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Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy

Journal article
Authors Erik Fernström
Karolina Minta
Ulf Andreasson
Åsa P Sandelius
Pontus Wasling
Ann Brinkmalm
Kina Höglund
Kaj Blennow
Jan Nyman
Henrik Zetterberg
Marie Kalm
Published in Journal of Internal Medicine
Volume 284
Issue 2
Pages 211-225
ISSN 0954-6820
Publication year 2018
Published at Institute of Clinical Sciences, Department of Oncology
Institute of Neuroscience and Physiology, Department of Physiology
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 211-225
Language en
Links dx.doi.org/10.1111/joim.12763
Keywords cranial irradiation, CSF biomarkers, neuronal damage, small-cell lung cancer, amyloid precursor protein, chondroitin sulfate proteoglycans, growth-associated protein-43, central-nervous-system, cell lung-cancer, quality-of-life, alzheimers-disease, hippocampal neurogenesis, frontotemporal dementia, perineuronal nets, General & Internal Medicine
Subject categories Neurochemistry, Psychiatry

Abstract

Background Advances in the treatment of brain tumours have increased the number of long-term survivors, but at the cost of side effects following cranial radiotherapy ranging from neurocognitive deficits to outright tissue necrosis. At present, there are no tools reflecting the molecular mechanisms underlying such side effects, and thus no means to evaluate interventional effects after cranial radiotherapy. Therefore, fluid biomarkers are of great clinical interest. Objective Cerebrospinal fluid (CSF) levels of proteins involved in inflammatory signalling, synaptic plasticity and extracellular matrix (ECM) integrity were investigated following radiotherapy to the brain. Methods Patients with small-cell lung cancer (SCLC) eligible for prophylactic cranial irradiation (PCI) were asked to participate in the study. PCI was prescribed either as 2 Gy/fraction to a total dose of 30 Gy (limited disease) or 4 Gy/fraction to 20 Gy (extensive disease). CSF was collected by lumbar puncture at baseline, 3 months and 1 year following PCI. Protein concentrations were measured using immunobased assays or mass spectrometry. Results The inflammatory markers IL-15, IL-16 and MCP-1/CCL2 were elevated in CSF 3 months following PCI compared to baseline. The plasticity marker GAP-43 was elevated 3 months following PCI, and the same trend was seen for SNAP-25, but not for SYT1. The investigated ECM proteins, brevican and neurocan, showed a decline following PCI. There was a strong correlation between the progressive decline of soluble APP and brevican levels. Conclusion To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.

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