Toward a Biomarker Panel measured in CNS-originating Extracellular Vesicles for Improved Differential Diagnosis of Parkinson’s Disease and Multiple System Atrophy

Abstract

Synucleinopathies are neurodegenerative diseases characterized by accumulation of misfolded α-synuclein (α-syn) inclusions in neuronal and/or glial cells. Different synucleinopathies may affect different brain regions and cell types. In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), α-syn deposits predominantly in neuronal Lewy bodies (LBs) and Lewy neurites (LNs), whereas in multiple system atrophy (MSA), α-syn-rich glial cytoplasmic inclusions (GCIs) are found in oligodendrocytes (1). Despite differences in the underlying pathophysiology, synucleinopathies often are misdiagnosed, especially by non-experts in the early-stages, due to the overlapping clinical symptoms (2, 3). Several studies have demonstrated the utility of measuring α-syn in neuronal EVs (nEVs) as a diagnostic biomarker for PD and atypical parkinsonian disorders (4). Recently, our group has shown that α-syn measured in both nEVs and oligodendroglial EVs (oEVs) in the same samples, and in particular the oEV:nEV α-syn concentration ratio, yielded a discriminative model distinguishing between PD and MSA with 89.8% sensitivity and 86.0% specificity and between healthy controls (HC) and MSA with 96.0% sensitivity and 84.3% specificity. In contrast, the model offered moderate separation between PD and HC – 71.4% sensitivity and 62.7% specificity (5).

Development of a Novel Electrochemiluminescence ELISA for Quantification of α-Synuclein Phosphorylated at Ser129 in Biological Samples

“…The analysis showed concentrations between 1.5 and 248.9 pg/mL in nEVs and between 2.2 and 379.9 pg/mL in oEVs. When the measurements of pS 129 -α-syn in the CNS-originating EVs were combined with the previous analysis of total α-syn, the separation improved among all the groups, demonstrating the importance and utility of the new assay.…”

Evaluation of α-Synuclein in CNS-originating Extracellular Vesicles for Parkinsonian Disorders: A Systematic Review and Meta-analysis.

“…As such, it was removed from the meta-analysis. In total, thirteen articles (1,5,11,23,24,33,36,44,45,47,56,58,59) were included in the meta-analysis. A detailed description of each individual study is provided in Table 1.…”

“…As measurement of α-syn in nEVs and oEVs is an objective measure, the index test domain was deemed to be low bias because prior knowledge of the clinical status (patients with a parkinsonian disorder or HCs) should not in uence the objective measurement of α-syn. Most of the articles (n = 10, 76.9%) had low bias regarding Reference Standard, while three studies (44,47,56) that have used an in-house test were deemed as high risk of bias. With respect to Flow and Timing domain, all studies were deemed low risk of bias because the time interval from clinical diagnosis to the index test (i.e., α-syn proteoforms measurement) could be estimated.…”

“…Adding α-syn in oEVs (11,47,56) to the meta-analysis did not alter the results, although the p-value almost reached signi cance (k = 26, SMD = 0.18; 95% CI -0.01, 0.38; p = 0.062; Fig. S1).…”

Editorial: Trends in biomarkers for neurodegenerative diseases: Current research and future perspectives

“…For most of these diseases, analysis of brain tissue postmortem is required for accurate diagnosis. Major advancements have been made in the development of cerebrospinal fluid (CSF), imaging, and blood-based biomarkers for several neurodegenerative diseases (Ashton et al, 2020 ; Kaipainen et al, 2020 ; Dutta et al, 2021 ; Taha et al, 2022 ), which are proof of concept for the possibilities of early diagnosis. Moreover, advances in proteomics, transcriptomics, and metabolomics have provided valuable insights into the mechanisms of these conditions and have opened the door to the development of novel diagnostic and therapeutic approaches (Peplow and Martinez, 2021 ).…”