Abstract
BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a reversible CNS disease characterized by disturbed cerebrospinal fluid (CSF) dynamics. Changes in the extracellular matrix (ECM) composition might be involved in the pathophysiology of iNPH. The aim of this study was to explore possible differences between lumbar and ventricular CSF concentrations of the ECM markers brevican and neurocan, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and their relation to clinical symptoms in iNPH patients before and after shunt surgery.MethodsPaired lumbar and ventricular CSF was collected from 31 iNPH patients, before and four months after shunt surgery. CSF was analysed for concentrations of tryptic peptides originating from brevican and neurocan using a mass spectrometry-based panel, and for MMP-1, -2, -9, -10 and TIMP-1 using fluorescent or electrochemiluminescent immunoassays.ResultsBrevican and neurocan peptide levels were not influenced by CSF origin, but MMP-1, -2, -10 and TIMP-1 were increased (p ≤ 0.0005), and MMP-9 decreased (p ≤ 0.0003) in lumbar CSF compared with ventricular CSF. There was a general trend of ECM proteins to increase following shunt surgery. Ventricular TIMP-1 was inversely correlated with overall symptoms (rho = − 0.62, p < 0.0001). CSF concentrations of the majority of brevican and neurocan peptides were increased in iNPH patients with a history of cardiovascular disease (p ≤ 0.001, AUC = 0.84–0.94) compared with those without.ConclusionLevels of the CNS-specific proteins brevican and neurocan did not differ between the lumbar and ventricular CSF, whereas the increase of several CNS-unspecific MMPs and TIMP-1 in lumbar CSF suggests contribution from peripheral tissues. The increase of ECM proteins in CSF following shunt surgery could indicate disturbed ECM dynamics in iNPH that are restored by restitution of CSF dynamics.
Highlights
Idiopathic normal pressure hydrocephalus is a reversible CNS disease characterized by disturbed cerebrospinal fluid (CSF) dynamics
The concentrations of Matrix metalloproteinase (MMP)-1, -2 and -10 were higher in lumbar CSF compared with ventricular CSF before shunt surgery and after (MMP-2 and -3) (p ≤ 0.0005), whereas MMP-9 showed the opposite pattern—its levels were elevated in ventricular CSF both pre- and postoperatively (p ≤ 0.0003) (Fig. 1)
The lumbar CSF concentrations of Tissue inhibitor of metalloproteinases (TIMP)-1 were higher compared with ventricular CSF in Idiopathic normal pressure hydrocephalus (iNPH) patients before and after shunt surgery (p ≤ 0.0005) (Fig. 1)
Summary
Idiopathic normal pressure hydrocephalus (iNPH) is a reversible CNS disease characterized by disturbed cerebrospinal fluid (CSF) dynamics. The aim of this study was to explore possible differences between lumbar and ventricular CSF concentrations of the ECM markers brevican and neurocan, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and their relation to clinical symptoms in iNPH patients before and after shunt surgery. Changes in concentrations of CSF biomarkers reflecting a variety of pathological changes in iNPH patients have been previously reported These include elevated neurofilament light (NFL) levels indicating damage to large myelinated axons [7,8,9] and increased glial fibrillary acidic protein (GFAP) levels implying astrogliosis [8, 10], while decreased levels of products derived from amyloid precursor protein (APP) might be explained by the reduced brain metabolism in the periventricular zone [9, 11]. Identifying CSF-based markers with such an ability would aid in the selection of patients who could benefit from this procedure
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