title: Association of lipocalin-type prostaglandin D synthase with disproportionately enlarged subarachnoid-space in idiopathic normal pressure hydrocephalus.
abstract: BACKGROUND
  Idiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Aβ) implicated in Alzheimer's disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers.
  
  
  METHODS
  We evaluated 22 patients (age: 76.4 ± 4.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Aβ42, Aβ40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score.
  
  
  RESULTS
  L-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (p = 0.013 and p = 0.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman r = 0.753, p < 0.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman r = 0.602, p = 0.004), callosal angle (Spearman r = 0.592, p = 0.004), and ARWMC scores (Spearman r = 0.652, p = 0.001), but were negatively correlated with FAB scores (Spearman r = 0.641, p = 0.004).
  
  
  CONCLUSIONS
  Our data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.
authors.affiliation: Department of Neurosurgery, Tazuke Kofukai Foundation, Medical Research Institute and Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan. n-nishida@kitano-hp.or.jp.
authors.forename: Namiko
authors.initials: N
authors.lastname: Nishida
authors.forename: Nanae
authors.initials: N
authors.lastname: Nagata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toda
authors.forename: Naoto
authors.initials: N
authors.lastname: Jingami
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ozaki
authors.forename: Mitsuhito
authors.initials: M
authors.lastname: Mase
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Sadayuki
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ishikawa
references.citation: J Neurol Neurosurg Psychiatry. 2004 Nov;75(11):1614-6
references.pmid: 15489398
references.citation: J Am Geriatr Soc. 1991 Feb;39(2):142-8
references.pmid: 1991946
references.citation: Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006247
references.pmid: 22762014
references.citation: Stroke. 2001 Jun;32(6):1318-22
references.pmid: 11387493
references.citation: Neurol Med Chir (Tokyo). 2008;48 Suppl:S1-23
references.pmid: 18408356
references.citation: Stroke. 2000 Dec;31(12):2952-7
references.pmid: 11108755
references.citation: Proc Natl Acad Sci U S A. 1975 May;72(5):1858-62
references.pmid: 1057175
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6412-7
references.pmid: 17404210
references.citation: Biochim Biophys Acta. 2000 Oct 18;1482(1-2):259-71
references.pmid: 11058767
references.citation: Clin Chem. 1996 Dec;42(12):1984-91
references.pmid: 8969637
references.citation: Dement Geriatr Cogn Disord. 2008;25(1):37-45
references.pmid: 18025828
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: Acta Neurol Scand. 2007 Nov;116(5):333-9
references.pmid: 17922727
references.citation: Neurology. 2000 Dec 12;55(11):1621-6
references.pmid: 11113214
references.citation: Neurosci Res. 2003 Dec;47(4):455-9
references.pmid: 14630351
references.citation: Psychiatry Clin Neurosci. 2000 Apr;54(2):199-202
references.pmid: 10803815
references.citation: J Psychiatr Res. 2011 Apr;45(4):539-47
references.pmid: 20828718
references.citation: Neurol Med Chir (Tokyo). 2012;52(11):775-809
references.pmid: 23183074
references.citation: Eur Radiol. 2008 Nov;18(11):2678-83
references.pmid: 18500524
references.citation: Cerebrospinal Fluid Res. 2010 Oct 31;7:18
references.pmid: 21040519
references.citation: Eur J Neurol. 2009 Jun;16(6):760-70
references.pmid: 19475759
references.citation: Eur J Neurol. 2013 Feb;20(2):236-42
references.pmid: 22672777
references.citation: Lancet Neurol. 2003 Aug;2(8):506-11
references.pmid: 12878439
references.citation: Neurology. 1984 Jul;34(7):939-44
references.pmid: 6610841
references.citation: Fluids Barriers CNS. 2013 Jun 10;10(1):22
references.pmid: 23758953
references.citation: Mol Chem Neuropathol. 1995 Dec;26(3):231-45
references.pmid: 8748926
references.citation: Eur J Neurol. 2007 Feb;14(2):168-73
references.pmid: 17250725
references.citation: Neurol Med Chir (Tokyo). 2010;50(2):119-23; disucussion 123
references.pmid: 20185875