Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jul;11(4):e200257.
doi: 10.1212/NXI.0000000000200257. Epub 2024 May 16.

Synaptic Protein Loss in Extracellular Vesicles Reflects Brain and Retinal Atrophy in People With Multiple Sclerosis

Dimitrios C Ladakis  1 , Michael Vreones  1 , Joseph Blommer  1 , Kimystian L Harrison  1 , Matthew D Smith  1 , Eleni S Vasileiou  1 , Hussein Moussa  1 , Gelareh Ahmadi  1 , Omar Ezzedin  1 , Anna L DuVal  1 , Blake E Dewey  1 , Jerry L Prince  1 , Kathryn C Fitzgerald  1 , Elias S Sotirchos  1 , Shiv Saidha  1 , Peter A Calabresi  1 , Dimitrios Kapogiannis  1 , Pavan Bhargava  1
Affiliations

Synaptic Protein Loss in Extracellular Vesicles Reflects Brain and Retinal Atrophy in People With Multiple Sclerosis

Dimitrios C Ladakis et al. Neurol Neuroimmunol Neuroinflamm. 2024 Jul.

Abstract

Objectives: To assess whether the rate of change in synaptic proteins isolated from neuronally enriched extracellular vesicles (NEVs) is associated with brain and retinal atrophy in people with multiple sclerosis (MS).

Methods: People with MS were followed with serial blood draws, MRI (MRI), and optical coherence tomography (OCT) scans. NEVs were immunocaptured from plasma, and synaptopodin and synaptophysin proteins were measured using ELISA. Subject-specific rates of change in synaptic proteins, as well as brain and retinal atrophy, were determined and correlated.

Results: A total of 50 people with MS were included, 46 of whom had MRI and 45 had OCT serially. The rate of change in NEV synaptopodin was associated with whole brain (rho = 0.31; p = 0.04), cortical gray matter (rho = 0.34; p = 0.03), peripapillary retinal nerve fiber layer (rho = 0.37; p = 0.01), and ganglion cell/inner plexiform layer (rho = 0.41; p = 0.006) atrophy. The rate of change in NEV synaptophysin was also correlated with whole brain (rho = 0.31; p = 0.04) and cortical gray matter (rho = 0.31; p = 0.049) atrophy.

Discussion: NEV-derived synaptic proteins likely reflect neurodegeneration and may provide additional circulating biomarkers for disease progression in MS.

PubMed Disclaimer

Conflict of interest statement

D.C. Ladakis, M. Vreones, J. Blommer, K.L. Harrison, M.D. Smith, E.S. Vasileiou, H. Moussa, G. Ahmadi, O. Ezzedin, A. DuVal, B. Dewey, J.L. Prince, and K.C. Fitzgerald reports no disclosures relevant to the manuscript; E.S. Sotirchos has received consulting fees from Alexion, Viela Bio, Horizon Therapeutics, Genentech and Ad Scientiam and speaking honoraria from Alexion, Viela Bio and Biogen. S. Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen, Novartis, Genentech Corporation, TG therapeutics, Clene Pharmaceuticals & ReWind therapeutics. He has performed consulting for Novartis, Genentech Corporation, JuneBrain LLC, Innocare Pharma, Kiniksa pharmaceuticals and Lapix therapeutics. He is the PI of investigator-initiated studies funded by Genentech Corporation, Biogen, and Novartis. He previously received support from the Race to Erase MS foundation. He has received equity compensation for consulting from JuneBrain LLC and Lapix therapeutics. He was also the site investigator of trials sponsored by MedDay Pharmaceuticals, Clene Pharmaceuticals, and is the site investigator of trials sponsored by Novartis, as well as Lapix therapeutics. P.A. Calabresi received funding from MRF for this work and is PI on a grant from Genentech to JHU. He has received consulting fees from Lilly, Idorsia, and Novartis; D. Kapogiannis reports no disclosures relevant to the manuscript; P. Bhargava has received grant funding to JHU from Amylyx pharmaceuticals, Genentech, EMD-Serono, and GSK. Go to Neurology.org/NN for full disclosures.

Figures

Figure
Figure. Relationship Between Synaptic Proteins and Imaging Outcomes Rates of Change
(A) Scatter plots of synaptopodin (left panels) and synaptophysin (right panels) rates of change in relationship with cortical gray matter (top panels) and whole brain volume (bottom panels) atrophy. (B) Scatter plot of synaptopodin rates of change in relationship with pRNFL and GCIPL atrophy. Gray lines derive from unadjusted linear models. Rho estimates and p-values derived from Spearman partial correlations adjusted for sex, age, and MS subtype. cGM = cortical gray matter; GCIPL = ganglion cell and inner plexiform layer; pRNFL = peripapillary retinal nerve fiber layer; WBV = whole brain volume.
See this image and copyright information in PMC

References

    1. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169-180. doi:10.1056/NEJMra1401483 - DOI - PMC - PubMed
    1. Jürgens T, Jafari M, Kreutzfeldt M, et al. . Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain. 2016;139(Pt 1):39-46. doi:10.1093/brain/awv353 - DOI - PubMed
    1. Petrova N, Nutma E, Carassiti D, et al. . Synaptic loss in multiple sclerosis spinal cord. Ann Neurol. 2020;88(3):619-625. doi:10.1002/ana.25835 - DOI - PubMed
    1. Dutta R, Chang A, Doud MK, et al. . Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol. 2011;69(3):445-454. doi:10.1002/ana.22337 - DOI - PMC - PubMed
    1. Michailidou I, Willems JGP, Kooi E-J, et al. . Complement C1q-C3–associated synaptic changes in multiple sclerosis hippocampus. Ann Neurol. 2015;77(6):1007-1026. doi:10.1002/ana.24398 - DOI - PubMed

MeSH terms

LinkOut - more resources