of PD patients with dopamine-responsive FOG (PD-FOG) and without FOG (PD-nFOG) during "ON state" and explore the ability of "ON state" voice features in distinguishing PD-FOG from PD-nFOG. METHODS: A total of 120 subjects, including 40 PD patients with dopamine-responsive FOG, 40 PD-nFOG, and 40 healthy controls (HCs) were recruited. All subjects underwent neuropsychological tests. Speech samples were recorded through the sustained vowel pronunciation tasks during the "ON state" and then analyzed by the Praat software. A set of 27 voice features was extracted from each sample for comparison. Support vector machine (SVM) was used to build mathematical models to classify PD-FOG and PD-nFOG. RESULTS: Compared with PD-nFOG, the jitter, the standard deviation of fundamental frequency (F0SD), the standard deviation of pulse period (pulse period SD) and the noise-homophonic-ratio (NHR) were increased, and the maximum phonation time (MPT) was decreased in PD-FOG. The above voice features were correlated with the freezing of gait questionnaire (FOGQ). The average accuracy, specificity, and sensitivity of SVM models based on 27 voice features for classifying PD-FOG and PD-nFOG were 73.57%, 75.71%, and 71.43%, respectively. CONCLUSIONS: PD-FOG have more severe voice impairment than PD-nFOG during "ON state".