Serum Biomarker Signatures of Choroid Plexus Volume Changes in Multiple Sclerosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. MRI Acquisition and Analysis
2.3. Blood-Based Biomarker Analysis
2.4. Statistical Analyses
3. Results
3.1. Demographic and Clinical Characteristics of the Study Population
3.2. Cross-Sectional and Longitudinal Relationships between Choroid Plexus and Blood-Based Biomarkers
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Blood-Based Measure (Median and IQR) | pwRRMS (n = 148) | pwPMS (n = 54) | p-Value |
---|---|---|---|
APLP1 in ng/mL | 11.1 (8.7–13.9) | 12.1 (9.5–13.4) | 0.283 |
CCL20 | 10 (5.8–18.6) | 8.8 (5.8–16.1) | 0.628 |
CD6 | 132.1 (100–172.9) | 130.4 (90–187.8) | 0.532 |
CDCP1 | 102.4 (69.3–142.2) | 114 (80–141.5) | 0.226 |
CNTN2 in ng/mL | 1.6 (1.2–2.2) | 1.9 (1.4–2.4) | 0.058 |
COL4A1 in ng/mL | 1.3 (0.9–2.1) | 12.1 (1.0–1.9) | 0.553 |
CXCL13 | 49.1 (41–67.3) | 50.3 (36.4–65.1) | 0.644 |
CXCL9 | 48.2 (33.7–84) | 70.9 (49.9–89.7) | 0.009 |
FLRT2 | 108 (87.9–134.4) | 113.8 (96.1–129) | 0.507 |
GFAP | 105.8 (77.4–147) | 145.8 (115–177.3) | <0.001 |
GH | 175.8 (73.1–460.7) | 185.3 (69–1134.2) | 0.368 |
IL-12B | 108.8 (78.5–179.6) | 124.4 (74.6–172) | 0.883 |
MOG | 27.1 (21.4–33.3) | 28.4 (22.6–33.7) | 0.456 |
NfL | 8.6 (6.4–12.3) | 12.5 (9.5–15.5) | <0.001 |
OPG | 742.9 (589.2–923) | 827.4 (613.7–940) | 0.348 |
OPN in ng/mL | 18.8 (15.1–25.1) | 19.7 (15.1–23.7) | 0.817 |
PRTG | 127.9 (108.1–148.2) | 127.3 (114.4–148.5) | 0.87 |
SERPINA9 | 50 (34.6–75.9) | 57.1 (37.6–90.6) | 0.111 |
TNFRSF10A | 5.6 (4.7–7.3) | 6 (4.9–7.1) | 0.617 |
TNFSF13B in ng/mL | 4.8 (4.1–5.9) | 4.6 (3.9–5.5) | 0.135 |
VCAN | 436.1 (367.1–512.5) | 451 (387.6–537) | 0.404 |
References
- Jakimovski, D.; Bittner, S.; Zivadinov, R.; Morrow, S.A.; Benedict, R.H.; Zipp, F.; Weinstock-Guttman, B. Multiple sclerosis. Lancet 2024, 403, 183–202. [Google Scholar] [CrossRef] [PubMed]
- Machado-Santos, J.; Saji, E.; Tröscher, A.R.; Paunovic, M.; Liblau, R.; Gabriely, G.; Bien, C.G.; Bauer, J.; Lassmann, H. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 2018, 141, 2066–2082. [Google Scholar] [CrossRef] [PubMed]
- Bergsland, N.; Dwyer, M.G.; Jakimovski, D.; Tavazzi, E.; Benedict, R.H.; Weinstock-Guttman, B.; Zivadinov, R. Association of Choroid Plexus Inflammation on MRI with Clinical Disability Progression over 5 Years in Patients with Multiple Sclerosis. Neurology 2023, 100, E911–E920. [Google Scholar] [CrossRef] [PubMed]
- Wilson, E.H.; Weninger, W.; Hunter, C.A. Trafficking of immune cells in the central nervous system. J. Clin. Investig. 2010, 120, 1368–1379. [Google Scholar] [CrossRef] [PubMed]
- Lazarevic, I.; Soldati, S.; Mapunda, J.A.; Rudolph, H.; Rosito, M.; de Oliveira, A.C.; Enzmann, G.; Nishihara, H.; Ishikawa, H.; Tenenbaum, T.; et al. The choroid plexus acts as an immune cell reservoir and brain entry site in experimental autoimmune encephalomyelitis. Fluids Barriers CNS 2023, 20, 39. [Google Scholar] [CrossRef]
- Rodríguez-Lorenzo, S.; Francisco, D.M.F.; Vos, R.; Hof, B.v.H.; Rijnsburger, M.; Schroten, H.; Ishikawa, H.; Beaino, W.; Bruggmann, R.; Kooij, G.; et al. Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis. Acta Neuropathol. Commun. 2020, 8, 35. [Google Scholar] [CrossRef] [PubMed]
- Pardini, M.; Brown, J.W.L.; Magliozzi, R.; Reynolds, R.; Chard, D.T. Surface-in pathology in multiple sclerosis: A new view on pathogenesis? Brain 2021, 144, 1646–1654. [Google Scholar] [CrossRef] [PubMed]
- Klistorner, S.; Barnett, M.H.; Parratt, J.; Yiannikas, C.; Graham, S.L.; Klistorner, A. Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy. Ann. Clin. Transl. Neurol. 2022, 9, 1528–1537. [Google Scholar] [CrossRef]
- Kuhle, J.; Barro, C.; Andreasson, U.; Derfuss, T.; Lindberg, R.; Sandelius, Å.; Liman, V.; Norgren, N.; Blennow, K.; Zetterberg, H. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin. Chem. Lab. Med. 2016, 54, 1655–1661. [Google Scholar] [CrossRef]
- Jakimovski, D.; Dwyer, M.G.; Bergsland, N.; Weinstock-Guttman, B.; Zivadinov, R. Disease biomarkers in multiple sclerosis: Current serum neurofilament light chain perspectives. Neurodegener. Dis. Manag. 2021, 11, 329–340. [Google Scholar] [CrossRef]
- Qureshi, F.; Hu, W.; Loh, L.; Patel, H.; DeGuzman, M.; Becich, M.; Rubio da Costa, F.; Gehman, V.; Zhang, F.; Foley, J.; et al. Analytical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis. Proteom. Clin. Appl. 2023, 17, 2200018. [Google Scholar] [CrossRef] [PubMed]
- Jakimovski, D.; Zivadinov, R.; Ramanthan, M.; Hagemeier, J.; Weinstock-Guttman, B.; Tomic, D.; Kropshofer, H.; Fuchs, T.A.; Barro, C.; Leppert, D.; et al. Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study. Mult. Scler. J. 2019, 26, 1670–1681. [Google Scholar] [CrossRef]
- Jakimovski, D.; Kuhle, J.; Ramanathan, M.; Barro, C.; Tomic, D.; Hagemeier, J.; Kropshofer, H.; Bergsland, N.; Leppert, D.; Dwyer, M.G.; et al. Serum neurofilament light chain levels associations with gray matter pathology: A 5-year longitudinal study. Ann. Clin. Transl. Neurol. 2019, 6, 1757–1770. [Google Scholar] [CrossRef] [PubMed]
- Jakimovski, D.; Qureshi, F.; Ramanathan, M.; Gehman, V.; Keshavan, A.; Leyden, K.; Dwyer, M.G.; Bergsland, N.; Weinstock-Guttman, B.; Zivadinov, R. Proteomics and relationship with axonal pathology in multiple sclerosis: 5-year diffusion tensor imaging study. Brain Commun. 2023, 5, fcad183. [Google Scholar] [CrossRef]
- Jalaleddini, K.; Jakimovski, D.; Keshavan, A.; McCurdy, S.; Leyden, K.; Qureshi, F.; Ghoreyshi, A.; Bergsland, N.; Dwyer, M.G.; Ramanathan, M.; et al. Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis. Ann. Clin. Transl. Neurol. 2024, 11, 729–743. [Google Scholar] [CrossRef]
- Thompson, A.J.; Banwell, B.L.; Barkhof, F.; Carroll, W.M.; Coetzee, T.; Comi, G.; Correale, J.; Fazekas, F.; Filippi, M.; Freedman, M.S.; et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018, 17, 162–173. [Google Scholar] [CrossRef] [PubMed]
- Kurtzke, J.F. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983, 33, 1444–1452. [Google Scholar] [CrossRef]
- Lublin, F.D.; Reingold, S.C.; Cohen, J.A.; Cutter, G.R.; Sørensen, P.S.; Thompson, A.J.; Wolinsky, J.S.; Balcer, L.J.; Banwell, B.; Barkhof, F.; et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014, 83, 278–286. [Google Scholar] [CrossRef] [PubMed]
- Fischl, B.; Salat, D.H.; Busa, E.; Albert, M.; Dieterich, M.; Haselgrove, C.; Van Der Kouwe, A.; Killiany, R.; Kennedy, D.; Klaveness, S.; et al. Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron 2002, 33, 341–355. [Google Scholar] [CrossRef]
- Tadayon, E.; Moret, B.; Sprugnoli, G.; Monti, L.; Pascual-Leone, A.; Santarnecchi, E.; Initiative, F.T.A.D.N. Improving Choroid Plexus Segmentation in the Healthy and Diseased Brain: Relevance for Tau-PET Imaging in Dementia. J. Alzheimer’s Dis. 2020, 74, 1057–1068. [Google Scholar] [CrossRef]
- Bouhrara, M.; Walker, K.A.; Alisch, J.S.R.; Gong, Z.; Mazucanti, C.H.; Lewis, A.; Moghekar, A.R.; Turek, L.; Collingham, V.; Shehadeh, N.; et al. Association of Plasma Markers of Alzheimer’s Disease, Neurodegeneration, and Neuroinflammation with the Choroid Plexus Integrity in Aging. Aging Dis. 2024, 15, 2. [Google Scholar] [CrossRef]
- Ricigliano, V.A.G.; Morena, E.; Colombi, A.; Tonietto, M.; Hamzaoui, M.; Poirion, E.; Bottlaender, M.; Gervais, P.; Louapre, C.; Bodini, B.; et al. Choroid Plexus Enlargement in Inflammatory Multiple Sclerosis: 3.0-T MRI and Translocator Protein PET Evaluation. Radiology 2021, 301, 166–177. [Google Scholar] [CrossRef] [PubMed]
- Ricigliano, V.A.; Louapre, C.; Poirion, E.; Colombi, A.; Panah, A.Y.; Lazzarotto, A.; Morena, E.; Martin, E.; Bottlaender, M.; Bodini, B.; et al. Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis a Retrospective Study. Neurol. Neuroimmunol. Neuroinflamm. 2022, 9, e200026. [Google Scholar] [CrossRef] [PubMed]
- Dani, N.; Herbst, R.H.; McCabe, C.; Green, G.S.; Kaiser, K.; Head, J.P.; Cui, J.; Shipley, F.B.; Jang, A.; Dionne, D.; et al. A cellular and spatial map of the choroid plexus across brain ventricles and ages. Cell 2021, 184, 3056–3074.e21. [Google Scholar] [CrossRef] [PubMed]
- Chunder, R.; Schropp, V.; Marzin, M.; Amor, S.; Kuerten, S. A Dual Role of Osteopontin in Modifying B Cell Responses. Biomedicines 2023, 11, 1969. [Google Scholar] [CrossRef] [PubMed]
- Hildesheim, F.E.; Ramasamy, D.P.; Bergsland, N.; Jakimovski, D.; Dwyer, M.G.; Hojnacki, D.; Lizarraga, A.A.; Kolb, C.; Eckert, S.; Weinstock-Guttman, B.; et al. Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis. Mult. Scler. Relat. Disord. 2020, 47, 102653. [Google Scholar] [CrossRef] [PubMed]
- Marastoni, D.; Magliozzi, R.; Bolzan, A.; Pisani, A.I.; Rossi, S.; Crescenzo, F.; Montemezzi, S.; Pizzini, F.B.; Calabrese, M. CSF Levels of CXCL12 and Osteopontin as Early Markers of Primary Progressive Multiple Sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 2021, 8, e1083. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Shinoda, Y.; Ogawa, S.; Ikegaya, S.; Li, S.; Matsuyama, Y.; Sato, K.; Yamagishi, S. Expression of FLRT2 in Postnatal Central Nervous System Development and After Spinal Cord Injury. Front. Mol. Neurosci. 2021, 14, 756264. [Google Scholar] [CrossRef] [PubMed]
- Fleischer, V.; Gonzalez-Escamilla, G.; Ciolac, D.; Albrecht, P.; Küry, P.; Gruchot, J.; Dietrich, M.; Hecker, C.; Müntefering, T.; Bock, S.; et al. Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans. Proc. Natl. Acad. Sci. USA 2021, 118, e2025000118. [Google Scholar] [CrossRef]
- Jakimovski, D.; Kavak, K.S.; Vaughn, C.B.; Goodman, A.D.; Coyle, P.K.; Krupp, L.; Gottesman, M.; Edwards, K.R.; Lenihan, M.; Perel, A.; et al. Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age. Mult. Scler. Relat. Disord. 2021, 57, 103406. [Google Scholar] [CrossRef]
Demographic and Clinical Characteristics | pwMS (n = 202) | pwRRMS (n = 148) | pwPMS (n = 54) | p-Value |
---|---|---|---|---|
Female, n (%) | 151 (74.8) | 106 (71.6) | 45 (83.3) | 0.09 a |
Age at baseline, mean (SD) | 47.1 (11.1) | 44.1 (10.6) | 55.3 (7.9) | <0.001 b |
Time of follow-up, mean (SD) | 5.4 (0.6) | 5.4 (0.6) | 5.5 (0.6) | 0.732 b |
BMI at baseline, mean (SD) | 27.5 (5.8) | 27.9 (6.2) | 26.5 (4.5) | 0.1 b |
Age of disease onset, mean (SD) | 32.9 (9.8) | 32.6 (9.0) | 33.6 (11.8) | 0.6 b |
Disease duration at baseline, mean (SD) | 13.4 (10.2) | 11.1 (8.5) | 21.7 (10.5) | <0.001 b |
EDSS at baseline, median (IQR) | 2.5 (1.5–5.0) | 1.5 (1.5–2.5) | 6.0 (4.0–6.5) | <0.001 c |
EDSS at follow-up, median (IQR) | 3.0 (1.6–6.0) | 2.0 (1.5–3.5) | 6.5 (4.0–6.5) | <0.001 c |
EDSS absolute change, mean (SD) | 0.4 (0.9) | 0.4 (0.9) | 0.4 (0.7) | <0.001 b |
Disability progression, n (%) * | 56 (30.9) | 38 (28.6) | 18 (37.5) | 0.251 a |
Relapse rate over the follow-up, mean (SD) | 0.172 (0.369 | 0.204 (0.4) | 0.09 (0.24) | <0.001 d |
DMT at baseline, n (%) | ||||
IFN-β | 85 (42.1) | 60 (40.5) | 25 (46.3) | 0.271 a |
Glatiramer acetate | 37 (18.3) | 24 (16.2) | 13 (24.1) | |
Natalizumab | 29 (14.4) | 25 (16.9) | 4 (7.4) | |
Off-label DMT | 5 (2.5) | 3 (2.0) | 2 (3.7) | |
No DMT | 46 (22.8) | 36 (24.3) | 10 (18.5) | |
DMT at follow-up, n (%) | ||||
IFN-β | 68 (33.7) | 52 (35.1) | 16 (29.6) | 0.797 a |
Glatiramer acetate | 45 (22.3) | 31 (20.9) | 14 (25.9) | |
Natalizumab | 15 (7.4) | 12 (8.1) | 3 (5.6) | |
Oral DMT | 28 (13.9) | 22 (14.9) | 6 (11.1) | |
Off-label DMT | 12 (5.9) | 8 (5.4) | 4 (7.4) | |
No DMT | 34 (16.8) | 23 (15.5) | 11 (20.4) | |
CP volume at baseline, mean (SD) | 2.59 (0.9) | 2.54 (0.9) | 2.7 (0.88) | 0.862 e |
CP volume at follow-up, mean (SD) | 2.68 (0.8) | 2.6 (0.7) | 2.9 (1.1) | 0.406 e |
CP volume % change, mean (SD) | 9.2 (31.9) | 9.0 (33.5) | 10.0 (27.8) | 0.487 e |
Predictors of CP Volume at Follow-Up | R2 | Standardized B | t-Statistics | p-Value | 95% CI LB | 95% CI UP | Tolerance | VIF |
---|---|---|---|---|---|---|---|---|
Age | 0.095 | −0.066 | −0.751 | 0.454 | −434.5 | 195.8 | 0.987 | 1.013 |
Sex | 0.087 | 0.859 | 0.392 | −8.9 | 22.5 | 0.758 | 1.319 | |
BMI | −0.077 | −0.829 | 0.409 | −36.9 | 15.2 | 0.905 | 1.105 | |
Log10 NfL | 0.146 | 0.373 | 3.324 | 0.001 | 548.4 | 2169.9 | 0.613 | 1.630 |
Log10 OPN | 0.19 | −0.230 | −2.366 | 0.020 | −2250.8 | −198.5 | 0.814 | 1.228 |
Predictors of CP % Volume Change | R2 | Standardized B | t-Statistics | p-Value | 95% CI LB | 95% CI UP | Tolerance | VIF |
Age | 0.008 | −0.111 | −1.286 | 0.201 | −0.853 | 0.181 | 0.899 | 1.112 |
Sex | 0.021 | 0.249 | 0.804 | −10.21 | 13.151 | 0.957 | 1.045 | |
BMI | 0.115 | 1.283 | 0.202 | −0.35 | 1.641 | 0.831 | 1.203 | |
Log10 GFAP | 0.04 | 0.277 | 2.914 | 0.004 | 12.4 | 65.0 | 0.737 | 1.357 |
Log10 FLRT2 | 0.081 | −0.226 | −2.492 | 0.014 | −105.8 | −12.2 | 0.812 | 1.232 |
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Jakimovski, D.; Zivadinov, R.; Qureshi, F.; Ramanathan, M.; Weinstock-Guttman, B.; Tavazzi, E.; Dwyer, M.G.; Bergsland, N. Serum Biomarker Signatures of Choroid Plexus Volume Changes in Multiple Sclerosis. Biomolecules 2024, 14, 824. https://doi.org/10.3390/biom14070824
Jakimovski D, Zivadinov R, Qureshi F, Ramanathan M, Weinstock-Guttman B, Tavazzi E, Dwyer MG, Bergsland N. Serum Biomarker Signatures of Choroid Plexus Volume Changes in Multiple Sclerosis. Biomolecules. 2024; 14(7):824. https://doi.org/10.3390/biom14070824
Chicago/Turabian StyleJakimovski, Dejan, Robert Zivadinov, Ferhan Qureshi, Murali Ramanathan, Bianca Weinstock-Guttman, Eleonora Tavazzi, Michael G. Dwyer, and Niels Bergsland. 2024. "Serum Biomarker Signatures of Choroid Plexus Volume Changes in Multiple Sclerosis" Biomolecules 14, no. 7: 824. https://doi.org/10.3390/biom14070824