Elevated Surfactant Protein Levels and Increased Flow of Cerebrospinal Fluid in Cranial Magnetic Resonance Imaging

Abstract

Surfactant proteins (SPs) are a multifunctional group of proteins, responsible for the regulation of rheological properties of body fluids, host defense, and cellular waste clearance. Their concentrations are changed in cerebrospinal fluid (CSF) of patients suffering from communicating hydrocephalus. Hydrocephalic conditions are accompanied by altered CSF flow dynamics; however, the association of CSF-SP concentrations and CSF flow has not yet been investigated. Hence, the aim of this study was to evaluate the association between SP concentrations in the CSF and marked CSF flow phenomena at different anatomical landmarks of CSF spaces. Sixty-one individuals (15 healthy subjects and 46 hydrocephalus patients) were included in this study. CSF specimens were analyzed for SP-A, SP-B, SP-C, and SP-D concentrations by the use of enzyme-linked immunosorbent assays (ELISA). CSF flow was evaluated in axial T2_turbo inversion recovery magnitude (TIRM)-weighted and sagittal T2-weighted magnetic resonance imaging sections using a 4-grade scale (1-no flow, 2-subtle flow, 3-moderate flow, and 4-strong flow). CSF-SP concentrations (mean ± standard deviation) of the overall collective were as follows: SP-A = 0.73 ± 0.58 ng/ml, SP-B = 0.17 ± 0.93 ng/ml, SP-C = 0.95 ± 0.75 ng/ml, and SP-D = 7.43 ± 5.17 ng/ml. The difference between healthy controls and hydrocephalic patients regarding CSF concentrations of SP-A (0.34 ± 0.22 vs. 0.81 ± 0.59 ng/ml) and SP-C (0.48 ± 0.29 vs. 1.10 ± 0.79 ng/ml) revealed to be statistically significant as calculated by means of ANOVA (p values of 0.022 and 0.007, respectively). CSF flow voids were detectable at all investigated landmarks of the CSF spaces (foramina of Monro, third ventricle, mesencephalic aqueduct, prepontine cistern, fourth ventricle, cisterna magna, and craniocervical junction). CSF flow voids, reported as mean ± standard deviation, revealed to be significantly increased in hydrocephalic patients compared to controls as calculated by means of ANOVA (respective p values are given in brackets following values of descriptive statistics) at the following sites: foramina of Monro (1.60 ± 0.91 vs. 2.37 ± 0.99, p = 0.01), fourth ventricle (1.67 ± 0.98 vs. 2.52 ± 1.05, p = 0.007), and the cisterna magna (1.93 ± 1.10 vs. 2.72 ± 1.13, p = 0.022). Spearman's rank order calculation identified significant correlations for CSF flow voids at the foramina of Monro and the third ventricle with SP-A (r = 0.429, p = 0.001 and r = 0.464, p < 0.001) and CSF flow void at the mesencephalic duct with SP-D (r = - 0.371, p = 0.039). Furthermore, SP-C showed a moderate inverse correlation with age (r = - 0.302, p = 0.022). The present study confirmed statistically significant differences in SP-CSF concentrations between healthy controls and hydrocephalic patients. Additionally, significant correlations between SP concentrations in CSF with increased CSF flow were identified. These findings underline the role of SPs as regulators of CSF rheology.

Surfactant protein C, a modulator of paravascular brain waste clearance, is associated with perineuronal nets and shows age-dependent changes of brain content and characteristic deposits in wildtype and 3xTg mice

“…In detail, SP-C pro les in the CSF were not linked to CSF bulk ow, but signi cantly associated with white matter changes in context of impaired CSF clearance, indicating involvement of the paravascular clearance system [19,20,21]. Furthermore, a signi cant decline of CSF SP-C with increasing age has been demonstrated [20].…”

“…In detail, SP-C pro les in the CSF were not linked to CSF bulk ow, but signi cantly associated with white matter changes in context of impaired CSF clearance, indicating involvement of the paravascular clearance system [19,20,21]. Furthermore, a signi cant decline of CSF SP-C with increasing age has been demonstrated [20].Considering the complex physiological pro le of SP-C and its precursor proSP-C in the lungs, especially with respect to its function as chaperon and surface-active peptide, together with its expression in the CNS, comparable roles for CNS physiology are assumable.The majority of neurodegenerative diseases, for example Parkinson's disease, Lewy Body dementia, and, most importantly Alzheimer's disease (AD), are related to protein misfolding and impaired paravascular clearance [22,23], causing accumulation of detrimental metabolites, such as beta-amyloid, predominantly in the brain's extracellular matrix (ECM). Our study therefore aims to elucidate, whether SP-C / proSP-C are associated with the pathobiology of AD, for example the aggregation of non-functional Reelin deposits -a histological hallmark of disturbed Reelin signalling [24,25].…”

“…In fact, the protein and its precursor are abundant at various physiological interfaces, for example the blood-testis-barrier [16], the blood-brainbarrier [15] and the blood-cerebrospinal-uid-barrier [17], More recent studies substantiate that SP-C, together with the other SPs, is involved in CSF rheology [18]. In detail, SP-C pro les in the CSF were not linked to CSF bulk ow, but signi cantly associated with white matter changes in context of impaired CSF clearance, indicating involvement of the paravascular clearance system [19,20,21]. Furthermore, a signi cant decline of CSF SP-C with increasing age has been demonstrated [20].Considering the complex physiological pro le of SP-C and its precursor proSP-C in the lungs, especially with respect to its function as chaperon and surface-active peptide, together with its expression in the CNS, comparable roles for CNS physiology are assumable.The majority of neurodegenerative diseases, for example Parkinson's disease, Lewy Body dementia, and, most importantly Alzheimer's disease (AD), are related to protein misfolding and impaired paravascular clearance [22,23], causing accumulation of detrimental metabolites, such as beta-amyloid, predominantly in the brain's extracellular matrix (ECM).…”

“…In fact, the protein and its precursor are abundant at various physiological interfaces, for example the blood-testis-barrier [16], the blood-brainbarrier [15] and the blood-cerebrospinal-uid-barrier [17], More recent studies substantiate that SP-C, together with the other SPs, is involved in CSF rheology [18]. In detail, SP-C pro les in the CSF were not linked to CSF bulk ow, but signi cantly associated with white matter changes in context of impaired CSF clearance, indicating involvement of the paravascular clearance system [19,20,21]. Furthermore, a signi cant decline of CSF SP-C with increasing age has been demonstrated [20].…”

CSF Surfactant Protein Changes in Preterm Infants After Intraventricular Hemorrhage

“…In parallel the opsonins SP-A and SP-D are found at the sites of the blood-brain and the blood-CSF barrier, respectively (3). Furthermore, the SPs are also present in significant concentrations in cerebrospinal fluid (CSF) (2,4,5).…”