Biomarker For Parkinson's Disease Research Articles

Current trends in blood biomarkers detection and neuroimaging for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and cognitive impairments. A significant challenge in managing PD is the variability of symptoms and disease progression rates. This variability is primarily attributed to unclear biomarkers associated with the disease and the lack of early diagnostic technologies and effective imaging methods. PD-specific biomarkers are essential for developing practical tools that facilitate accurate diagnosis, patient stratification, and monitoring of disease progression. Hence, creating valuable tools for detecting and diagnosing PD based on specific biomarkers is imperative. Blood testing, less invasive than obtaining cerebrospinal fluid through a lumbar puncture, is an ideal source for these biomarkers. Although such biomarkers were previously lacking, recent advancements in various detection techniques related to PD biomarkers and new imaging methods have emerged. However, basic research requires more detailed guidelines on effectively implementing these biomarkers in diagnostic procedures to enhance the diagnostic accuracy of PD blood testing in clinical practice. This review discusses the developmental trends of PD-related blood biomarker detection technologies, including optical analysis platforms. Despite the progress in developing various biomarkers for PD, their specificity and sensitivity remain suboptimal. Therefore, the integration of multimodal biomarkers along with optical and imaging technologies is likely to significantly improve diagnostic accuracy and facilitate the implementation of personalized medicine. This review forms valid research hypotheses for PD research and guides future empirical studies.

Does age, sex, and area of substantia nigra echogenicity predict the MRI appearance of nigrosome-1?

The appearance of the substantia nigra (SN) can aid diagnosis of Parkinson's disease (PD). The effect of age and sex on the appearance of nigrosome-1 (SN subregion) on magnetic resonance imaging (MRI), and the relationship between nigrosome-1 (viewed with MRI) and SN echogenicity (viewed with transcranial ultrasound) is unknown. The study aimed to address these knowledge gaps. It was hypothesized that age, sex, and area of SN echogenicity predict area of MRI hyperintense signal in nigrosome-1. The cross-sectional study involved a group of healthy adults (n=105; aged 21-79years) and adults diagnosed with PD (n=37; aged 51-80years). Multilevel mixed-effects regression analysis was used to investigate if age, sex, side, and area of SN echogenicity predict area of nigrosome-1 hyperintense signal. Area of nigrosome-1 hyperintense signal increased by an average of 0.045mm2/year in healthy adults (p=0.016) but not in adults living with PD. Sex, side, and area of SN echogenicity did not predict area of nigrosome-1 hyperintense signal in either group. Disease duration predicted area of nigrosome-1 hyperintense signal in the PD group (coefficient=-0.41, p=0.014). The expected between-group differences (p<0.001) in median area of nigrosome-1 hyperintense signal (smallest area across sides: healthy=7.6mm2, PD=0.0mm2) and SN echogenicity (largest area across sides: healthy=14.3mm2, PD=29.3mm2) were observed. The results suggest that the MRI appearance of nigrosome-1 can vary with age but not sex or area of SN echogenicity. The results further understanding of the nigrosome-1 biomarker for PD and aid interpretation of nigrosome-1 MRI findings in clinical settings.

Human Endogenous Retrovirus K in Astrocytes Is Altered in Parkinson's Disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disease. Human endogenous retroviruses (HERVs) are proviral remnants of ancient retroviral infection of germ cells that now constitute about 8% of the human genome. Under certain disease conditions, HERV genes are activated and partake in the disease process. However, virtually nothing is known about the pathological relationship, if any, between HERV and PD. The objectives of this study were to unravel the pathological relationship between human endogenous retrovirus K (HERV-K) and PD, determine the localization of HERV-K in the brain, determine whether HERV-K levels are altered in PD brain and blood, and examine whether HERV-K could serve as a biomarker for PD. In situ HERV-K and glial fibrillary acidic protein (GFAP) expression in the superior frontal and fusiform cortices of PD and control brain were analyzed using immunofluorescence and confocal microscopy. HERV-K load and copy number in PD and control blood were measured by digital droplet polymerase chain reaction and GFAP by single-molecule array. HERV-K load was analyzed in relation to the Hoehn and Yahr Scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. HERV-K is predominantly expressed in astrocytes and colocalized with astrocytic GFAP, with decreased expression of both HERV-K and GFAP in PD brain compared with controls. Consistent with this, HERV-K levels were decreased in PD blood compared with controls and were correlated to blood GFAP levels. HERV-K levels were inversely correlated to PD severity and duration. These findings suggest that HERV-K is related to astrocyte function and to PD progression, and that HERV-K could be neuroprotective. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evolving Landscape of Parkinson's Disease Research: Challenges and Perspectives.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects movement. It occurs due to a gradual deficit of dopamine-producing brain cells, particularly in the substantia nigra. The precise etiology of PD is not fully understood, but it likely involves a combination of genetic and environmental factors. The therapies available at present alleviate symptoms but do not stop the disease's advancement. Research endeavors are currently directed at inventing disease-controlling therapies that aim at the inherent mechanisms of PD. PD biomarker breakthroughs hold enormous potential: earlier diagnosis, better monitoring, and targeted treatment based on individual response could significantly improve patient outcomes and ease the burden of this disease. PD research is an active and evolving field, focusing on understanding disease mechanisms, identifying biomarkers, developing new treatments, and improving care. In this report, we explore data from the CAS Content Collection to outline the research progress in PD. We analyze the publication landscape to offer perspective into the latest expertise advancements. Key emerging concepts are reviewed and strategies to fight disease evaluated. Pharmacological targets, genetic risk factors, as well as comorbid diseases are explored, and clinical usage of products against PD with their production pipelines and trials for drug repurposing are examined. This review aims to offer a comprehensive overview of the advancing landscape of the current understanding about PD, to define challenges, and to assess growth prospects to stimulate efforts in battling the disease.

New insights on the regulators and inhibitors of RhoA-ROCK signalling in Parkinson's disease.

A multifaceted and widely prevalent neurodegenerative disease, Parkinson's disease (PD) is typified by the loss of dopaminergic neurons in the midbrain. The discovery of novel treatment(s) that can reverse or halt the course of the disease progression along with identifying the most reliable biomarker(s) in PD remains the crucial concern. RhoA in its active state has been demonstrated to interact with three distinct domains located in the central coiled-coil region of ROCK. RhoA appears to activate effectors most frequently by breaking the intramolecular autoinhibitory connections, which releases functional domains from the effector protein. Additionally, RhoA is highly expressed in the nervous system and it acts as a central molecule for its several downstream effector proteins in multiple signalling pathways both in neurons and glial cells. Mitochondrial dysfunction, vesicle transport malfunction and aggregation of α-Synuclein, a presynaptic neuronal protein genetically and neuropathologically associated with PD. While the RhoA-ROCK signalling pathway appears to have a significant role in PD symptoms, suggesting it could be a promising target for therapeutic interventions. Thus, this review article addresses the potential involvement of the RhoA-ROCK signalling system in the pathophysiology of neurodegenerative illnesses, with an emphasis on its biology and function. We also provide an overview of the state of research on RhoA regulation and its downstream biological activities, focusing on the role of RhoA signalling in neurodegenerative illnesses and the potential benefits of RhoA inhibition as a treatment for neurodegeneration.

Association between deep gray matter iron deposition and clinical symptoms in Parkinson's disease: a quantitative susceptibility mapping study.

This study aimed to assess the association between motor and non-motor symptoms of Parkinson's disease (PD) and iron accumulation within the deep gray matter of the brain by Quantitative Susceptibility Mapping (QSM). Fifty-six PD patients and twenty-nine healthy controls were recruited in this study. According to the Hoehn and Yahr (H-Y) stage score, PD patients were divided into early stage (H-Y ≤ 2) and advanced stage (H-Y > 2) groups. Specifically, the Regions of Interest (ROIs) encompassed the substantia nigra (SN), red nucleus (RN), caudate nucleus (CN), globus pallidus (GP) and putamen (PT). Meanwhile, various rating scales were used to assess the clinical symptoms of PD. Compared to healthy controls (HCs), PD patients showed a significant increase in magnetic susceptibility values (MSVs) within the SN and GP. Further comparisons indicated that the MSVs of the SN, PT, GP and CN are all higher in advanced stages than in early stages. Significant positive correlations were observed between the MSVs of the SN and scores on the UPDRS-III, HAMA, and HAMD (r = 0.310, p = 0.020; r = 0.273, p = 0.042; r = 0.342, p = 0.010, respectively). Likewise, the MSVs of the GP demonstrated notable correlations with HAMA and HAMD scores (r = 0.275, p = 0.040; r = 0.415, p = 0.001). Additionally, a significant correlation was found between the MSVs of the PT and HAMD scores (r = 0.360, p = 0.006). Furthermore, we identified a significant negative correlation between MMSE scores and the MSVs of both the PT and GP (r = -0.268, p = 0.046; r = -0.305, p = 0.022). Our study revealed that QSM possesses the capability to serve as a biomarker for PD. Significant correlations were found between clinical features and the iron deposition in the nigrostriatal system.

Neuroprotective role of CHCHD2 in Parkinson's disease: Insights into the GPX4-related ferroptosis pathway.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by pathogenesis involving mitochondrial dysfunction, oxidative stress, and ferroptosis. Unfortunately, there are currently no effective interventions to slow down the progression of PD. The mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is implicated in neurodegeneration and serves as a biomarker for PD, has been reported to have neuroprotective effects against oxidative stress, but the potential molecular mechanisms involved remain elusive. In this study, we uncovered a critical mechanism by which CHCHD2 protected neuronal cells against oxidative stress with the ferroptosis pathway playing a pivotal role, as determined through tandem mass tags (TMT)-based proteomic analysis. The overexpression of CHCHD2 was observed to enhance cell viability, reduce levels of lipid peroxidation and reactive oxygen species (ROS), and upregulate the expression of the ferroptosis negative regulatory protein Glutathione peroxidase 4 (GPX4) in PD cells. Conversely, CHCHD2 knockdown led to reduced cell viability, elevated lipid peroxidation, and a decreased expression of GPX4. Additionally, CHCHD2 overexpression ameliorated motor function impairment, reduced α-synuclein levels, and mitigated dopaminergic (DA) neuron loss in the substantia nigra and striatum of PD mice. Importantly, we show that the inhibitory effect of CHCHD2 on ferroptosis in PD is related to the GPX4 signaling pathway. In summary, our study elucidates the neuroprotective role of CHCHD2 in regulating the GPX4-related ferroptosis pathway in PD, providing new targets and ideas for future PD drug development and therapy.

Digital measurement of ocular microtremor in Parkinson's disease: Protocol for a pilot study to assess reliability and clinical validation.

Ocular microtremor (OMT) is a fixational eye movement that cannot be seen with the naked eye but is always present, even when the eye appears motionless/still. The link between OMT and brain function provides a strong rationale for investigation as there lies potential for its use as a biomarker in populations with neurological impairments. OMT frequency is typically 70-80Hz in healthy adults and research suggests that this will be reduced in those with neurological disease such as Parkinson's Disease (PD). This study aims to examine OMT in people with PD compared to healthy older adults. This is an exploratory, observational study that will use a novel handheld device-The iTremor ONE, which has been developed to rapidly, non-invasively assess and evaluate OMT frequency. This device uses incident laser technology directed at the sclera. People with PD who meet the inclusion criteria will participate in a home-based assessment involving cognitive, motor (using the UPDRS-III) and OMT measures. With OMT as the primary outcome, assessment with the iTremor is quick, taking just three seconds to obtain a reading. People with PD will be invited into the laboratory to perform extensive cognitive assessments along with an assessment of balance, gait, and turning using wearable sensors. People with PD will be assessed both off, and on, their anti-parkinsonian medication following a 12 hour washout period. We will recruit 30 People with PD, 30 people with suspected PD and 30 age-matched healthy control participants for assessment of OMT. 20 People with PD will complete a test-retest reliability assessment at the same approximate time, exactly one week after their initial visit under the same conditions to explore consistency. This will be the first study of its kind to non-invasively investigate OMT frequency as a marker/monitor for PD with advanced technology that could be used within the clinic, laboratory, or home. Identifying OMT as a PD biomarker could better support clinical assessment, enabling improved provision of care to patients with advanced disease monitoring. Clinical trial registration: This trial is registered at clinicaltrials.gov (NCT06051877; September 2023).

Multimodal magnetic resonance imaging studies on non-motor symptoms of Parkinson's disease.

This study aims to investigate the diagnostic value of multi-modal magnetic resonance imaging (MRI) utilizing arterial spin labeling (ASL), quantitative susceptibility mapping (QSM), and 3D T1-weighted imaging (3DT1WI) in patients with Parkinson's disease (PD). Additionally, it evaluates the relationship between MRI findings and non-motor symptoms associated with PD. ASL, QSM, and 3DT1WI scans were performed on 48 PD patients and 46 healthy controls (HC). We extracted and analyzed differences in regional cerebral blood flow (rCBF), magnetic susceptibility, and gray matter density parameters between the two groups. These MRI parameters were correlated with clinical scale scores assessing non-motor symptoms, including cognitive function, sleep quality, olfaction, autonomic function, anxiety, depression, and fatigue. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic accuracy of each imaging modality in distinguishing PD from HC. The areas under the ROC curve (AUC) for rCBF, magnetic susceptibility, and gray matter density were 0.941, 0.979, and 0.624, respectively. In PD patients, a negative correlation was found between Unified Parkinson's Disease Rating Scale Part II (UPDRS II) scores and rCBF in the bilateral precuneus. The Pittsburgh Sleep Quality Index (PSQI) scores negatively correlated with rCBF in the left middle temporal gyrus and right middle occipital gyrus. Hamilton Depression Rating Scale (HAMD) scores positively correlated with QSM values in the right supplementary motor area, while scores on the Argentine Smell Identification Test (AHRS) negatively correlated with QSM values in the same area. Disease duration showed a positive correlation with QSM values in the right middle cingulate gyrus. Additionally, PSQI scores positively correlated with QSM values in the left middle cingulate gyrus, and fatigue severity scale (FSS) scores also positively correlated with QSM values in the left middle cingulate gyrus. Gray matter atrophy in the left inferior temporal gyrus was associated with cognitive impairment in PD. Occipital hypoperfusion and cortical atrophy in the left inferior temporal gyrus may serve as novel imaging biomarkers for PD and are associated with sleep disturbances and cognitive impairment in PD patients. Extensive iron deposition in the bilateral cerebral cortex of PD patients may be a contributing factor to non-motor symptoms such as sleep disturbances and fatigue. Multimodal imaging techniques, including ASL, QSM, and 3DT1WI, can enhance the diagnostic accuracy for PD.

Differences in Blood and Cerebrospinal Fluid Between Parkinson’s Disease and Related Diseases

It is difficult to distinguish Parkinson’s disease (PD) in the early stage from those of various disorders including atypical Parkinson’s syndrome (APS), vascular parkinsonism (VP), and even essential tremor (ET), because of the overlap of symptoms. Other, more challenging problems will arise when Parkinson’s disease develops into Parkinson’s disease dementia (PDD) in the middle and late stages. At this time, the differential diagnosis of PDD and DLB becomes thorny. These complicate the diagnostic process for PD, which traditionally heavily relies on symptomatic assessment and treatment response. Recent advances have identified several biomarkers in the blood and cerebrospinal fluid (CSF), including α-synuclein, lysosomal enzymes, fatty acid-binding proteins, and neurofilament light chain, whose concentration differs in PD and the related diseases. However, not all these molecules can effectively discriminate PD from related disorders. This review advocates for a paradigm shift toward biomarker-based diagnosis to effectively distinguish between PD and similar conditions. These biomarkers may reflect the diversity that exist among different diseases and provide an effective way to accurately understand their mechanisms. This review focused on blood and CSF biomarkers of PD that may have differential diagnostic value and the related molecular measurement methods with high diagnostic performance due to emerging technologies.Graphical

Transcranial magneto-acoustic stimulation enhances motor function and modulates cortical excitability of motor cortex in a Parkinson's disease mouse model

Parkinson's disease (PD) is a neurodegenerative disorder characterized primarily by motor dysfunction. Transcranial magneto-acoustic stimulation (TMAS), an emerging non-invasive brain neuromodulation technology, is increasingly being applied in the treatment of brain diseases. However, the effects of TMAS on PD are unknown, which is not well studied. Here, we utilized TMAS on PD model mice induced by MPTP to investigate the underlying mechanism of therapy. Our study found that TMAS improved the behavioral performance of PD model mice, enhancing the motor function and motivation for movement. Besides, it inhibited the increased beta oscillations in the motor cortex, while also reducing gamma oscillations. Moreover, the abnormally exaggerated beta-broad gamma phase amplitude coupling (PAC) was decreased after TMAS, and there was a significant negative correlation between PAC and both distance traveled and mean speed during the open filed test. Additionally, the ongoing stimulation could provide neuroprotection, implying that TMAS could ameliorate the loss of dopaminergic neurons, with no damage observed in the brain tissue of mice. Our findings suggest that TMAS could provide a non-invasive tool for the treatment of Parkinson's disease and beta-broad gamma phase amplitude coupling could be employed as a biomarker for PD.

Probing the diagnostic values of plasma cf-nDNA and cf-mtDNA for Parkinson's disease and multiple system atrophy.

Cell loss and mitochondrial dysfunction are key pathological features of idiopathic Parkinson's disease (PD) and multiple system atrophy (MSA). It remains unclear whether disease-specific changes in plasma circulating cell-free nuclear DNA (cf-nDNA) and mitochondrial DNA (cf-mtDNA) occur in patients with PD and MSA. In this study, we investigated whether plasma cf-nDNA, cf-mtDNA levels, as well as cf-mtDNA integrity, are altered in patients with PD and MSA. TaqMan probe-based quantitative PCR was employed to measure plasma cf-nDNA levels, cf-mtDNA copy numbers, and cf-mtDNA deletion levels in 171 participants, including 76 normal controls (NC), 62 PD patients, and 33 MSA patients. A generalized linear model was constructed to analyze differences in circulating cell-free DNA (cfDNA) biomarkers across clinical groups, while a logistic regression model was applied to assess the predictive values of these biomarkers for developing PD or MSA. Spearman correlations were used to explore associations between the three cfDNA biomarkers, demographic data, and clinical scales. No significant differences in plasma cf-nDNA levels, cf-mtDNA copy numbers, or cf-mtDNA deletion levels were observed among the PD, MSA, and NC groups (all P > 0.05). Additionally, these measures were not associated with the risk of developing PD or MSA. In PD patients, cf-nDNA levels were positively correlated with Hamilton Anxiety Rating Scale scores (Rho = 0.382, FDR adjusted P = 0.027). In MSA patients, cf-nDNA levels were positively correlated with International Cooperative Ataxia Rating Scale scores (Rho = 0.588, FDR adjusted P = 0.011) and negatively correlated with Montreal Cognitive Assessment scores (Rho = -0.484, FDR adjusted P = 0.044). Subgroup analysis showed that PD patients with constipation had significantly lower plasma cf-mtDNA copy numbers than those without constipation (P = 0.049). MSA patients with cognitive impairment had significantly higher cf-nDNA levels compared to those without (P = 0.008). Plasma cf-nDNA level, cf-mtDNA copy number, and cf-mtDNA deletion level have limited roles as diagnostic biomarkers for PD and MSA. However, their correlations with clinical symptoms support the hypothesis that cell loss and mitochondrial dysfunction are involved in PD and MSA development.

Autophagic signatures in peripheral blood mononuclear cells from Parkinson's disease patients.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor impairments and the accumulation of misfolded α-synuclein. Dysregulation of the autophagy-lysosomal pathway (ALP), responsible for degrading misfolded proteins, has been implicated in PD pathogenesis. However, current diagnostic approaches rely heavily on motor symptoms, which occur due to substantial neurodegeneration, limiting early detection and intervention. This study investigated the potential of ALP-associated proteins in peripheral blood mononuclear cells (PBMCs) as diagnostic biomarkers for early-stage PD. Quantitative analysis revealed a significant reduction in optineurin (OPTN) levels in PBMCs from PD patients, and the expression levels of various ALP-associated proteins were tightly correlated, suggesting a coordinated dysregulation of the pathway. Correlation analyses revealed associations between ALP-associated features and clinical characteristics, such as age of onset and motor impairment. Furthermore, the study identified multiple positive correlations among ALP-associated proteins and functional readouts, highlighting the interconnectivity within the pathway. Notably, a PBMC biomarker model incorporating lysosomal-associated membrane protein 1 (LAMP1) and OPTN exhibited high diagnostic accuracy (86%) in distinguishing PD patients from controls. These findings highlight the potential of ALP-associated protein signatures in PBMCs as novel diagnostic biomarkers for early detection and intervention in PD, offering insights into the systemic manifestations of the disease.

Corticostriatal glutamate-mediated dynamic therapeutic efficacy of electroacupuncture in a parkinsonian rat model.

Motor impairments are the defining cardinal features of Parkinson's disease (PD), resulting from malfunction of the cortico-basal ganglia circuit. Clinical data have demonstrated that electroacupuncture (EA) stimulation may benefit motor symptoms in PD without adverse effects. However, the specific effects of EA on PD and the underlying mechanisms remain largely unclear. This study investigated the effects of EA stimulation during and after 100Hz application in a rat model of PD created by unilateral injection of 6-hydroxydopamine (6-OHDA). To establish optimal treatment parameters of EA, motor behaviours were dynamically assessed using open field and rotarod tests. Additionally, we evaluated corticostriatal spine plasticity using immunoelectron microscopy and measured the levels of dopaminergic and glutamatergic neurotransmitters through microdialysis, in vivo electrochemistry and high-performance liquid chromatography. Neural activity dynamics were recorded by measuring local field potentials in both the motor cortex and thestriatum. Furthermore, chemogenetic techniques were employed to manipulate corticostriatal glutamatergic neurons and clarify the mechanisms that contribute to the therapeutic benefits of EA in the PD rat model. Chronic EA stimulation resulted in a gradual and long-lasting alleviation of motor symptoms, independent of nigrostriatal dopamine (DA) restoration. Notably, EA stimulation modulated corticostriatal spine plasticity and reduced excessive glutamate transmission in PD model rats. Moreover, EA effectively inhibited aberrant corticostriatal synchronised high-beta (25-40Hz) oscillations, which serves as a pathological biomarker of PD. Conversely, chronic chemogenetic activation of corticostriatal glutamatergic neurons hindered these positive outcomes of EA treatment in PD model rats. This study sheds light on the temporal dynamics and optimal parameters of EA treatment in PD. It emphasises the significance of inhibiting corticostriatal glutamate transmission in EA's therapeutic benefits for PD. Targeting glutamatergic neurons with EA holds promise as a non-dopaminergic intervention for managing motor symptoms and abnormal neural activity with PD. EA commonly protects dopaminergic neuronsby reducing neuroinflammation, oxidative stress, and apoptosis. New findings reveal that EA alleviates motor symptoms in a parkinsonian rat model without restoring striatal dopamine levels. EA effectively suppresses excessiveglutamate transmission and high-beta synchronization, contributing to motorsymptom relief. Activation of corticostriatalglutamatergic projections may hinder the efficacy of EA.

Characterization and Evaluation of Alpha‐Synuclein Aggregates: Unveiling Their Potential as a Biomarker for Parkinson's Disease (PD)

AbstractBackgroundParkinson's disease (PD) is a debilitating condition that affects millions of people worldwide, yet there are currently no reliable biomarkers for its diagnosis. Alpha‐synuclein aggregation is a well‐known hallmark of PD pathology, but the behavior and kinetics of these aggregates are poorly understood. To address this gap in knowledge, this study utilized several approaches to evaluate the potential of alpha‐synuclein aggregates as potential biomarker for PD.MethodFirstly, the aggregation behavior of alpha‐synuclein (aSyn) oligomers and fibrils was evaluated using a Real‐time quaking induced conversion (RT‐QuIC) assay. This assay differentiated PD from healthy samples in human skin, brain homogenates, and cerebrospinal fluid (CSF) samples. Secondly, a symmetric ECL assay was used to quantify alpha‐synuclein oligomers and fibrils. Finally, direct stochastic optical reconstruction microscopy (dSTORM) was utilized to visualize the size and shape of recombinant alpha‐synuclein fibrils and RT‐QuIC end products (fibrils) at high resolution.ResultThe results demonstrated that fast‐aggregating samples had higher concentrations of aSyn oligomers in skin and other samples compared to slow‐aggregating samples. Interestingly, human skin as a biological matrix showed a better and significant differentiation of healthy and PD samples, compared to brain or CSF indicating skin as a promising specimen for detecting alpha‐synuclein aggregation. Preliminary analysis of the average length and width of alpha‐synuclein aggregates showed promise, and further experiments with a larger sample size are required to prove whether different species of alpha‐synuclein fibrils/oligomers exist in healthy and disease samples.ConclusionThese results provide a foundation for the continued investigation of alpha‐synuclein aggregation as a potential biomarker for PD.

Human Leukocyte Antigen Polymorphism and Blood Biomarker Profiles in Parkinson's Disease: A Pilot Study in a Latvian Cohort.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterised by a high prevalence of sporadic cases. Various molecular mechanisms are involved in its pathogenesis. This pilot study aimed to identify potential risk and protective human leukocyte antigen (HLA) alleles in PD, discover candidate alleles for further research, and evaluate potential blood biomarkers. Methods: A total of 43 PD patients and 79 unrelated sex-matched controls were enrolled in this study. We analysed the polymorphism of HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the blood levels of biomarkers such as S100 calcium-binding protein A9 (S1000A9), kynurenic acid (KYNA), neurofilament light chain (NfL), and glutamate decarboxylase (GAD1). Results: We found that the frequencies of the HLA-DRB1*04, -DQA1*02:01, and -DQA1*03:01 alleles were significantly higher in the PD patients than in the controls, suggesting that these alleles are potential risk factors. Furthermore, the HLA-DQA1*02:01 allele was detected more frequently in the PD group when the disease onset was at 60 years or older. On the contrary, the HLA-DRB1*01 and HLA-DQA1*05:01 alleles were less common in the PD patients, indicating a possible protective effect. Regarding biomarkers, the blood levels of S100 calcium-binding protein A9 were significantly higher, and the kynurenic acid levels were significantly lower in the PD group. The NfL levels were also higher in the PD group but did not reach statistical significance, possibly due to the sensitivity limitations of the ELISA method used. The GAD1 levels showed no significant differences between the two groups. Conclusions: Our findings indicate that the HLA-DRB1*01 and -DRB1*04 alleles and the HLA-DQA1*02:01, -DQA1*03:01, and -DQA1*05:01 alleles are associated with PD. Moreover, S100 calcium-binding protein A9 and kynurenic acid can be considered potential blood biomarkers for PD. These findings contribute to the growing body of knowledge on PD and offer new directions for further research in Latvian cohorts.

Plasma long noncoding RNA expression profiles in patients with Parkinson's disease and the role of lnc-CTSD-5:1 in a PD cell model: a ceRNA microarray-based study

To explore the key genes and long non-coding RNAs (lncRNAs) associated with Parkinson's disease (PD). Peripheral blood plasma samples were collected from 6 PD patients and 6 healthy individuals. The mRNA and lncRNA expression profiles were detected using ceRNA microarray technology, and the differentially expressed genes were analyzed using bioinformatics methods. The differentially expressed mRNAs transcribed within 10 kb upstream or downstream of the differentially expressed lncRNAs were defined as potential cis-regulatable (Cis) target genes of the lncRNAs. A PD-specific protein-protein interaction network (PPI) was constructed. Competitive endogenous RNA (ceRNA) networks were also constructed using the differential lncRNAs with mRNAs and known microRNAs. Using MPP+-treated SHSY5Y cells as a PD cell model, the expressions of the key lncRNAs and their functions were examined. We identified 316 genes and 986 lncRNAs showing significant differential expressions in PD patients (P< 0.05). The differentially expressed mRNAs and the potential cis-regulatable target genes of these lncRNAs were functionally annotated using GO and KEGG enrichment analysis, and the targeting relationship of the differentially expressed mRNAs and lncRNAs with microRNAs were predicted. Analysis of the ceRNA networks constructed based on the differentially expressed lncRNAs suggested that lncMTG2-1:1, lnc-CTSD-5:1, lnc-PCCA-3:1, lnc-VTCN1-3:1, lnc-ZNF25-7:1, and lnc-DAZ3-1:1 might be the key lncRNAs in PD. In MPP+-treated SH-SY5Y cells, the expression of lnc-CTSD-5:1 showed the most significant changes, and silencing lnc-CTSD-5:1 obviously restored the expression level of tyrosine hydroxylase. PD patients have significant changes in plasma lncRNA expression profile, and the differentially expressed genes and lncRNAs found in this study may provide new clues for exploring the pathogenesis and identifying potential biomarkers of PD.

Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson's Disease Adjusting for Lymphocytes.

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson's Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals. In this study, we performed differential expression (DE) analysis of whole-blood RNA sequencing data from PD cohorts, incorporating a correction for immune cell-enriched gene expression, particularly neutrophil-related pathways, to improve the resolution of PD-associated molecular changes. Using 1,254 Parkinson's Progression Markers Initiative (PPMI) samples with complete blood count (CBC) data, we developed a predictive model to estimate neutrophil percentages in a 6,987 PPMI and Parkinson's Disease Biomarkers Program (PDBP) samples. We mitigated the confounding effects of immune cell-enriched gene expression by integrating predicted neutrophil percentages as a covariate in DE analysis. This approach revealed a consistent and significant downregulation of SNCA across all PD cohorts, a finding previously obscured by immune cell signatures. Lowered SNCA expression was found in individuals with known predisposition genes (e.g., SNCA, GBA, LRRK2) and in non-genetic PD cohorts lacking known pathogenic mutations, suggesting it may represent a key transcriptomic hallmark of the disease.

Peripheral biomarkers of Parkinson’s disease and its correlation with clinical symptoms: a case-control study

BackgroundInflammation significantly impacts Parkinson’s disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive.ObjectiveTo identify the peripheral biomarkers of PD and its correlation with the motor and non-motor symptoms of PD.Methods79 PD patients and 65 controls were included in this study. Clinical information and the serum levels of IL-8, IL-27, IL-33, β-NGF, AgRP, and TRAILR2 in the participants were collected. Appropriate scales were used to assess the symptoms of PD. For the factors with significant differences in the two groups, multivariable logistic regression was used to determine its relationship with PD. Moreover, spearman correlation was conducted to explore the correlation between the factors and PD related symptoms. The IL-27 level was compared between the cognitively healthy PD group and the mild cognitive impairment in PD (PD-MCI). The serum level of TRAILR2 was positively correlated with age and was not associated with other clinical characteristics related to PD.ResultsCompared to controls, the serum levels of IL-27(P = 0.013) were increased whereas the levels of TRAILR2(P = 0.008) were decreased in PD patients. IL-8, IL-33, β-NGF, and AgRP showed no significant differences between the two groups. After controlling for the other variables, IL-27 was considered as an independent risk factor for PD in the multivariable logistic regression model. The receiver operating characteristic (ROC) curve for diagnosing PD with IL-27 yielded an area under the curve (AUC) of 0.621. Additionally, IL-27 level in PD patients was positively correlated with age, the disease duration, LEDD and negatively correlated with the MoCA scores. However, no significant difference was found in IL-27 levels between cognitively healthy PD and PD-MCI groups.ConclusionElevated serum IL-27 was a risk factor for PD and positively correlated with the cognitive decline in PD.

Microbial biomarker discovery in Parkinson’s disease through a network-based approach

Associations between the gut microbiota and Parkinson’s disease (PD) have been widely investigated. However, the replicable biomarkers for PD diagnosis across multiple populations remain elusive. Herein, we performed a meta-analysis to investigate the pivotal role of the gut microbiome in PD and its potential diagnostic implications. Six 16S rRNA gene amplicon sequence datasets from five independent studies were integrated, encompassing 550 PD and 456 healthy control samples. The analysis revealed significant alterations in microbial composition and alpha and beta diversity, emphasizing altered gut microbiota in PD. Specific microbial taxa, including Faecalibacterium, Roseburia, and Coprococcus_2, known as butyrate producers, were notably diminished in PD, potentially contributing to intestinal inflammation. Conversely, genera such as Akkermansia and Bilophila exhibited increased relative abundances. A network-based algorithm called NetMoss was utilized to identify potential biomarkers of PD. Afterwards, a classification model incorporating 11 optimized genera demonstrated high performance. Further functional analyses indicated enrichment in pathways related to neurodegeneration and metabolic pathways. These findings illuminate the intricate relationship between the gut microbiota and PD, offering insights into potential therapeutic interventions and personalized diagnostic strategies.