Plasma extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease. (1st February 2022)

• Record Type: Journal Article
• Authors: Blommer, Joseph M.; Pitcher, Toni; Mustapic, Maja; Meissner, Wassilios; Anderson, Tim; Kapogiannis, Dimitrios
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-01
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.052378
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Parkinson's Disease (PD) pathogenesis involves intraneuronal a‐synuclein accumulation, but also insulin resistance, characterized by decreased Tyr and increased Ser insulin receptor substrate‐1 (IRS‐1) phosphorylations. Besides motor symptoms, some PD patients develop mild cognitive impairment (PD‐MCI) or dementia (PD‐D), partly due to overlapping Alzheimer's disease (AD) pathology. For PD prognosis, there is a need for biomarkers distinguishing PD with normal cognition (PD‐N) from PD‐MCI/D. Neuronal‐origin extracellular vesicles (NEVs) contain signaling and pathogenic proteins that may serve as biomarkers. Method: From 104 PD‐N, 83 PD‐MCI, 39 PD‐D patients and 48 age/sex‐matched Controls, we immunocaptured plasma NEVs using anti‐L1CAM antibody. We measured biomarkers by immunoassays for: 1) PD and AD pathogenic proteins (a‐synuclein, Aβ42, total tau and p181‐tau) 2) insulin signaling mediators (pTyr20 and pSer312 IRS‐1). Particle concentration was measured by Nanoparticle Tracking Analysis and immunoblots were used to characterize NEV preparations. Result: a‐synuclein was lower in PD compared to Controls (p = 0.005) and stepwise lower in PD‐MCI (p = 0.007) and PD‐D (p < 0.001) compared to PD‐N; it tended to decrease with increasing motor symptom severity by MDS‐UPDRS III (p = 0.06). Aβ42 trended towards being higher in PD‐MCI compared to PD‐N (p = 0.06). pTau181 was higher in PD patients compared to Controls (p = 0.003) and in PD‐MCI compared to PD‐N (p = 0.02). Total Tau was not different between groups. pTyr20‐IRS‐1 was lower in PD compared to Controls (p = 0.03) and in PD‐MCI compared to PD‐N (p = 0.01) and decreased with increasing motor symptom severity by MDS‐UPDRS III (p = 0.008). The ratio pSer312/pTyr20 IRS‐1 (indicating insulin resistance) was higher in PD patients compared to Controls (p = 0.02) and in PD‐MCI and PD‐D compared to PD‐N (p = 0.01). Conclusion: PD patients with cognitive impairment exhibited lower NEV levels of a‐synuclein and pTyr20‐IRS‐1 and higher levels of pTau181 than cognitively intact PD patients. Additionally, a‐synuclein and IRS‐1pTyr20 were associated with PD motor symptom severity. Plasma NEVs offer novel biomarkers for PD and indicate Alzheimer's pathology and insulin resistance partially underly cognitive impairment in the disease.