Parkinson’s disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype–dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1 , ITPR2 , and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.

BACKGROUND: Hematoma expansion (HE) is a preventable cause of disability and death in patients with acute intracerebral hemorrhage (ICH). Platelet activity is essential for coagulation, and antiplatelet medications (eg, aspirin, clopidogrel) increase HE risk. General markers of platelet activity are associated with later HE, but specific biomarkers of platelet activity could enhance our understanding. We hypothesized that hemostatic biomarkers of platelet activity would correlate with later HE. METHODS: We conducted a tri-center observational cohort study of spontaneous ICH patients with multiple imaging scans for HE calculation. The thromboelastography 6s Platelet Mapping assay assessed platelet activity with 3 biomarkers: (1) adenosine diphosphate receptor-induced platelet activation, (2) platelet-fibrin network clot strength measured by heparinized kaolin with heparinase, and (3) fibrinogen-only clot strength measured by activator F (ActF). Spearman rank measured the correlation between HE and platelet activity. A linear regression model predicted HE from ActF. We tested whether the relationship between ActF and HE interacted with pre-ICH antiplatelet medication. RESULTS: Thirty-five patients were included. Eleven (35.48%) took pre-ICH antiplatelet medication. Heparinized kaolin with heparinase negatively correlated with HE ( ρ =−0.34, P =0.02), indicating that stronger platelet-fibrin clots were associated with less subsequent HE. ActF’s association with HE depended on pre-ICH antiplatelet medication use (interaction P =0.005). More ActF (fibrinogen) was associated with less HE in patients who did not take pre-ICH antiplatelet medication. CONCLUSIONS: Hemostatic biomarkers from the thromboelastography 6s Platelet Mapping assay predicted subsequent HE and may aid in determining neurosurgical need. Strengthening platelet-mediated coagulation may be a target for reducing HE and improving ICH outcomes.

Background and ObjectivesHematoma expansion (HE), an increase in bleeding into the brain, is a modifiable cause of disability and death after intracerebral hemorrhage (ICH). Some specialized hemost...

Human Pegivirus (HPgV) is an understudied flavivirus that is highly prevalent and often persists in the blood and tissues of humans. HPgV-infected brain tissue from individuals with Parkinson’s disease has shown significant transcriptomic and immune signaling differences compared to non-infected Parkinson’s brains. The HPgV genome is similar to Hepatitis C Virus (HCV), a well-characterized flavivirus with multiple approved small-molecule therapeutics. Here, we used HCV crystal structures to create homology models for two HPgV non-structural (NS) proteins, the serine protease (NS3) and the RNA-dependent RNA polymerase (NS5B), and performed molecular dynamic simulations. HCV and HPgV proteins had minimal structural differences, as seen by the Root Mean Square Deviation (RMSD) difference between NS3 (1.00 Å) and NS5B (1.26 Å). FDA-approved small molecules were then docked in silico to the NS3 and NS5B subunits of HCV and HPgV. HCV had weak to moderate correlated docking scores with HPgV NS3 (R² = 0.21, p < 0.001) and NS5B (R² = 0.58, p < 0.001). The predicted protein–ligand interactions showed potential binding between HCV antivirals and conserved residues of HPgV, including the catalytic triad for NS3 or the GDD motif for NS5B. Together, these results provide structural insights for key HPgV proteins and highlight possibilities for therapeutic repurposing of HCV antivirals.