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Research paper
CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics
  1. Anna Jeppsson1,2,
  2. Carsten Wikkelsö1,2,
  3. Kaj Blennow3,4,
  4. Henrik Zetterberg3,4,5,6,
  5. Radu Constantinescu2,
  6. Anne M Remes7,8,
  7. Sanna-Kaisa Herukka9,
  8. Tuomas Rauramaa10,
  9. Katarina Nagga11,
  10. Ville Leinonen8,12,13,
  11. Mats Tullberg1,2
  1. 1 Hydrocephalus Research Unit, Department of clinical neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  2. 2 Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  3. 3 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  4. 4 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  5. 5 Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  6. 6 UK Dementia Research Institute at UCL, London, UK
  7. 7 Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland
  8. 8 Medical Research Center, Oulu University Hospital, Oulu, Finland
  9. 9 Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland
  10. 10 Department of Pathology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland
  11. 11 Department of Acute Internal Medicine and Geriatrics, Linköping University, Linköping, Sweden
  12. 12 Unit of Clinical Neuroscience, Neurosurgery, University of Oulu, Oulu, Finland
  13. 13 Department of Neurosurgery, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland
  1. Correspondence to Dr Anna Jeppsson, Department of Clinical Neuroscience, University of Gothenburg Institute of Neuroscience and Physiology, Goteborg 405 30, Sweden; anna.jeppsson{at}gu.se

Abstract

Objective To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.

Methods The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).

Results Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.

Conclusions The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

  • idiopathic normal pressure hydrocephalus
  • Alzheimer’s disease
  • Parkinson’s disease
  • Multiple systems atrophy
  • Progressive supranuclear palsy
  • corticobasal degeneration
  • frontotemporal dementia
  • vascular dementia
  • biomarkers
  • CSF

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Footnotes

  • Contributors Anna Jeppsson: participated in the design of the study; coordinated the study; statistical analysis; interpretation of data; drafted the manuscript for intellectual content. Carsten Wikkelsø: participated in the design of the study; coordination of the study; CSF collection; interpretation of data; drafted the manuscript for intellectual content. Kaj Blennow: participated in the design of the study; coordination of the study; laboratory analyses; interpretation of data; revised the manuscript for intellectual content. Henrik Zetterberg: participated in the design of the study; coordination of the study; laboratory analyses; interpretation of data; revised the manuscript for intellectual content. Radu Constantinescu: patient recruitment; CSF collection; interpretation of data; revised the manuscript for intellectual content. Anne M Remes: patient recruitment; revised the manuscript for intellectual content. Sanna-Kaisa Herukka: patient recruitment, CSF collection; revised the manuscript for intellectual content. Toumas Rauramaa: patient recruitment, CSF collection; revised the manuscript for intellectual content. Katarina Nägga: patient recruitment, CSF collection; revised the manuscript for intellectual content. Ville Leinonen: patient recruitment; interpretation of data; revised the manuscript for intellectual content. Mats Tullberg: participated in the design of the study; coordination of the study; CSF collection; interpretation of data; drafted the manuscript for intellectual content. All authors read and approved the final manuscript.

  • Funding This study was supported by grants from the Swedish Research Council (#2017-00915), Swedish State under the agreement between the Swedish government and the country councils, the ALF agreement (2017-04961; ALFGBG-720931, -720121 and ALFGBG715986), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), Kuopio University Hospital VTR-fund and the Göteborg Foundation for Neurological Research. HZ is a Wallenberg Academy Fellow. KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences.

  • Disclaimer Dr Wikkelsø receives honorarium for lecturing by Codman, Integra. Dr Zetterberg has served at scientific advisory boards for Roche Diagnostics, Wave,Samumed and CogRx and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Dr Blennow has served as a consultant or at advisory boards for Alzheon, CogRx, Biogen, Lilly, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available upon reasonable request.

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