title: Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus.
abstract: BACKGROUND
  Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ) and α- and β-cleaved soluble forms of amyloid precursor protein (sAPPα and sAPPβ). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery.
  
  
  METHODS
  Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), Aβ isoforms Aβ38, Aβ40 and Aβ42, sAPPα, sAPPβ, APLP1 β-derived peptides APL1β25, APL1β 27 and APL1β 28 and YKL40 by immunochemical methods.
  
  
  RESULTS
  The concentrations of all soluble forms of APP, all Aβ isoforms and APL1β28 were lower, whilst APL1β25 and APL1β27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged.
  
  
  CONCLUSIONS
  The reduced CSF concentrations of Aβ38, Aβ40, Aβ42, sAPPα and sAPPβ suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1β25 and APL1β27 in combination with a slight decreased APL1β28 could be caused by more available γ-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness.
authors.affiliation: Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden. anna.jeppsson@neuro.gu.se.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-5908-1904
authors.initials: A
authors.lastname: Jeppsson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Mikko
authors.initials: M
authors.lastname: Höltta
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Wikkelsø
authors.affiliation: Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Tullberg
mesh_terms: D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002557:Cerebrospinal Fluid Shunts; D000071451:Chitinase-3-Like Protein 1 / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000134:cerebrospinal fluid* / Q000601:surgery; D008297:Male; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid*; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013129:Spinal Puncture; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D016900:Neurofilament Proteins; C044882:neurofilament protein L
keywords: APLP1; Amyloid; Cerebrospinal fluid; NFL; Neurodegeneration; Normal pressure hydrocephalus; Prediction; YKL40