Objective. The aim of this systematic review was to evaluate existing literature on inflammatory markers in CSF from patients with hydrocephalus and identify potential markers capable of promoting hydrocephalus development and progression. Methods. Relevant studies published before December 3^rd 2020 were identified from PubMed, Embase, and reference lists. Studies were screened for eligibility using the predefined inclusion and exclusion criteria. Data from eligible studies were extracted, and sources of bias were evaluated. We included articles written in English investigating inflammatory markers in CSF from patients with hydrocephalus and control subjects. The review was conducted according to the PRISMA guidelines by three independent reviewers. Results. Twenty-two studies analyzed CSF from 311 patients with idiopathic normal pressure hydrocephalus (iNPH), 178 with posthemorrhagic hydrocephalus (PHH), 151 with other hydrocephalus diagnoses, and 394 control subjects. Fifty-eight inflammatory markers were investigated. The CSF of iNPH patients had increased CSF levels of IL-6, IL-1β, and LRG compared with control subjects, whereas the CSF of PHH patients had increased levels of IL-6, IL-18, and VEGF. CSF from patients with other hydrocephalus diagnoses had elevated IFN-γ compared to control subjects, and VEGF was increased in congenital hydrocephalus, spina bifida, and hydrocephalus associated with tuberculous meningitis compared with controls. Conclusion. IL-6, IL-1β, LRG, IL-18, VEGF, and IFN-γ are elevated in CSF from patients with hydrocephalus and may be involved in promotion of hydrocephalus development and progression. They may serve as novel disease biomarkers, and their signaling pathways may represent targets for pharmacological management of hydrocephalus.

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β₄₂, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

The mechanisms underlying post-hemorrhagic hydrocephalus (PHH) development following subarachnoid hemorrhage (SAH) are not fully understood, which complicates informed clinical decisions regarding the duration of external ventricular drain (EVD) treatment and prevents the prediction of shunt-dependency in the individual patient. The aim of this study was to identify potential inflammatory cerebrospinal fluid (CSF) biomarkers of PHH and, thus, shunt-dependency and functional outcome in patients with SAH. This study was a prospective observational study designed to evaluate inflammatory markers in ventricular CSF. In total, 31 Patients with SAH who required an EVD between June 2019 and September 2021 at the Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark, were included. CSF samples were collected twice from each patient and analyzed for 92 inflammatory markers via proximity extension assay (PEA), and the prognostic ability of the markers was investigated. In total, 12 patients developed PHH, while 19 were weaned from their EVD. Their 6-month functional outcome was determined with the modified Rankin Scale. Of the 92 analyzed inflammatory biomarkers, 79 were identified in the samples. Seven markers (SCF, OPG, LAP TGFβ1, Flt3L, FGF19, CST5, and CSF1) were found to be predictors of shunt dependency, and four markers (TNFα, CXCL5, CCL20, and IL8) were found to be predictors of functional outcome. In this study, we identified promising inflammatory biomarkers that are able to predict (i) the functional outcome in patients with SAH and (ii) the development of PHH and, thus, the shunt dependency of the individual patients. These inflammatory markers may have the potential to be employed as predictive biomarkers of shunt dependency and functional outcome following SAH and could, as such, be applied in the clinic.

Patients with subarachnoid hemorrhage (SAH) may develop posthemorrhagic hydrocephalus (PHH), which is treated with surgical cerebrospinal fluid (CSF) diversion. This diversion is associated with risk of infection and shunt failure. Biomarkers for PHH etiology, CSF dynamics disturbances, and potentially subsequent shunt dependency are therefore in demand. With the recent demonstration of lipid-mediated CSF hypersecretion contributing to PHH, exploration of the CSF lipid signature in relation to brain pathology is of interest. Despite being a relatively new addition to the omic’s landscape, lipidomics are increasingly recognized as a tool for biomarker identification, as they provide a comprehensive overview of lipid profiles in biological systems. We here employ an untargeted mass spectroscopy-based platform and reveal the complete lipid profile of cisternal CSF from healthy control subjects and demonstrate its bimodal fluctuation with age. Various classes of lipids, in addition to select individual lipids, were elevated in the ventricular CSF obtained from patients with SAH during placement of an external ventricular drain. The lipidomic signature of the CSF in the patients with SAH suggests dysregulation of the lipids in the CSF in this patient group. Our data thereby reveal possible biomarkers present in a brain pathology with a hemorrhagic event, some of which could be potential future biomarkers for hypersecretion contributing to ventriculomegaly and thus pharmacological targets for pathologies involving disturbed CSF dynamics.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

Background: By applying an unbiased proteomic approach, we aimed to search for cerebrospinal fluid (CSF) protein biomarkers distinguishing between obstructive and communicating hydrocephalus in order to improve appropriate surgical selection for endoscopic third ventriculostomy vs. shunt implants. Our second study purpose was to look for potential CSF biomarkers distinguishing between patients with adult chronic hydrocephalus benefitting from surgery (responders) vs. those who did not (non-responders). Methods: Ventricular CSF samples were collected from 62 patients with communicating hydrocephalus and 28 patients with obstructive hydrocephalus. CSF was collected in relation to the patients’ surgical treatment. As a control group, CSF was collected from ten patients with unruptured aneurysm undergoing preventive surgery (vascular clipping). Results: Mass spectrometry-based proteomic analysis of the samples identified 1251 unique proteins. No proteins differed significantly between the communicating hydrocephalus group and the obstructive hydrocephalus group. Four proteins were found to be significantly less abundant in CSF from communicating hydrocephalus patients compared to control subjects. A PCA plot revealed similar proteomic CSF profiles of obstructive and communicating hydrocephalus and control samples. For obstructive hydrocephalus, ten proteins were found to predict responders from non-responders. Conclusion: Here, we show that the proteomic profile of ventricular CSF from patients with hydrocephalus differs slightly from control subjects. Furthermore, we find ten predictors of response to surgical outcome (endoscopic third ventriculostomy or ventriculo-peritoneal shunt) in patients with obstructive hydrocephalus.