title: Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease.
abstract: A major goal of current clinical research in Huntington's disease (HD) has been to identify preclinical and manifest disease biomarkers, as these may improve both diagnosis and the power for therapeutic trials. Although the underlying biochemical alterations and the mechanisms of neuronal degeneration remain unknown, energy metabolism defects in HD have been chronicled for many years. We report that the brain isoenzyme of creatine kinase (CK-BB), an enzyme important in buffering energy stores, was significantly reduced in presymptomatic and manifest disease in brain and blood buffy coat specimens in HD mice and HD patients. Brain CK-BB levels were significantly reduced in R6/2 mice by approximately 18% to approximately 68% from 21 to 91 days of age, while blood CK-BB levels were decreased by approximately 14% to approximately 44% during the same disease duration. Similar findings in CK-BB levels were observed in the 140 CAG mice from 4 to 12 months of age, but not at the earliest time point, 2 months of age. Consistent with the HD mice, there was a grade-dependent loss of brain CK-BB that worsened with disease severity in HD patients from approximately 28% to approximately 63%, as compared to non-diseased control patients. In addition, CK-BB blood buffy coat levels were significantly reduced in both premanifest and symptomatic HD patients by approximately 23% and approximately 39%, respectively. The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from HD mice and HD patients may provide a powerful means to assess disease progression and to predict the potential magnitude of therapeutic benefit in this disorder.
authors.affiliation: Geriatric Research Education Clinical Center, New England Veterans Administration VISN 1, Bedford, MA 01730, USA.
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Amante
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Moody
authors.forename: Christina K
authors.initials: CK
authors.lastname: Edgerly
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Bordiuk
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Matson
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Matson
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
authors.forename: H Diana
authors.initials: HD
authors.lastname: Rosas
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D002490:Central Nervous System / Q000378:metabolism*; D052276:Creatine Kinase, BB Form / Q000097:blood* / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000097:blood* / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008875:Middle Aged; D011180:Postmortem Changes
chemical_list: D015415:Biomarkers; D052276:Creatine Kinase, BB Form
references.citation: Subcell Biochem. 2007;46:205-43
references.pmid: 18652079
references.citation: Expert Opin Investig Drugs. 2007 Dec;16(12):1933-53
references.pmid: 18042002
references.citation: Subcell Biochem. 2007;46:17-26
references.pmid: 18652070
references.citation: Curr Opin Neurol. 2005 Dec;18(6):698-705
references.pmid: 16280682
references.citation: J Neurochem. 1997 Nov;69(5):2064-74
references.pmid: 9349552
references.citation: NeuroRx. 2004 Jul;1(3):298-306
references.pmid: 15717031
references.citation: Subcell Biochem. 2007;46:309-34
references.pmid: 18652084
references.citation: Neurochem Res. 2004 Mar;29(3):531-46
references.pmid: 15038601
references.citation: J Neurol. 2010 Mar;257(3):399-404
references.pmid: 19784856
references.citation: Acta Neurol Scand. 1996 Jan;93(1):72-5
references.pmid: 8825277
references.citation: Biochim Biophys Acta. 2006 Jun;1762(6):616-26
references.pmid: 16647250
references.citation: Neurology. 2002 Nov 12;59(9):1325-30
references.pmid: 12427878
references.citation: Lancet. 1990 Sep 22;336(8717):749
references.pmid: 1975918
references.citation: Neurobiol Dis. 2004 Apr;15(3):610-7
references.pmid: 15056469
references.citation: FEBS Lett. 1997 Sep 8;414(2):253-7
references.pmid: 9315696
references.citation: Biochim Biophys Acta. 2010 Jan;1802(1):52-61
references.pmid: 19682570
references.citation: Subcell Biochem. 2007;46:149-66
references.pmid: 18652076
references.citation: Brain. 1990 Oct;113 ( Pt 5):1405-23
references.pmid: 2147116
references.citation: Cell. 1985 May;41(1):325-34
references.pmid: 3995586
references.citation: Am J Physiol. 1984 May;246(5 Pt 1):C365-77
references.pmid: 6372517
references.citation: Neurology. 2006 Jan 24;66(2):250-2
references.pmid: 16434666
references.citation: Res Publ Assoc Res Nerv Ment Dis. 1985;63:199-209
references.pmid: 3161165
references.citation: J Comp Neurol. 2005 Oct 3;490(4):354-70
references.pmid: 16127709
references.citation: Neurology. 1992 Apr;42(4):733-8
references.pmid: 1314341
references.citation: Biochim Biophys Acta. 2009 Jun;1792(6):506-20
references.pmid: 19362590
references.citation: Basic Clin Pharmacol Toxicol. 2009 Aug;105(2):92-7
references.pmid: 19389042
references.citation: Ann Neurol. 1997 Feb;41(2):160-5
references.pmid: 9029064
references.citation: J Neurochem. 2001 Jan;76(2):425-34
references.pmid: 11208905
references.citation: J Neurochem. 2004 Sep;90(6):1321-30
references.pmid: 15341516
references.citation: Nat Neurosci. 2002 Aug;5(8):731-6
references.pmid: 12089530
references.citation: Neurobiol Dis. 2010 Feb;37(2):423-33
references.pmid: 19879361
references.citation: Neurology. 1990 Aug;40(8):1231-4
references.pmid: 2143271
references.citation: J Neurochem. 2001 Dec;79(6):1246-9
references.pmid: 11752065
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:79-92
references.pmid: 19076433
references.citation: Ann Neurol. 1996 Mar;39(3):385-9
references.pmid: 8602759
references.citation: Behav Brain Res. 2005 Feb 28;157(2):219-34
references.pmid: 15639173
references.citation: J Neuropathol Exp Neurol. 1985 Nov;44(6):559-77
references.pmid: 2932539
references.citation: Brain. 2008 Feb;131(Pt 2):389-96
references.pmid: 18222993
references.citation: Eur J Neurosci. 2004 Jul;20(1):144-60
references.pmid: 15245487
references.citation: Neurobiol Dis. 2008 Oct;32(1):1-9
references.pmid: 18638556
references.citation: Biochem Biophys Res Commun. 1965 Nov 22;21(4):346-53
references.pmid: 5865501
references.citation: Annu Rev Biochem. 1985;54:831-62
references.pmid: 3896131
references.citation: Subcell Biochem. 2007;46:67-81
references.pmid: 18652072
references.citation: J Comp Neurol. 2003 Oct 6;465(1):11-26
references.pmid: 12926013
references.citation: Neurodegeneration. 1996 Mar;5(1):27-33
references.pmid: 8731379
references.citation: Mol Cell Proteomics. 2005 Dec;4(12):1849-61
references.pmid: 15968004
references.citation: Free Radic Res. 2005 Apr;39(4):383-8
references.pmid: 16028363
references.citation: Free Radic Biol Med. 2000 Oct 1;29(7):652-8
references.pmid: 11033417
references.citation: J Cell Physiol. 1983 Aug;116(2):221-6
references.pmid: 6863402
references.citation: J Neurochem. 1985 Jun;44(6):1948-50
references.pmid: 2985766