Investigating the Genetic Association of 40 Biochemical Indicators with Parkinson's Disease.

The mechanisms of Parkinson's disease (PD) are not fully understood, which hinders the development of effective therapies. Research indicates that lower levels of biochemical indicators like bilirubin, vitamin D, and cholesterol may elevate the risk of PD. However, clinical studies on abnormal levels of biochemical indicators in PD patients' circulation are inconsistent, leading to ongoing debate about their association with PD. Here, we investigate the genetic correlation between 40 biochemical indicators and PD using a bidirectional two-sample Mendelian randomization (MR) approach to uncover potential causal relationships. Data from genome-wide association studies (GWAS) were utilized, with genetic variations from specific lineages serving as instrumental variables (IVs). The methodology followed the STROBE-MR checklist and adhered to the three principal assumptions of MR. Statistical analyses employed methods including inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode. Biochemical indicators including albumin, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) showed significant associations with PD risk. Elevated levels of albumin (OR = 1.246, 95% CI 1.006-1.542, P = 0.043) and SHBG (OR = 1.239, 95% CI 1.065-1.439, P = 0.005) were linked to higher PD risk. Conversely, increased CRP levels (OR = 0.663, 95% CI 0.517-0.851; P = 0.001) could potentially lower PD risk. The robustness of the results was confirmed through various MR analysis techniques, including assessments of directional pleiotropy and heterogeneity using MR-Egger intercept and MR-PRESSO methods. This study systematically reveals, for the first time at the genetic level, the relationship between 40 biochemical indicators and PD risk. Our research verifies the role of inflammation in PD and provides new genetic evidence, further advancing the understanding of PD pathogenesis. The study shows a positive correlation between albumin and SHBG with PD risk and a negative correlation between CRP and PD risk. This study identifies for the first time that SHBG may be involved in the onset of PD and potentially worsen disease progression.

Association between the Val66Met (rs6265) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, BDNF protein level in the blood and the risk of developing early­onset Parkinson's disease.

Brain-derived neurotrophic factor (BDNF) is involved in the maintenance of dopamine level and the survival of dopaminergic neurons, which may affect the functionality of brain structures responsible for motor and cognitive function. The aim of the study was to assess the association of individual and combined single nucleotide polymorphism (SNP) in the rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes with early­onset of Parkinson's disease (PD) patients. Moreover, we assessed the association between the BDNF Val66Met polymorphism and the level of BDNF protein in the serum of patients with PD and controls. The study involved 163 patients with idiopathic PD divided into early onset (<55 years) and late­onset (>55 years) groups and 91 healthy age­matched people (Control). The SNP were determined using the TaqMan Real­Time PCR method. Serum BDNF levels were determined by ELISA assay. The risk of developing early PD in people with the BDNF genotype AG increases threefold in comparison with the carriers of the BDNF genotype GG. In PD patients and healthy people with the BDNF genotypes AG and AA, a lower serum BDNF level was found compared to those with the BDNF genotype GG in both groups. The results of our study indicate that the presence of the Val66Met BDNF gene polymorphism is associated with reduced blood BDNF levels and an elevated risk of developing early­onset PD. This effect appears to be more pronounced in men.

Association between neutrophil-to-lymphocyte ratio and motor subtypes in idiopathic Parkinson's disease: a prospective observational study.

BACKGROUND: Peripheral immunity and neuroinflammation interact with each other and they play important roles in the pathophysiology of idiopathic Parkinson's disease (IPD). There have been very few real-world reports on the relationship between peripheral immune inflammation and motor phenotypes of IPD. This study aimed to investigate the potential correlation between peripheral inflammatory indicators and motor subtypes in patients with IPD. METHODS: This observational, prospective case-control study examined patients with IPD and healthy controls (HC) matched for age and sex between September 2021 and July 2023 at the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University. The levels of peripheral inflammatory indicators were collected from each patient with IPD and HCs. Differences in the levels of peripheral inflammatory indicators among groups were compared. Binary logistic regression analysis was used to explore the inflammatory mechanism underlying the motor subtype of IPD. RESULTS: A total number of 94 patients with IPD were recruited at the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University between September 2021 and July 2023, including 49 males and 45 females, and 37 healthy volunteers matched for age and sex were also enrolled as the control group. Of the 94 patients with IPD, 42.6% performed as the TD motor subtype and 57.4% performed as the AR motor subtype. NLR and the plasma levels of IL-1ßand TNF-α in the IPD group were higher than those in the HC group (P < 0.05). The disease duration, Hoehn and Yahr (H-Y) stage, NLR, and the levels of IL-1ß in the AR group were higher than those in the TD group (P < 0.05). Additionally, IL-1ß plasma levels and NLR were positively correlated with disease duration, H-Y stage, movement disorder society-Unified Parkinson's Disease Rating Scale-III motor score, and AR subtype. The binary logistic regression model revealed that the plasma level of IL-1ß was mildly associated with the AR motor subtype and NLR was strongly associated with the AR motor subtype. The combination of NLR and IL-1ß showed better performance in identifying the AR motor subtype. CONCLUSION: NLR is strongly associated with the AR motor subtype in IPD, and peripheral immunity is probably involved in the pathogenesis of AR motor subtype in IPD.

Relationships between Serum Lipid, Uric Acid Levels and Mild Cognitive Impairment in Parkinson's Disease and Multiple System Atrophy.

BACKGROUND: Mild cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD) and multiple system atrophy (MSA). Few studies have previously been conducted on the correlation between serum uric acid (SUA) and lipid levels and mild cognitive impairment in PD and MSA. METHODS: Participants included 149 patients with PD and 99 patients with MSA. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Evaluations were conducted on SUA and lipid levels, which included triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC). RESULTS: Patients with PD and MSA diagnosed with mild cognitive impairment demonstrated multiple cognitive domain impairment when compared with patients with normal cognition. Attentional impairment was more pronounced in patients with MSA when compared with PD (p = 0.001). In PD, the risk of mild cognitive impairment was lower in the highest quartiles and secondary quartile of SUA than in the lowest quartiles (odds ratio [OR] = 0.281, 95% confidence intervals [CI]: 0.097-0.810, p = 0.019; and OR = 0.317, 95% CI: 0.110-0.911, p = 0.033). In MSA, the risk of mild cognitive impairment was lower in the third and highest quartile of SUA than in the lowest quartile (OR = 0.233, 95% CI: 0.063-0.868, p = 0.030; and OR = 0.218, 95% CI: 0.058-0.816, p = 0.024). In patients with PD, the MoCA scores were negatively correlated with TC levels (r = -0.226, p = 0.006) and positively correlated with SUA levels (r = 0.206, p = 0.012). In MSA, the MoCA scores were positively correlated with SUA levels (r = 0.353, p = 0.001). CONCLUSIONS: Lower SUA levels and higher TC levels are a possible risk factor for the risk and severity of mild cognitive impairment in PD. Lower SUA levels are a possible risk factor for the risk and severity of mild cognitive impairment in MSA.

Relationships of B12 and Homocysteine with Outcomes in the SURE-PD, SURE-PD3, and STEADY-PDIII Trials.

Background: DATATOP was a study of early Parkinson's disease (PD) conducted in the 1980 s, before mandatory folic acid fortification in the United States. Our analysis of its baseline serum samples revealed a geometric mean vitamin B12 of 369 pg/mL and homocysteine (tHcy) of 9.5µmol/l. We also found that low B12 predicted greater worsening of ambulatory capacity (AC) and elevated tHcy (>15µmol/L) predicted greater declines in cognitive function. Objective: We sought to measure B12 and tHcy in contemporary trial participants with early PD who had not started dopaminergic treatment and to determine whether these analytes were associated with clinical progression. Methods: We measured B12 and tHcy from baseline and end-of-study blood samples from three recent clinical trials. Results: Baseline geometric mean B12 levels for these studies ranged from 484- 618 pg/ml and for tHcy ranged from 7.4- 10µmol/L. Use of B12-containing supplements ranged from 41- 61%, and those taking supplements had higher B12 and lower tHcy. Those who began levodopa, but were not taking B12-supplements, had greater end-of-study tHcy. There was no association of baseline tHcy > 15µmol/L with annualized change in Montreal Cognitive Assessment and no association of baseline B12 tertiles with change in AC. Conclusions: In these longitudinal trials, B12 levels were higher than for DATATOP, due in large part to increased B12-supplement intake, while tHcy levels were similar. Initiation of levodopa was associated with increases of tHcy in those not taking a B12-containing supplement. These smaller studies did not replicate prior findings of low B12 and elevated tHcy with features of progression, possibly due to higher baseline B12.

Aging-related biomarkers for the diagnosis of Parkinson's disease based on bioinformatics analysis and machine learning.

Parkinson's disease (PD) is a multifactorial disease that lacks reliable biomarkers for its diagnosis. It is now clear that aging is the greatest risk factor for developing PD. Therefore, it is necessary to identify novel biomarkers associated with aging in PD. In this study, we downloaded aging-related genes from the Human Ageing Gene Database. To screen and verify biomarkers for PD, we used whole-blood RNA-Seq data from 11 PD patients and 13 healthy control (HC) subjects as a training dataset and three datasets retrieved from the Gene Expression Omnibus (GEO) database as validation datasets. Using the limma package in R, 1435 differentially expressed genes (DEGs) were found in the training dataset. Of these genes, 29 genes were found to occur in both DEGs and 307 aging-related genes. By using machine learning algorithms (LASSO, RF, SVM, and RR), Venn diagrams, and LASSO regression, four of these genes were determined to be potential PD biomarkers; these were further validated in external validation datasets and by qRT-PCR in the peripheral blood mononuclear cells (PBMCs) of 10 PD patients and 10 HC subjects. Based on the biomarkers, a diagnostic model was developed that had reliable predictive ability for PD. Two of the identified biomarkers demonstrated a meaningful correlation with immune cell infiltration status in the PD patients and HC subjects. In conclusion, four aging-related genes were identified as robust diagnostic biomarkers and may serve as potential targets for PD therapeutics.

Circulating microRNAs as potential biomarkers for the diagnosis of Parkinson's disease: A meta-analysis.

BACKGROUND AND OBJECTIVE: Parkinson's disease (PD) is the one of the most common neurodegenerative diseases. Many investigators have confirmed the possibility of using circulating miRNAs to diagnose PD. However, the results were inconsistent. Therefore, the aim of this meta-analysis was to systematically evaluate the diagnostic accuracy of circulating miRNAs in the diagnosis of PD. METHODS: We carefully searched PubMed, Embase, Web of Science, Cochrane Library, Wanfang database and China National Knowledge Infrastructure for relevant studies (up to January 1, 2022) based on PRISMA statement. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), the diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated to test the diagnostic accuracy. Furthermore, subgroup analyses were performed to identify the potential sources of heterogeneity, and the Deeks' funnel plot asymmetry test was used to evaluate the potential publication bias. RESULTS: Forty-four eligible studies from 16 articles (3298 PD patients and 2529 healthy controls) were included in the current meta-analysis. The pooled sensitivity was 0.79 (95% CI: 0.76-0.81), specificity was 0.82 (95% CI: 0.78-0.84), PLR was 4.3 (95% CI: 3.6-5.0), NLR was 0.26 (95% CI: 0.23-0.30), DOR was 16 (95% CI: 13-21), and AUC was 0.87 (95% CI: 0.84-0.90). Subgroup analysis suggested that miRNA cluster showed a better diagnostic accuracy than miRNA simple. Moreover, there was no significant publication bias. CONCLUSIONS: Circulating miRNAs have great potential as novel non-invasive biomarkers for PD diagnosis.

Association between metabolic syndrome and the risk of Parkinson's disease: a meta-analysis.

BACKGROUND: There is still a lack of knowledge about the relationship between metabolic syndrome (MetS) and Parkinson's disease (PD). This study aimed to determine whether MetS increases PD risk. METHODS: To identify relevant clinical studies, databases such as PubMed, Embase, and the Cochrane Library were searched in depth from the inception of databases until March 31, 2024. The study evaluated the correlation between MetS and the likelihood of developing PD through the computation of aggregated relative risks (RR) and their respective 95% confidence intervals (CIs) utilizing selnRR and lnRR. RESULTS: Seven studies were included in our systematic review. The meta-analysis revealed that patients with MetS have a 0.3-fold increased risk of developing PD (p = 0.001). Furthermore, the analysis revealed a positive correlation between central obesity and the incidence of PD, with an RR of 1.19 (95% CI, 1.16-1.22; p = 0.001), as well as a greater risk of PD in patients with elevated blood pressure, with an RR of 1.13 (95% CI, 1.07-1.19; p = 0.001); elevated serum triglyceride levels, with an RR of 1.09 (95% CI, 1.02-1.15; p = 0.001); lower serum HDL cholesterol levels, with an RR of 1.21 (95% CI, 1.15-1.28; p = 0.001); and elevated plasma fasting glucose levels, with an RR of 1.18 (95% CI, 1.11-1.26; p = 0.001). CONCLUSION: MetS can contribute to the incidence of Parkinson's disease, with individual components of MetS demonstrating comparable effects.

GFAP and NfL as fluid biomarkers for clinical disease severity and disease progression in multiple system atrophy (MSA).

BACKGROUND: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA. METHODS: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores). RESULTS: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00). DISCUSSION: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD.

Associations between Thyroid Hormones and Cognitive Impairment in Patients with Parkinson's Disease.

This study aims to explore the correlation of serum thyroid hormone levels to cognitive impairments in Parkinson's disease (PD) patients. In this retrospective study, 106 Chinese patients without cognitive impairments and 94 patients with cognitive impairments, including 55 with mild cognitive impairment (PD-MCI) and 39 with PD dementia (PDD), were analyzed. Clinical data regarding the PD assessments, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 scores, and Hoehn and Yahr (H-Y) staging, were analyzed. Cognitive functions were evaluated using the Montreal Cognitive Assessment score. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were measured using ELISA. Significantly altered H-Y staging, disease duration, and UPDRS Part 3 scores were observed in PD patients with cognitive impairment compared with those without. Serum levels of FT3 were significantly decreased, while FT4 and TSH levels were significantly elevated in PD patients with cognitive impairment compared with those without. Combined detection of TSH, FT3, and FT4 showed value in distinguishing PD patients with and without cognitive impairment. Furthermore, a comparison of serum levels between PD-MCI and PDD patients revealed significant association between thyroid hormone levels and the degree of cognitive impairment in PD patients. Our findings suggest a relationship between changes in serum thyroid hormone levels and cognitive impairments in PD patients. Thyroid hormone levels, particularly FT3, may serve as potential markers for cognitive dysfunction in PD.

Molecular Gene Expression Testing to Identify Alzheimer's Disease with High Accuracy from Fingerstick Blood.

Background: There is no molecular test for Alzheimer's disease (AD) using self-collected samples, nor is there a definitive molecular test for AD. We demonstrate an accurate and potentially definitive TempO-Seq® gene expression test for AD using fingerstick blood spotted and dried on filter paper, a sample that can be collected in any doctor's office or can be self-collected. Objective: Demonstrate the feasibility of developing an accurate test for the classification of persons with AD from a minimally invasive sample of fingerstick blood spotted on filter paper which can be obtained in any doctor's office or self-collected to address health disparities. Methods: Fingerstick blood samples from patients clinically diagnosed with AD, Parkinson's disease (PD), or asymptomatic controls were spotted onto filter paper in the doctor's office, dried, and shipped to BioSpyder for testing. Three independent patient cohorts were used for training/retraining and testing/retesting AD and PD classification algorithms. Results: After initially identifying a 770 gene classification signature, a minimum set of 68 genes was identified providing classification test areas under the ROC curve of 0.9 for classifying patients as having AD, and 0.94 for classifying patients as having PD. Conclusions: These data demonstrate the potential to develop a screening and/or definitive, minimally invasive, molecular diagnostic test for AD and PD using dried fingerstick blood spot samples that are collected in a doctor's office or clinic, or self-collected, and thus, can address health disparities. Whether the test can classify patients with AD earlier then possible with cognitive testing remains to be determined.

Association between plasma Netrin-1 levels and motor and nonmotor symptoms in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron degeneration and diverse motor and nonmotor symptoms. Early diagnosis and intervention are crucial but challenging due to reliance on clinical presentation. Recent research suggests potential biomarkers for early detection, including plasma netrin-1 (NTN-1), a protein implicated in neuronal survival. METHODS: This cross-sectional study recruited 105 PD patients and 65 healthy controls, assessing plasma NTN-1 levels and correlating them with clinical characteristics. Statistical analyses explored associations between NTN-1 levels and PD symptoms, considering demographic factors. RESULTS: PD patients exhibited significantly lower plasma NTN-1 levels compared to controls. NTN-1 demonstrated moderate potential as a PD biomarker. Positive correlations were found between NTN-1 levels and motor, depression, and cognitive symptoms. Multiple regression analysis revealed disease duration and NTN-1 levels as key factors influencing symptom severity. Gender also impacted symptom scores. CONCLUSION: Reduced plasma NTN-1 levels correlate with PD severity, suggesting its potential as a biomarker. However, further research is needed to elucidate the roles of NTN-1 in PD pathophysiology and validate its diagnostic and therapeutic implications. Understanding the involvement of NTN-1 may lead to personalized management strategies for PD.

Serum phosphorus levels associated with nigrostriatal dopaminergic deficits in drug-naïve Parkinson's disease.

INTRODUCTION: A major component of Lewy bodies is phosphorylated α-synuclein. This post-translational modification of α-synuclein, phosphorylation, may consume a great amount of serum phosphorus. We aimed to investigate serum phosphorus levels and their associations with clinical phenotype and the degeneration of cardiac sympathetic and nigrostriatal dopaminergic neurons in patients with Parkinson's disease (PD). MATERIALS AND METHODS: We examined serum phosphorus levels in 127 participants (drug-naïve PD, 97; age- and sex-matched controls, 30). Associations of serum phosphorus levels with clinical features, heart-to-mediastinum (H/M) ratio on cardiac 123I-metaiodobenzylguanidine scintigraphy and striatal specific binding ratio of 123I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) were examined. RESULTS: Serum phosphorus levels were 3.4 ± 0.5 mg/dL in patients with PD and were not different from those in controls after controlling for age and sex (p = 0.850). Serum phosphorus levels were significantly lower in patients with PD and decreased H/M ratio than in those with PD and normal H/M ratio (3.3 ± 0.4 mg/dL vs. 3.6 ± 0.5 mg/dL, p = 0.003). Lower serum phosphorus levels were significantly associated with more severe degeneration of nigrostriatal dopaminergic neurons in patients with PD and decreased H/M ratio. However, this association was not observed in patients with PD and normal H/M ratio. CONCLUSIONS: Serum phosphorus levels and their association with nigrostriatal dopaminergic degeneration are different between patients with decreased H/M ratio and those with normal H/M ratio. Serum phosphorus levels may reflect the degree of nigrostriatal dopaminergic degeneration in patients with decreased H/M ratio, namely, Body-First PD.

Stage-dependent phosphoproteome remodeling of Parkinson's disease blood cells.

The complexity and heterogeneity of PD necessitate advanced diagnostic and prognostic tools to elucidate its molecular mechanisms accurately. In this study, we addressed this challenge by conducting a pilot phospho-proteomic analysis of peripheral blood mononuclear cells (PBMCs) from idiopathic PD patients at varying disease stages to delineate the functional alterations occurring in these cells throughout the disease course and identify key molecules and pathways contributing to PD progression. By integrating clinical data with phospho-proteomic profiles across various PD stages, we identify potential stage-specific molecular signatures indicative of disease progression. This integrative approach allows for the discernment of distinct disease states and enhances our understanding of PD heterogeneity.

Gastrointestinal dysfunction in Parkinson's Disease: absence of anti-gliadin antibodies.

BACKGROUND AND OBJECTIVES: Parkinson disease (PD), which is a neurodegenerative disorder, includes several gastrointestinal symptoms that are similar to those of Celiac disease (CD). However, the presence of celiac antibodies in PD patients has not yet been studied. Our aim in this study is to compare anti-transglutaminase (ATA) and antigliadin antibodies (AGA) as well as gastrointestinal symptoms and nutrition habits between patients with Parkinson's disease (PD) and healthy controls. METHODS AND STUDY DESIGN: Serum AGA IgG and IgA and the ATA antibodies IgA and IgG were studied in 102 PD patients and 91 healthy controls. Gastrointestinal symptoms, specifically constipation, were investigated using the gastrointestinal system rating scale (GSRS) and the constipation rating scale (CRS). Dietary habits were also investigated and compared between the groups. RESULTS: No significant differences were found between the two groups in terms of celiac antibodies. As expected, the hypokinetic GSRS and CRS scores were significantly higher in the PD group (p<0.001). Dietary habits, especially carbohydrate-rich diets, had a negative impact on gastrointestinal symptoms in the PD patients. CONCLUSIONS: Studies have suggested a connection between PD and CD, which infers a probable non-celiac gluten intolerance and the need to offer PD patients an elimination diet. However, the results of our study did not support any link between celiac antibodies and PD. Notwithstanding, the negative impact of a carbohydrate-rich diet in PD patients still leaves a question regarding gluten sensitivity in these patients.

Metabolomics Unveils Disrupted Pathways in Parkinson's Disease: Toward Biomarker-Based Diagnosis.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by diverse symptoms, where accurate diagnosis remains challenging. Traditional clinical observation methods often result in misdiagnosis, highlighting the need for biomarker-based diagnostic approaches. This study utilizes ultraperformance liquid chromatography coupled to an electrospray ionization source and quadrupole time-of-flight untargeted metabolomics combined with biochemometrics to identify novel serum biomarkers for PD. Analyzing a Brazilian cohort of serum samples from 39 PD patients and 15 healthy controls, we identified 15 metabolites significantly associated with PD, with 11 reported as potential biomarkers for the first time. Key disrupted metabolic pathways include caffeine metabolism, arachidonic acid metabolism, and primary bile acid biosynthesis. Our machine learning model demonstrated high accuracy, with the Rotation Forest boosting model achieving 94.1% accuracy in distinguishing PD patients from controls. It is based on three new PD biomarkers (downregulated: 1-lyso-2-arachidonoyl-phosphatidate and hypoxanthine and upregulated: ferulic acid) and surpasses the general 80% diagnostic accuracy obtained from initial clinical evaluations conducted by specialists. Besides, this machine learning model based on a decision tree allowed for visual and easy interpretability of affected metabolites in PD patients. These findings could improve the detection and monitoring of PD, paving the way for more precise diagnostics and therapeutic interventions. Our research emphasizes the critical role of metabolomics and machine learning in advancing our understanding of the chemical profile of neurodegenerative diseases.

Association of Serum Extracellular Vesicle miRNAs with Cognitive Functioning and Quality of Life in Parkinson's Disease.

The identification of mechanisms associated with Parkinson disease (PD) development in cognitive functioning would be of great usefulness to clarify PD pathogenesis and to develop preventive and therapeutic strategies. In this study, blood serum extracellular vesicle (EV) levels of the candidate microRNAs (small noncoding RNAs that play a role in gene expression regulation):,miR-7, miR-21, miR-153, miR-155, miR-200a and miR-214, have been investigated for association with PD in a group of 93 patients with cognitive parameters, PD symptoms, affected quality of life and some clinical characteristics. MiRNA was extracted from patients' blood serum EVs, transcribed into cDNA and their expression was evaluated using RT-PCR. The miR-153 and miR-200a showed the most plausible correlations with cognitive functioning parameters such as general intellectual functioning, psychomotor speed, mental flexibility, and nonverbal executive functions. Moreover, lower levels of miR-153 were associated with attention span, working memory and psychomotor speed with learning. Increased levels of miR-200a, miR-7, miR-214, and miR-155 were also linked with neurological functioning, such as bradykinesia, tremor, balance and others. Despite the fact that due to small sample size, our results should be considered as preliminary, our study suggests that miRNA expression in EVs could be associated with symptom severity, cognitive impairment and quality of life in PD.

Neurosteroid Levels in GBA Mutated and Non-Mutated Parkinson's Disease: A Possible Factor Influencing Clinical Phenotype?

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids' serum levels in a cohort of Parkinson's Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher's exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn's test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention.

Effect of concomitant use of esomeprazole on levodopa pharmacokinetics and clinical symptoms in patients with Parkinson's disease.

BACKGROUND: Proton pump inhibitors (PPIs), which inhibit gastric acid secretion, are frequently prescribed to patients with Parkinson's disease (PD). Levodopa, the gold-standard treatment for PD, demonstrates enhanced solubility in acidic environments. Although PPIs increase gastric pH and may affect levodopa absorption, the effect of concomitant PPI use on levodopa pharmacokinetics in patients with PD remains unknown. This study aimed to investigate the effect of the concomitant use of esomeprazole, a PPI, on the pharmacokinetics of levodopa and carbidopa and clinical symptoms in patients with PD. METHODS: We prospectively enrolled 40 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and clinical symptoms before and two weeks after the concomitant use of esomeprazole. RESULTS: The plasma concentrations of levodopa 30 min after concomitant oral administration of levodopa and esomeprazole were significantly lower (4.92 ± 4.10 µmol/L) than those without concomitant esomeprazole use (6.26 ± 3.75 µmol/L; p = 0.027). The plasma concentrations of carbidopa showed no significant differences with respect to concomitant esomeprazole use. Significant elevation was recorded in all subscores of the Movement Disorder Society-sponsored revision of the Unified Parkinson's disease Rating Scale scores after concomitant use of esomeprazole. No significant differences were observed between Helicobacter pylori-negative and Helicobacter pylori-positive patients. Non-elderly patients (age ≤ 70 years) tended to be more susceptible to the effect of esomeprazole on levodopa pharmacokinetics and clinical symptoms. CONCLUSIONS: The unnecessary use of PPIs should be avoided in patients with PD, especially in non-elderly patients, to improve absorption of levodopa.

Blunted Melatonin Circadian Rhythm in Parkinson's Disease: Express Bewilderment.

Melatonin (MTN) is a neuro-hormone released from the pineal gland. MTN secretion is regulated by different neuronal circuits, including the retinohypothalamic tract and suprachiasmatic nucleus (SCN), which are affected by light. MTN is neuroprotective in various neurodegenerative diseases, including Parkinson's disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD.