Increased L1CAM-Positive Extracellular Vesicle-Associated α-Synuclein Linked With High Risk of Parkinson Disease

Newly published in JAMA Neurology, a cross-sectional study showed serum L1CAM-positive extracellular vesicle (L1EV) α-synuclein levels increased in patients at risk of developing Parkinson disease (PD) and related dementia; those with REM sleep behavior disorder (iRBD) had a 2-fold increase in L1EV α-synuclein levels compared with controls. These findings suggest a combination of prodromal markers and L1EV α-synuclein should be reviewed in the stratification of those at high risk of developing PD and related Lewy body diseases.¹

Among 576 participants (mean, age 64.30 [SD, 8.27] years; men, n = 394 [68.4%]; women, n = 182 [31.6%]), investigators observed that a derived threshold of serum L1EV α-synuclein distinguished patients with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96). In addition, it also distinguished those with more than 80% probability of having prodromal PD from patients with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Notably, L1EV α-synuclein increased in at-risk patients with a positive cerebrospinal fluid seed amplification assay and was observed above the identified threshold in 80% of cases (n = 40) of patients that phenoconverted to PD or related dementia.

Top Clinical Takeaways

Elevated L1EV α-synuclein levels in blood may serve as a valuable biomarker for identifying individuals at risk of developing PD and related Lewy body diseases.
The study highlighted the association between increased L1EV α-synuclein and specific prodromal markers, offering potential insights into early detection and intervention strategies.
While promising, further validation in longitudinal cohorts is necessary to establish the clinical utility of L1EV α-synuclein as a routine practice biomarker for PD.

"Our assay utilizes antibodies against this neuronal marker that are hinged onto otherwise nonsticky magnetic beads. Antibody-bead composites bind to neuronal extracellular vesicles in the serum and are then extracted with a magnet with minimal contamination from other blood proteins or free floating α-synuclein," senior author George Tofaris, MBBChir, PhD, FRCP, professor of neurology and translational neuroscience at University of Oxford, told NeurologyLive®. "The extracellular vesicles are washed and opened up with detergents so that the fraction of α-synuclein in them can be measured. We believe that this fraction reflects changes in nerve cells and therefore offers a more accurate snapshot of the disease process."

Conducted by lead author Shijun (Victor) Yan, MSc, DPhil student in Clinical Neuroscience at University of Oxford, and colleagues, the study included serum samples from the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Patients were recruited between July 2013 and August 2023 and samples were analyzed between April 2022 and September 2023. The derivation group (n = 170) included patients with isolated iRBD and controls. Researchers used 2 validation groups in the analysis. The first group (n = 122) included participants with iRBD and controls and the second group (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD.

Overall, the study had 199 patients with iRBD, 20 hyposmic patients with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants who had confirmed polysomnographically iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included.²Among the 580 potential participants, 4 were excluded because of alternative diagnoses.

Investigators had L1EV immunocaptured from serum samples and used electrochemiluminescence to measure the α-Synuclein and syntenin-1. Authors evaluated the biomarker performance and conducted multiple linear regression models to assess the association between L1EV α-synuclein and prodromal markers. In the subgroup analyses, findings demonstrated that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all of the cohorts, investigators observed that L1EV α-synuclein differentiated patients with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), regardless of their initial diagnosis.

Although authors observed group validation across the different cohorts, they noted that the clinical value of this biomarker at single-participant level for routine practice is not yet fully established. Investigators also noted that cutoff values may need further refinement ideally in neuropathologically confirmed cases where at-risk cohort patients eventually reach postmortem examination. The researcher noted that cohorts contained clinical phenotypes highly predictive of α-synuclein pathology and the analyses of subgroups in the cohort showed associations with specific prodromal markers despite the small sample. In addition, most of the participants were White and authors were underpowered to test differences in analyte levels across racial and ethnic groups, suggesting that the findings may not be generalized to other populations.

"We are performing further validation of the biomarker in longitudinal cohorts, i.e. studying serial samples in patients who went on to develop PD sometime in the future or are closer to developing the disease," Tofaris, who also serves as a consultant neurologist at John Radcliffe Hospital, said. "In collaboration with colleagues in Oxford Chemistry, we have also developed a microfluidic platform for on-chip extraction of these extracellular vesicles in 30 minutes using minimal volume of blood and we continue to optimize and develop such platforms. This is needed to minimize manual handling (which may introduce variability) and increase scalability for wider use in clinical practice."