Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus

The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown. To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuron...

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Published in:	PloS one Vol. 9; no. 3; p. e91974
Main Authors:	Pyykkö, Okko T, Lumela, Miikka, Rummukainen, Jaana, Nerg, Ossi, Seppälä, Toni T, Herukka, Sanna-Kaisa, Koivisto, Anne M, Alafuzoff, Irina, Puli, Lakshman, Savolainen, Sakari, Soininen, Hilkka, Jääskeläinen, Juha E, Hiltunen, Mikko, Zetterberg, Henrik, Leinonen, Ville
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 17-03-2014 Public Library of Science (PLoS)
Subjects:	Advertising executives Aged Aged, 80 and over Alzheimer Disease Alzheimer's disease Alzheimers disease Amyloid beta-Peptides - cerebrospinal fluid Amyloid beta-Peptides - metabolism Amyloid beta-protein Amyloid beta-Protein Precursor - cerebrospinal fluid Amyloid beta-Protein Precursor - metabolism Amyloid precursor protein Apolipoprotein E Apolipoprotein E4 - cerebrospinal fluid Apolipoprotein E4 - genetics Biological response modifiers Biology and Life Sciences Biomarkers Biomarkers - cerebrospinal fluid Biopsy Brain Brain - metabolism Brain - pathology Brain damage Brain research Cerebrospinal fluid Clinical medicine Correlation Cortex Cytokines Cytokines - cerebrospinal fluid Cytokines - metabolism Deoxyribonucleic acid DNA Female Finland Fluid Fluids Hospitals Humans Hydrocephalus Hydrocephalus, Normal Pressure - cerebrospinal fluid Hydrocephalus, Normal Pressure - diagnosis Hydrocephalus, Normal Pressure - etiology Hydrocephalus, Normal Pressure - pathology Inflammation Inflammation Mediators - cerebrospinal fluid Inflammation Mediators - metabolism Interferon Interleukin 8 Interleukins Isoforms Male Medical research Medicine Medicine and Health Sciences Middle Aged Monocyte chemoattractant protein Monocyte chemoattractant protein 1 Myelin Myelin basic protein Myelin proteins Nervous system Neurochemistry Neurodegenerative diseases Neurology Neurons Neurophysiology Neurosciences Neurosurgery Neurovetenskaper Normal pressure hydrocephalus Pathology Patients Patologi Population studies Pressure Proteins Registries Studies Tau protein Tumor necrosis factor-TNF Tumor necrosis factor-α Ventricle Finland
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Summary:	The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown. To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings. The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE. Lumbar CSF levels of sAPPα were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPPβ showed a similar trend (p = 0.06). CSF sAPP isoform levels showed no association to Aβ or HPτ in the brain biopsy. Quantified Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ42 in ventricular (r = -0.295, p = 0.003) and lumbar (r = -0.356, p = 0.01) samples, while the levels of Aβ38 and Aβ40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure. The role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: IA HS JEJ MH VL. Performed the experiments: OTP ML JR ON TTS S-KH AMK IA LP SS HZ VL. Analyzed the data: OTP ML JR ON TTS S-KH AMK IA LP MH VL. Contributed reagents/materials/analysis tools: IA HS JEJ MH HZ VL. Wrote the paper: OTP VL. Critical revision of the manuscript for important intellectual content: OTP ML JR ON TTS S-KH AMK IA LP SS HS JEJ MH HZ VL. Statistical analysis: OTP ML VL. Obtained funding: HS MH HZ VL. Study supervision: HS MH VL. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0091974