Early-life tobacco smoke exposure and stroke risk: a prospective study of 341,783 and 352,737 UK Biobank participants.

INTRODUCTION: Stroke is a life-threatening condition that causes a major medical burden globally. The currently used methods for the prevention or prediction of stroke have certain limitations. Exposure to tobacco in early life, including smoking during adolescence and maternal smoking during pregnancy, can affect adolescent development and lead to several negative outcomes. However, the association between early-life tobacco exposure and stroke is not known. METHODS: In this prospective cohort study, for the analyses involving exposure to maternal smoking during pregnancy and age of smoking initiation, we included 304,984 and 342,893 participants, respectively., respectively from the UK Biobank. Cox proportional hazard regression model and subgroup analyses were performed to investigate the association between early-life tobacco exposure and stroke. Mediation analyses were performed to identify the mediating role of biological aging in the association between early tobacco exposure and stroke. RESULTS: Compared with participants whose mothers did not smoke during pregnancy, participants whose mothers smoked during pregnancy showed an 11% increased risk of stroke (HR: 1.11, 95% CI: 1.05-1.18, P < 0.001). Compared with participants who never smoked, participants who smoked during adulthood, adolescence and childhood showed a 22%, 24%, and 38% increased risk of stroke during their adulthood, respectively. Mediation analysis indicated that early-life tobacco exposure can cause stroke by increasing biological aging. CONCLUSION: This study reveals that exposure to tobacco during early life is associated with an increased risk of experiencing a stroke, and increased biological aging can be the underlying mechanism.

Association of pro-inflammatory diet with increased risk of all-cause dementia and Alzheimer's dementia: a prospective study of 166,377 UK Biobank participants.

BACKGROUND: Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored the association between pro-inflammatory diets and dementia using the dietary inflammatory index (DII). Additionally, the relationship between DII and different subtypes of dementia, such as Alzheimer's dementia and vascular dementia, remains largely unexplored. Given the changes in brain structure already observed in patients with dementia, we also investigated the association between DII and magnetic resonance imaging (MRI) measures of brain structure to provide some hints to elucidate the potential mechanisms between pro-inflammatory diet and cognitive decline. METHODS: A total of 166,377 UK Biobank participants without dementia at baseline were analyzed. DII calculations were based on the information collected by the 24-h recall questionnaire. Brain structural anatomy and tissue-specific volumes were measured using brain MRI. Cox proportional hazards models, competing risk models, and restricted cubic spline were applied to assess the longitudinal associations. The generalized linear model was used to assess the association between DII and MRI measurements. RESULTS: During a median follow-up time of 9.46 years, a total of 1372 participants developed dementia. The incidence of all-cause dementia increased by 4.6% for each additional unit of DII [hazard ratio (HR): 1.046]. Besides, DII displayed a "J-shaped" non-linear association with Alzheimer's dementia (Pnonlinear = 0.003). When DII was above 1.30, an increase in DII was significantly associated with an increased risk of Alzheimer's dementia (HR: 1.391, 95%CI: 1.085-1.784, P = 0.009). For brain MRI, the total volume of white matter hyperintensities increased with an increase in DII, whereas the volume of gray matter in the hippocampus decreased. CONCLUSIONS: In this cohort study, higher DII was associated with a higher risk of all-cause dementia and Alzheimer's dementia. However, our findings suggested that the association with DII and vascular and frontotemporal dementia was not significant.

Efficacy of short pulse and conventional deep brain stimulation in Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Deep brain stimulation (DBS) is a common treatment for Parkinson's disease. However, the clinical efficacy of short pulse width DBS (spDBS) compared with conventional DBS (cDBS) is still unknown. OBJECTIVE: This meta-analysis investigated the effectiveness of spDBS versus cDBS in patients with PD. METHODS: Four databases (PubMed, Cochrane, Web of Science, and Embase) were independently searched until October 2021 by two reviewers. We utilized the following scales and items: therapeutic windows (TW), efficacy threshold, side effect threshold, Movement Disorder Society-Sponsored Revision Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off-medication score, Speech Intelligence Test (SIT), and Freezing of Gait Questionnaire (FOG-Q). RESULTS: The analysis included seven studies with a total of 87 patients. The results indicated that spDBS significantly widened the therapeutic windows (0.99, 95% CI = 0.61 to 1.38) while increasing the threshold amplitudes of side effects (2.25, 95% CI = 1.69 to 2.81) and threshold amplitudes of effects (1.60, 95% CI = 0.84 to 2.36). There was no statistically significant difference in UPDRS part III, SIT, and FOG-Q scores between spDBS and cDBS groups, suggesting that treatment with both cDBS and spDBS may result in similar effects of improved dysarthria and gait disorders. CONCLUSIONS: Compared with cDBS, spDBS is effective in expanding TW. Both types of deep brain stimulation resulted in improved gait disorders and speech intelligibility.

Comparison of efficacy of deep brain stimulation and focused ultrasound in parkinsonian tremor: a systematic review and network meta-analysis.

To compare the efficacy of deep brain stimulation (DBS) and MRI-guided focused ultrasound (MRIgFUS) in parkinsonian tremor. We performed a network meta-analysis based on a Bayesian framework. We searched the literature for articles published between January 1990 and October 2020 using three databases: PubMed, Embase and Cochrane Library (The Cochrane Database of Systematic Reviews). A total of 24 studies were included in our analysis, comprising data from 784 participants. Our findings revealed similar efficacy of DBS and MRIgFUS in parkinsonian tremor suppression. Compared with internal globus pallidus (GPi)-MRIgFUS, GPi-DBS -1.84 (-6.44, 2.86), pedunculopontine nucleus (PPN)_DBS -3.28 (-9.28, 2.78), PPN and caudal zona incerta (cZI)-DBS 0.40 (-6.16, 6.87), subthalamic nucleus (STN)_DBS 0.89 (-3.48, 5.30), STN and cZI-DBS 1.99 (-4.74, 8.65), ventral intermediate nucleus(VIM)_DBS 1.75 (-2.87, 6.48), VIM_FUS 0.72 (-5.27, 6.43), cZI-DBS 0.27 (-4.75, 5.36) were no significantly difference. Compared with VIM-MRIgFUS, GPi-DBS -2.55(-6.94, 2.21), GPi-FUS -0.72 (-6.43, 5.27), PPN_DBS -4.01(-9.97, 2.11), PPN and cZI-DBS -0.32 (-6.73, 6.36), STN_DBS 0.16 (-3.98, 4.6), STN and cZI-DBS 1.31(-5.18,7.87), VIM-DBS 1.00(-3.41, 5.84)and cZI-DBS -0.43 (-5.07, 4.68) were no significantly difference. With respect to the results for the treatment of motor symptoms, GPi-DBS, GPi-MRIgFUS, STN-DBS and cZI-DBS were significantly more efficacious than baseline (GPi-DBS 15.24 (5.79, 24.82), GPi-MRIgFUS 13.46 (2.46, 25.10), STN-DBS 19.62 (12.19, 27.16), cZI-DBS 14.18 (1.73, 26.89). The results from the surface under the cumulative ranking results showed that STN-DBS ranked first, followed by combined PPN and cZI-DBS, and PPN-DBS ranked last. MRIgFUS, an efficacious intervention for improving parkinsonian tremor, has not demonstrated to be inferior to DBS in parkinsonian tremor suppression. Hence, clinicians should distinguish individual patients' symptoms to ensure that the appropriate intervention and therapeutic approach are applied.

Prevalence and profile of nocturnal disturbances in Chinese patients with advanced-stage Parkinson's disease: a cross-sectional epidemiology study.

BACKGROUND: The impact of nocturnal disturbance (ND) in Parkinson's disease on quality of life of patients in Western Countries is increasingly understood. Our study aimed to investigate ND prevalence and its quality of life impact in patients with advanced Parkinson's disease in China. METHODS: In a multicenter, tertiary-care hospital, outpatient-based, cross-sectional study, patients with advanced Parkinson's disease (Modified Hoehn & Yahr [H&Y] Stage II-IV with ≥3 h awake "off" time/day) from 10 tertiary hospitals throughout China completed the Parkinson's Disease Sleep Scale-2 (PDSS-2) and Parkinson's Disease Questionnaire-39 (PDQ-39). The primary endpoint was the percentage of patients with significant ND (PDSS-2 total score ≥ 15). Additional endpoints were demographic and clinical characteristics, PDSS-2 and PDQ-39 total and subscale scores, correlation between PDSS-2 and PDQ-39, and risk factors for ND and higher PDSS-2 or PDQ-39 scores. RESULTS: Of 448 patients analyzed (mean age 63.5 years, 47.3% female), 70.92% (95% confidence interval: 66.71, 75.13) had significant ND. Presence of ND and higher PDSS-2 scores were associated with longer disease duration and higher H&Y stage. Presence of ND was also associated with more awake "off" time/day and female sex. PDQ-39 scores were significantly worse for patients with ND versus those without ND; worse scores were associated with more awake "off" time/day, female sex, and higher H&Y stage. PDSS-2 and PDQ-39 total scores were associated: Pearson correlation coefficient 0.62 (p < 0.001). CONCLUSIONS: In China, ND was highly prevalent in patients with advanced Parkinson's disease and adversely impacted quality of life. This study highlights the importance of early diagnosis and optimized management of ND in patients with Parkinson's disease in China.

Pedunculopontine Nucleus Deep Brain Stimulation Improves Gait Disorder in Parkinson's Disease: A Systematic Review and Meta-analysis.

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been proposed as a treatment strategy for gait disorder in patients with Parkinson's disease (PD). We thus performed a systematic review and meta-analysis of randomized and nonrandomized controlled trials to assess the effect of this treatment on gait disorder in patients with PD. We systematically searched PubMed, Cochrane, Web of Knowledge, Wan Fang and WIP for randomized and nonrandomized controlled trials (published before July 29, 2014; no language restrictions) comparing PPN-DBS with other treatments. We assessed pooled data using a random effects model and a fixed effects model. Of 130 identified studies, 14 were eligible and were included in our analysis (N = 82 participants). Compared to those presurgery, the Unified Parkinson Disease Rating Scale (UPDRS) 27-30 scores for patients were lowered by PPN-DBS [3.94 (95% confidence interval, CI = 1.23 to 6.65)]. The UPDRS 13 and 14 scores did not improve with levodopa treatment [0.43 (- 0.35 to 1.20); 0.35 (- 0.50 to 1.19)], whereas the UPDRS 27-30 scores could be improved by the therapy [1.42 (95% CI 0.34 to 2.51)]. The Gait and Falls Questionnaire and UPDRS 13 and 14 scores showed significant improvements after PPN-DBS under the medication-off (MED-OFF) status [15.44 (95% CI = 8.44 to 22.45); 1.57 (95% CI = 0.84 to 2.30); 1.34 (95% CI = 0.84 to 1.84)]. PPN-DBS is a potential therapeutic target that could improve gait and fall disorders in patients with PD. Our findings will help improve the clinical application of DBS in PD patients with gait disorder.

High positive end expiratory pressure levels affect hemodynamics in elderly patients with hypertension admitted to the intensive care unit: a prospective cohort study.

BACKGROUND: To study the effects of different positive end expiratory pressure (PEEP) on blood pressure and heart function in elderly patients with hypertension. METHODS: Forty elderly patients above 65 years of age treated with mechanical ventilation were divided into two groups: a control group of non-hypertensive subjects (n = 18) and a hypertension group (n = 22) patients with essential hypertension. Changes in blood pressure, central venous pressure (CVP), central venous oxygen saturation (ScvO2), heart rate, and airway pressure were determined in response to different selected PEEP levels of 0, 2, 4, 6, 8, 10 and 12 cm H2O under SIMV(PC) + PSV mode throughout the study. RESULTS: In both groups, the increase in PEEP led to an increase in CVP and airway pressure. When PEEP was above 4 cm H2O in the hypertension group, a decrease in blood pressure and ScvO2, and an increase of heart rate were observed. These results indicated that cardiac output significantly decreased. CONCLUSION: High levels of PEEP can significantly influence changes in blood pressure and heart function in elderly patients with hypertension. TRIAL REGISTRATION: This trial was retrospectively registered, The Chinese trial registration number is ChiCTR-ROC-17012873. The date of registration is 10-2-2017.

Continuous quantitative monitoring of physical activity in Parkinson's disease patients by using wearable devices: a case-control study.

The objective of this study was to explore the feasibility of using wearable devices to quantitatively measure the daily activity in patients with Parkinson's disease (PD) and to monitor medication-induced motor fluctuations. In this case-controlled study, we used monitored daily movement function in 21 patients with Parkinson's disease and 20 healthy volunteers. We analyzed the exercise types and sleep duration in the two groups and evaluated the correlation between daily movement function and age, gender, education, disease duration, Hohn-Yahr stage, UPDRS-II score, UPDRS-III score, and levodopa dose. We also determined the amount of exercise performed by PD patients at 1 h after taking levodopa and at 1 h before the next dose. The type of activity, average speed, and sleep duration in patients were significantly lower in PD patients than in healthy controls (P < 0.05). One hour after taking levodopa, patients were significantly more active than 1 h before the next dose (P < 0.05).Correlation analysis showed that age, gender, education, disease duration, Hohn-Yahr stage, UPDRS-II and UPDRS-III scores, and dosage of levodopa do not correlate with the daily movement function (P > 0.05) in patients with Parkinson's disease. In the control group, age and education were associated with daily movement function (P < 0.05), while gender was unrelated (P > 0.05). Continuous monitoring of daily activity may be useful to reveal medication-induced motor fluctuations in Parkinson's disease. The daily movement function may depend on age and education, but not on other parameters.

Increase of p25 associated with cortical neuronal death induced by hypoxia.

The mechanisms of neuronal damage in hypoxic cerebral cortex are complicated. Recent studies indicated that deregulation of Cdk5 was involved in neuronal death induced by hypoxia (1% O2). However, the pathological effect of Cdk5 is not fully elucidated. Therefore, in order to decipher the effect of Cdk5 on cellular death in hypoxic condition, the Cdk5 and its activator p35/p25 were investigated in cortical neurons at 10 DIV (Days In Vitro). Upon exposure to hypoxia, the cortical neurons showed a time-dependent increase of neuronal death compared to normoxia-treated control neurons. In correlation to the increase of neuronal death under hypoxia, the level of p25, a truncated form of p35, also increased in a time-dependent manner. Importantly, inhibition of Cdk5 kinase activity by roscovitine protected neurons from death under hypoxic stress. In contrast, ectopic upregulation of Cdk5 kinase activity in neurons expressing p25 led to an increase of neuronal death in comparison to control neurons expressing GFP. It suggests that ectopic increase of Cdk5 kinase activity through conversion of p35 to p25 is involved in the process of neuronal death induced by hypoxia.

[Possible effect of N-Acetyl-L-cysteine on Aß(25-35)-induced tau hyperphosphorylation].

OBJECTIVE: To investigate the possible effect and mechanism of N-Acetyl-L-cysteine (NAC) on fibrillar Aß(25-35)-induced tau hyperphosphorylation. METHODS: The phosphorylation of tau was induced by Aß(25-35) in primary cortical neuron. Neurons were incubated in the absent or present Aß(25-35), or pre-incubated NAC then co-incubated in Aß. The measurement of ROS was performed on a microplate fluorometer. The proteins of p35/p25, cdk5, pT205 and pS404 were detected by Western blot. RESULTS: In Aß treated group, the ROS, pT205 and pS404 level were obviously higher than that in non-treated with Aß group for 12 h (t=-6.35, P<0.05; t=-5, P<0.05; t=-4.57, P<0.05). However, in neurons pre-incubated with (10 mmol/L) NAC and then co-incubated with 20 µmol/L Aß, the ROS, pT205 and pS404 level were significantly decreased compared with that of Aß group (t=3.47, P<0.05; t=3.88, P<0.05 and t=3.64, P<0.05); Upon Aß exposure for 12 h, cortical neurons showed a statistically significant increase in p25 when compared to the control group (t=-6.20, P<0.05). However, pre-treatment with NAC showed a decrease in p25 as compared to neurons treated with Aß alone for 12 h (t=4.72, P<0.05). CONCLUSION: NAC attenuated the Aß(25-35)-induced tau hyperphosphorylation through CDK5 pathway.

Association between 2,4-dichlorophenoxyacetic acid and cognitive impairment in older adults: a cross-sectional study from NHANES 2001-2002 and 2011-2014.

BACKGROUND: 2,4-Dichlorophenoxyacetic acid (2,4-D) is reported to be the most widely used herbicide in home and garden environments, rendering it commonly encountered in daily life. Despite being ubiquitous, there is a scarcity of studies that have comprehensively assessed the relationship between 2,4-D exposure and cognition using multiple models. OBJECTIVE: To explore the association between 2,4-D exposure and cognition among older American people. METHODS: This was a cross-sectional study that included 3 cycles of data from the National Health and Nutrition Examination Survey. Generalized linear models (GLMs), restricted cubic spline (RCS) regression, and generalized additive models (GAMs) were used to assess the relationship between exposure to 2,4-D and cognitive performance by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning sub-test, Digit Symbol Substitution Test (DSST), and Animal Fluency Test (AFT). RESULTS: A total of 1364 older U.S. adults (60+ years) were included in the study. The GLMs revealed a negative association between median high levels (0.315-0.566 µg/L) of 2,4-D and cognitive impairment on the DSST and AFT, with multivariate-adjusted ORs of 0.403 (95% CI: 0.208-0.781, P = 0.009) and 0.396 (95% CI: 0.159-0.986, P = 0.047); the RCS regression and GAMs revealed a "U" shaped curve, the left part of which is consistent with the result of the GLMs. IMPACT STATEMENT: There is a U-shaped relationship between human urinary 2,4-D concentrations and cognitive impairment in older U.S. adults, especially in males, so controlling 2,4-D exposure within an appropriate range is particularly important for cognitive function.

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer's Disease.

The association between dysfunctional microglia and amyloid-ß (Aß) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aß anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery ß-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aß and its nerve repair function. In addition, siRNA reduces the production of Aß plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aß, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD.

LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIα and ERK.

BACKGROUND: LHPP was recently shown to be a risk gene for major depressive disorder. LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown about how LHPP contributes to depression. METHODS: In the current study, we addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing, and electrophysiology. RESULTS: We found that levels of LHPP were upregulated in glutamatergic neurons of the ventral hippocampus in mice that displayed stress-induced depression-like behaviors. Knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPPflox/flox·CaMKIIαCre+ (conditional knockout) mice. Adeno-associated virus-mediated LHPP knockdown in the ventral hippocampus enhanced resistance against chronic social defeat stress in mice. Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF (brain-derived neurotrophic factor) and PSD95 via the modulation of the dephosphorylation of CaMKIIα and ERK. Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIα/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP upregulation-induced depression-like behaviors. CONCLUSIONS: These findings provide evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, thereby identifying LHPP as a potential therapeutic target in treating patients with major depressive disorder.

Association between ethylene oxide levels and depressive symptoms: A cross-sectional study based on NHANES 2013-2018 database.

BACKGROUND AND AIM: Ethylene oxide (EO) is a commonly used compound with known health risks. However, the specific association between EO exposure and the development of depressive symptoms has not been well established. Therefore, this study aimed to examine the potential association between EO exposure, as indicated by hemoglobin adduct of ethylene oxide (HbEO) levels, and the occurrence of depressive symptoms. METHODS: We employed logistic regression, restricted cubic spline, and subgroup analysis to investigate the association between EO exposure and the occurrence of depressive symptoms. Additionally, we conducted a mediating effect analysis to explore the potential factors influencing the association between EO exposure and depressive symptoms. RESULTS: Elevated HbEO levels were associated with the development of depressive symptoms. After adjusting for potential confounders, the highest quartile of HbEO levels showed an odds ratio (OR) of 3.37 [95 % confidence interval (CI): 1.87-6.10, P = 0.002] compared with the lowest quartile. Additionally, a linear association was observed between HbEO levels and the risk of depressive symptoms. We also revealed that the levels of several inflammatory factors and triglycerides mediated the association between EO exposure and the occurrence of depressive symptoms. CONCLUSIONS: Higher levels of EO exposure were related to an increased risk of developing depressive symptoms. The analysis also suggested that the inflammatory response might play a mediating role in the pathway from EO exposure to depressive symptoms.

Left corticospinal tract could be a biomarker to identify the dual prodromal LRRK2/GBA mutated Parkinson's disease.

INTRODUCTION: Prodromal Parkinson's disease (PD) carriers of dual leucine-rich repeat kinase 2 (LRRK2) and glucosylceramidase ß (GBA) variants are rare, and their biomarkers are less well developed. OBJECTIVE: This study aimed to investigate the biomarkers for diagnosing the prodromal phase of LRRK2-GBA-PD (LRRK2-GBA-prodromal). METHODS: We assessed the clinical and whole-brain white matter microstructural characteristics of 54 prodromal PD carriers of dual LRRK2 (100% M239T) and GBA (95% N409S) variants, along with 76 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort. RESULTS: By analyzing the four values of 100 nodes on 20 fiber bundles, totaling 8000 data points, we identified the smallest p value in the fractional anisotropy (FA) value of the 38th segment of left corticospinal tract (L-CST) with differences between LRRK2-GBA-prodromal and HCs (p = 8.94 × 10-9). The FA value of the 38th node of the L-CST was significantly lower in LRRK2-GBA-prodromal (FA value, 0.65) compared with HCs (FA value, 0.71). The receiver-operating characteristic curve showed a cut-off value of 0.218 for the FA value of L-CST, providing sufficient sensitivity (79.2%) and specificity (72.2%) to distinguish double mutation prodromal PD from the healthy population. CONCLUSION: L-CST, especially the 38th node, may potentially serve as a biomarker for distinguishing individuals with double mutation prodromal PD from the healthy population.

Association of Exposure to Ambient Air Pollutants With Cognitive Performance and Dementia Risk and the Mediating Role of Pulmonary Function: Evidence From the UK Biobank.

BACKGROUND: The pathways by which air pollution affects cognition remain to be explored. This study aimed to explore how single air pollutants [including nitrogen oxide (NOX), nitrogen dioxide (NO2), particulate matter with a diameter of 2.5 micrometers (PM2.5), PM10, and PM2.5-10], and air pollution mixture could affect cognitive function and the incidence of dementia, and determine whether pulmonary function (PF) could play a mediating role in the relationship. METHODS: Multiple statistical methods were employed to evaluate association of 5 air pollutants (NOX, NO2, PM2.5, PM10, and PM2.5-10) with cognitive function. Bootstrap method was used to estimate mediating role of PF in the association of air pollutants with cognition or the incidence of dementia. RESULTS: A mixture of air pollutants was associated with performance on 5 cognitive tests, and global cognition (p < .05). Significantly negative association was also identified between mixture of air pollutants and PF (ß= -0.020, 95% confidence interval (CI) = -0.029 to -0.011). In addition, as PF scores increase, performance on all cognitive tests significantly improve, although the risk of dementia correspondingly decreases. It was noted that PF was shown to mediate the effects of air pollution mixtures on all cognitive tests as well as global cognition. For global cognition, PF mediated 6.08% of the association. PF was also found to have a mediating role in the association between NOX, NO2, PM2.5, and the risk of dementia. CONCLUSIONS: Mixed air pollution may impact cognitive function, with PF potentially mediating this relationship.

Associative role of HLA-DRB1 as a protective factor for susceptibility and progression of Parkinson's disease: a Chinese cross-sectional and longitudinal study.

Background: Previous genome-wide association studies investigating the relationship between the HLA-DRB1 and the risk of Parkinson's disease (PD) have shown limited racial diversity and have not explored clinical heterogeneity extensively. Methods: The study consisted of three parts: a case-control study, a cross-sectional study, and a longitudinal cohort study. The case-control study included 477 PD patients and 477 healthy controls to explore the relationship between rs660895 and PD susceptibility. The cross-sectional study utilized baseline data from 429 PD patients to examine the correlation between rs660895 and PD features. The longitudinal study included 388 PD patients who completed a 3-year follow-up to investigate the effects of rs660895 on PD progression. Results: In the case-control study, HLA-DRB1 rs660895-G allele was associated with a decreased risk of PD in allele model (adjusted OR=0.72, p = 0.003) and dominant model (AG + GG vs. AA: adjusted OR = 0.67, p = 0.003). In the cross-sectional analysis, there was no association between rs660895 and the onset age, motor phenotype, or initial motor symptoms. In the longitudinal analysis, PD patients with the G allele exhibited a slower progression of motor symptoms (MDS-UPDRS-III total score: ß = -5.42, p < 0.001, interaction ptime × genotype < 0.001) and non-motor symptoms (NMSS score: ß = -4.78, p = 0.030, interaction ptime × genotype < 0.001). Conclusion: Our findings support HLA-DRB1 rs660895-G allele is a protective genetic factor for PD risk in Chinese population. Furthermore, we also provide new evidence for the protective effect of rs660895-G allele in PD progression.

Accelerated biological aging as potential mediator mediates the relationship between pro-inflammatory diets and the risk of depression and anxiety: A prospective analysis from the UK biobank.

BACKGROUND: The relationship between inflammatory dietary patterns and the risk of depression/anxiety has not been clearly established due to differences in study populations, geographic regions, sex, and methods of calculating the inflammatory index. METHODS: We drew upon a prospective cohort in the UK Biobank and calculated the energy-adjusted dietary inflammatory index (E-DII). The follow-up time was defined from the date of completing the last dietary survey questionnaire to the date of diagnosis of depression, anxiety, phobic anxiety, other types of anxiety, death, loss to follow-up, or the respective censoring dates for England (September 30, 2021), Scotland (July 31, 2021), and Wales (February 28, 2018). The final follow-up times end on September 30, 2021, July 31, 2021, and February 28, 2018, for England, Scotland, and Wales, respectively. During the follow-up process, if a participant develops the condition, dies, or is lost to follow-up, the follow-up is terminated. We used Cox regression to evaluate the connection between E-DII and depression/anxiety. We employed restricted cubic spline curves for nonlinear relationships. We also conducted mediation analyses to explore whether biological age mediated the relationship between E-DII and depression. Additionally, we investigated whether genetic susceptibility modified the relationship between E-DII and depression through interaction modeling. RESULTS: In the final analysis, we included a total of 151,295, 159,695, 165,649, and 160,097 participants for the analysis of depression, all types of anxiety, specific phobia anxiety, and other types of anxiety, respectively. For every one-unit increase in E-DII, the risk of experiencing depression and anxiety increased by 5 % and 4 %, respectively. We identified a "J"-shaped nonlinear relationship (P for nonlinear = 0.003) for both depression and anxiety. A significant association with an elevated risk of depression was observed when E-DII exceeded 0.440, and an increased risk of anxiety was noted when E-DII was more than -0.196. Mediation analysis demonstrated that PhenoAge age acceleration (AA) (For depression, proportion of mediation = 9.6 %; For anxiety, proportion of mediation = 10.1 %) and Klemera-Doubal method Biological Age (KDM AA) (For depression, proportion of mediation = 2.9 %; For anxiety, proportion of mediation = 5.1 %) acted as mediators between E-DII and the development of depression and anxiety (P < 0.05). CONCLUSIONS: Diets with pro-inflammatory characteristics are associated with a heightened risk of depression and anxiety. Furthermore, the association of pro-inflammatory diets and depression is mediated by biological age.

Association of physical activity pattern and risk of Parkinson's disease.

Increasing evidence suggests an association between exercise duration and Parkinson's disease. However, no high-quality prospective evidence exists confirming whether differences exist between the two modes of exercise, weekend warrior and equal distribution of exercise duration, and Parkinson's risk. Hence, this study aimed to explore the association between different exercise patterns and Parkinson's risk using exercise data from the UK Biobank. The study analyzed data from 89,400 UK Biobank participants without Parkinson's disease. Exercise data were collected using the Axivity AX3 wrist-worn triaxial accelerometer. Participants were categorized into three groups: inactive, regularly active, and engaged in the weekend warrior (WW) pattern. The relationship between these exercise patterns and Parkinson's risk was assessed using a multifactorial Cox model. During a mean follow-up of 12.32 years, 329 individuals developed Parkinson's disease. In a multifactorial Cox model, using the World Health Organization-recommended threshold of 150 min of moderate-to-vigorous physical activity per week, both the active WW group [hazard ratio (HR) = 0.58; 95% confidence interval (CI) = 0.43-0.78; P < 0.001] and the active regular group (HR = 0.44; 95% CI = 0.34-0.57; P < 0.001) exhibited a lower risk of developing Parkinson's disease compared with the inactive group. Further, no statistically significant difference was observed between the active WW and the active regular groups (HR = 0.77; 95% CI = 0.56-1.05; P = 0.099). In conclusion, in this cohort study, both the WW exercise pattern and an equal distribution of exercise hours were equally effective in reducing Parkinson's risk.

Distance-based novelty detection model for identifying individuals at risk of developing Alzheimer's disease.

Introduction: Novelty detection (ND, also known as one-class classification) is a machine learning technique used to identify patterns that are typical of the majority class and can discriminate deviations as novelties. In the context of Alzheimer's disease (AD), ND could be employed to detect abnormal or atypical behavior that may indicate early signs of cognitive decline or the presence of the disease. To date, few research studies have used ND to discriminate the risk of developing AD and mild cognitive impairment (MCI) from healthy controls (HC). Methods: In this work, two distinct cohorts with highly heterogeneous data, derived from the Australian Imaging Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing project and the Fujian Medical University Union Hospital (FMUUH) China, were employed. An innovative framework with built-in easily interpretable ND models constructed solely on HC data was introduced along with proposing a strategy of distance to boundary (DtB) to detect MCI and AD. Subsequently, a web-based graphical user interface (GUI) that incorporates the proposed framework was developed for non-technical stakeholders. Results: Our experimental results indicate that the best overall performance of detecting AD individuals in AIBL and FMUUH datasets was obtained by using the Mixture of Gaussian-based ND algorithm applied to single modality, with an AUC of 0.8757 and 0.9443, a sensitivity of 96.79% and 89.09%, and a specificity of 89.63% and 90.92%, respectively. Discussion: The GUI offers an interactive platform to aid stakeholders in making diagnoses of MCI and AD, enabling streamlined decision-making processes. More importantly, the proposed DtB strategy could visually and quantitatively identify individuals at risk of developing AD.