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• W4386467488 abstract "Similar molecular processes have been identified in the development of Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM).1 Insulin resistance is a central feature of T2DM pathology, and recent evidence supports its occurrence in the brain and its contribution in neurodegeneration.2 Insulin receptor substrate (IRS)-1 is the initial node in the pathway of insulin signaling and its activity is modified through phosphorylation of specific tyrosine (activation) and serine (inhibition) residues.3 L1 cell adhesion molecule (L1CAM) extracellular vesicles (EVs) in plasma have been suggested as potential markers of neuronal origin,4 which may provide a non-invasive method to assess brain insulin resistance in PD.5 Here, we present evidence independent from the research group that originally developed the L1CAM-EVs method, supporting the presence of brain insulin resistance in PD. In total, 80 persons with PD (PwPD) and 25 healthy controls (HCs) were included in the project (Supplementary Appendix S1). EVs were isolated and enriched for neural origin following the method of Mustapic et al4 (Supplementary Appendix S1). Plasma samples were available in 78/80 PwPD and 24/25 HCs (Supplementary Table S1 and Supplementary Appendix S1). Male sex was more frequent in PwPD. Peripheral fasting insulin levels, glucose levels, and homeostatic model assessment for insulin resistance (HOMA-IR) index did not differ between PwPD and HCs (P = 0.8; P = 0.4, and P = 0.9, respectively) (Supplementary Appendix S1). L1CAM-EV ratio of p-Ser/p-Tyr IRS-1 was significantly higher in the PD-group compared to HCs (median, interquartile range [IQR]: 0.44, 0.52 vs. 0.27, 0.35; P = 0.039) (Supplementary Fig. S1). L1CAM-EV insulin, active gastric inhibitory polypeptide (GIPa), active glucagon-like peptide 1 (GLP1a), glucagon, and leptin levels did not differ between PwPD and HCs, whereas pancreatic polypeptide was lower in PwPD compared to HCs (median, IQR: 0.8, 0.87 vs. 1.1, 1.07 pg/mL; P = 0.006) (Supplementary Fig. S2). HOMA-IR did not correlate with any of L1CAM-EV protein levels except for a weak correlation with GLP1a (Spearman ρ, −0.2; P = 0.04) (Supplementary Fig. S3). Logistic regression analysis showed that sex, University of Pennsylvania Smell Identification Test score, Hospital Anxiety and Depression Scale-Depression Score, and pancreatic polypeptide were strongly associated with PD after adjustment for age (area under curve, 0.974) (Fig. 1). Our results show reduced IRS-1 activity in PwPD compared to HCs demonstrated as significantly higher L1CAM-EV ratio of p-Ser/p-Tyr IRS-1. This may indicate impaired insulin signaling in the brain in PwPD, despite similar levels of L1CAM insulin levels and absence of peripheral insulin resistance. Our study is limited by the lack of age-, sex-, and body mass index-matching between HCs and PwPD, which is accounted for in the analyses. A validation cohort would further strengthen our results. Our measured insulin and HOMA-IR values were higher than the range of routine clinical assessments; however, we used the 75th percentile as cutoff value to objectively define high/low HOMA-IR groups. Finally, and most importantly, the true origin of L1CAM-EVs is intensively debated despite significant supporting data on their neuronal origin and use as biomarkers in Alzheimer's disease and PD.5, 6 Critique suggests that, although L1CAM is a neuronal surface protein, L1CAM in plasma represents soluble products of alternative splicing or proteolytic cleavage.7 To omit that problem, we first isolated EVs from plasma, therefore, removing any soluble L1CAM, and subsequently performed immunoprecipitation of L1CAM-positive vesicles. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. I.M.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B W.P.: 1A, 1B, 1C, 2C, 3A, 3B T.N.: 1B, 1C, 2C, 3A, 3B L.E.: 1C, 2C, 3B S.B.C.: 1C, 2C, 3B P.S.: 1A, 1B, 1C, 2C, 3B. P.S. received grants from Knut and Alice Wallenberg Foundation and the Parkinson Research Foundation. I.M. received grants from Stockholm County Council and Parkinsonfonden. W.P received grants from Parkinsonfonden, The Michael J. Fox Foundation, and the Karolinska Institutet Research Foundation. S.B.C. received grants from Stockholm County Research Council, von Kantzows Foundation, and Kung Gustaf V's och Drottning Victorias Frimurarestifelse. T.N. has nothing to report. L.E. has nothing to report. The data used and analyzed in this study are available from the corresponding author on reasonable request. Appendix S1. Supporting Information. Figure S1. Box plots showing the difference in the ratio of pSer/pTyr of IRS-1 in patients with Parkinson''s disease versus healthy controls. Figure S2. Box plots of L1CAM-protein levels in patients with Parkinson''s Disease vs. Healthy Controls. Figure S3. Linear predicition plots for HOMA index on each of L1CAM-EV proteins with 95% confidence intervals. Table S1. Demographic and clinical characteristics. Table S2. Range of L1 Cell Adhesion Molecule (L1CAM)-exosome analytes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W4386467488 date "2023-09-05" @default.
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• W4386467488 title "Isolation of <scp>L1CAM</scp>‐Extracellular Vesicles Reveals Signs of Insulin Resistance in Parkinson's Disease" @default.
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• W4386467488 doi "https://doi.org/10.1002/mds.29601" @default.
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