Study results published in JAMA Neurology demonstrated an association between elevated L1CAM-positive extracellular vesicle (L1EV) α-synuclein serum levels and the risk of developing Parkinson disease (PD) or related dementia.

The retrospective, cross-sectional multicenter study included 4 cohorts (Oxford Discovery, Marburg, Cologne, and Parkinson’s Progression Markers Initiative) comprised of individuals at-risk of developing PD (ie, those with prodromal PD symptoms or nonmanifest genetic risk factors for PD [n=365]), individuals with genetic (GBA1N409S gene carriers) or sporadic PD (n=71) and healthy controls (n=140). Researchers used electrochemiluminescence to measure α-synuclein immunocaptured from serum L1EVs to determine if elevated L1EV α-synuclein levels are associated with a higher risk of developing PD, defined as either isolated rapid eye movement sleep behavior disorder (iRBD) or >80% probability of prodromal PD based on the updated Movement Disorder Society (MDS) prodromal research criteria.

• There was an approximately 2-fold increase in L1EV α-synuclein levels in participants with iRBD (24.21; interquartile range [IQR] 13.75 pg/mL) compared with controls (12.20; IQR, 7.39 pg/mL).
• L1EV α-synuclein levels differentiated participants with more than 80% probability of having prodromal PD from healthy control populations (area under the curve [AUC]=0.90; 95% CI, 0.87 to 0.93), irrespective of initial diagnosis.
• In a small subgroup of individuals (n=40) who eventually develop PD or related dementia, L1EV α-synuclein levels were above the identified threshold (17.75 pg/ml) in more than 80% of cases up to as many as 7 years before the PD diagnosis.
• L1EV α-synuclein levels also were assessed in relation to the presence of dopaminergic neurodegeneration in participants with available dopamine transporter single-photon emission CT (DaT SPECT). L1EV α-synuclein levels were highest in participants with an abnormal DaT SPECT (26.55 [IQR, 18.31] pg/mL), intermediate in those with a normal DaT SPECT (18.92 [IQR, 14.57] pg/mL), and lowest in healthy controls (12.60 [IQR, 6.68] pg/mL).

Although additional studies are needed to extend the applicability of these findings to the general population, these results demonstrate the first easily accessible blood-based test for the identification of prodromal PD and related dementia.

Study author Dr. George Tofaris notes, "Collectively our studies demonstrate how fundamental investigations in α-synuclein biology can be translated into a biomarker for clinical application, in this case for the identification and stratification of Parkinson's risk. A screening test that could be implemented at scale to identify the disease process early is imperative for the eventual instigation of targeted therapies as is currently done with screening programs for common types of cancer."