Parkinson’s disease (PD) lacks reliable non-invasive biomarkers for early diagnosis. Peripheral blood-derived exosomes, which carry central nervous system (CNS)-derived cargo across the blood-brain barrier, represent a promising liquid biopsy platform. Here, we performed integrated miRNA and proteomic profiling of blood exosomes, leveraging multiple public datasets for biomarker discovery and an in-house cohort for independent validation. Consensus feature selection integrating five methods identified robust biomarker panels evaluated by four classification models. A 69-miRNA consensus signature achieved strong PD classification performance, with Random Forest demonstrating the best generalization (AUC = 0.952), whereas the 63-protein proteomics signature showed limited cross-study reproducibility (best AUC = 0.611), attributable to inter-platform heterogeneity. Tissue origin profiling revealed that signature miRNAs derive from both CNS and peripheral immune compartments. Functional enrichment across omics layers consistently highlighted mitochondrial energetics failure and suppression of complement and coagulation cascades. Deconvolution and independent single-cell RNA sequencing validation traced exosomal origins to a distinct immune-metabolic axis involving B cells and CD4 + T cells. Our study identifies a robust exosomal miRNA signature for PD classification and reveals the convergence of mitochondrial dysfunction and peripheral immune dysregulation as core pathological features, establishing a foundation for exosome-based liquid biopsy and mechanistic biomarker development.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation in dopaminergic neurons. Emerging evidence implicates gut microbiota dysbiosis in PD-associated inflammation through the gut microbiota-brain axis (GMBA). As gut microbial composition varies geographically, population-specific studies are essential to understand this relationship. The present study employed 16S rRNA gene amplicon sequencing to characterize the gut microbiome of PD patients and healthy controls (HCs) from Kerala. Significant differences in microbial diversity and taxonomic composition were observed. PD patients exhibited increased abundances of pro-inflammatory genera, including Akkermansia, Bifidobacterium, Escherichia-Shigella, Collinsella, Eggerthellaceae_insertae_sedis_genus, Intestinimonas, and Enterobacterales_unclassified, alongside reduced levels of anti-inflammatory genera such as Bacteroides, Lachnospira, Agathobacter, Prevotella, and Erysipelotrichaceae UCG-003. Predictive functional profiling indicated alterations in pathways related to neurotransmitter metabolism, including dopaminergic, glutamatergic, and GABAergic metabolism, as well as amino acid, polyamine, nucleotide, and energy metabolism. Integrative network analysis further linked PD-enriched taxa with dysregulated metabolic pathways, suggesting functional interactions between microbial composition and metabolic potential. These findings provide the first comprehensive insights into gut microbial alterations in a South Indian PD cohort, identify candidate microbial signatures associated with PD, and offer an exploratory framework for future multi-omics studies to validate microbiome-related mechanisms in PD pathophysiology.
The cortico-subthalamic hyperdirect pathway provides a rapid route for cortical influence over basal ganglia processing and is a key target of deep brain stimulation (DBS) in Parkinson’s disease (PD). However, to what degree dopamine modulates signal transmission along this pathway in humans remains unclear. Using bidirectional cortical and subthalamic electrical stimulation while invasively recording evoked responses in 15 PD patients undergoing DBS surgery, we examined cortico-subthalamic communication across dopaminergic states. Cortical stimulation evoked a short-latency subthalamic response consistent with monosynaptic hyperdirect activation that was preserved across medication conditions. In contrast, longer-latency subthalamic responses showed significant dopaminergic modulation, while cortical responses to subthalamic stimulation remained unchanged. These results reveal a temporal dissociation within the cortex–basal ganglia network, whereby fast cortical transmission is unaffected by dopamine, which in turn amplifies slower network level communication to the subthalamic nucleus. This separation of fast and delayed components provides a mechanistic framework for understanding how dopamine shapes information flow in the cortex–basal ganglia system.
Alzheimer’s disease (AD) co-pathology is associated with a worse prognosis in Parkinson’s disease (PD). To elucidate the pathogenic basis of this malignant subtype, we performed a multidimensional immunological analysis of 47 patients with early-stage PD, grouped into PDAD and PDnoAD according to the ATNPD framework, and 50 healthy controls. Subtle changes observed in the whole PD population were more pronounced when patients were stratified by co-pathology. In particular, PDAD exhibited heightened inflammation (as evidenced by blood cell counts and plasma mediators) and a hypermetabolic state of circulating mononuclear cells, with upregulated mitochondrial respiration and glycolysis; the regulatory innate cells were depleted, and the effector CD8 and B-cell populations expanded, with T-cell cytotoxic hyperresponsiveness. No associations were observed with the APOE genotype. PDAD entails a multilayered signature of peripheral immunity, suggesting a systemic pathogenic construct. Immunometabolism constitutes a pivotal axis of biological heterogeneity in PD, providing a framework for biomarker discovery and intervention.
