NPJ Parkinson's Disease最新文献

Alpha synuclein (asyn) is expressed in neurons and is associated with the pathogenesis of synucleinopathies like Parkinson's Disease. Asyn aggregates are associated with phosphorylation at serine position 129 (pS129), which can be induced by environmental triggers, including viral infection, and the risk increases with aging. We show that brain tissue from West Nile Virus (WNV) infected patients exhibit increased expression of pS129 asyn in neurons of brain tissue. We found that WNV infection, Poly I:C treatment, and type 1 interferon (T1 IFN) treatment elicit the acute induction, followed by rapid degradation of pS129 asyn in olfactory pathways and primary cortical neurons. Induction of pS129 asyn was induced at these early time points independent of asyn aggregates. In IFN receptor knockout neurons, virus infection and Poly I:C stimulation do not induce pS129 asyn, implying that pS129 asyn is dependent on the type 1 interferon receptor. Our findings suggest that infections with DNA and RNA viruses and subsequent antiviral immunity can trigger the acute formation of pS129 asyn, and T1 IFN stimulation in neurons can trigger post-translational modifications in asyn. Further studies evaluating the interactions between pS129 asyn and interferon signaling may provide a common trigger for the formation of pathogenic asyn species.

Detection of alpha-synuclein (α-Syn) seeding activity in tear fluid (TF) offers a promising non-invasive biomarker for Parkinson's disease (PD). α-Syn seeding amplification assay (αSynSAA) detected seeding activity in 67% of PD-TF, while non-synucleinopathy samples remained negative. Electron microscopy of seeding-positive end products revealed fibrillar structures morphologically consistent with results of αSynSAA. αSynSAA effectively distinguished PD from controls and prion diseases based on seeding activity in TF.

Cognitive impairment is a core non-motor symptom of Parkinson's disease (PD), yet its biological substrates remain poorly defined. Emerging evidence implies cerebrovascular involvement, although direct investigations of the cerebrovasculature are scarce. This study used 4D flow MRI and Bayesian multi-level modelling to explore the health of the circle of Willis in PD, and to examine whether anatomical or haemodynamic changes within this network relate to cognitive and motor symptoms. Arterial anatomy (cross sectional area) and haemodynamics (mean flow, total cerebral blood flow, mean and maximum velocity, pulsatility, and resistance) were assessed in 80 individuals with PD with varying levels of cognitive and motor impairment, and 34 controls. Compared to controls, PD was associated with lower mean flow, total cerebral blood flow, and mean velocity across the CoW network. Altered haemodynamics (lower mean flow and mean velocity) were associated with both cognitive and motor impairment, while vascular stiffening (increased pulsatility and resistance) exclusively co-occurred with cognitive decline. Our results identify CoW dysfunction as a pathophysiological feature of PD and implicate compromised haemodynamics in symptom severity. Findings position the cerebrovasculature as a potential target for therapeutic focus.

Early and accurate diagnosis of Parkinson's disease (PD) remains challenging due to reliance on clinical assessment of motor symptoms. This retrospective study compared the diagnostic performance of neuromelanin (NM)-sensitive MRI and free water (FW) imaging in 247 patients with early PD and 78 controls from a single tertiary center, with independent external validation in a separate cohort acquired at another institution. NM volumes were measured in the substantia nigra pars compacta and its functional subregions (limbic, associative, and sensorimotor), while FW values were extracted from corresponding substantia nigra regions using diffusion tensor imaging. A combined NM model incorporating subregional volumes was developed through multivariable logistic regression. NM volumes were reduced across all regions in early PD patients compared to controls, while FW values showed no significant group differences. NM measurements consistently outperformed FW imaging across all regions, with the combined NM model achieving superior diagnostic accuracy, and NM-based measures also demonstrated higher diagnostic performance than FW in the external validation cohort. These results highlight the clinical utility of NM-MRI for early diagnostic assessment and its potential integration into emerging multimodal biomarker frameworks for PD.