title: Relationships between clinicopathological features and cerebrospinal fluid biomarkers in Japanese patients with genetic prion diseases.
abstract: A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrP(Sc)) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrP(Sc) was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrP(Sc) in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrP(Sc) in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrP(Sc). The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.
authors.affiliation: Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Higuma
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sanjo
authors.forename: Katsuya
authors.initials: K
authors.lastname: Satoh
authors.forename: Yusei
authors.initials: Y
authors.lastname: Shiga
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakai
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nozaki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Yosikazu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Kitamoto
authors.forename: Susumu
authors.initials: S
authors.lastname: Shirabe
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Jun
authors.initials: J
authors.lastname: Tateishi
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
mesh_terms: D048948:14-3-3 Proteins / Q000134:cerebrospinal fluid / Q000235:genetics; D000328:Adult; D000368:Aged; D044466:Asian People; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D005260:Female; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D017096:Prion Diseases / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000473:pathology*; D000072002:Prion Proteins; D011328:Prions / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D015415:Biomarkers; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions
references.citation: Ann Neurol. 1996 Jun;39(6):767-78
references.pmid: 8651649
references.citation: Cell Mol Neurobiol. 2006 Feb;26(1):45-52
references.pmid: 16633900
references.citation: Acta Neurol Scand. 2012 Nov;126(5):315-23
references.pmid: 22211828
references.citation: Hum Genet. 2005 Nov;118(2):166-74
references.pmid: 16187142
references.citation: Neurology. 2004 Feb 10;62(3):502-5
references.pmid: 14872044
references.citation: Neurology. 2000 Jun 13;54(11):2133-7
references.pmid: 10851377
references.citation: Ann Neurol. 2012 Aug;72(2):278-85
references.pmid: 22926858
references.citation: Brain. 2012 Feb;135(Pt 2):e209; author reply e210
references.pmid: 22108575
references.citation: Brain. 2008 Oct;131(Pt 10):2632-46
references.pmid: 18757886
references.citation: J Neurol. 2002 Dec;249(12):1740-1
references.pmid: 12529802
references.citation: Nat Med. 2011 Feb;17(2):175-8
references.pmid: 21278748
references.citation: Brain Pathol. 1995 Jan;5(1):53-9
references.pmid: 7767491
references.citation: J Korean Med Sci. 2010 Jul;25(7):1097-100
references.pmid: 20592908
references.citation: Am J Pathol. 1992 Jun;140(6):1285-94
references.pmid: 1351366
references.citation: J Neurol. 2009 Oct;256(10):1620-8
references.pmid: 19444528
references.citation: Protein Eng Des Sel. 2009 Aug;22(8):461-8
references.pmid: 19602567
references.citation: J Neurol. 2007 Nov;254(11):1509-17
references.pmid: 17965961
references.citation: J Neurol. 2011 Feb;258(2):255-62
references.pmid: 20827556
references.citation: BMC Infect Dis. 2009 Aug 22;9:132
references.pmid: 19698114
references.citation: Neuropathology. 2009 Dec;29(6):735-43
references.pmid: 19422537
references.citation: Lab Invest. 2010 Nov;90(11):1637-44
references.pmid: 20697380
references.citation: Nat Methods. 2007 Aug;4(8):645-50
references.pmid: 17643109
references.citation: Arch Neurol. 1999 Mar;56(3):357-62
references.pmid: 10190828
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8322-7
references.pmid: 9653185
references.citation: Neurology. 1999 Jul 13;53(1):181-8
references.pmid: 10408557
references.citation: Biochem Biophys Res Commun. 1993 Mar 15;191(2):709-14
references.pmid: 8461023
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):938-44
references.pmid: 18425766
references.citation: Neuropathology. 2011 Oct;31(5):540-8
references.pmid: 21269331
references.citation: Neuropathology. 2009 Dec;29(6):727-34
references.pmid: 19422533
references.citation: Science. 1991 Jun 14;252(5012):1515-22
references.pmid: 1675487
references.citation: Brain. 2010 Oct;133(10):3043-57
references.pmid: 20855418
references.citation: Neurosci Lett. 2006 Nov 20;408(3):165-9
references.pmid: 17029785
references.citation: Clin Neurol Neurosurg. 2009 Sep;111(7):606-9
references.pmid: 19443103