title: Biomarkers and surrogate outcomes in neurodegenerative disease: lessons from multiple sclerosis.
abstract: Multiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.
authors.affiliation: Multiple Sclerosis NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, London WC1N 3BG, United Kingdom. d.miller@ion.ucl.ac.uk
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
mesh_terms: D015415:Biomarkers; D006801:Humans; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis / Q000473:pathology* / Q000628:therapy*; D009410:Nerve Degeneration / Q000473:pathology / Q000628:therapy
chemical_list: D015415:Biomarkers
references.citation: Brain. 1997 Jul;120 ( Pt 7):1149-61
references.pmid: 9236628
references.citation: Brain. 1991 Dec;114 ( Pt 6):2437-50
references.pmid: 1782525
references.citation: Brain. 2003 Apr;126(Pt 4):770-82
references.pmid: 12615637
references.citation: Neurology. 2001 Oct 9;57(7):1253-8
references.pmid: 11591845
references.citation: Neurology. 2003 Apr 8;60(7):1157-62
references.pmid: 12682324
references.citation: Ann Neurol. 2001 Sep;50(3):389-400
references.pmid: 11558796
references.citation: Brain. 1998 Feb;121 ( Pt 2):225-31
references.pmid: 9549501
references.citation: J Magn Reson Imaging. 2002 Mar;15(3):259-67
references.pmid: 11891970
references.citation: Mult Scler. 2003 Dec;9(6):566-73
references.pmid: 14664468
references.citation: Neurology. 1999 Nov 10;53(8):1698-704
references.pmid: 10563615
references.citation: Neurology. 1992 Jan;42(1):60-3
references.pmid: 1734325
references.citation: Brain. 2000 Nov;123 ( Pt 11):2321-37
references.pmid: 11050032
references.citation: J Neurol. 1999 Nov;246(11):1023-6
references.pmid: 10631633
references.citation: Neurology. 2001 Dec 26;57(12):2185-90
references.pmid: 11756595
references.citation: J Neurol Neurosurg Psychiatry. 1995 Sep;59(3):306-8
references.pmid: 7673962
references.citation: IEEE Trans Med Imaging. 1997 Oct;16(5):598-609
references.pmid: 9368115
references.citation: J Neurol. 2003 Dec;250(12):1407-19
references.pmid: 14673572
references.citation: Neuroimage. 2000 Jun;11(6 Pt 1):805-21
references.pmid: 10860804
references.citation: Brain. 1997 Jan;120 ( Pt 1):1-13
references.pmid: 9055793
references.citation: Neuroradiology. 2001 Feb;43(2):123-8
references.pmid: 11326556
references.citation: Brain. 1996 Dec;119 ( Pt 6):2009-19
references.pmid: 9010005
references.citation: J Neurol. 2001 Nov;248(11):979-86
references.pmid: 11757963
references.citation: Brain. 2002 Oct;125(Pt 10):2342-52
references.pmid: 12244090
references.citation: Neurology. 2000 Dec 12;55(11):1714-8
references.pmid: 11113227
references.citation: J Neurol. 2000 Dec;247(12):960-5
references.pmid: 11200690
references.citation: Brain. 1999 Mar;122 ( Pt 3):513-21
references.pmid: 10094259
references.citation: Arch Neurol. 2003 Aug;60(8):1073-81
references.pmid: 12925362
references.citation: Brain. 2002 Aug;125(Pt 8):1676-95
references.pmid: 12135961
references.citation: J Comput Assist Tomogr. 2001 May-Jun;25(3):466-75
references.pmid: 11351200
references.citation: N Engl J Med. 1998 Jan 29;338(5):278-85
references.pmid: 9445407
references.citation: J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):141-7
references.pmid: 12122170
references.citation: Brain. 2003 Nov;126(Pt 11):2528-36
references.pmid: 12902314
references.citation: J Neurol Neurosurg Psychiatry. 2003 Aug;74(8):1090-4
references.pmid: 12876240
references.citation: N Engl J Med. 2000 Nov 16;343(20):1430-8
references.pmid: 11078767
references.citation: Mult Scler. 2002 May;8(3):207-10
references.pmid: 12120691
references.citation: J Neurol. 2003 Mar;250(3):287-92
references.pmid: 12638018
references.citation: Brain. 1998 Apr;121 ( Pt 4):687-97
references.pmid: 9577394
references.citation: IEEE Trans Med Imaging. 2002 May;21(5):505-12
references.pmid: 12071621
references.citation: N Engl J Med. 2003 Jan 2;348(1):15-23
references.pmid: 12510038
references.citation: N Engl J Med. 2002 Jan 17;346(3):158-64
references.pmid: 11796849
references.citation: Neurology. 1999 Feb;52(3):588-94
references.pmid: 10025793
references.citation: Mult Scler. 2002 Feb;8(1):40-51
references.pmid: 11936488
references.citation: Brain. 2000 Nov;123 ( Pt 11):2256-63
references.pmid: 11050025
references.citation: Arch Ophthalmol. 2003 Jul;121(7):944-9
references.pmid: 12860795
references.citation: Ann Neurol. 1992 Dec;32(6):758-66
references.pmid: 1471866
references.citation: Ann Neurol. 2001 Jul;50(1):121-7
references.pmid: 11456302
references.citation: J Neurol Neurosurg Psychiatry. 1996 Mar;60(3):339-41
references.pmid: 8609517
references.citation: Ann Neurol. 1991 Jan;29(1):53-62
references.pmid: 1996879
references.citation: Neurology. 1999 Jul 13;53(1):139-48
references.pmid: 10408550
references.citation: Neurology. 1996 Feb;46(2):379-84
references.pmid: 8614498
references.citation: Mult Scler. 2002 Apr;8(2):119-23
references.pmid: 11990868
references.citation: J Neurol Neurosurg Psychiatry. 1998 Jan;64(1):50-5
references.pmid: 9436727
references.citation: Neurology. 2002 Nov 12;59(9):1412-20
references.pmid: 12427893
references.citation: Ann Neurol. 1999 Sep;46(3):296-304
references.pmid: 10482259
references.citation: J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):950-2
references.pmid: 12810788
references.citation: Ann Neurol. 1991 May;29(5):548-55
references.pmid: 1859184
references.citation: Ann Neurol. 2000 Dec;48(6):893-901
references.pmid: 11117546
references.citation: N Engl J Med. 2003 Jul 10;349(2):139-45
references.pmid: 12853586
references.citation: Ann Neurol. 1994;36 Suppl:S42-6
references.pmid: 8017888
references.citation: IEEE Trans Med Imaging. 1997 Oct;16(5):623-9
references.pmid: 9368118
references.citation: Neurology. 2000 Jan 11;54(1):15-9
references.pmid: 10636119
references.citation: J Neurol. 2003 Feb;250(2):171-8
references.pmid: 12574947
references.citation: Neurology. 1998 May;50(5):1282-8
references.pmid: 9595975
references.citation: Brain. 2002 Feb;125(Pt 2):327-37
references.pmid: 11844733
references.citation: Magn Reson Med. 1993 Dec;30(6):672-9
references.pmid: 8139448
references.citation: Brain. 1998 Mar;121 ( Pt 3):495-503
references.pmid: 9549525
references.citation: Lancet. 1999 Mar 20;353(9157):964-9
references.pmid: 10459905
references.citation: AJNR Am J Neuroradiol. 1997 Aug;18(7):1279-85
references.pmid: 9282855
references.citation: Ann Neurol. 1997 Nov;42(5):783-93
references.pmid: 9392578
references.citation: J Neurol Neurosurg Psychiatry. 2000 May;68(5):627-32
references.pmid: 10766895
references.citation: J Neurol. 2001 Mar;248(3):215-24
references.pmid: 11355156
references.citation: Eur J Neurol. 2003 May;10(3):257-64
references.pmid: 12752399
references.citation: Neurology. 1999 Sep 11;53(4):751-7
references.pmid: 10489036
references.citation: Ann Neurol. 2000 Mar;47(3):391-5
references.pmid: 10716264
references.citation: Brain. 1994 Feb;117 ( Pt 1):49-58
references.pmid: 8149214
references.citation: J Neurol Neurosurg Psychiatry. 1997 Dec;63(6):736-42
references.pmid: 9416807
references.citation: J Neurol Sci. 1979 Mar;41(1):81-91
references.pmid: 438845
references.citation: Ann Neurol. 1993 Nov;34(5):661-9
references.pmid: 8239560
references.citation: Neurology. 2001 Aug 28;57(4):731-3
references.pmid: 11524494
references.citation: J Neurol. 2004 Aug;251(8):996-1005
references.pmid: 15316805
references.citation: Brain. 2003 Feb;126(Pt 2):433-7
references.pmid: 12538409
references.citation: J Comput Assist Tomogr. 1998 Sep-Oct;22(5):838-43
references.pmid: 9754126
references.citation: Brain. 2001 Sep;124(Pt 9):1803-12
references.pmid: 11522582
references.citation: Neurology. 1996 Feb;46(2):373-8
references.pmid: 8614497
references.citation: J Neurol. 2004 Apr;251(4):407-13
references.pmid: 15083284
references.citation: Neurology. 1993 Apr;43(4):662-7
references.pmid: 8469319
references.citation: Mult Scler. 1998 Oct;4(5):408-12
references.pmid: 9839300
references.citation: J Neurol Neurosurg Psychiatry. 2000 Jun;68(6):713-8
references.pmid: 10811693
references.citation: Radiology. 1986 Dec;161(3):721-5
references.pmid: 3786722
references.citation: Brain. 1998 Jan;121 ( Pt 1):103-13
references.pmid: 9549491
references.citation: Brain. 1996 Jun;119 ( Pt 3):701-8
references.pmid: 8673483
references.citation: Ann Neurol. 2002 Nov;52(5):650-3
references.pmid: 12402265
references.citation: Brain. 1995 Dec;118 ( Pt 6):1583-92
references.pmid: 8595487
references.citation: Neurology. 2000 Mar 14;54(5):1145-55
references.pmid: 10720289
references.citation: Radiology. 2000 Mar;214(3):665-70
references.pmid: 10715027
references.citation: Mult Scler. 2002 Dec;8(6):532-3
references.pmid: 12474997