Precision Medicine in Multiple Sclerosis: Future of PET Imaging of Inflammation and Reactive Astrocytes.
Non-invasive molecular imaging techniques can enhance diagnosis to achieve successful treatment, as well as reveal underlying pathogenic mechanisms in disorders such as multiple sclerosis (MS). The cooperation of advanced multimodal imaging techniques and increased knowledge of the MS disease mechanism allows both monitoring of neuronal network and therapeutic outcome as well as the tools to discover novel therapeutic targets. Diverse imaging modalities provide reliable diagnostic and prognostic platforms to better achieve precision medicine. Traditionally, magnetic resonance imaging (MRI) has been considered the golden standard in MS research and diagnosis. However, positron emission tomography (PET) imaging can provide functional information of molecular biology in detail even prior to anatomic changes, allowing close follow up of disease progression and treatment response. The recent findings support three major neuroinflammation components in MS: astrogliosis, cytokine elevation, and significant changes in specific proteins, which offer a great variety of specific targets for imaging purposes. Regardless of the fact that imaging of astrocyte function is still a young field and in need for development of suitable imaging ligands, recent studies have shown that inflammation and astrocyte activation are related to progression of MS. MS is a complex disease, which requires understanding of disease mechanisms for successful treatment. PET is a precise non-invasive imaging method for biochemical functions and has potential to enhance early and accurate diagnosis for precision therapy of MS. In this review we focus on modulation of different receptor systems and inflammatory aspect of MS, especially on activation of glial cells, and summarize the recent findings of PET imaging in MS and present the most potent targets for new biomarkers with the main focus on experimental MS research.
Athinoula A Martinos Biomedical Imaging Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School Charlestown, MA, USA.
Pekka
P
Poutiainen
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School Boston, MA, USA.
Merja
M
Jaronen
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School Boston, MA, USA.
Francisco J
FJ
Quintana
Athinoula A Martinos Biomedical Imaging Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School Charlestown, MA, USA.
Anna-Liisa
AL
Brownell
astrocyte; inflammation; microglia; multiple sclerosis; neuroreceptors; positron emission tomography; precision medicine
Neurobiol Aging. 2013 Nov;34(11):2694.e13-8
23820589
Acta Neuropathol. 2010 Jan;119(1):7-35
20012068
Eur J Nucl Med Mol Imaging. 2014 May;41(5):995-1003
24499866
Trends Pharmacol Sci. 2010 Sep;31(9):411-7
20599282
J Nucl Med. 2004 Sep;45(9):1480-7
15347714
J Neurosci. 2009 Jun 24;29(25):8063-74
19553446
Psychopharmacology (Berl). 1992;108(1-2):16-22
1329130
PLoS One. 2013;8(2):e56375
23441184
Mult Scler. 2011 Aug;17(8):931-8
21372113
Nat Rev Neurol. 2015 Mar;11(3):134-42
25686758
Nat Rev Cancer. 2002 Sep;2(9):683-93
12209157
J Neurosci. 2011 Sep 14;31(37):13028-38
21917786
Eur J Nucl Med Mol Imaging. 2015 Mar;42(3):503-11
25351507
Angew Chem Int Ed Engl. 2008;47(47):8998-9033
18988199
Nat Rev Drug Discov. 2010 Dec;9(12):971-88
21119734
J Nucl Med. 2003 Oct;44(10):1700-6
14530489
Genes Dev. 2003 Mar 1;17(5):545-80
12629038
Biochem Biophys Res Commun. 2010 Jan 1;391(1):91-5
19896463
Brain. 2011 Jul;134(Pt 7):1914-24
21653539
Ann Nucl Med. 1999 Oct;13(5):309-15
10582800
J Nucl Med. 2011 Jul;52(7):1102-9
21680683
Brain. 2000 Nov;123 ( Pt 11):2321-37
11050032
Brain Res. 2013 Oct 2;1533:152-62
23973859
Immunol Rev. 2012 Jul;248(1):170-87
22725961
J Neurosci. 2007 Feb 28;27(9):2396-402
17329437
J Nucl Med. 2009 Jun;50(6):982-90
19443600
Curr Opin Neurol. 2015 Jun;28(3):220-9
25923124
Mult Scler. 2012 Nov;18(11):1633-5
22419673
Glia. 2006 Jan 15;53(2):212-24
16206168
Pathophysiology. 2011 Feb;18(1):21-9
20537877
EJNMMI Res. 2013 Apr 24;3(1):30
23618062
Front Cell Neurosci. 2013 Apr 19;7:49
23626522
J Nucl Med. 2006 Apr;47(4):698-705
16595505
Nucl Med Biol. 2008 Jan;35(1):35-42
18158941
Biochim Biophys Acta. 2011 May;1813(5):878-88
21296109
Clin Neurosci Res. 2006 Dec;6(5):237-245
19169437
Adv Neurol. 2006;98:125-46
16400831
Ann Neurol. 2011 Apr;69(4):673-80
21337603
Science. 2013 Jan 11;339(6116):156-61
23307732
J Med Chem. 2007 Nov 15;50(23):5752-64
17956082
Nat Neurosci. 2007 Nov;10(11):1387-94
17965659
Brain. 2003 Aug;126(Pt 8):1755-66
12805104
Glia. 2007 Nov 1;55(14):1459-68
17680643
J Nucl Med. 2007 Apr;48(4):573-81
17401094
Org Med Chem Lett. 2013 Sep 24;3(1):11
24063584
Nat Rev Immunol. 2009 Jun;9(6):393-407
19444307
Nature. 2012 Apr 12;484(7393):S1
22509502
Bioorg Med Chem. 2010 Jul 15;18(14):5202-7
20554448
Mult Scler. 1997 Feb;3(1):8-17
9160342
Atherosclerosis. 2014 Mar;233(1):55-63
24529123
Expert Rev Clin Pharmacol. 2012 Jul;5(4):413-25
22943121
Immunity. 2009 Nov 20;31(5):722-35
19836264
Trends Immunol. 2007 Mar;28(3):138-45
17276138
J Neuroinflammation. 2010 Jun 09;7:33
20534165
BMC Neurol. 2006 Mar 02;6:12
16512913
J Neurocytol. 1997 Feb;26(2):77-82
9181482
Ann Neurol. 2013 Nov;74(5):688-98
23818306
Curr Top Microbiol Immunol. 2008;318:193-212
18219819
Front Cell Neurosci. 2014 May 22;8:138
24904283
Cell. 2010 Mar 19;140(6):918-34
20303880
J Cereb Blood Flow Metab. 2015 May;35(5):766-72
25649991
Handb Clin Neurol. 2014;122:59-87
24507513
J Neurol. 2005 Sep;252 Suppl 3:iii10-iii14
16170494
J Neurochem. 2004 Jun;89(5):1206-14
15147513
Bioorg Med Chem. 2010 Dec 15;18(24):8592-9
21071233
Exp Neurol. 2014 Dec;262 Pt A:8-17
24530639
F1000Prime Rep. 2014 Mar 03;6:13
24669294
Presse Med. 2015 Apr;44(4 Pt 2):e159-67
25818312
J Neuroimmunol. 2009 May 29;210(1-2):3-12
19269040
J Cereb Blood Flow Metab. 2012 Jul;32(7):1426-54
22434067
Parkinsonism Relat Disord. 2009 Aug;15(7):500-5
19167259
Curr Top Med Chem. 2010;10(15):1558-68
20583985
Brain. 2008 Jul;131(Pt 7):1749-58
18515322
Nat Rev Neurol. 2009 May;5(5):256-66
19488083
J Neuroimaging. 1998 Oct;8(4):228-34
9780855
Phys Med Biol. 2012 Jun 21;57(12):3931-43
22643300
J Exp Med. 2014 Jul 28;211(8):1533-49
25002752
Eur J Nucl Med Mol Imaging. 2011 Dec;38(12):2198-201
21997721
Bioconjug Chem. 2014 Feb 19;25(2):442-50
24400917
Glia. 2011 Jan;59(1):166-76
21046558
Handb Clin Neurol. 2014;122:101-13
24507515
Neurology. 1996 Apr;46(4):907-11
8780061
Glia. 2014 Jul;62(7):1125-41
24692237
Lancet. 2008 Oct 25;372(9648):1502-17
18970977
Synapse. 2015 Jan;69(1):60-5
25196273
J Neuropathol Exp Neurol. 2008 Oct;67(10):1001-10
18800007
Nat Genet. 2007 Aug;39(8):969-76
17643102
NeuroRehabilitation. 2014;35(4):813-23
25323085
Neuroimage. 2014 Feb 15;87:395-402
24188813
N Engl J Med. 2006 Mar 2;354(9):942-55
16510748
J Neurosci. 2001 Sep 1;21(17):6480-91
11517237
Pharmacoeconomics. 2014 Jun;32(6):559-72
24643323
Am J Pathol. 2001 Jun;158(6):2057-66
11395383
Clin Dev Immunol. 2013;2013:708659
24174971
J Nucl Med. 2015 Jan;56(1):76-81
25525182
Brain. 2015 May;138(Pt 5):1138-59
25823474
J Neurosci. 2009 Nov 18;29(46):14663-9
19923299
Br J Pharmacol. 2010 Jun;160(3):467-79
20590558
Neurol Neuroimmunol Neuroinflamm. 2014 Aug 21;1(2):e26
25340076
Nat Med. 2014 Oct;20(10):1092-3
25295934
Neurologist. 2011 Jul;17(4):185-204
21712664
J Nucl Med. 2013 May;54(5):815-24
23492887
Ann Neurol. 2006 Jul;60(1):56-64
16685699
J Histochem Cytochem. 2006 Sep;54(9):997-1004
16709728
Nature. 2008 Jul 24;454(7203):428-35
18650913
Nat Neurosci. 2009 Jul;12(7):872-8
19525944
Adv Neurol. 2006;98:27-45
16400825
Nat Rev Immunol. 2003 Jan;3(1):23-35
12511873
Bioorg Med Chem Lett. 2012 Feb 1;22(3):1308-13
22244939
Nat Clin Pract Neurol. 2006 Dec;2(12):679-89
17117171
Neuroscientist. 2011 Dec;17(6):659-76
22130640
Mult Scler. 2005 Apr;11(2):127-34
15794383
Pharmacol Rev. 2006 Sep;58(3):389-462
16968947
J Nucl Med. 2013 Mar;54(3):388-96
23404089
J Cereb Blood Flow Metab. 2015 Jan;35(1):157-65
25370856
Radiology. 2011 Jun;259(3):659-81
21602503
J Neurol Neurosurg Psychiatry. 2003 Jan;74(1):113-5
12486280
Neuroimage. 1996 Oct;4(2):87-96
9345500
Lancet Neurol. 2012 Apr;11(4):349-60
22441196
J Neuroimmune Pharmacol. 2014 Sep;9(4):468-82
24809810
Annu Rev Immunol. 2009;27:451-83
19105661
Acta Neuropathol Commun. 2014 Jun 16;2:65
24934666
Phys Med Biol. 2007 Jul 7;52(13):3881-94
17664583
Biol Psychiatry. 2015 Feb 1;77(3):266-275
25156701
Neurology. 2012 Aug 7;79(6):523-30
22764258
Trends Immunol. 2004 Dec;25(12):677-86
15530839
Expert Opin Ther Targets. 2008 Feb;12(2):185-95
18208367
Eur J Nucl Med Mol Imaging. 2010 May;37(5):962-72
20069292
AJNR Am J Neuroradiol. 2010 Jun;31(6):983-9
20019103
Handb Clin Neurol. 2014;122:563-77
24507535
J Cereb Blood Flow Metab. 2012 Jul;32(7):1393-415
22549622
Nat Rev Neurosci. 2006 Jan;7(1):41-53
16371949
Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2203-11
18536913
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9304-9
16754874
Ther Adv Neurol Disord. 2013 Jul;6(4):249-68
23858328
Nat Neurosci. 2012 Jul 26;15(8):1074-7
22837037
FEBS Lett. 2011 Dec 1;585(23):3770-80
21550344
Brain. 2009 May;132(Pt 5):1175-89
19339255
Appl Radiat Isot. 2013 Aug;78:102-7
23688715
Nat Commun. 2014 Nov 19;5:5452
25406832
J Nucl Med. 2014 Jun;55(6):939-44
24711650
Trends Pharmacol Sci. 1997 Nov;18(11):425-9
9426470
Antioxid Redox Signal. 2006 May-Jun;8(5-6):929-47
16771683
J Neurosci. 2012 Aug 8;32(32):10809-18
22875916
J Neuroinflammation. 2014 Jun 03;11:98
24889886
J Nucl Med. 2010 Jan;51(1):1-4
20008995
J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1396-404
24769473
Nat Med. 2014 Oct;20(10):1147-56
25216636
Glia. 2004 Dec;48(4):267-77
15390110
Cochrane Database Syst Rev. 2014 Jul 23;(7):CD010386
25052054
Neurology. 2005 May 24;64(10):1823; author reply 1823
15911833
J Neuropathol Exp Neurol. 2010 Dec;69(12):1256-69
21107138
Neurochem Res. 1982 Jun;7(6):727-35
7121719
Ann Neurol. 1992 Mar;31(3):333-6
1637140
Int J Cell Biol. 2010;2010:214074
20182529
Acta Neurol Scand Suppl. 2008;188:72-6
18439226
Nucl Med Biol. 2005 Aug;32(6):631-40
16026710
Glia. 2013 Apr;61(4):453-65
23322421
Neurosci Lett. 2007 Jan 16;411(3):200-5
17127001
Insights Imaging. 2012 Feb;3(1):111-9
22696004
Nat Rev Neurosci. 2015 May;16(5):249-63
25891508
J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):872-7
12810770
J Neurosci. 2013 Feb 6;33(6):2718-27
23392698
Acta Neuropathol. 2009 Dec;118(6):723-36
19763593
Nat Rev Neurosci. 2010 Apr;11(4):275-83
20216548
Bioorg Med Chem. 2011 Aug 1;19(15):4499-505
21737287
Drug Metab Dispos. 2013 Jan;41(1):122-31
23065531
J Nucl Med. 2014 Mar;55(3):466-72
24516258
Future Lipidol. 2007 Aug;2(4):403-422
18176634
PLoS One. 2013;8(2):e55859
23409068
Eur J Med Chem. 2015 Mar 6;92:554-64
25599952
Neuroimage. 2008 Aug 1;42(1):248-51
18501638
Nat Rev Drug Discov. 2008 Jul;7(7):575-90
18591979
Nat Rev Neurol. 2009 Apr;5(4):182-3
19347020
Chem Pharm Bull (Tokyo). 2009 Oct;57(10):1029-39
19801854
Purinergic Signal. 2007 Mar;3(1-2):117-27
18404425
J Neuroinflammation. 2005 Dec 12;2:29
16343349
J Neurol. 2008 Mar;255 Suppl 1:3-11
18317671
Eur J Neurol. 2011 Feb;18(2):226-231
20636368
Glia. 2014 Jan;62(1):122-32
24272707
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3070-5
15710875
J Neuroimmunol. 2010 Apr 15;221(1-2):7-14
19931190
Appl Immunohistochem Mol Morphol. 2011 May;19(3):246-52
21494180
Synapse. 2004 Jun 15;52(4):283-91
15103694
Curr Opin Rheumatol. 2012 Jul;24(4):424-8
22617821
Bioorg Med Chem. 2011 Sep 15;19(18):5698-707
21872477
Cell Death Differ. 2015 Feb;22(2):215-24
25168240
Trends Endocrinol Metab. 2015 Jul;26(7):341-8
25801473
Appl Radiat Isot. 2009 Apr;67(4):606-10
19167232
Nat Rev Immunol. 2007 Nov;7(11):904-12
17917672
Cell Mol Life Sci. 2008 Sep;65(17):2702-20
18516496
Neurochem Int. 2013 Jul;63(1):47-53
23619393
J Neurochem. 2013 Sep;126(5):616-24
23795580
N Engl J Med. 2002 Jan 17;346(3):165-73
11796850
Neurochem Int. 2015 Mar;82:33-41
25684072
J Neurol Sci. 2007 Apr 15;255(1-2):17-22
17346749
Open J Med Psychol. 2014 Apr;3(3):202-211
25419490
Neurochem Int. 2011 Jan;58(1):60-8
21075154
Eur J Nucl Med Mol Imaging. 2015 Jun;42(7):1081-92
25833352
Appl Radiat Isot. 2014 Dec;94:349-354
25305528
Nat Rev Drug Discov. 2008 Nov;7(11):909-25
18974749
Lancet Neurol. 2005 Mar;4(3):195-202
15721830
Ann Neurol. 2000 Jun;47(6):707-17
10852536
Mult Scler. 2014 Mar;20(3):304-12
23886826
Nucl Med Biol. 2012 Apr;39(3):389-99
22154685
J Nucl Med. 2009 Aug;50(8):1276-82
19617321
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1937-42
17261805
Clin Nucl Med. 2014 Aug;39(8):750-1
24686217
J Clin Invest. 2001 Jul;108(2):311-8
11457884
Cold Spring Harb Perspect Biol. 2012 Oct 01;4(10):
23028121
J Neurosci. 2006 Feb 8;26(6):1880-7
16467537
J Inflamm (Lond). 2007 Mar 16;4:5
17367517
Bioorg Med Chem Lett. 2015 May 1;25(9):1965-70
25819093
J Biol Chem. 2009 Jun 5;284(23):15629-39
19364772
J Neurosci. 2009 Sep 16;29(37):11511-22
19759299
Handb Clin Neurol. 2014;122:231-66
24507521
Acta Neurol Scand. 2011 Sep;124(3):151-64
21070192
J Neuroimmunol. 2004 Apr;149(1-2):40-9
15020063
Eur J Neurol. 2003 May;10(3):257-64
12752399
Lancet Neurol. 2015 Apr;14(4):406-19
25792099
J Neurol Sci. 2008 Jan 15;264(1-2):9-17
17727889
J Cereb Blood Flow Metab. 2013 Sep;33(9):1394-401
23695433
Am J Pathol. 1999 Sep;155(3):995-1004
10487857
Cancer Imaging. 2006 Oct 31;6:S102-6
17114061
Annu Rev Neurosci. 2008;31:247-69
18558855
J Labelled Comp Radiopharm. 2014 Jun 30;57(8):509-16
24995673
J Immunol. 2000 Jun 15;164(12):6166-73
10843666
Br J Pharmacol. 2008 Jan;153(2):240-51
18037916
J Neuroinflammation. 2012 Dec 23;9:275
23259598
J Neurovirol. 2014 Jun;20(3):219-32
24567030
Glia. 2009 Apr 1;57(5):550-60
18816644
Acta Neuropathol. 2011 Sep;122(3):313-22
21691765
J Pharmacol Exp Ther. 2008 May;325(2):349-56
18203948
PLoS One. 2008 Feb 20;3(2):e1616
18286173
Handb Clin Neurol. 2014;122:15-58
24507512
J Leukoc Biol. 2009 Mar;85(3):352-70
19028958
J Nucl Med. 2013 Feb;54(2):291-8
23321458
Eur J Radiol. 2014 Jan;83(1):84-94
23791129
Synapse. 2007 Dec;61(12):951-61
17787003
Discov Med. 2013 Aug;16(86):53-63
23911232
Brain. 2012 Sep;135(Pt 9):2817-25
22961552
Brain. 2008 Nov;131(Pt 11):3092-102
18772223
J Nucl Med. 2008 May;49(5):814-22
18413395
PLoS One. 2014 Nov 04;9(11):e111598
25369426
Curr Opin Neurobiol. 2009 Oct;19(5):498-504
19765974
J Nucl Med. 2015 Feb;56(2):305-10
25572093
J Neuroimmunol. 2008 Feb;194(1-2):62-9
18164423
Br J Pharmacol. 2011 Oct;164(4):1079-106
21371012
J Nucl Med. 2012 Aug;53(8):1269-76
22738927
Brain. 2002 Oct;125(Pt 10):2202-12
12244078
Brain. 2015 Jan;138(Pt 1):110-9
25416179
Curr Opin Immunol. 2003 Aug;15(4):378-84
12900267
Eur J Nucl Med Mol Imaging. 2007 Nov;34(11):1832-42
17541586
J Nucl Med. 2014 Jul;55(7):1112-8
24904112
Glia. 1999 Feb 1;25(3):216-28
9932868
Br J Clin Pharmacol. 2012 Feb;73(2):175-86
21838787
Neurology. 2013 Mar 5;80(10):952-6
23460618
Epilepsia. 2012 Nov;53 Suppl 6:14-21
23134491
Front Pharmacol. 2012 Apr 30;3:74
22557971
Anal Chem. 2012 Oct 16;84(20):8549-56
22954250
Lancet Neurol. 2009 Mar;8(3):280-91
19233038
Neurology. 2011 Jul 26;77(4):355-63
21775734
Int J Appl Radiat Isot. 1985 Dec;36(12):971-6
3002988
J Neurosci. 2008 Nov 19;28(47):12255-67
19020019
J Neurosci. 2006 Apr 12;26(15):3887-8
16611803
Mult Scler. 2014 Sep;20(10):1288-95
24812046
J Biol Chem. 2005 Apr 8;280(14):13742-51
15668227
J Neurosci. 2003 Apr 1;23(7):2627-33
12684448
Clin Pharmacol Ther. 2012 Apr;91(4):621-34
22398971
Neurobiol Dis. 2005 Nov;20(2):550-61
15916899
Eur J Nucl Med Mol Imaging. 2011 Mar;38(3):509-14
20936410
Nat Med. 2013 Oct;19(10):1345-50
24013701
Mol Neurobiol. 2010 Jun;41(2-3):242-7
20195798
Neurology. 2015 May 26;84(21):2185-92
25911108
Semin Nucl Med. 1994 Oct;24(4):324-49
7817203
Front Neurosci. 2014 Oct 07;8:315
25339862
Neuropathol Appl Neurobiol. 2013 Feb;39(1):3-18
23252647
Curr Neuropharmacol. 2010 Sep;8(3):305-15
21358979
Front Cell Neurosci. 2015 Mar 17;9:91
25852482
Neurosci Bull. 2013 Apr;29(2):144-54
23558587
Clin Exp Immunol. 1998 Aug;113(2):147-56
9717962
Neurology. 2004 Nov 9;63(9):1579-85
15534239
Brain Behav Immun. 2015 Aug;48:313-25
25937052
Bioorg Med Chem. 2011 May 1;19(9):2997-3004
21482120
AJNR Am J Neuroradiol. 2006 Jun-Jul;27(6):1165-76
16775258
J Nucl Med. 2012 Jun;53(6):994-1001
22582045
PLoS One. 2013;8(2):e54722
23431360
Nucl Med Biol. 2009 May;36(4):455-65
19423014
J Neurosci. 2009 Mar 25;29(12):3781-91
19321774
Nucl Med Biol. 2014 Nov-Dec;41(10):871-5
25156039
Brain Sci. 2013 Jul 22;3(3):1109-27
24961523
Glia. 2011 Mar;59(3):452-62
21264951
Nat Rev Neurol. 2014 Apr;10(4):225-38
24638138
Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2304-19
18828015
Radiology. 2013 Apr;267(1):26-44
23525716
FEBS Lett. 2011 Dec 1;585(23):3781-8
21443873
Am J Nucl Med Mol Imaging. 2012;2(1):33-47
23133801
J Nucl Med. 2009 Mar;50(3):468-76
19223401
Nat Rev Drug Discov. 2008 Sep;7(9):759-70
18758473
J Neuroimmune Pharmacol. 2011 Sep;6(3):354-61
20872081
Eur J Pharm Sci. 2015 Jan 25;67:85-96
25447744
Biol Psychiatry. 2001 Feb 1;49(3):211-20
11230872
J Neurosci. 2012 Apr 25;32(17):5728-36
22539835
Brain Pathol. 2014 Nov;24(6):631-53
25345894
J Nucl Med. 2007 Mar;48(3):420-8
17332620
Nat Rev Neurol. 2012 Jan 17;8(2):61
22249838