Advanced brain aging in Parkinson's disease with cognitive impairment.

Patients with Parkinson's disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, Padjusted = 0.011; WM: 4.87 ± 7.88, Padjusted = 0.049) and controls (GM: -0.58 ± 7.04, Padjusted = 0.004; WM: 0.88 ± 7.45, Padjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (Padjusted = 0.011) and MoCA (Padjusted = 0.013) and positively correlated with UPDRS Part II (Padjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (Padjusted = 0.003 and Padjusted < 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.

FastEval Parkinsonism: an instant deep learning-assisted video-based online system for Parkinsonian motor symptom evaluation.

The Motor Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is designed to assess bradykinesia, the cardinal symptoms of Parkinson's disease (PD). However, it cannot capture the all-day variability of bradykinesia outside the clinical environment. Here, we introduce FastEval Parkinsonism ( https://fastevalp.cmdm.tw/ ), a deep learning-driven video-based system, providing users to capture keypoints, estimate the severity, and summarize in a report. Leveraging 840 finger-tapping videos from 186 individuals (103 patients with Parkinson's disease (PD), 24 participants with atypical parkinsonism (APD), 12 elderly with mild parkinsonism signs (MPS), and 47 healthy controls (HCs)), we employ a dilated convolution neural network with two data augmentation techniques. Our model achieves acceptable accuracies (AAC) of 88.0% and 81.5%. The frequency-intensity (FI) value of thumb-index finger distance was indicated as a pivotal hand parameter to quantify the performance. Our model also shows the usability for multi-angle videos, tested in an external database enrolling over 300 PD patients.

Prosaposin variants in sporadic, familial, and early-onset Parkinson's disease: a Taiwanese case-control study and meta-analysis.

Polymorphisms in the PSAP gene, which encodes prosaposin and is involved in the lysosomal function, yielded conflicting results regarding the association with Parkinson's disease (PD). Therefore, this study aims to investigate the role of PSAP in familial PD (FPD), early onset PD (EOPD) with age at onset before 50 years old, and sporadic PD (SPD) among Taiwanese population, and summarize relevant studies via meta-analysis. By sequencing exon 1 to 14 in 183 FPD and 219 EOPD, two novel exonic variants were found in EOPD, including p.A146E (c.437C > A) on exon 5 and p.Y248C (c.743A > G) on exon 7. Furthermore, four previously reported intronic variants (rs142614739/rs74733861), rs749823, rs4747203 and rs885828) in intron 11 and 12 were analyzed in 485 SPD and 712 in-hospital controls, in addition to the aforementioned FPD and EOPD groups. The adjusted odd ratios (ORs) by age and sex, only rs142614739 was significantly associated with higher risk of EOPD (OR = 1.85, 95% CI = 1.33-2.58). The risk effect was further confirmed by the meta-analysis of the association between rs142614739 and the risk of PD in both common effect (OR = 1.29, 95% CI = 1.11-1.50) and random effect (OR = 1.29, 95% CI = 1.11-1.50). Our findings suggest that the PSAP rs142614739 variant is associated with the risk of EOPD. Further functional studies are warranted to elucidate the biochemical mechanisms.

Pathological Gait Analysis With an Open-Source Cloud-Enabled Platform Empowered by Semi-Supervised Learning-PathoOpenGait.

We present PathoOpenGait, a cloud-based platform for comprehensive gait analysis. Gait assessment is crucial in neurodegenerative diseases such as Parkinson's and multiple system atrophy, yet current techniques are neither affordable nor efficient. PathoOpenGait utilizes 2D and 3D data from a binocular 3D camera for monitoring and analyzing gait parameters. Our algorithms, including a semi-supervised learning-boosted neural network model for turn time estimation and deterministic algorithms to estimate gait parameters, were rigorously validated on annotated gait records, demonstrating high precision and consistency. We further demonstrate PathoOpenGait's applicability in clinical settings by analyzing gait trials from Parkinson's patients and healthy controls. PathoOpenGait is the first open-source, cloud-based system for gait analysis, providing a user-friendly tool for continuous patient care and monitoring. It offers a cost-effective and accessible solution for both clinicians and patients, revolutionizing the field of gait assessment. PathoOpenGait is available at https://pathoopengait.cmdm.tw.

Characterization of markers, functional properties, and microbiome composition in human gut-derived bacterial extracellular vesicles.

Past studies have confirmed the etiologies of bacterial extracellular vesicles (BEVs) in various diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). This study aimed to investigate the characteristics of stool-derived bacterial extracellular vesicles (stBEVs) and discuss their association with stool bacteria. First, three culture models - gram-positive (G+)BcBEVs (from B.coagulans), gram-negative (G-)EcBEVs (from E.coli), and eukaryotic cell-derived EVs (EEV, from Colo205 cell line) - were used to benchmark various fractions of stEVs separated from optimized density gradient approach (DG). As such, WB, TEM, NTA, and functional assays, were utilized to analyze properties and distribution of EVs in cultured and stool samples. Stool samples from healthy individuals were interrogated using the approaches developed. Results demonstrated successful separation of most stBEVs (within DG fractions 8&9) from stEEVs (within DG fractions 5&6). Data also suggest the presence of stBEV DNA within vesicles after extraction of BEV DNA and DNase treatment. Metagenomic analysis from full-length (FL) region sequencing results confirmed significant differences between stool bacteria and stBEVs. Significantly, F8&9 and the pooled sample (F5-F9) exhibited a similar microbial composition, indicating that F8&9 were enriched in most stBEV species, primarily dominated by Firmicutes (89.6%). However, F5&6 and F7 still held low-density BEVs with a significantly higher proportion of Proteobacteria (20.5% and 40.7%, respectively) and Bacteroidetes (24% and 13.7%, respectively), considerably exceeding the proportions in stool and F8&9. Importantly, among five healthy individuals, significant variations were observed in the gut microbiota composition of their respective stBEVs, indicating the potential of stBEVs as a target for personalized medicine and research.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-term efficacy of bilateral subthalamic deep brain stimulation in the parkinsonism of SCA 3: A rare case report.

BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV SCA3, pure parkinsonism is the only symptom. Currently, no disease-modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3 remain unclear. METHODS: A 39-year-old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young-onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3 mutation. Excellent response to levodopa and dopamine agonists in the first 3 years was noted, but wearing-off phenomena, levodopa-induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug-induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in the absence of cerebellar signs, depression, and cognitive impairment. RESULTS: As of 2019, no impulsive control disorders, motor fluctuations, or DBS-related complications were observed during a 4-year follow-up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half. CONCLUSIONS: STN-DBS may be considered as adjunct treatment for severe dopa-related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3.

COQ2 and SNCA polymorphisms interact with environmental factors to modulate the risk of multiple system atrophy and subtype disposition.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) has no definitive genetic or environmental (G-E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G-E factors associated with MSA and its subtypes, MSA-P and MSA-C. METHODS: A consecutive case-control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model. RESULTS: A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G-E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671-0.847). Modulated risk of MSA-C, with MSA-P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p < 0.05), with an AUC of 0.749 (95% CI = 0.683-0.815). CONCLUSIONS: Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G-E interactions and MSA etiopathogenesis warrant further investigation.

Validation of neuroimaging-based brain age gap as a mediator between modifiable risk factors and cognition.

Neuroimaging-based brain age gap (BAG) is presumably a mediator linking modifiable risk factors to cognitive changes, but this has not been verified yet. To address this hypothesis, modality-specific brain age models were constructed and applied to a population-based cohort (N = 326) to estimate their BAG. Structural equation modeling was employed to investigate the mediation effect of BAG between modifiable risk factors (assessed by 2 cardiovascular risk scores) and cognitive functioning (examined by 4 cognitive assessments). The association between higher burden of modifiable risk factors and poorer cognitive functioning can be significantly mediated by a larger BAG (multimodal: p = 0.014, 40.8% mediation proportion; white matter-based: p = 0.023, 15.7% mediation proportion), which indicated an older brain. Subgroup analysis further revealed a steeper slope (p = 0.019) of association between cognitive functioning and multimodal BAG in the group of higher modifiable risks. The results confirm that BAG can serve as a mediating indicator linking risk loadings to cognitive functioning, implicating its potential in the management of cognitive aging and dementia.

Advanced brain aging in multiple system atrophy compared to Parkinson's disease.

Multiple system atrophy (MSA) and Parkinson's disease (PD) belong to alpha-synucleinopathy, but they have very different clinical courses and prognoses. An imaging biomarker that can differentiate between the two diseases early in the disease course is desirable for appropriate treatment. Neuroimaging-based brain age paradigm provides an individualized marker to differentiate aberrant brain aging patterns in neurodegenerative diseases. In this study, patients with MSA (N = 23), PD (N = 33), and healthy controls (N = 34; HC) were recruited. A deep learning approach was used to estimate brain-predicted age difference (PAD) of gray matter (GM) and white matter (WM) based on image features extracted from T1-weighted and diffusion-weighted magnetic resonance images, respectively. Spatial normative models of image features were utilized to quantify neuroanatomical impairments in patients, which were then used to estimate the contributions of image features to brain age measures. For PAD of GM (GM-PAD), patients with MSA had significantly older brain age (9.33 years) than those with PD (0.75 years; P = 0.002) and HC (-1.47 years; P < 0.001), and no significant difference was found between PD and HC (P = 1.000). For PAD of WM (WM-PAD), it was significantly greater in MSA (9.27 years) than that in PD (1.90 years; P = 0.037) and HC (-0.74 years; P < 0.001); there was no significant difference between PD and HC (P = 0.087). The most salient image features that contributed to PAD in MSA and PD were different. For GM, they were the orbitofrontal regions and the cuneus in MSA and PD, respectively, and for WM, they were the central corpus callosum and the uncinate fasciculus in MSA and PD, respectively. Our results demonstrated that MSA revealed significantly greater PAD than PD, which might be related to markedly different neuroanatomical contributions to brain aging. The image features with distinct contributions to brain aging might be of value in the differential diagnosis of MSA and PD.

The role of noncoding RNAs in Parkinson's disease: biomarkers and associations with pathogenic pathways.

The discovery of various noncoding RNAs (ncRNAs) and their biological implications is a growing area in cell biology. Increasing evidence has revealed canonical and noncanonical functions of long and small ncRNAs, including microRNAs, long ncRNAs (lncRNAs), circular RNAs, PIWI-interacting RNAs, and tRNA-derived fragments. These ncRNAs have the ability to regulate gene expression and modify metabolic pathways. Thus, they may have important roles as diagnostic biomarkers or therapeutic targets in various diseases, including neurodegenerative disorders, especially Parkinson's disease. Recently, through diverse sequencing technologies and a wide variety of bioinformatic analytical tools, such as reverse transcriptase quantitative PCR, microarrays, next-generation sequencing and long-read sequencing, numerous ncRNAs have been shown to be associated with neurodegenerative disorders, including Parkinson's disease. In this review article, we will first introduce the biogenesis of different ncRNAs, including microRNAs, PIWI-interacting RNAs, circular RNAs, long noncoding RNAs, and tRNA-derived fragments. The pros and cons of the detection platforms of ncRNAs and the reproducibility of bioinformatic analytical tools will be discussed in the second part. Finally, the recent discovery of numerous PD-associated ncRNAs and their association with the diagnosis and pathophysiology of PD are reviewed, and microRNAs and long ncRNAs that are transported by exosomes in biofluids are particularly emphasized.

Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia.

Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood-brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.

Analysis of GWAS-linked variants in multiple system atrophy.

A recent genome-wide association study performed in European population identified 4 potentially interesting gene loci of multiple system atrophy (MSA), including the EDN1 rs16872704, MAPT rs9303521, FBXO47 rs78523330, and ELOVL7 rs7715147. Because of the genetic heterogeneity, we aimed to explore the possible genetic association between above 4 single nucleotide polymorphisms (SNPs) and MSA in Chinese Han population from Mainland China, Taiwan, and Singapore. A total of 1847 subjects comprising 906 MSA patients and 941 unrelated healthy controls were genotyped by directly sequencing for these SNPs. No significant differences in the genotype distributions, minor allele frequency of EDN1 rs16872704, MAPT rs9303521, FBXO47 rs78523330, and ELOVL7 rs7715147 between MSA patients and healthy controls, and between subtypes of MSA patients (MSA-C and MSA-P), were found. In conclusion, we demonstrated that genome-wide association study-linked SNPs in Caucasians do not confer a significant risk for MSA in the Chinese population.