Qing Wang

Cystatin C (CysC) is emerging as a key regulator and intercellular signaling mediator within the neuro-glial-vascular unit (NGVU). This review comprehensively examines its multifaceted roles across NGVU components, detailing mechanisms by which CysC preserves blood–brain barrier integrity, modulates neuroinflammation, and influences pathological protein aggregation. Rather than providing a merely descriptive catalogue, we emphasize its context-dependent nature. In cerebrovascular and neurodegenerative diseases, CysC exhibits functional duality along the neuron–glia axis, either restraining or perpetuating inflammation and proteinopathy depending on cellular context and disease stage. Similarly, along the endothelial–oligodendrocyte precursor cell crosstalk, its coordination of angiogenesis and myelination may shift from protective to detrimental under chronic hypoperfusion. We evaluate its dual utility as a clinical biomarker and therapeutic target, addressing challenges in brain delivery, target selectivity, and safety. This integrative synthesis provides a critical perspective on unresolved controversies and future research priorities regarding CysC in neurological disorders.

Neurodegenerative diseases (NDDs) are a heterogeneous group of disorders characterized by progressive neuronal loss that leads to cognitive, motor, and behavioral impairment. With population aging, NDDs impose an expanding medical and socioeconomic burden, yet most available treatments remain symptomatic rather than disease modifying. Disease mechanisms are increasingly understood as multicellular processes involving neurons, astrocytes, microglia, and other cell types, which complicates target selection and limits translation from conventional models. Intranasal administration offers a noninvasive route for delivering therapeutics to the central nervous system by leveraging olfactory and trigeminal pathways and reducing dependence on blood-brain barrier penetration. This review summarizes recent advances in intranasal strategies for NDDs across diverse therapeutic classes, including peptides and proteins, small molecules and metabolic modulators, nucleic acid-based cargos, and nanocarrier enabled formulations designed to improve retention, stability, and brain deposition. We further highlight emerging organelle centered and bioengineered approaches, such as mitochondrial delivery and other cell organelle or organelle derived systems, alongside cell-based and cell-free biologics including stem cells, secretomes, and extracellular vesicles that provide multi target neuroprotective and immunomodulatory effects. Finally, we discuss key translational challenges, including limited delivery efficiency due to mucociliary clearance, uncertainty in dosing regimens, manufacturing and quality control for complex biologics and organelles, and the need for robust biomarkers and imaging readouts to confirm central target engagement. Collectively, these advances position intranasal delivery as a versatile but evolving platform for next generation interventions in NDDs.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the pathological misfolding and aggregation of α‐synuclein (α‐syn), which leads to dopaminergic neuronal loss and multisystem dysfunction. Conventional clinical diagnosis is often delayed until after substantial neuronal degeneration has occurred. Recent advances in α‐syn seed amplification assays (α‐syn SAAs), including real‐time quaking‐induced conversion (RT‐QuIC) and protein misfolding cyclic amplification (PMCA), have revolutionized PD biomarker research. These assays exploit the prion‐like seeding and propagation properties of pathological α‐syn to amplify trace aggregates in biological samples with exceptional sensitivity and specificity. Here, we summarize the mechanistic principles and biophysical underpinnings of α‐syn SAAs, compare their diagnostic performance across biospecimens such as cerebrospinal fluid, skin, blood, and saliva, and evaluate their potential for differential diagnosis among synucleinopathies. We further discuss the integration of SAAs with other biomarkers including α‐syn oligomer ELISAs, neurofilament light chain assays, and dopaminergic PET/SPECT imaging. Emerging developments, such as same‐day RT‐QuIC, quantitative kinetic readouts, and peripheral blood‐based assays, are accelerating clinical translation. Despite challenges in assay standardization, strain discrimination, and regulatory validation, α‐syn SAAs hold transformative potential for early diagnosis, patient stratification, and monitoring of therapeutic efficacy in PD. Their convergence with artificial intelligence, organoid modeling, and multimodal biomarker frameworks promises to redefine precision medicine in PD and other synucleinopathies.

Background and purpose: Previous studies have shown that serum cystatin C (CysC) is associated with cerebral small vessel disease (CSVD) and that elevated CysC levels are linked to an increased risk of cognitive impairment in the elderly. However, whether CysC is specifically associated with cognitive impairment in patients with CSVD remains unclear. Method: A total of 334 CSVD patients with available demographic, blood biomarker, and brain imaging data were included. Patients were divided into vascular cognitive impairment and normal cognition groups. Univariate analysis was used to compare baseline data, blood biomarkers, imaging features, and behavioral scores between the two groups. Binary logistic regression was used to evaluate the diagnostic value of cystatin C for CSVD-related cognitive impairment. Results: Compared with the normal cognition group, the VCI group exhibited significantly elevated serum levels of CysC, homocysteine, urea nitrogen, creatinine, uric acid, fibrinogen, and D-dimer, along with a lower red blood cell count. The VCI group also showed a higher prevalence of severe periventricular white matter hyperintensity, severe deep white matter hyperintensity, severe total white matter hyperintensity, and brain atrophy. The combination of these eight blood biomarkers markedly improved the diagnostic performance for VCI (AUC = 0.672, 95% CI: 0.615–0.730, p < 0.001). Multivariate analysis revealed that elevated CysC levels (OR = 2.677, p = 0.041), age (OR = 1.067, p < 0.001), and severe total WMH (OR = 2.713, p < 0.001) were associated with CSVD-related cognitive impairment. After adjusting for confounding variables, serum CysC levels remained independently correlated with cognitive impairment (OR = 3.257, 95% CI: 1.192–8.899, p = 0.021). Conclusion: Serum CysC levels are independently associated with cognitive impairment in CSVD patients.

There is considerable evidence linking alterations in gut microbiome composition with Parkinson’s disease, leading to several recent randomized controlled faecal microbiota transplantation (FMT) trials in patients with Parkinson’s disease targeting gut dysbiosis with the aim to modulate the gut–brain axis. Some FMT trials have observed motor and non-motor symptoms improvements in patients with Parkinson’s disease, possibly through microbiota linked enhanced short-chain fatty acid or other metabolite effects and reduced systemic inflammation. While the findings are exciting and can potentially open a new treatment paradigm, crital questions on donor selection, the optimal screening and selection of the donor microbiome, delivery routes and the timing and frequency of transplantation need to be addressed. We suggest that future FMT trials should incorporate blood, metabolites, urine and functional neuroimaging biological markers and to control for dietary, lifestyle comorbidities, medication intake and/or other potential variables to ensure optimal evaluation of interactions between the gut microbes and brain outcomes prospectively over a longer time frame.