Yuanyuan Li

Restoring striatal dopamine synthesis is a promising gene therapy strategy for Parkinson's disease. Previous adeno-associated virus-mediated aromatic L-amino acid decarboxylase (AADC) monotherapies remain dependent on exogenous levodopa, whereas multigene delivery is constrained by strict adeno-associated virus packaging limits. A 'dual approach' targeting the two rate-limiting enzymes, tyrosine hydroxylase (TH) and AADC, offers the potential for autonomous dopamine synthesis. We report the 12-month primary safety and tolerability outcomes of a multicenter, open-label, dose-escalation, phase 1 trial evaluating BBM-P002, a new adeno-associated virus vector-AAVT42-codelivering constitutively active TH and AADC. Ten participants with moderate-to-advanced Parkinson's disease were enrolled and received bilateral intraputaminal infusions across doses of 4.0 × 10¹¹ vg (Cohort 1; n = 1), 6.0 × 10¹¹ vg (Cohort 2; n = 2), 1.0 × 10¹² vg (Cohort 3; n = 2) and 1.2 × 10¹² vg (Cohort 4; n = 5). The trial achieved its primary outcome, as BBM-P002 demonstrated a favorable safety and tolerability profile within 12 months post-treatment. No dose-limiting toxicities or drug-related serious adverse events occurred. A total of 23 adverse events were reported, all judged unrelated to BBM-P002 and primarily mild and transient. Systemic toxicity and clinically meaningful immunogenicity were absent. In conclusion, intraputaminal delivery of BBM-P002 was safe and well tolerated in this phase 1 trial, supporting continued clinical development. ClinicalTrials.gov registration: NCT05822739 .

Immunoglobulin G4–related disease (IgG4-RD) is a systemic fibroinflammatory disorder capable of multiorgan involvement, though its association with cerebral vasculitis and large-vessel occlusion re...

While VPS13C is a recessively inherited Parkinson’s disease (PD) gene, its potential dominant effects in idiopathic Rapid-eye movement (REM) sleep behavior disorder (iRBD) remain unexplored. The relation between its monogenic form and the onset of PD suggested that subtype specificity may need to be considered. We examined the presence of likely pathogenic VPS13C variants in 150 iRBD and 180 α-synucleinopathy patients (iRBD-first and movement disorder-first). VPS13C variants were significantly enriched in iRBD patients, and ten iRBD risk variants have been identified. iRBD risk VPS13C variant carriers demonstrated more severe RBD symptoms and greater autonomic dysfunction, correlating with REM sleep EEG and autonomic network activity abnormalities. Notably, enrichment was specific to the iRBD-first α-synucleinopathy subtype, and iRBD risk VPS13C variant carriers showed accelerated progression to overt α-synucleinopathy. These results suggest that VPS13C not only contributes to iRBD susceptibility but also serves as a marker for the iRBD-first α-synucleinopathy and faster disease conversion.

Creutzfeldt–Jakob disease is a rare and invariably fatal neurodegenerative disorder classified among the prion diseases. Primarily affecting the brain, this condition precipitates neuronal cell demise, culminating in swiftly advancing dementia and neurological impairments. Despite its rarity, once Creutzfeldt–Jakob disease manifests, it exhibits a remarkably rapid progression, subjecting patients to a spectrum of neuropsychiatric manifestations, encompassing cognitive decline, behavioral alterations, and motor dysfunction. This case study details the medical journey of a 74-year-old East Asian male patient, previously in good health and without any evident familial predisposition to the disease. The patient initially sought medical attention owing to episodic dizziness, headaches, and notable memory lapses, particularly concerning recent events. Over time, his condition deteriorated, marked by a progressive weakening that compromised his ambulatory capacity. Within a span of 2 months, from the initial diagnosis of cerebral infarction, the clinical picture evolved to raise suspicions of Creutzfeldt–Jakob disease. Through a comprehensive diagnostic process involving cerebrospinal fluid analysis, including real-time quaking-induced conversion, cranial magnetic resonance imaging, and electroencephalographic evaluation, the patient was ultimately diagnosed with probable sporadic Creutzfeldt–Jakob disease. This case report describes a confirmed diagnosis of sporadic Creutzfeldt–Jakob disease, supported by clinical manifestations and auxiliary diagnostic tests. The patient initially presented with rapidly progressing cognitive impairment and cerebellar ataxia, which prompted clinical suspicion. Subsequent magnetic resonance imaging findings revealed progressively expanding multifocal punctate and linear diffusion-weighted imaging hyperintense lesions in both cortical and subcortical areas, reinforcing the diagnosis. The definitive diagnostic evidence was obtained through a positive real-time quaking-induced conversion assay, a highly specific test for detecting prion aggregates. Continuous follow-up and careful monitoring remain essential to refine diagnostic precision and facilitate appropriate clinical management.

Background: MicroRNAs (miRNAs) have emerged as key regulators in Alzheimer's disease (AD), yet their function as biomarkers remains uncertain due to inconsistent findings in blood and cerebrospinal fluid (CSF). Objective: We aimed to identify miRNAs that track disease progression, providing valuable insights into AD pathophysiology. Methods: This study focused on analyzing alterations in miRNA expression levels in CSF and plasma samples, and their association with cognitive decline and hippocampal volume changes in AD patients using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results: Integrative analyses identified a consistent set of miRNA alterations associated with AD. While a t-test showed a selective decrease of CSF miR-185-5p in AD versus healthy controls, logistic regression identified broader signatures in plasma (hsa-miR-125b-5p, hsa-miR-26a-5p, hsa-miR-376a-3p) and CSF (hsa-miR-499a-3p, alongside CSF hsa-miR-146a-5p, hsa-miR-16-5p, and hsa-miR-185-5p). LASSO regression further refined these to a reproducible decrease in plasma hsa-miR-125b-5p and CSF hsa-miR-185-5p, alongside an increase in plasma hsa-miR-26a-5p in AD. Together, these approaches reveal convergent miRNA dysregulation in plasma and CSF, suggesting their relevance to AD pathophysiology. Further analysis showed that lower plasma hsa-miR-125b-5p and hsa-miR-26a-5p, as well as lower CSF hsa-miR-185-5p, were associated with accelerated cognitive decline measured by ADAS13 scores. Reduced CSF hsa-miR-185-5p was significantly linked to hippocampal atrophy, with similar trends for the plasma miRNAs. Furthermore, CSF hsa-miR-185-5p levels correlated with amyloid pathology, suggesting a potential role in AD pathology. Conclusions: These results highlight the role of CSF and plasma miRNA biomarkers in predicting cognitive and clinical decline in patients with AD.

Mechanism remains unclear. The study investigated the role of DJ-1 in mediating microglia–neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson’s disease. In this study, we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1 (CX3CL1) in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown. Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines, namely monocyte chemoattractant protein-1 and interleukin-8. Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells, thereby decreasing CX3CL1 secretion. This subsequently led to abnormal microglial activation, with a shift toward the proinflammatory M1 phenotype, exacerbating neuroinflammatory responses. These effects were mitigated by exogenous CX3CL1 administration. Concurrently, exogenous CX3CL1 improved motor function in Parkinson’s disease model mice with the Park7 knockout, promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation. These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation, suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons. DJ-1, also known as Parkinson’s disease protein 7 (PARK7), is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection. Previous studies have shown that DJ-1 affects early-onset Parkinson’s disease by regulating neuroinflammation, but its specific mechanism remains unclear. The study investigated the role of DJ-1 in mediating microglia–neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson’s disease. In this study, we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1 (CX3CL1) in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown. Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines, namely monocyte chemoattractant protein-1 and interleukin-8. Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells, thereby decreasing CX3CL1 secretion. This subsequently led to abnormal microglial activation, with a shift toward the proinflammatory M1 phenotype, exacerbating neuroinflammatory responses. These effects were mitigated by exogenous CX3CL1 administration. Concurrently, exogenous CX3CL1 improved motor function in Parkinson’s disease model mice with the Park7 knockout, promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation. These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation, suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons. © 2025 Neural Regeneration Research...