Pathogenesis of multiple sclerosis: Insights from molecular and metabolic imaging

The Lancet Neurology

Volumn 13, Issue 8, 2014, Pages 807-822

  Ciccarelli, Olga ^a,b   Barkhof, Frederik ^c   Bodini, Benedetta ^d,e   Stefano, Nicola De ^f   Golay, Xavier ^a   Nicolay, Klaas ^g   Pelletier, Daniel ^h   Pouwels, Petra J W ^c   Smith, Seth A ⁱ   Wheeler Kingshott, Claudia A M ^a   Stankoff, Bruno ^d,e   Yousry, Tarek ^a   Miller, David H ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON HOSPITALS   (United Kingdom)

^c VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^d INSTITUT DU CERVEAU ET DE LA MOELLE ÉPINIÈRE   (France)

^e SERVICE HOSPITALIER FRÉDÉRIC JOLIOT   (France)

^f UNIVERSITY OF SIENA   (Italy)

^g EINDHOVEN UNIVERSITY OF TECHNOLOGY   (Netherlands)

^h YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁱ VANDERBILT UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUTAMIC ACID; IRON;

ACIDOSIS; BLOOD BRAIN BARRIER; CELL INFILTRATION; CELL PROLIFERATION; DEMYELINATION; EXCITOTOXICITY; GRAY MATTER; HUMAN; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; INFLAMMATION; INNATE IMMUNITY; MICROGLIA; MOLECULAR IMAGING; MONOCYTE; MULTIPLE SCLEROSIS; NERVE FIBER DEGENERATION; OUTCOME ASSESSMENT; PRIORITY JOURNAL; REMYELINIZATION; REVIEW; SODIUM CELL LEVEL; WHITE MATTER;

ANIMALS; HUMANS; MAGNETIC RESONANCE IMAGING; MOLECULAR IMAGING; MULTIPLE SCLEROSIS; NERVE FIBERS, MYELINATED;

EID: 84907024513     PISSN: 14744422     EISSN: 14744465     Source Type: Journal    
DOI: 10.1016/S1474-4422(14)70101-2     Document Type: Review

References (144)

1. Compston A, Coles A Multiple sclerosis. Lancet 2008, 372:1502-1517.
2. Tang J, van Panhuys N, Kastenmüller W, Germain RN The future of immunoimaging-deeper, bigger, more precise, and definitively more colorful. Eur J Immunol 2013, 43:1407-1412.
3. Stoll G, Bendszus M New approaches to neuroimaging of central nervous system inflammation. Curr Opin Neurol 2010, 23:282-286.
4. Owen DR, Piccini P, Matthews PM Towards molecular imaging of multiple sclerosis. Mult Scler 2011, 17:262-272.
5. Vinogradov E, Sherry AD, Lenkinski RE CEST: from basic principles to applications, challenges and opportunities. J Magn Reson 2013, 229:155-172.
6. Paling D, Golay X, Wheeler-Kingshott C, Kapoor R, Miller D Energy failure in multiple sclerosis and its investigation using MR techniques. J Neurol 2011, 258:2113-2127.
7. van Horssen J, Witte ME, Ciccarelli O The role of mitochondria in axonal degeneration and tissue repair in MS. Mult Scler 2012, 18:1058-1067.
8. Jacobs AH, Tavitian B Noninvasive molecular imaging of neuroinflammation. J Cereb Blood Flow Metab 2012, 32:1393-1415. the INMiND consortium.
9. Serres S, Mardiguian S, Campbell SJ, et al. VCAM-1-targeted magnetic resonance imaging reveals subclinical disease in a mouse model of multiple sclerosis. FASEB J 2011, 25:4415-4422.
10. Serres S, Anthony DC, Jiang Y, et al. Systemic inflammatory response reactivates immune-mediated lesions in rat brain. J Neurosci 2009, 29:4820-4828.
11. Pirko I, Johnson A, Ciric B, et al. In vivo magnetic resonance imaging of immune cells in the central nervous system with superparamagnetic antibodies. FASEB J 2004, 18:179-182.
12. Anderson SA, Shukaliak-Quandt J, Jordan EK, et al. Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann Neurol 2004, 55:654-659.
13. Engberink RD, van der Pol SM, Walczak P, et al. Magnetic resonance imaging of monocytes labeled with ultrasmall superparamagnetic particles of iron oxide using magnetoelectroporation in an animal model of multiple sclerosis. Mol Imaging 2010, 9:268-277.
14. Tourdias T, Roggerone S, Filippi M, et al. Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging. Radiology 2012, 264:225-233.
15. Debruyne JC, Versijpt J, Van Laere KJ, et al. PET visualization of microglia in multiple sclerosis patients using [11C]PK11195. Eur J Neurol 2003, 10:257-264.
16. Versijpt J, Debruyne JC, Van Laere KJ, et al. Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study. Mult Scler 2005, 11:127-134.
17. Politis M, Giannetti P, Su P, et al. Increased PK11195 PET binding in the cortex of patients with MS correlates with disability. Neurology 2012, 79:523-530.
18. Takano A, Piehl F, Hillert J, et al. In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106. EJNMMI Res 2013, 3:30.
19. Oh U, Fujita M, Ikonomidou VN, et al. Translocator protein PET imaging for glial activation in multiple sclerosis. J Neuroimmune Pharmacol 2011, 6:354-361.
20. Chen JW, Breckwoldt MO, Aikawa E, Chiang G, Weissleder R Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis. Brain 2008, 131:1123-1133.
21. Gray E, Thomas TL, Betmouni S, Scolding N, Love S Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 2008, 18:86-95.
22. Cader S, Johansen-Berg H, Wylezinska M, et al. Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis. Neuroimage 2007, 36:19-27.
23. De Stefano N, Matthews PM, Arnold DL Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 1995, 34:721-727.
24. Ciccarelli O, Altmann DR, McLean MA, et al. Spinal cord repair in MS: does mitochondrial metabolism play a role?. Neurology 2010, 74:721-727.
25. Inglese M, Madelin G, Oesingmann N, et al. Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla. Brain 2010, 133:847-857.
26. Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain 2013, 136:2305-2317.
27. Zaaraoui W, Konstandin S, Audoin B, et al. Distribution of brain sodium accumulation correlates with disability in multiple sclerosis: a cross-sectional 23Na MR imaging study. Radiology 2012, 264:859-867.
28. Dula AN, Asche EM, Landman BA, et al. Development of chemical exchange saturation transfer at 7 T. Magn Reson Med 2011, 66:831-838.
29. Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 2005, 128:1016-1025.
30. Muhlert N, Atzori M, De Vita E, et al. Memory in multiple sclerosis is linked to glutamate concentration in grey matter regions. J Neurol Neurosurg Psychiatry 2014, published online Jan 15. 10.1136/jnnp-2013-306662.
31. Vrenken H, Barkhof F, Uitdehaag BM, Castelijns JA, Polman CH, Pouwels PJ MR spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter. Magn Reson Med 2005, 53:256-266.
32. Geurts JJ, Reuling IE, Vrenken H, et al. MR spectroscopic evidence for thalamic and hippocampal, but not cortical, damage in multiple sclerosis. Magn Reson Med 2006, 55:478-483.
33. Haris M, Nath K, Cai K, et al. Imaging of glutamate neurotransmitter alterations in Alzheimer's disease. NMR Biomed 2013, 26:386-391.
34. Cai K, Haris M, Singh A, et al. Magnetic resonance imaging of glutamate. Nat Med 2012, 18:302-306.
35. Matusiak N, van Waarde A, Bischoff R, et al. Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT. Curr Pharm Des 2013, 19:4647-4672.
36. Frullano L, Zhu J, Wang C, Wu C, Miller RH, Wang Y Myelin imaging compound (MIC) enhanced magnetic resonance imaging of myelination. J Med Chem 2012, 55:94-105.
37. Frullano L, Zhu J, Miller RH, Wang Y Synthesis and characterization of a novel gadolinium-based contrast agent for magnetic resonance imaging of myelination. J Med Chem 2013, 56:1629-1640.
38. Stankoff B, Freeman L, Aigrot MS, et al. Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4'-methylaminophenyl)- 6-hydroxybenzothiazole. Ann Neurol 2011, 69:673-680.
39. Bodini B, Bottin L, Freeman L, et al. Assessment of myelin content by positron emission tomography with [methyl-11C]-2-(4'-methylaminophenyl)- 6-hydroxybenzothiazole in relapsing-remitting MS. Mult Scle 2012, 18(suppl):279-508. (abstr P865).
40. Bodini B, Veronese M, Garcia-Lorenzo D, et al. Positron emission tomography with [11C]-PIB: a clinically relevant tool for voxel-wise myelin quantification in multiple sclerosis. Mult Scler 2013, 19(suppl):74-558. (abstr P451).
41. Pirko I, Ciric B, Gamez J, et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 2004, 18:1577-1579.
42. Caramanos Z, Narayanan S, Arnold DL 1H-MRS quantification of tNA and tCr in patients with multiple sclerosis: a meta-analytic review. Brain 2005, 128:2483-2506.
43. Stromillo ML, Giorgio A, Rossi F, et al. Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. Neurology 2013, 80:2090-2094.
44. Freeman L, Leory C, Galanaud D, et al. Early neuronal damage in patients with MS detected by PET using [11C]-flumazenil. Multiple Sclerosis 2010, 16(suppl):S7-S39. (abstr 117).
45. Freeman L, Garcia-Lorenzo D, Bottin L, et al. Evidence of widespread cortical neuronal damage in patients with multiple sclerosis: a surface-based study using PET with [11C]-flumazenil. Mult Scler 2013, 19(suppl):18-73. (abstr 205).
46. Ciccarelli O, Thomas D, De Vita E, et al. Low myo-inositol indicating astrocytic damage in a case series of NMO. Ann Neurol 2013, 74:301-305.
47. Fernando KT, McLean MA, Chard DT, et al. Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 2004, 127:1361-1369.
48. Haris M, Singh A, Cai K, et al. MICEST: a potential tool for non-invasive detection of molecular changes in Alzheimer's disease. J Neurosci Methods 2013, 212:87-93.
49. Haris M, Cai K, Singh A, Hariharan H, Reddy R In vivo mapping of brain myo-inositol. Neuroimage 2011, 54:2079-2085.
50. Stys PK, Zamponi GW, van Minnen J, Geurts JJ Will the real multiple sclerosis please stand up?. Nat Rev Neurosci 2012, 13:507-514.
51. Takeshita Y, Ransohoff RM Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models. Immunol Rev 2012, 248:228-239.
52. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006, 354:899-910. the AFFIRM Investigators.
53. Pesic M, Bartholomäus I, Kyratsous NI, Heissmeyer V, Wekerle H, Kawakami N 2-photon imaging of phagocyte-mediated T cell activation in the CNS. J Clin Invest 2013, 123:1192-1201.
54. Oude Engberink RD, Blezer EL, Dijkstra CD, van der Pol SM, van der Toorn A, de Vries HE Dynamics and fate of USPIO in the central nervous system in experimental autoimmune encephalomyelitis. NMR Biomed 2010, 23:1087-1096.
55. Weinstein JS, Varallyay CG, Dosa E, et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 2010, 30:15-35.
56. Muldoon LL, Sàndor M, Pinkston KE, Neuwelt EA Imaging, distribution, and toxicity of superparamagnetic iron oxide magnetic resonance nanoparticles in the rat brain and intracerebral tumor. Neurosurgery 2005, 57:785-796.
57. Bendszus M, Ladewig G, Jestaedt L, et al. Gadofluorine M enhancement allows more sensitive detection of inflammatory CNS lesions than T2-w imaging: a quantitative MRI study. Brain 2008, 131:2341-2352.
58. van Kasteren SI, Campbell SJ, Serres S, Anthony DC, Sibson NR, Davis BG Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease. Proc Natl Acad Sci USA 2009, 106:18-23.
59. McAteer MA, Sibson NR, von Zur Muhlen C, et al. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med 2007, 13:1253-1258.
60. Stoll G, Bendszus M Imaging of inflammation in the peripheral and central nervous system by magnetic resonance imaging. Neuroscience 2009, 158:1151-1160.
61. Ladewig G, Jestaedt L, Misselwitz B, et al. Spatial diversity of blood-brain barrier alteration and macrophage invasion in experimental autoimmune encephalomyelitis: a comparative MRI study. Exp Neurol 2009, 220:207-211.
62. Vellinga MM, Oude Engberink RD, Seewann A, et al. Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement. Brain 2008, 131:800-807.
63. Dousset V, Brochet B, Deloire MS, et al. MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol 2006, 27:1000-1005.
64. Varallyay CG, Nesbit E, Fu R, et al. High-resolution steady-state cerebral blood volume maps in patients with central nervous system neoplasms using ferumoxytol, a superparamagnetic iron oxide nanoparticle. J Cereb Blood Flow Metab 2013, 33:780-786.
65. Farrell BT, Hamilton BE, Dósa E, et al. Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL. Neurology 2013, 81:256-263.
66. Krumbholz M, Derfuss T, Hohlfeld R, Meinl E B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 2012, 8:613-623.
67. Howell OW, Reeves CA, Nicholas R, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011, 134:2755-2771.
68. Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007, 130:1089-1104.
69. Magliozzi R, Howell OW, Reeves C, et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010, 68:477-493.
70. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS ONE 2013, 8:e66308.
71. Bahar-Fuchs A, Villemagne V, Ong K, et al. Prediction of amyloid-β pathology in amnestic mild cognitive impairment with neuropsychological tests. J Alzheimers Dis 2013, 33:451-462.
72. Höglund J, Shirvan A, Antoni G, et al. 18F-ML-10, a PET tracer for apoptosis: first human study. J Nucl Med 2011, 52:720-725.
73. Malviya G, Anzola KL, Podestà E, et al. (99m)Tc-labeled rituximab for imaging B lymphocyte infiltration in inflammatory autoimmune disease patients. Mol Imaging Biol 2012, 14:637-646.
74. Perry VH, Nicoll JA, Holmes C Microglia in neurodegenerative disease. Nat Rev Neurol 2010, 6:193-201.
75. Waxman SG Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 2006, 7:932-941.
76. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 2011, 14:1142-1149.
77. van der Veen BS, de Winther MP, Heeringa P Myeloperoxidase: molecular mechanisms of action and their relevance to human health and disease. Antioxid Redox Signal 2009, 11:2899-2937.
78. Forghani R, Wojtkiewicz GR, Zhang Y, et al. Demyelinating diseases: myeloperoxidase as an imaging biomarker and therapeutic target. Radiology 2012, 263:451-460.
79. Venneti S, Lopresti BJ, Wiley CA Molecular imaging of microglia/macrophages in the brain. Glia 2013, 61:10-23.
80. Venneti S, Lopresti BJ, Wiley CA The peripheral benzodiazepine receptor (translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol 2006, 80:308-322.
81. Banati RB, Newcombe J, Gunn RN, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000, 123:2321-2337.
82. Lavisse S, Guillermier M, Hérard AS, et al. Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J Neurosci 2012, 32:10809-10818.
83. Kropholler MA, Boellaard R, Schuitemaker A, et al. Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J Cereb Blood Flow Metab 2005, 25:842-851.
84. Turkheimer FE, Edison P, Pavese N, et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med 2007, 48:158-167.
85. Chauveau F, Boutin H, Van Camp N, Dollé F, Tavitian B Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging 2008, 35:2304-2319.
86. Colasanti A, Guo Q, Muhlert N, et al. In vivo assessment of brain white matter inflammation in multiple sclerosis with 18F-PBR111 PET. J Nucl Med 2014, 55:1-6.
87. Owen DR, Yeo AJ, Gunn RN, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2012, 32:1-5.
88. Owen DR, Gunn RN, Rabiner EA, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 2011, 52:24-32.
89. Pelletier D, Gallezot J, Dlegadillo A, Seneca N, Leppert D, Carson R In vivo [11C]PBR28 PET in multiple sclerosis: a reproducibility study at high resolution. Neurology 2013, 80. (meeting abstracts 1): PD6.010.
90. Turkman N, Shavrin A, Paolillo V, et al. Synthesis and preliminary evaluation of [18F]-labeled 2-oxoquinoline derivatives for PET imaging of cannabinoid CB2 receptor. Nucl Med Biol 2012, 39:593-600.
91. Benito C, Romero JP, Tolón RM, et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci 2007, 27:2396-2402.
92. Rissanen E, Virta JR, Paavilainen T, et al. Adenosine A2A receptors in secondary progressive multiple sclerosis: a [(11)C]TMSX brain PET study. J Cereb Blood Flow Metab 2013, 33:1394-1401.
93. Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009, 132:1175-1189.
94. Lassmann H, van Horssen J, Mahad D Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012, 8:647-656.
95. Trapp BD, Stys PK Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009, 8:280-291.
96. Waxman SG Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nat Clin Pract Neurol 2008, 4:159-169.
97. Friese MA, Craner MJ, Etzensperger R, et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med 2007, 13:1483-1489.
98. Lassmann H Mechanisms of white matter damage in multiple sclerosis. Glia 2014, published online Jan 28. 10.1002/glia.22597.
99. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 2007, 81:89-131.
100. Hattingen E, Magerkurth J, Pilatus U, Hübers A, Wahl M, Ziemann U Combined (1)H and (31)P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis. NMR Biomed 2011, 24:536-546.
101. Ciccarelli O, Toosy AT, De Stefano N, Wheeler-Kingshott CA, Miller DH, Thompson AJ Assessing neuronal metabolism in vivo by modeling imaging measures. J Neurosci 2010, 30:15030-15033.
102. Fisher E, Chang A, Fox RJ, et al. Imaging correlates of axonal swelling in chronic multiple sclerosis brains. Ann Neurol 2007, 62:219-228.
103. Moll NM, Rietsch AM, Thomas S, et al. Multiple sclerosis normal-appearing white matter: pathology-imaging correlations. Ann Neurol 2011, 70:764-773.
104. Périer O, Grégoire A Electron microscopic features of multiple sclerosis lesions. Brain 1965, 88:937-952.
105. Ward KM, Aletras AH, Balaban RS A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson 2000, 143:79-87.
106. Wemmie JA, Taugher RJ, Kreple CJ Acid-sensing ion channels in pain and disease. Nat Rev Neurosci 2013, 14:461-471.
107. Arun T, Tomassini V, Sbardella E, et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 2013, 136:106-115.
108. Ropele S, de Graaf W, Khalil M, et al. MRI assessment of iron deposition in multiple sclerosis. J Magn Reson Imaging 2011, 34:13-21.
109. Khalil M, Langkammer C, Ropele S, et al. Determinants of brain iron in multiple sclerosis: a quantitative 3T MRI study. Neurology 2011, 77:1691-1697.
110. Bagnato F, Hametner S, Yao B, et al. Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla. Brain 2011, 134:3602-3615.
111. Hammond KE, Metcalf M, Carvajal L, et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 Tesla with sensitivity to iron. Ann Neurol 2008, 64:707-713.
112. Werner P, Pitt D, Raine CS Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol 2001, 50:169-180.
113. Ransohoff RM, Perry VH Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 2009, 27:119-145.
114. Bakiri Y, Burzomato V, Frugier G, Hamilton NB, Káradóttir R, Attwell D Glutamatergic signaling in the brain's white matter. Neuroscience 2009, 158:266-274.
115. Pitt D, Werner P, Raine CS Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000, 6:67-70.
116. Patel AJ, Hunt A, Gordon RD, Balázs R The activities in different neural cell types of certain enzymes associated with the metabolic compartmentation glutamate. Brain Res 1982, 256:3-11.
117. Petroff OA, Spencer DD, Alger JR, Prichard JW High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy. Neurology 1989, 39:1197-1202.
118. Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006, 67:960-967.
119. Kaiser LG, Schuff N, Cashdollar N, Weiner MW Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging 2005, 26:665-672.
120. Dutta R, Chang A, Doud MK, et al. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 2011, 69:445-454.
121. Shiryaev SA, Savinov AY, Cieplak P, et al. Matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in autoimmune multiple sclerosis. PLoS One 2009, 4:e4952.
122. Cauwe B, Van den Steen PE, Opdenakker G The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 2007, 42:113-185.
123. Stankoff B, Wang Y, Bottlaender M, et al. Imaging of CNS myelin by positron-emission tomography. Proc Natl Acad Sci USA 2006, 103:9304-9309.
124. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005, 128:2705-2712.
125. Irvine KA, Blakemore WF Remyelination protects axons from demyelination-associated axon degeneration. Brain 2008, 131:1464-1477.
126. Franklin RJ, Ffrench-Constant C Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 2008, 9:839-855.
127. Wu C, Zhu J, Baeslack J, et al. Longitudinal PET imaging for monitoring myelin repair in the spinal cord. Ann Neurol 2013, 74:688-698.
128. de Paula Faria D, de Vries EF, Sijbesma JW, Dierckx RA, Buchpiguel CA, Copray S PET imaging of demyelination and remyelination in the cuprizone mouse model for multiple sclerosis: a comparison between [11C]CIC and [11C]MeDAS. Neuroimage 2014, 87:395-402.
129. Campbell GR, Ziabreva I, Reeve AK, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 2011, 69:481-492.
130. Abdel-Aziz K, Solanky B, Wheeler-Kingshott C, et al. Evidence for early neuronal damage in the cervical cord of patients with primary progressive multiple sclerosis. Multiple Sclerosis J 2013, 19(suppl):18-73. (abstr 197).
131. Delforge J, Spelle L, Bendriem B, et al. Quantitation of benzodiazepine receptors in human brain using the partial saturation method. J Nucl Med 1996, 37:5-11.
132. Mullins PG, McGonigle DJ, O'Gorman RL, et al. Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage 2014, 86:43-52. the Cardiff Symposium on MRS of GABA.
133. Magistretti PJ, Pellerin L Cellular mechanisms of brain energy metabolism. Relevance to functional brain imaging and to neurodegenerative disorders. Ann N Y Acad Sci 1996, 777:380-387.
134. Roelcke U, Kappos L, Lechner-Scott J, et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology 1997, 48:1566-1571.
135. Blinkenberg M, Rune K, Jensen CV, et al. Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology 2000, 54:558-564.
136. Radu CG, Shu CJ, Shelly SM, Phelps ME, Witte ON Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2007, 104:1937-1942.
137. Buck D, Förschler A, Lapa C, et al. 18F-FDG PET detects inflammatory infiltrates in spinal cord experimental autoimmune encephalomyelitis lesions. J Nucl Med 2012, 53:1269-1276.
138. Caprariello AV, Mangla S, Miller RH, Selkirk SM Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination. Ann Neurol 2012, 72:395-405.
139. Cambron M, D'Haeseleer M, Laureys G, Clinckers R, Debruyne J, De Keyser J White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis. J Cereb Blood Flow Metab 2012, 32:413-424.
140. Bannerman P, Hahn A, Soulika A, Gallo V, Pleasure D Astrogliosis in EAE spinal cord: derivation from radial glia, and relationships to oligodendroglia. Glia 2007, 55:57-64.
141. Barnett SC, Linington C Myelination: do astrocytes play a role?. Neuroscientist 2013, 19:442-450.
142. Brand A, Richter-Landsberg C, Leibfritz D Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993, 15:289-298.
143. Kirov II, Tal A, Babb JS, Herbert J, Gonen O Serial proton MR spectroscopy of gray and white matter in relapsing-remitting MS. Neurology 2013, 80:39-46.
144. Llufriu S, Kornak J, Ratiney H, et al. Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis. JAMA Neurol 2014, published online May 19. 10.1001/jamaneurol.2014.895.