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.

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 time spent outdoors with the risk of Parkinson's disease: a prospective cohort study of 329,359 participants.

BACKGROUND: Studies on the association between time spent outdoors and the development of Parkinson's disease (PD) are lacking, and whether this relationship differs in different subgroups (age, sex) remains unclear. OBJECTIVE: We here examined the association between time spent outdoors and the incidence of PD in different seasons. METHODS: This study included 329,359 participants from the UK Biobank. Data regarding hours spent outdoors during a typical day were obtained through questionnaires. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) for the association between exposure to outdoors duration and PD incidence. Restricted cubic spline was used to explore the potential nonlinear relationship between time spent outdoors and PD risk. To explore the potential mechanisms of time spent outdoors effecting the risk of PD incidence, their association with serum vitamin D was further analysed separately. RESULTS: During a median follow-up of 13.57 years, 2,238 participants developed PD. In summer, time spent outdoors > 5.0 h/day was associated with a reduced PD risk compared with ≤ 2.0 h/day (HR = 0.84, 95% CI, 0.74-0.95). In winter too, time spent outdoors > 2.0 h/day was also associated with a reduced PD risk compared with ≤ 1.0 h/day (HR = 0.85, 95% CI, 0.76-0.94). For annual average time spent outdoors, participants who went outdoors for more than 3.5 h/day had a reduced PD risk than those who went outdoors for ≤ 1.5 h/day (HR = 0.85, 95% CI, 0.75-0.96). Additionally, sex and age differences were observed in the association between time spent outdoors and the PD risk. Moreover, Time spent outdoors was observed to be positively associated with serum vitamin D levels. Compared with serum vitamin D-deficient participants, the risk of PD was reduced by 15% in the sufficient participants. CONCLUSION: In the total population, higher time spent outdoors was linked to a reduced PD risk. However, this association may vary among different age or sex groups.

Cortical thickness and white matter microstructure predict freezing of gait development in Parkinson's disease.

The clinical applications of the association of cortical thickness and white matter fiber with freezing of gait (FoG) are limited in patients with Parkinson's disease (PD). In this retrospective study, using white matter fiber from diffusion-weighted imaging and cortical thickness from structural-weighted imaging of magnetic resonance imaging, we investigated whether a machine learning-based model can help assess the risk of FoG at the individual level in patients with PD. Data from the Parkinson's Disease Progression Marker Initiative database were used as the discovery cohort, whereas those from the Fujian Medical University Union Hospital Parkinson's Disease database were used as the external validation cohort. Clinical variables, white matter fiber, and cortical thickness were selected by random forest regression. The selected features were used to train the support vector machine(SVM) learning models. The median area under the receiver operating characteristic curve (AUC) was calculated. Model performance was validated using the external validation cohort. In the discovery cohort, 25 patients with PD were defined as FoG converters (15 men, mean age 62.1 years), whereas 60 were defined as FoG nonconverters (38 men, mean age 58.5 years). In the external validation cohort, 18 patients with PD were defined as FoG converters (8 men, mean age 66.9 years), whereas 37 were defined as FoG nonconverters (21 men, mean age 65.1 years). In the discovery cohort, the model trained with clinical variables, cortical thickness, and white matter fiber exhibited better performance (AUC, 0.67-0.88). More importantly, SVM-radial kernel models trained using random over-sampling examples, incorporating white matter fiber, cortical thickness, and clinical variables exhibited better performance (AUC, 0.88). This model trained using the above mentioned features was successfully validated in an external validation cohort (AUC, 0.91). Furthermore, the following minimal feature sets that were used: fractional anisotropy value and mean diffusivity value for right thalamic radiation, age at baseline, and cortical thickness for left precentral gyrus and right dorsal posterior cingulate gyrus. Therefore, machine learning-based models using white matter fiber and cortical thickness can help predict the risk of FoG conversion at the individual level in patients with PD, with improved performance when combined with clinical variables.

Transcriptome sequencing of circular RNA reveals the involvement of hsa-SCMH1_0001 in the pathogenesis of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. Exosomes are endosome-derived extracellular vesicles that can take part in intercellular communication. Circular RNAs (circRNAs) are noncoding RNAs characterized by covalently closed-loop structures, which perform a crucial function in many diseases. AIM: To clarify the expression and function of exosomal circRNSs of PD patients and look for circRNAs that might be related to the pathogenesis of PD. MATERIALS AND METHODS: We examined circRNA and mRNA expression profiles in peripheral exosomes from PD patients (n = 23) and healthy controls (n = 15) using next-generation sequencing (NGS) technology, functional annotation, and quantitative polymerase chain reaction. Correlation analysis was performed between the expression levels of the circRNAs and the clinical characteristics of PD patients. The binding miRNAs and target genes were predicted using TargetScanHuman, miRDB, and miRTarBase. The predicted target genes were compared with the differentially expressed mRNAs in sequencing results. RESULTS: According to the NGS, 62 upregulated and 37 downregulated circRNAs in the PD group were screened out. Correlation analysis revealed that hsa-SCMH1_0001 has strong clinical relevance. We identified 17 potential binding miRNAs of hsa-SCMH1_0001 with 149 potential target genes. ARID1A and C1orf115 belong to the intersection of the predicted target genes and the differentially expressed mRNAs obtained by sequencing. CONCLUSION: This study suggested that hsa-SCMH1_0001 and its target genes ARID1A and C1orf115 are downregulated in PD patients and may be involved in the occurrence of PD.

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.

Corrigendum: Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's mouse model.

[This corrects the article DOI: 10.3389/fnins.2022.1035444.].

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.

Coffee consumption and all-cause and cardiovascular mortality in older adults: should we consider cognitive function?

Background: The association between coffee and mortality risk has been found in most previous studies, and recent studies have found an association between coffee consumption and cognition. However, there is still a lack of research exploring whether the association between coffee and mortality is influenced by cognitive function. Objective: The purpose of this study was to explore the association of coffee, caffeine intake in coffee and decaffeinated coffee with all-cause mortality and cardiovascular disease (CVD) mortality in older adults with different cognitive performances. Methods: The study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Coffee and caffeine consumption data were obtained from two 24-h dietary recalls. Individual cognitive functions were assessed by CERAD-word learning test (CERAD-WLT), animal fluency test (AFT), and digit symbol substitution test (DSST). In addition, principal component analysis (PCA) was performed with the above test scores to create global cognitive score. The lowest quartile of scores was used to classify cognitive performance. Cox regression and restricted cubic spline (RCS) were applied to assess the relationship between coffee and caffeine consumption and mortality. Results: In the joint effects analysis, we found that those with cognitive impairment and who reported without drinking coffee had the highest risk of all-cause and cardiovascular mortality compared with others. In the analysis of population with cognitive impairment, for all-cause mortality, those who showed cognitive impairment in the AFT displayed a significant negative association between their total coffee consumption and mortality {T3 (HR [95% CI]), 0.495 [0.291-0.840], p = 0.021 (trend analysis)}. For DSST and global cognition, similar results were observed. Whereas for CERAD-WLT, restricted cubic spline (RCS) showed a "U-shaped" association between coffee consumption and mortality. For CVD mortality, a significant negative trend in coffee consumption and death was observed only in people with cognitive impairment in AFT or DSST. In addition, we observed that decaffeinated coffee was associated with reduced mortality in people with cognitive impairment. Conclusion: Our study suggested that the association between coffee consumption and mortality is influenced by cognition and varies with cognitive impairment in different cognitive domains.

Diffusion tensor imaging techniques show that parkin gene S/N167 polymorphism is responsible for extensive brain white matter damage in patients with Parkinson's disease.

Objective: To explore the influence of disease and genetic factors on the white matter microstructure in patients with PD. The white matter microstructural changes in the substantia nigra-striatum system were detected by diffusion tensor imaging (DTI) using the region of interest (ROI) and diffusion tensor tracer (DTT) methods. Methods: Patients with primary Parkinson's disease (PD) without a family history of PD were selected and divided into PD-G/G and PD-G/A groups according to their parkin S/N167 polymorphism. Control groups matched for age, sex, and gene type (G/G and G/A) were also included. Three-dimensional brain volume imaging (3D-BRAVO) and DTI were performed. The microstructural changes in the substantia nigra-striatum system were evaluated by the ROI and DTT methods. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hoehn-Yahr (H-Y) staging, and the third part of the Unified Parkinson's Disease Rating (UPDRS-III) scales evaluated the cognitive and motor function impairment in patients with PD. Independent samples t-test compared normally-distributed data, and the Wilcoxon rank sum test compared measurement or categorical non-normally distributed data. Multiple regression analysis was used to analyze the correlation between various DTI indicators and the MMSE, MoCA, UPDRS-III, and H-Y scores in the PD-G/G and PD-G/A groups. P < 0.05 was considered statistically significant. Results: The white matter microstructural changes in the nigrostriatal pathway differed significantly between the PD or PD-G/A and the control group (P < 0.05)The ROI method showed that the left globus pallidus radial diffusivity (RD) value was negatively correlated with the MMSE score (r = -0.404, P = 0.040), and the left substantia nigra (LSN) fractional anisotropy (FA) value was positively correlated with the MoCA score (r = 0.405, P = 0.040) and negatively with the H-Y stage (r = -0.479, P = 0.013).The DTT method showed that the MMSE score was positively correlated with the right substantia nigra (RSN) FA value (r = 0.592, P = 0.001) and negatively with its RD value (r = -0.439, P = 0.025). The H-Y grade was negatively correlated with the number of fibers in the RSN (r = -0.406, P = 0.040). The UPDRS-Ⅲ score was positively correlated with the mean diffusivity (r = 0.420, P = 0.033) and RD (r = 0.396, P = 0.045) values of the LSN, and the AD value of the RSN (r = 0.439, P = 0.025). Conclusion: The DTI technique detected extensive white matter fiber damage in patients with PD, primarily in those with the G/A genotype, that led to motor and cognitivesymptoms.

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.

The effect of Parkin gene S/N 167 polymorphism on resting spontaneous brain functional activity in Parkinson's Disease.

BACKGROUND: Genetic susceptibility plays a significant role in Parkinson's disease (PD) development. Carriers of the Parkin S/N167 mutation may have an increased risk of PD and altered spontaneous brain activity. OBJECTIVE: This study aims to investigate the potential pathogenesis of PD through a comparative analysis of the amplitude of low-frequency fluctuations (ALFF) in resting-state functional magnetic resonance imaging (rs-fMRI) of subjects with Parkin gene S/N 167 polymorphisms, and to examine the association between spontaneous brain activity and clinical scale scores of PD. METHODS: A total of 69 PD patients and 84 healthy controls (HC) were included in the study. Each subject was genotyped for the Parkin gene S/N 167 polymorphism and underwent rs-fMRI scans. ALFF analysis was employed to evaluate the relationship among genotypes, interactive brain regions, and clinical symptoms in PD. RESULTS: PD patients exhibited decreased ALFF values in the right anterior lobe and vermis of the cerebellum compared to HC. No significant interaction was found between the gene's main effect and the "group × genotype" effect on brain ALFF values. One-factor ANOVA revealed no significant difference in ALFF values between PD subgroups; however, the ALFF values in the right anterior lobe and vermis of the cerebellum were lower in the PD-G and PD-GA groups compared to the HC-G and HC-GA groups. Spearman correlation analysis demonstrated that ALFF values in the PD-GG and PD-GA groups were negatively associated with UPDRS-III scores in the bilateral lingual gyrus (Lingual R/L). CONCLUSION: Parkin gene S/N 167 polymorphisms may influence brain functional activity in specific brain regions, and ALFF values are associated with motor symptoms in PD patients.

A Reactive Oxygen Species-Responsive Targeted Nanoscavenger to Promote Mitophagy for the Treatment of Alzheimer's Disease.

Mitophagy modulators are proposed as potential therapeutic intervention that enhance neuronal health and brain homeostasis in Alzheimer's disease (AD). Nevertheless, the lack of specific mitophagy inducers, low efficacies, and the severe side effects of nonselective autophagy during AD treatment have hindered their application. In this study, the P@NB nanoscavenger is designed with a reactive-oxygen-species-responsive (ROS-responsive) poly(l-lactide-co-glycolide) core and a surface modified with the Beclin1 and angiopoietin-2 peptides. Notably, nicotinamide adenine dinucleotide (NAD+ ) and Beclin1, which act as mitophagy promoters, are quickly released from P@NB in the presence of high ROS levels in lesions to restore mitochondrial homeostasis and induce microglia polarization toward the M2-type, thereby enabling it to phagocytose amyloid-peptide (Aß). These studies demonstrate that P@NB accelerates Aß degradation and alleviates excessive inflammatory responses by restoring autophagic flux, which ameliorates cognitive impairment in AD mice. This multitarget strategy induces autophagy/mitophagy through synergy, thereby normalizing mitochondrial dysfunction. Therefore, the developed method provides a promising AD-therapy strategy.

ß Oscillations of Dorsal STN as a Potential Biomarker in Parkinson's Disease Motor Subtypes: An Exploratory Study.

Parkinson's disease (PD) can be divided into postural instability and difficult gait (PIGD) and tremor dominance (TD) subtypes. However, potential neural markers located in the dorsal ventral side of the subthalamic nucleus (STN) for delineating the two subtypes of PIGD and TD have not been demonstrated. Therefore, this study aimed to investigate the spectral characteristics of PD on the dorsal ventral side. The differences in the ß oscillation spectrum of the spike signal on the dorsal and ventral sides of the STN during deep brain stimulation (DBS) were investigated in 23 patients with PD, and coherence analysis was performed for both subtypes. Finally, each feature was associated with the Unified Parkinson's Disease Rating Scale (UPDRS). The ß power spectral density (PSD) in the dorsal STN was found to be the best predictor of the PD subtype, with 82.6% accuracy. The PSD of dorsal STN ß oscillations was greater in the PIGD group than in the TD group (22.17% vs. 18.22%; p < 0.001). Compared with the PIGD group, the TD group showed greater consistency in the ß and γ bands. In conclusion, dorsal STN ß oscillations could be used as a biomarker to classify PIGD and TD subtypes, guide STN-DBS treatment, and relate to some motor symptoms.

Diagnosis of Parkinson's Disease via the Metabolic Fingerprint in Saliva by Deep Learning.

Parkinson's disease (PD) is the second cause of the neurodegenerative disorder, affecting over 6 million people worldwide. The World Health Organization estimated that population aging will cause global PD prevalence to double in the coming 30 years. Optimal management of PD shall start at diagnosis and requires both a timely and accurate method. Conventional PD diagnosis needs observations and clinical signs assessment, which are time-consuming and low-throughput. A lack of body fluid diagnostic biomarkers for PD has been a significant challenge, although substantial progress has been made in genetic and imaging marker development. Herein, a platform that noninvasively collects saliva metabolic fingerprinting (SMF) by nanoparticle-enhanced laser desorption-ionization mass spectrometry with high-reproducibility and high-throughput, using ultra-small sample volume (down to 10 nL), is developed. Further, excellent diagnostic performance is achieved with an area-under-the-curve of 0.8496 (95% CI: 0.7393-0.8625) by constructing deep learning model from 312 participants. In conclusion, an alternative solution is provided for the molecular diagnostics of PD with SMF and metabolic biomarker screening for therapeutic intervention.

Specific Distribution of Digital Gait Biomarkers in Parkinson's Disease Using Body-Worn Sensors and Machine Learning.

Gait impairment leads to reduced social activities and low quality of life in people with Parkinson's disease (PD). PD is associated with unique gait signs and distributions of gait features. The assessment of gait characteristics is crucial in the diagnosis and treatment of PD. At present, the number and distribution of gait features associated with different PD stages are not clear. Here, we used whole-body multinode wearable devices combined with machine learning to build a classification model of early PD (EPD) and mild PD (MPD). Our model exhibited significantly improved accuracy for the EPD and MPD groups compared with the healthy control (HC) group (EPD vs HC accuracy = 0.88, kappa = 0.75, AUC = 0.88; MPD vs HC accuracy = 0.94, kappa = 0.84, AUC = 0.90). Furthermore, the distribution of gait features was distinguishable among the HC, EPD, and MPD groups (EPD based on variability features [40%]; MPD based on amplitude features [30%]). Here, we showed promising gait models for PD classification and provided reliable gait features for distinguishing different PD stages. Further multicenter clinical studies are needed to generalize the findings.

Novel mutations in the ABCD1 gene caused adrenomyeloneuropathy in the Chinese population.

Background: As a rare genetic disease, adrenomyeloneuropathy (AMN) is the most common adult phenotype of X-linked adrenoleukodystrophy (X-ALD). Mutations in the ABCD1 gene have been identified to cause AMN. Methods: We applied clinical evaluation, laboratory tests, and neuroimaging on three patients with progressive spastic paraparesis. In genetic analysis, we investigated ABCD1 gene mutations by whole-exome sequencing and Sanger sequencing. Bioinformatics tools were used to predict the effects of identified ABCD1 mutations on the protein. Results: All three patients were men with adult-onset disease, mainly characterized by progressive spastic paraparesis. Among them, two patients had peripheral neuropathy and one patient had signs of adrenal insufficiency. All three patients showed cerebral involvement on brain MRI, while two patients were found with diffuse cord atrophy on spinal MRI. High-VLCFA levels in plasma, as well as C24:0/C22:0 and C26:0/C22:0 ratios, were found in all three patients. In addition, three different ABCD1 mutations were identified in three unrelated Chinese families, including one known mutation (c.1415_1416delAG) and two novel mutations (c.217C>T and c.160_170delACGCAGGAGGC). Based on the clinical assessment, radiographic, biochemical, and genetic testing, the final diagnosis was AMN in these patients with spastic paraparesis. Conclusion: This study reported three patients with AMN and identified two novel mutations in the ABCD1 in the Chinese population. Our finding emphasized that X-ALD is an important cause of adult-onset spastic paraplegia. Thus, neuroimaging, VLCFA testing, and especially the detection of the ABCD1 gene have important implications for the etiological diagnosis of adult patients with spastic paraplegia.

Association between Beta Oscillations from Subthalamic Nucleus and Quantitative Susceptibility Mapping in Deep Gray Matter Structures in Parkinson's Disease.

This study aimed to investigate the association between beta oscillations and brain iron deposition. Beta oscillations were filtered from the microelectrode recordings of local field potentials (LFP) in the subthalamic nucleus (STN), and the ratio of the power spectral density of beta oscillations (PSDXb) to that of the LFP signals was calculated. Iron deposition in the deep gray matter (DGM) structures was indirectly assessed using quantitative susceptibility mapping (QSM). The Unified Parkinson's Disease Rating Scale (UPDRS), part III, was used to assess the severity of symptoms. Spearman correlation coefficients were applied to assess the associations of PSDXb with QSM values in the DGM structures and the severity of symptoms. PSDXb showed a significant positive correlation with the average QSM values in DGM structures, including caudate and substantia nigra (SN) (p = 0.008 and 0.044). Similarly, the PSDXb showed significant negative correlations with the severity of symptoms, including axial symptoms and the gait in the medicine-off state (p = 0.006 for both). The abnormal iron metabolism in the SN and striatum pathways may be one of the underlying mechanisms for the occurrence of abnormal beta oscillations in the STN, and beta oscillations may serve as important pathophysiological biomarkers of PD.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.