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24-04-2023 | Magnetic Resonance Imaging | Original Communication

Unraveling the heterogeneous pathological substrates of relapse-onset multiple sclerosis: a multiparametric voxel-wise 3 T MRI study

Authors: Monica Margoni, Elisabetta Pagani, Paolo Preziosa, Mor Gueye, Matteo Azzimonti, Maria A. Rocca, Massimo Filippi

Published in: Journal of Neurology | Issue 8/2023

Abstract

Background

In multiple sclerosis (MS), pathological processes affecting brain gray (GM) and white matter (WM) are heterogeneous.

Objective

To apply a multimodal MRI approach to investigate the regional distribution of the different pathological processes occurring in the brain WM and GM of relapse-onset MS patients.

Methods

Fifty-seven MS patients (forty-two relapsing remitting [RR], fifteen secondary progressive [SP]) and forty-seven age- and sex-matched healthy controls (HC) underwent a multimodal 3 T MRI acquisition. Between-group voxel-wise differences of brain WM and GM volumes, magnetization transfer ratio (MTR), T₁-weighted(w)/T₂w ratio, intracellular volume fraction (ICV_f), and quantitative susceptibility mapping (QSM) maps were investigated.

Results

Compared to HC, RRMS showed significant WM, deep GM and cortical atrophy, significantly lower MTR and T₁w/T₂w ratio of periventricular and infratentorial WM, deep GM and several cortical areas, lower ICV_f in supratentorial and cerebellar WM and in some cortical areas, and lower QSM values in bilateral periventricular WM (p < 0.001). Compared to RRMS, SPMS patients showed significant deep GM and widespread cortical atrophy, significantly lower MTR of periventricular WM, deep GM and cerebellum, lower T₁w/T₂w ratio of fronto-temporal WM regions, lower ICV_f of some fronto-tempo-occipital WM and cortical areas. They also had increased QSM and T₁w/T₂w ratio in the pallidum, bilaterally (p < 0.001).

Conclusion

A periventricular pattern of demyelination and widespread GM and WM neuro-axonal loss are detectable in RRMS and are more severe in SPMS. Higher T₁w/T₂w ratio and QSM in the pallidum, possibly reflecting iron accumulation and neurodegeneration, may represent a relevant MRI marker to differentiate SPMS from RRMS.

Audoin B, Ranjeva JP, Au Duong MV, Ibarrola D, Malikova I, Confort-Gouny S, Soulier E, Viout P, Ali-Cherif A, Pelletier J, Cozzone PJ (2004) Voxel-based analysis of MTR images: a method to locate gray matter abnormalities in patients at the earliest stage of multiple sclerosis. J Magn Reson Imaging 20:765–771PubMedCrossRef

Bergsland N, Schweser F, Dwyer MG, Weinstock-Guttman B, Benedict RHB, Zivadinov R (2018) Thalamic white matter in multiple sclerosis: a combined diffusion-tensor imaging and quantitative susceptibility mapping study. Hum Brain Mapp 39:4007–4017PubMedPubMedCentralCrossRef

Collorone S, Cawley N, Grussu F, Prados F, Tona F, Calvi A, Kanber B, Schneider T, Kipp L, Zhang H, Alexander DC, Thompson AJ, Toosy A, Wheeler-Kingshott CAG, Ciccarelli O (2020) Reduced neurite density in the brain and cervical spinal cord in relapsing-remitting multiple sclerosis: A NODDI study. Mult Scler 26:1647–1657PubMedCrossRef

Collorone S, Prados F, Kanber B, Cawley NM, Tur C, Grussu F, Solanky BS, Yiannakas M, Davagnanam I, Wheeler-Kingshott C, Barkhof F, Ciccarelli O, Toosy AT (2021) Brain microstructural and metabolic alterations detected in vivo at onset of the first demyelinating event. Brain 144:1409–1421PubMedPubMedCentralCrossRef

Dousset V, Grossman RI, Ramer KN, Schnall MD, Young LH, Gonzalez-Scarano F, Lavi E, Cohen JA (1992) Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging. Radiology 182:483–491PubMedCrossRef

Eshaghi A, Marinescu RV, Young AL, Firth NC, Prados F, Jorge Cardoso M, Tur C, De Angelis F, Cawley N, Brownlee WJ, De Stefano N, Laura Stromillo M, Battaglini M, Ruggieri S, Gasperini C, Filippi M, Rocca MA, Rovira A, Sastre-Garriga J, Geurts JJG, Vrenken H, Wottschel V, Leurs CE, Uitdehaag B, Pirpamer L, Enzinger C, Ourselin S, Gandini Wheeler-Kingshott CA, Chard D, Thompson AJ, Barkhof F, Alexander DC, Ciccarelli O (2018) Progression of regional grey matter atrophy in multiple sclerosis. Brain 141:1665–1677PubMedPubMedCentralCrossRef

Eshaghi A, Prados F, Brownlee WJ, Altmann DR, Tur C, Cardoso MJ, De Angelis F, van de Pavert SH, Cawley N, De Stefano N, Stromillo ML, Battaglini M, Ruggieri S, Gasperini C, Filippi M, Rocca MA, Rovira A, Sastre-Garriga J, Vrenken H, Leurs CE, Killestein J, Pirpamer L, Enzinger C, Ourselin S, Wheeler-Kingshott C, Chard D, Thompson AJ, Alexander DC, Barkhof F, Ciccarelli O, group Ms (2018) Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol 83:210–222PubMedPubMedCentralCrossRef

Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA (2018) Multiple sclerosis. Nat Rev Dis Primers 4:43PubMedCrossRef

Filippi M, Bruck W, Chard D, Fazekas F, Geurts JJG, Enzinger C, Hametner S, Kuhlmann T, Preziosa P, Rovira A, Schmierer K, Stadelmann C, Rocca MA, Attendees of the Correlation between P, workshop MRIfiM (2019) Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol 18:198–210PubMedCrossRef

10.

Filippi M, Preziosa P, Rocca MA (2017) Microstructural MR imaging techniques in multiple sclerosis. Neuroimaging Clin N Am 27:313–333PubMedCrossRef

11.

Filli L, Hofstetter L, Kuster P, Traud S, Mueller-Lenke N, Naegelin Y, Kappos L, Gass A, Sprenger T, Nichols TE, Vrenken H, Barkhof F, Polman C, Radue EW, Borgwardt SJ, Bendfeldt K (2012) Spatiotemporal distribution of white matter lesions in relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 18:1577–1584PubMedCrossRef

12.

Fisher E, Lee JC, Nakamura K, Rudick RA (2008) Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 64:255–265PubMedCrossRef

13.

Gilmore CP, Donaldson I, Bo L, Owens T, Lowe J, Evangelou N (2009) Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord. J Neurol Neurosurg Psychiatry 80:182–187PubMedCrossRef

14.

Granziera C, Wuerfel J, Barkhof F, Calabrese M, De Stefano N, Enzinger C, Evangelou N, Filippi M, Geurts JJG, Reich DS, Rocca MA, Ropele S, Rovira A, Sati P, Toosy AT, Vrenken H, Gandini Wheeler-Kingshott CAM, Kappos L, Group MS (2021) Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis. Brain 144:1296–1311PubMedPubMedCentralCrossRef

15.

Haider L, Simeonidou C, Steinberger G, Hametner S, Grigoriadis N, Deretzi G, Kovacs GG, Kutzelnigg A, Lassmann H, Frischer JM (2014) Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron. J Neurol Neurosurg Psychiatry 85:1386–1395PubMedCrossRef

16.

Hametner S, Wimmer I, Haider L, Pfeifenbring S, Bruck W, Lassmann H (2013) Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 74:848–861PubMedPubMedCentralCrossRef

17.

Jonkman LE, Klaver R, Fleysher L, Inglese M, Geurts JJ (2016) The substrate of increased cortical FA in MS: A 7T post-mortem MRI and histopathology study. Mult Scler 22:1804–1811PubMedCrossRef

18.

Li DK, Held U, Petkau J, Daumer M, Barkhof F, Fazekas F, Frank JA, Kappos L, Miller DH, Simon JH, Wolinsky JS, Filippi M, Centre SL, for MSR, (2006) MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology 66:1384–1389PubMedCrossRef

19.

Margoni M, Gueye M, Meani A, Pagani E, Moiola L, Preziosa P, Filippi M, Rocca MA (2023) Choroid plexus enlargement in paediatric multiple sclerosis: clinical relevance and effect of sex. J Neurol Neurosurg Psychiatr 4:181–188CrossRef

20.

Margoni M, Pagani E, Meani A, Storelli L, Mesaros S, Drulovic J, Barkhof F, Vrenken H, Strijbis E, Gallo A, Bisecco A, Pareto D, Sastre-Garriga J, Ciccarelli O, Yiannakas M, Palace J, Preziosa P, Rocca MA, Filippi M, Group MS (2022) Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study. J Neurol Neurosurg Psychiatr 93:741–752CrossRef

21.

Margoni M, Villani U, Silvestri E, Franciotta S, Anglani MG, Causin F, Rinaldi F, Perini P, Bertoldo A, Gallo P (2022) Quantification of normal-appearing white matter damage in early relapse-onset multiple sclerosis through neurite orientation dispersion and density imaging. Mult Scler Relat Disord 58:103396PubMedCrossRef

22.

Moccia M, van de Pavert S, Eshaghi A, Haider L, Pichat J, Yiannakas M, Ourselin S, Wang Y, Wheeler-Kingshott C, Thompson A, Barkhof F, Ciccarelli O (2020) Pathologic correlates of the magnetization transfer ratio in multiple sclerosis. Neurology 95:e2965–e2976PubMedCrossRef

23.

Pardini M, Brown JWL, Magliozzi R, Reynolds R, Chard DT (2021) Surface-in pathology in multiple sclerosis: a new view on pathogenesis? Brain 144:1646–1654PubMedCrossRef

24.

Parmar K, Stadelmann C, Rocca MA, Langdon D, D’Angelo E, D’Souza M, Burggraaff J, Wegner C, Sastre-Garriga J, Barrantes-Freer A, Dorn J, Uitdehaag BMJ, Montalban X, Wuerfel J, Enzinger C, Rovira A, Tintore M, Filippi M, Kappos L, Sprenger T, group Ms (2018) The role of the cerebellum in multiple sclerosis-150 years after Charcot. Neurosci Biobehav Rev 89:85–98PubMedCrossRef

25.

Popescu V, Klaver R, Voorn P, Galis-de Graaf Y, Knol DL, Twisk JW, Versteeg A, Schenk GJ, Van der Valk P, Barkhof F, De Vries HE, Vrenken H, Geurts JJ (2015) What drives MRI-measured cortical atrophy in multiple sclerosis? Mult Scler 21:1280–1290PubMedCrossRef

26.

Preziosa P, Bouman PM, Kiljan S, Steenwijk MD, Meani A, Pouwels PJ, Rocca MA, Filippi M, Geurts JJG, Jonkman LE (2021) Neurite density explains cortical T1-weighted/T2-weighted ratio in multiple sclerosis. J Neurol Neurosurg Psychiatry 92:790–792PubMedCrossRef

27.

Preziosa P, Kiljan S, Steenwijk MD, Meani A, van de Berg WDJ, Schenk GJ, Rocca MA, Filippi M, Geurts JJG, Jonkman LE (2019) Axonal degeneration as substrate of fractional anisotropy abnormalities in multiple sclerosis cortex. Brain 142:1921–1937PubMedCrossRef

28.

Preziosa P, Pagani E, Bonacchi R, Cacciaguerra L, Falini A, Rocca MA, Filippi M (2022) In vivo detection of damage in multiple sclerosis cortex and cortical lesions using NODDI. J Neurol Neurosurg Psychiatry 93:628–636PubMedCrossRef

29.

Preziosa P, Pagani E, Meani A, Marchesi O, Conti L, Falini A, Rocca MA, Filippi M (2023) NODDI, diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis. J Neurol 270:810–823PubMedCrossRef

30.

Riccitelli G, Rocca MA, Pagani E, Martinelli V, Radaelli M, Falini A, Comi G, Filippi M (2012) Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis. Mult Scler 18:1027–1037PubMedCrossRef

31.

Righart R, Biberacher V, Jonkman LE, Klaver R, Schmidt P, Buck D, Berthele A, Kirschke JS, Zimmer C, Hemmer B, Geurts JJG, Muhlau M (2017) Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging. Ann Neurol 82:519–529PubMedPubMedCentralCrossRef

32.

Rocca MA, Mesaros S, Pagani E, Sormani MP, Comi G, Filippi M (2010) Thalamic damage and long-term progression of disability in multiple sclerosis. Radiology 257:463–469PubMedCrossRef

33.

Rocca MA, Preziosa P, Mesaros S, Pagani E, Dackovic J, Stosic-Opincal T, Drulovic J, Filippi M (2016) Clinically isolated syndrome suggestive of multiple sclerosis: dynamic patterns of gray and white matter changes-A 2-year MR imaging study. Radiology 278:841–853PubMedCrossRef

34.

Rocca MA, Valsasina P, Meani A, Gobbi C, Zecca C, Rovira A, Sastre-Garriga J, Kearney H, Ciccarelli O, Matthews L, Palace J, Gallo A, Bisecco A, Lukas C, Bellenberg B, Barkhof F, Vrenken H, Preziosa P, Filippi M (2021) Association of gray matter atrophy patterns with clinical phenotype and progression in multiple sclerosis. Neurol 96:e1561–e1573CrossRef

35.

Schweser F, Raffaini Duarte Martins AL, Hagemeier J, Lin F, Hanspach J, Weinstock-Guttman B, Hametner S, Bergsland N, Dwyer MG, Zivadinov R (2018) Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: a proposed mechanistic relationship between inflammation and oligodendrocyte vitality. Neuroimage 167:438–452PubMedCrossRef

36.

Spano B, Giulietti G, Pisani V, Morreale M, Tuzzi E, Nocentini U, Francia A, Caltagirone C, Bozzali M, Cercignani M (2018) Disruption of neurite morphology parallels MS progression. Neurol Neuroimmunol Neuroinflamm 5:e502PubMedPubMedCentralCrossRef

37.

Steenwijk MD, Geurts JJ, Daams M, Tijms BM, Wink AM, Balk LJ, Tewarie PK, Uitdehaag BM, Barkhof F, Vrenken H, Pouwels PJ (2016) Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant. Brain 139:115–126PubMedCrossRef

38.

Tonietto M, Poirion E, Lazzarotto A, Ricigliano V, Papeix C, Bottlaender M, Bodini B, Stankoff B (2022) Periventricular remyelination failure in multiple sclerosis: a substrate for neurodegeneration. Brain. https://doi.org/10.1093/brain/awac334CrossRef

39.

Valverde S, Cabezas M, Roura E, Gonzalez-Villa S, Pareto D, Vilanova JC, Ramio-Torrenta L, Rovira A, Oliver A, Llado X (2017) Improving automated multiple sclerosis lesion segmentation with a cascaded 3D convolutional neural network approach. Neuroimage 155:159–168PubMedCrossRef

40.

Vercellino M, Masera S, Lorenzatti M, Condello C, Merola A, Mattioda A, Tribolo A, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P (2009) Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J Neuropathol Exp Neurol 68:489–502PubMedCrossRef

41.

Yu FF, Chiang FL, Stephens N, Huang SY, Bilgic B, Tantiwongkosi B, Romero R (2019) Characterization of normal-appearing white matter in multiple sclerosis using quantitative susceptibility mapping in conjunction with diffusion tensor imaging. Neuroradiology 61:71–79PubMedCrossRef

42.

Zhang H, Schneider T, Wheeler-Kingshott CA, Alexander DC (2012) NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage 61:1000–1016PubMedCrossRef

43.

Zivadinov R, Tavazzi E, Bergsland N, Hagemeier J, Lin F, Dwyer MG, Carl E, Kolb C, Hojnacki D, Ramasamy D, Durfee J, Weinstock-Guttman B, Schweser F (2018) Brain iron at quantitative MRI is associated with disability in multiple sclerosis. Radiology 289:487–496PubMedCrossRef

Title: Unraveling the heterogeneous pathological substrates of relapse-onset multiple sclerosis: a multiparametric voxel-wise 3 T MRI study
Authors: Monica Margoni
Elisabetta Pagani
Paolo Preziosa
Mor Gueye
Matteo Azzimonti
Maria A. Rocca
Massimo Filippi
Publication date: 24-04-2023
Publisher: Springer Berlin Heidelberg
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Multiple Sclerosis
Published in: Journal of Neurology / Issue 8/2023
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-023-11736-9

2024 ASCO Annual Meeting

Springer Medicine

Unraveling the heterogeneous pathological substrates of relapse-onset multiple sclerosis: a multiparametric voxel-wise 3 T MRI study

Abstract

Background

Objective

Methods

Results

Conclusion

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusion

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