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The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the “brain-first” versus “body-first” model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice. Full article

Background/Objective: Parkinson’s disease (PD) has long been viewed from a neurocentric perspective; however, increasing evidence indicates that glial dysfunction also contributes to dopaminergic neurodegeneration. Although neurotoxic glial phenotypes have been described in amyotrophic lateral sclerosis and Alzheimer’s disease in vivo models, it remains unclear whether similar states arise in the pathological milieu of PD. This study aimed to determine whether glial cells with intrinsic neurotoxic properties emerge in the substantia nigra pars compacta (SNpc) in a PD context. Methods: The classical 6-hydroxydopamine rat model was used to obtain glial cultures from the ipsilateral, toxin-damaged SNpc. These cultures were characterized by quantifying cell number and morphology, as well as by assessing the expression of glial markers. Their neurotoxic potential was evaluated in vitro through co-cultures with PC12 cells, and in vivo by transplanting the isolated cells into the SNpc of naïve rats. Assessments included PC12 cell survival, and integrity of the nigrostriatal pathway and motor performance in the cylinder test. Results: Ipsilateral SNpc cultures yielded 25-fold more cells than contralateral controls. Cultured cells co-expressed astrocytic and microglial markers, thus defining a population of damage-derived reactive glia (DDRG). When co-cultured, DDRG reduced PC12 cell survival, whereas control glial cells showed no neurotoxic effects. In vivo, DDRG transplantation induced a dose-dependent loss of dopaminergic neurons and motor impairments, while vehicle and control glia produced no detectable effects. Conclusions: Our findings suggest that glial cells emerging from a neuroinflammatory/neurodegenerative environment in the SNpc may contribute to dopaminergic neuron loss. Within the context of the experimental PD model used, DDRG appears to represent a glial population with potential pathogenic relevance and may constitute a candidate target for further investigation as a therapeutic strategy in Parkinson’s disease. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded α-synuclein (aSyn). In addition to neuronal pathology, activated microglia are recognized as key mediators of the neuroinflammatory milieu in PD, contributing to DAergic neuron vulnerability. Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. A comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species was performed. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration, followed by neuronal regeneration and temporary CD4⁺ T-cell infiltration accompanied by an astroglial response and activation of microglia. In contrast, MPTP-treated mice showed a permanent neuronal loss, marked microglial activation, increased astrogliosis and CD8⁺ T-cell infiltration that was negatively correlated with neuronal survival. By contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis, mild activation of microglia and CD4⁺ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains exhibited DAergic degeneration, aSyn aggregation, and elevated CD3⁺ T-cell infiltration, and increased microglial activation. These changes correlated with neuronal loss and aSyn burden. These findings emphasize the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4⁺ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8⁺ or CD4⁺, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell–glial interactions to slow neurodegeneration and promote repair in PD. Full article

Rosemary (Salvia rosmarinus) has been linked to improvements in psychological wellbeing through cholinergic mechanisms. However, this study investigated whether individual differences in eye blink rate (EBR) and blink variability (EBV), which are proxies of dopaminergic activity and attentional control, influence the cognitive and mood-enhancing properties of a rosemary-containing drink. Forty-eight healthy adults completed a three-stimulus odd-ball cognitive task under rosemary or control conditions, while vertical electrooculograms were recorded. Event-related brain potentials (ERPs) were also measured using the P3a component at the Cz scalp electrode as an additional index of dopaminergic activity. Subjective mood and arousal (alert, contented, calm) were collected pre- and post-task using Bond–Lader visual analogue scales. Reaction times during the task were modelled with ex-Gaussian parameters (μ, σ, τ). Rosemary ingestion led to increased alertness and contentedness following the task. Cognitive effects were moderated by blink metrics, with significant interactions between rosemary and blink metrics for mean reaction time μ and response variability σ. Rosemary also increased P3a amplitudes, indicative of dopaminergic contribution. The effects of rosemary on cognition and mood were moderated by individual blink profiles, indicating that baseline neurocognitive state plays a role. Although cholinergic accounts are well established, this study highlights the use of proxies of dopamine to investigate broader neurotransmitter involvement in rosemary’s enhancing properties. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and abnormal α-synuclein aggregation. Circulating microRNAs (miRNAs) have emerged as promising biomarkers and potential modulators of PD-related molecular pathways. In this study, we investigated the expression levels of four candidate miRNAs—miR-15a-5p, miR-16-5p, miR-139-5p, and miR-34a-3p—in patients with PD compared with healthy controls. A total of 47 PD patients and 45 age- and sex-matched controls were enrolled. Plasma miRNA levels were quantified using standardized RNA extraction, cDNA synthesis, and qPCR protocols. We observed marked upregulation of miR-15a-5p and robust downregulation of both miR-139-5p and miR-34a-3p in PD patients, whereas miR-16-5p showed no significant difference between groups. Target gene prediction and functional enrichment analysis identified 432 unique genes, with enrichment in biological processes related to protein ubiquitination and catabolic pathways, and signaling cascades such as mTOR, PI3K-Akt, MAPK, and Hippo pathways, all of which are implicated in neurodegeneration. Elevated miR-15a-5p may contribute to pro-apoptotic mechanisms, while reduced miR-139-5p and miR-34a-3p expression may reflect impaired mitochondrial function, diminished neuroprotection, or compensatory regulatory responses. Together, these dysregulated circulating miRNAs provide novel insight into PD pathophysiology and highlight their potential as accessible, non-invasive biomarkers. Further longitudinal studies in larger and more diverse cohorts are warranted to validate their diagnostic and prognostic value and to explore their utility as therapeutic targets. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, resulting in cardinal motor symptoms such as tremor, rigidity, and bradykinesia. Neuroinflammation is increasingly recognized as a central driver of PD onset and progression in which oligodendrocytes, astrocytes, and microglia engage in complex bidirectional crosstalk that shapes the inflammatory milieu of the central nervous system. Pathological activation of glial cells triggers the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating neuronal injury and contributing to sustained disease progression. Modulating maladaptive glial activation states and their intercellular communication represents a promising therapeutic avenue aimed at mitigating neuroinflammation and slowing PD pathology. This review synthesizes current knowledge on neuroinflammation in PD, focusing on the distinct roles of microglia, astrocytes, and oligodendrocytes, their interaction networks, and emerging therapeutic strategies. Full article

Parkinson’s disease is a neurodegenerative disorder that affects the elderly population worldwide. Rotenone (ROT) is an environmental toxin that impairs mitochondrial dynamics by inhibiting respiratory chain complex I and thus inducing oxidative stress. Farnesol (FSL) is a dietary sesquiterpene with antioxidant and anti-inflammatory properties reported in various in vivo models. To evaluate the efficacy of FSL in the management of PD, Wistar rats were injected with ROT (2.5 mg/kg, i.p) and pretreated with FSL. Immunohistochemical staining measured tyrosine hydroxylase-positive cells in the substantia nigra and striatum. Western blotting was employed to determine protein expression of inflammatory, apoptotic, and autophagic markers. Our results indicate that FSL significantly protected against ROT-induced inflammation by suppressing microglial and astrocytic activation through the downregulation of Toll-Like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inhibitor of kappa B (IkB), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), matrix metalloproteinase-9 (MMP-9) expression. FSL has also demonstrated an antioxidant effect by enhancing the activity of superoxide dismutase and catalase while reducing the level of Malondialdehyde and nitric oxide. Moreover, it restored homeostasis in ROT-induced imbalance between pro- and anti-apoptotic proteins. Impaired autophagy observed in ROT-injected rats was corrected by FSL treatment, which upregulated phosphorylated mammalian target of rapamycin (p-mTOR) expression and downregulated P62, an autophagosome marker. The protective effect of FSL was further supported by preserving the brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase in the brain. These findings demonstrate the neuroprotective ability of FSL and its potential to be developed as a pharmaceutical or nutraceutical agent for the prevention and treatment of PD by mitigating neuropathological changes observed in dopaminergic neurodegeneration. Full article

Exercise-induced myokines have emerged as crucial mediators of the beneficial effects of physical activity on neurodegenerative diseases through complex molecular mechanisms involving oxidative stress reduction, neuroinflammation suppression, and synaptic plasticity enhancement. Among these myokines, irisin, encoded by the FNDC5 gene, has gained significant attention as a potential therapeutic target in neurodegenerative conditions due to its ability to cross the blood–brain barrier and exert pleiotropic neuroprotective effects. This review synthesizes current evidence from both preclinical and clinical studies examining the role of exercise-induced irisin in neurodegeneration, with particular emphasis on translational potential and therapeutic applications. A comprehensive search was conducted across PubMed, Web of Science, Scopus, and EMBASE databases (spanning January 2015 to December 2024) to identify peer-reviewed articles investigating irisin’s neuroprotective mechanisms in neurodegenerative diseases. Ten studies met the inclusion criteria (five rodent/primate model studies and five human clinical investigations), which were analyzed for methodological rigor, intervention protocols, biomarker quantification methods, and reported outcomes. Reviewed studies consistently demonstrated that exercise-induced endogenous irisin elevation correlates with improved cognitive function, reduced neuroinflammatory markers, enhanced synaptic plasticity, and modulation of neurodegenerative pathways, with exogenous irisin administration reproducing several neuroprotective benefits observed with exercise training in animal models. However, substantial heterogeneity exists regarding exercise prescription parameters (intensity, duration, frequency, modality), training-induced irisin quantification methodologies (ELISA versus mass spectrometry), and study designs (ranging from uncontrolled human observations to randomized controlled trials in animal models). Critical appraisal reveals that human studies lack adequate control for confounding variables including baseline physical fitness, comorbidities, concurrent medications, and potential sources of bias, while biochemical studies indicate distinct pharmacokinetics between endogenous training-induced irisin and exogenous bolus dosing, necessitating careful interpretation of therapeutic applicability. The translational potential of irisin as a therapeutic agent or drug target depends on resolving methodological standardization in biomarker measurement, conducting well-designed clinical trials with rigorous control for confounders, and integrating findings from molecular/biochemical studies to elucidate mechanisms linking irisin to disease modification. Future research should prioritize establishing clinical trial frameworks that harmonize exercise prescriptions, employ robust biomarker quantification (mass spectrometry), and stratify participants based on disease stage, comorbidities, and genetic predisposition to clarify irisin’s role as a potential therapeutic intervention in neurodegenerative disease management. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31^fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31^fl/fl controls, Slc6a3cre-BAP31^fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1–Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders. Full article

Motor disorders are increasingly recognized as a significant complication of chronic kidney disease (CKD), yet they remain underdiagnosed, undertreated, and often overlooked in clinical practice. Patients with CKD experience a broad spectrum of motor disturbances, including restless legs syndrome, myoclonus, flapping tremor, periodic limb movements in sleep, Parkinsonism, and peripheral neuropathy. These disorders arise from complex and often overlapping mechanisms such as uremic neurotoxicity, vascular injury, electrolyte and hormonal imbalances, or inflammatory processes, reflecting the systemic impact of impaired renal function on the central and peripheral nervous systems. The presence of motor disorders in CKD is associated with substantial clinical consequences for quality of life, contributing to impaired mobility, persistent insomnia, daytime fatigue, higher fall risk, and diminished independence. Moreover, these disturbances have been linked to increased cardiovascular morbidity and mortality, further exacerbating the already high burden of disease in this population. Current management approaches focus on optimizing kidney function through dialysis or transplantation, pharmacological therapies such as dopaminergic agents, gabapentinoids, and iron supplementation, as well as non-pharmacological interventions including structured exercise programs and sleep hygiene measures. Despite these strategies, robust evidence on long-term outcomes, comparative effectiveness, and optimal treatment algorithms remains limited. Greater recognition of the clinical impact of motor disorders in CKD, combined with targeted research efforts, is urgently needed to improve patient-centered outcomes and guide evidence-based care. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons, leading to significant motor and non-motor symptoms. This study investigates glycosylation patterns with a significant emphasis on male Parkinson’s Disease (PD) patients, revealing unique alterations distinguishing PD from healthy states, utilizing high-performance liquid chromatography coupled with mass spectrometry (HILIC-LC-MS). Findings reveal significantly altered serum N-glycosylation profiles between male and female patients, with increased levels of high-mannose glycans and reduced mono-sialylated glycans in male patients. ROC curve analysis indicates that these glycan changes are the most important features for distinguishing PD from healthy states, with AUC values of 0.71 for M5 and 0.85 for M6. This study underscores the critical role of glycosylation in the pathophysiology of Parkinson’s disease and highlights its potential in early detection and monitoring of disease progression. Full article

Background: Obesity is increasingly recognized as a complex condition characterized by the convergence of metabolic dysregulation and psychological vulnerability. Insulin resistance (IR) has been identified as a biological bridge linking metabolic imbalance with affective symptoms such as anxiety, depression, and disordered eating behaviors. Methods: Fifteen obese adults (mean age = 25 ± 4.3 years) were evaluated through clinical examination, anthropometric assessment (BMI), biochemical assays (fasting insulin, AST, ALT), and standardized psychological assessments (STAI, BDI-II). In parallel, a rapid systematic review (2019–2025) synthesized evidence on the association between IR, affective dysregulation, binge eating disorder (BED), and the clinical role of insulin-sensitizing or incretin-based therapies. Results: Participants exhibited marked hyperinsulinemia (M = 79 μU/mL, SD = 6.61) and elevated anxiety (STAI-Trait = 54.22 ± 22.4) and depression scores (BDI-II = 21.6 ± 7.5). Liver enzymes were within normal limits. Literature synthesis confirmed consistent associations between IR, mood symptoms, and BED, associated with biological processes including inflammation, HPA axis hyperactivity, and dopaminergic imbalance. Integrated treatment approaches combining cognitive-behavioral therapy, medical nutrition therapy, and insulin-sensitizing agents (metformin, GLP-1RA, and GLP-1/GIP RA) were supported as effective and safe options. Conclusions: The coexistence of insulin resistance and emotional dysregulation in obesity is consistent with the hypothesis of a bidirectional metabolic–emotional axis. Early, integrated interventions addressing both metabolic and psychological domains may improve clinical outcomes and reduce progression toward chronic metabolic and psychiatric comorbidity. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and pathological α-synuclein aggregation. Growing evidence identifies chronic neuroinflammation—particularly NLRP3 inflammasome activation in microglia—as a central driver for PD onset and progression. Misfolded α-synuclein, mitochondrial dysfunction, and environmental toxins act as endogenous danger signals that prime and activate NLRP3 inflammasome, leading to caspase-1–mediated maturation of IL-1β and IL-18 and subsequent pyroptotic cell death. Impaired mitophagy, due to defects in PINK1/Parkin pathways or receptor-mediated mechanisms, permits accumulation of dysfunctional mitochondria and release DAMPs, thereby amplifying NLRP3 activity. Studies demonstrate that promoting mitophagy or directly inhibiting NLRP3 attenuates neuroinflammation and protects dopaminergic neurons in PD models. Autophagy-inducing compounds, along with NLRP3 inhibitors, demonstrate neuroprotective potential, though their clinical translation remains limited due to poor blood–brain barrier penetration, off-target effects, and insufficient clinical data. Additionally, the context-dependent nature of mitophagy underscores the need for precise therapeutic modulation. This review summarizes current understanding of inflammasome–mitophagy crosstalk in PD, highlights major pharmacological strategies under investigation, and outlines its limitations. Future progress requires development of specific modulators, targeted delivery systems, and robust biomarkers of mitochondrial dynamics and inflammasome activity for slowing PD progression. Full article

Type 2 diabetes mellitus (T2D) affects hundreds of millions worldwide, with recent estimates indicating approximately 589 million adults living with diabetes, most with type 2 disease. Beyond classical insulin signaling pathways, increasing evidence implicates altered protein glycosylation in metabolic dysfunction. The solute carrier 35 (SLC35) family of nucleotide sugar transporters mediates the import of activated sugars into the endoplasmic reticulum and Golgi lumen, thereby influencing global glycosylation patterns. Dysregulation of these transporters can perturb glucose homeostasis, insulin responsiveness, and nutrient-sensing pathways through changes in glycosylation flux. In this review, we dissect the molecular mechanisms by which these transporters modulate glucose homeostasis, insulin signaling pathways, protein O-GlcN acylation, and broader glycosylation processes. We integrate findings from human genetic studies, rodent models, and in vitro functional analyses to characterize how altered SLC35 activity is associated with T2D and metabolic syndrome. Four members demonstrate particularly compelling evidence: SLC35B4 modulates hepatic glucose metabolism, SLC35D3 mutations impair dopaminergic signaling and energy balance, and SLC35F3 variants interact with high-carbohydrate intake to increase metabolic-syndrome risk. SLC35A3, though less studied, may influence glycosylation-dependent insulin signaling through its role in N-glycan biosynthesis. Beyond these characterized transporters, this review identifies potential metabolic roles for understudied family members, suggesting broader implications across the entire SLC35 family. We also discuss how such alterations can lead to disrupted hexosamine flux, impaired glycoprotein processing, aberrant cellular signaling, and micronutrient imbalances. Finally, we evaluate the therapeutic potential of targeting SLC35 transporters, outlining both opportunities and challenges in translating these insights into novel T2D treatments. Full article

Cerebral ischemia–reperfusion injury triggers mitochondrial dysfunction and oxidative stress, exacerbating neuronal apoptosis. Emerging evidence highlights hydrogen sulfide (H₂S) as a gasotransmitter modulating redox balance, autophagy, and apoptosis. This study investigates the neuroprotective mechanisms of Enriched Environment (EE) against ischemic injury, focusing on mitochondrial dynamics and H₂S-mediated pathways. Using MCAO mice and OGD/R-treated SH-SY5Y neurons, interventions targeting H₂S synthesis, hypoxia-inducible factor 1-alpha (HIF-1α), and mitophagy were implemented. Behavioral, histological, and molecular analyses demonstrated EE significantly improved neurological outcomes, suppressed apoptosis, and attenuated oxidative damage (reduced MDA, elevated MnSOD/glutathione). Mechanistically, EE enhanced mitophagy via dual pathways: canonical PINK1/parkin-mediated mitochondrial clearance, corroborated by transmission electron microscope and LC3B/parkin colocalization, and non-canonical HIF-1α/BNIP3L axis activation. Transcriptomic and Co-immunoprecipitation (Co-IP) data revealed EE upregulated endogenous H₂S biosynthesis post-injury by promoting dopamine-induced calcium influx, which activated calmodulin-dependent signaling to stimulate cystathionine β-synthase/γ-lyase expression. Pharmacological blockade of H₂S synthesis or HIF-1α abolished mitochondrial protection, confirming H₂S as a central mediator. Notably, H₂S exerted antiapoptotic effects by restoring mitochondrial integrity through synergistic mitophagy activation and oxidative stress mitigation. These findings propose a novel neuroprotective cascade: EE-induced dopaminergic signaling potentiates H₂S production, which coordinates PINK1/parkin and HIF-1α/BNIP3L pathways to eliminate dysfunctional mitochondria, thereby preserving neuronal homeostasis. This study elucidates therapeutic potential of EE via H₂S-driven mitochondrial quality control, offering insights for ischemic brain injury intervention. Full article