Potential Cerebrospinal Fluid Biomarkers Research Articles

175P Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric 5q-associated spinal muscular atrophy patients

175P Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric 5q-associated spinal muscular atrophy patients

Proteomic profile and predictive markers of outcome in patients with subarachnoid hemorrhage

BackgroundThe molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) following subarachnoid hemorrhage (SAH) remain incompletely understood. Consequently, treatment strategies tailored towards the individual patient remain limited. This study aimed to identify proteomic cerebrospinal fluid (CSF) biomarkers capable of predicting shunt dependency and functional outcome in patients with SAH in order to improve informed clinical decision making.MethodsVentricular CSF samples were collected twice from 23 patients with SAH who required external ventricular drain (EVD) insertion (12 patients with successful EVD weaning, 11 patients in need of permanent CSF shunting due to development of PHH). The paired CSF samples were collected acutely after ictus and later upon EVD removal. Cisternal CSF samples were collected from 10 healthy control subjects undergoing vascular clipping of an unruptured aneurysm. All CSF samples were subjected to mass spectrometry-based proteomics analysis. Proteomic biomarkers were quantified using area under the curve (AUC) estimates from a receiver operating curve (ROC).ResultsCSF from patients with SAH displayed a distinct proteomic profile in comparison to that of healthy control subjects. The CSF collected acutely after ictus from patients with SAH was moreover distinct from that collected weeks later but appeared similar in the weaned and shunted patient groups. Sixteen unique proteins were identified as potential predictors of shunt dependency, while three proteins were identified as potential predictors of functional outcome assessed six months after ictus with the modified Rankin Scale.ConclusionsWe here identified several potential proteomic biomarkers in CSF from patients with SAH capable of predicting (i) shunt dependency and thus development of PHH and (ii) the functional outcome assessed six months after ictus. These proteomic biomarkers may have the potential to aid clinical decision making by predicting shunt dependency and functional outcome following SAH.

Potential Biomarkers in Cerebrospinal Fluid and Plasma for Dementia

Background: The identification of biomarkers for different dementias in plasma and cerebrospinal fluid (CSF) has made substantial progress. However, they are observational studies, and there remains a lack of research on dementias with low incidence rates. Objective: We performed a comprehensive Mendelian randomization to identify potential biomarkers for different dementia type. Methods: The summary-level datasets encompassed 734 plasma and 154 cerebrospinal fluid proteins sourced from recently published genome-wide association studies (GWAS). Summary statistics for different dementias, including any dementia (refering to any type of dementia symptoms, 218,792 samples), Alzheimer’s disease (AD, 63,926 samples), vascular dementia (212,389 samples), frontotemporal dementia (3,024 samples), dementia with Lewy bodies (DLB, 6,618 samples), and dementia in Parkinson’s disease (216,895 samples), were collected from large GWAS. The primary method is inverse variance weighting, with additional sensitivity analyses conducted to ensure the robustness of the findings. Results: The molecules released into CSF, namely APOE2 for any dementia, APOE2 and Siglec-3 for AD, APOE2 for vascular dementia, and APOE2 for DLB, might be potential biomarkers. CD33 for AD and SNCA for DLB in plasma could be promising biomarkers. Conclusions: This is the first study to integrate plasma and CSF proteins to identify potential biomarkers for different dementias.

Biomarkers in Cerebrospinal Fluid for the Diagnosis and Monitoring of Gliomas.

Gliomas are the most common type of malignant brain tumor and are characterized by a plethora of heterogeneous molecular alterations. Current treatments require the emergence of reliable biomarkers that will aid personalized treatment decisions and increase life expectancy. Glioma tissues are not as easily accessible as other solid tumors; therefore, detecting prominent biomarkers in biological fluids is necessary. Cerebrospinal fluid (CSF) circulates adjacent to the cerebral parenchyma and holds promise for discovering useful prognostic, diagnostic, and predictive biomarkers. In this review, we summarize extensive research regarding the role of circulating DNA, tumor cells, proteins, microRNAs, metabolites, and extracellular vesicles as potential CSF biomarkers for glioma diagnosis, prognosis, and monitoring. Future studies should address discrepancies and issues of specificity regarding CSF biomarkers, as well as the validation of candidate biomarkers.

Single-cell atlas reveals the immunosuppressive microenvironment and Treg cells landscapes in recurrent Glioblastoma.

Patients diagnosed with glioblastoma (GBM) have the most aggressive tumor progression and lethal recurrence. Research on the immune microenvironment landscape of tumor and cerebrospinal fluid (CSF) is limited. At the single-cell level, we aim to reveal the recurrent immune microenvironment of GBM and the potential CSF biomarkers and compare tumor locations. We collected four clinical samples from two patients: malignant samples from one recurrent GBM patient and non-malignant samples from a patient with brain tumor. We performed single-cell RNA sequencing (scRNA-seq) to reveal the immune landscape of recurrent GBM and CSF. T cells were enriched in the malignant tumors, while Treg cells were predominately found in malignant CSF, which indicated an inhibitory microenvironment in recurrent GBM. Moreover, macrophages and neutrophils were significantly enriched in malignant CSF. This indicates that they an important role in GBM progression. S100A9, extensively expressed in malignant CSF, is a promising biomarker for GBM diagnosis and recurrence. Our study reveals GBM's recurrent immune microenvironment after chemoradiotherapy and compares malignant and non-malignant CSF samples. We provide novel targets and confirm the promise of liquid CSF biopsy for patients with GBM.

Unveiling Potential Biomarkers in Cerebrospinal Fluid for Amyloid Pathological Positivity in Non-Demented Individuals

Unveiling Potential Biomarkers in Cerebrospinal Fluid for Amyloid Pathological Positivity in Non-Demented Individuals

MiRNAs in Cerebrospinal Fluid Associated with Alzheimer’s Disease: a Systematic Review and Pathway Analysis

AbstractBackgroundApproximately 55 million people live with dementia, and 10 million cases are diagnosed each year worldwide (1). Alzheimer’s disease (AD) is the most common type of dementia and accounts for 60% ‐ 70% of reported cases (1). MicroRNAs are small non‐coding RNAs that present highly conserved sequences, involved in gene modulation and several molecular mechanisms (2). The miRNAs can be found in cerebrospinal fluid (CSF) and they are potential biomarkers for AD diagnosis (3). This study aimed to perform a systematic review about the expression of miRNAs in the CSF of AD patients compared to cognitive controls and carry out an analysis of the biological pathways regulated by these miRNAsMethodA systematic literature search was performed in Medline/PubMed, the Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Web of Science, Embase and gray literature, including observational studies that evaluated patients with AD and healthy individuals, which evaluated the miRNA expression in CSF. To verify the main signaling pathways regulated by the miRNAs, the software Gene Cards was used (table 1).Result2060 studies were retrieved and, after removing duplicates and reading titles, abstracts and full text, 26 studies met the inclusion criteria. We identified 171 differentially expressed miRNAs between AD and controls. Among them, the miRNAs ‐125b, ‐125‐5p, ‐138‐5p and ‐485‐5p presented differentiated expression between the groups commonly in these studies. The evaluation of signaling pathways showed that regulation of gene expression, cell proliferation, and gene silencing, are regulated by these miRNAs.ConclusionOur results suggest that the miRNAs ‐125b, ‐125‐5p, ‐138‐5p and ‐485‐5p are involved in AD‐related biological pathways and are potential CSF biomarkers to AD diagnosis.1. DEMENTIA. World Health Organization, 2022. Available at: <https://www.who.int/news‐room/fact‐sheets/detail/dementia>. Access at 21 jan. 2023.2. CORREIA DE SOUSA, Marta et al. Deciphering miRNAs’ action through miRNA editing. International Journal of Molecular Sciences, v. 20, n. 24, p. 6249, 2019.3. TAKOUSIS, Petros et al. Differential expression of microRNAs in Alzheimer’s disease brain, blood, and cerebrospinal fluid. Alzheimer’s & Dementia, v. 15, n. 11, p. 1468‐1477, 2019.

BIOM-65. NEW BIOMARKERS FOR THE DIAGNOSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA IN CEREBROSPINAL FLUID: AN EXPLORATORY MULTICENTER RETROSPECTIVE COHORT STUDY

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma which may be treated with curative intent. Diagnosis often requires a brain biopsy, which is associated with complications and delay of diagnosis. Cerebrospinal fluid (CSF) analysis can currently provide a diagnosis (without the need for a biopsy) in only a minority of PCNSL patients. The aim of this study is to identify new potential biomarkers in CSF for patients with clinical suspicion of PCNSL, to improve the diagnostic yield of CSF analysis. METHODS CSF samples were analyzed from a retrospective cohort that included patients with clinical suspicion of PCNSL at two Dutch hospitals between August 2020 and October 2021. First-step analysis consisted of targeted multiplex biomarker analysis using a proximity extension assay (Olink), allowing the simultaneous analysis (relative expression levels) of 184 protein markers in a small CSF volume. To validate the discovered biomarkers in a quantitative manner, a second analysis was performed in a subgroup of patients with a bead-based multiplex immune-assay (Luminex). RESULTS A total of 76 patients were included, of whom 11 patients (14%) were diagnosed with PCNSL. The mean age was 62 years (range 22-83 years), and 62% of the patients were male. In the primary analysis, 31 markers showed significant differences (p< 0.05) between PCNSL patients and controls. After correction for multiple testing, 6 markers remained significant, including the known chemokine marker CXCL13, as well as new markers. The quantitative analysis confirmed significant differences (p< 0.05) for 3 markers: CXCL10, programmed cell death protein 1 (PDCD1) and FAS natural ligand (FASLG). CONCLUSION We identified a novel panel of potential diagnostic markers in CSF for the diagnosis of PCNSL. The diagnostic value of these markers will be validated in an ongoing multicenter prospective study.

Ventricular CSF proteomic profiles and predictors of surgical treatment outcome in chronic hydrocephalus

BackgroundBy 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).MethodsVentricular 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).ResultsMass 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.ConclusionHere, 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.

Potential CSF biomarkers of postpartum depression following delivery via caesarian section

BackgroundPostpartum depression (PPD), the depressive episodes following delivery, is a serious and frequent psychiatric disorder. While numerous screening tools existed for depressive episodes, e.g., the Edinburgh Postnatal Depression Scale (EPDS), there are no objective biological measures for predicting PPD. Despite several studies done to identify biomarkers in PPD, there has been limited exploration into cerebrospinal fluid (CSF) which directly interfaces with the brain. Consequently, novel potential biomarkers of CSF are required to predict PPD, so as to target specific preventive interventions. MethodsSeventy-five parturients undergoing caesarean delivery were enrolled for CSF collection at delivery. Of the twenty-eight subjects who didn't meet any exclusion criteria, the number of the healthy parturients whose score of EPDS 6-weeks postpartum (6-wpp) < 5 and PPD patients whose EPDS 6-wpp ≥ 13 was ten respectively. Gas chromatography–mass spectrometry (GC–MS) analysis of CSF was used for metabolomic assessments. ResultsWe found that capric acid, dodecanoic acid, arachidic acid and behenic acid in CSF were significantly negatively correlated with PPD symptoms, meanwhile L-tryptophan had an obvious positive correlation. Moreover, these five biomarkers can be used as effective predictive biomarkers for PPD. LimitationsThe main limitations are the inclusion of only parturients who underwent caesarean sections and a small sample size. ConclusionsThis study innovatively investigated potential predictive biomarkers of PPD before the onset through intrapartum maternal CSF metabolomics, which offered a more objective approach to predict and diagnose PPD, leading to help identify high-risk parturients for early initiation of secondary prevention to reduce global PPD burden.

Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross-platform validation study.

Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts. We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing-Bablok regression analysis in a subset of CSF samples from the discovery cohort (n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform. THOP1 concentrations moderately correlated between proteomics analysis and our novel assays (Rho>0.580). In both validation cohorts, CSF THOP1 was increased in MCI-Aβ+ (>1.3-fold) and AD (>1.2-fold) compared with controls; and between MCI-Aβ+ and DLB (>1.2-fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t-tau), phosphorylated tau (p-tau), and Aβ40 (Rho>0.540) but not Aβ42. Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers.

Cerebrospinal fluid biomarkers in psychiatric autoimmune encephalitis: a retrospective cohort study.

Psychiatric autoimmune encephalitis (pAE) is a growing field of interest in diagnosis and therapy in psychiatric hospitals and institutions. This study investigates the relevant extent to which there are potential biomarkers in cerebrospinal fluid (CSF) that can differentiate against a cohort with neurodegenerative disease. We included in this study a total of 27 patients with possible and definite psychiatric autoimmune encephalitis and compared with a cohort with CSF-based AD (n = 27) different biomarkers in CSF such as lactate, cell count, % lymphocytes, % monocytes, total protein content, albumin, immunoglobulins G (IgG), M (IgM) and A (IgA), CSF/serum albumin ratio, CSF/serum IgG ratio, CSF/serum IgA ratio, intrathecal IgG synthesis, blood-brain barrier disruption, specific antibody synthesis for measles, rubella, herpes simplex virus, varicella zoster virus, Ebstein-Barr virus and cytomegalovirus, total tau protein (t-tau), phosphorylated tau protein 181 (p-tau181), amyloid beta 42 (Aß42), amyloid beta 40 (Aß40) and the amyloid beta 42/ amyloid beta 40 (Aß42/40) ratio. The p-tau 181 was elevated above cut-off values in both possible pAE and AD. However, in definitive pAE, p-tau181 levels were not elevated. When elevated p-tau181 levels in possible AE were compared with those in AD, we found relevant differences, such as a relative increase in p-tau181 in AD patients. Elevated p-tau181 levels were detected in possible psychiatric AEs with IgLON5, glycine, recoverin, titin, and nonspecific neuropil antibodies in serum and IgLON5, titin, Yo, and nonspecific neuropil autoantibodies in CSF. In addition, we detected elevated levels of p-tau181 and IgLON5 autoantibodies in serum and CSF, and Yo autoantibodies in CSF in patients with definitive pAE. Interestingly, we observed a higher CSF/serum IgM ratio in possible and definitive pAE than in AD patients. Our results suggest that neuroaxonal brain damage may occur in specific psychiatric AEs associated with IgLON5, glycine, recoverin, and titin autoantibodies. Further research should focus on the CSF/serum IgM ratio as an early marker of autoantibody production in pAE compared to AD as a potential biomarker for differential diagnosis.

The Importance of Cerebrospinal Fluid Investigation in First-episode Psychosis.

Despite being a reliable first-hand source of data on neuronal pathology, cerebrospinal fluid (CSF) analysis remains an often-overlooked evaluation method in first-episode psychosis (FEP). In this paper, we begin by discussing the current role of CSF testing during FEP evaluation in clinical practice. Given that anti-N-methyl-D-aspartate receptor encephalitis presents with a clinical picture indistinguishable from FEP in >85% of cases, we debate the importance of testing for CSF neuronal antibodies in at least a subset of patients. Then, we continue by reviewing the most important recent studies which sought to identify potential CSF biomarkers in FEP caused by a primary psychiatric disorder. By circumventing traditional psychiatric classifications, characteristic biomarker profiles have the potential to become integral components of early diagnosis, disease stratification, treatment choice, and outcome prediction. Along these lines, we aim to provide an updated perspective on the importance of CSF investigation in FEP.

Advanced Overview of Biomarkers and Techniques for Early Diagnosis of Alzheimer's Disease.

The development of early non-invasive diagnosis methods and identification of novel biomarkers are necessary for managing Alzheimer's disease (AD) and facilitating effective prognosis and treatment. AD has multi-factorial nature and involves complex molecular mechanism, which causes neuronal degeneration. The primary challenges in early AD detection include patient heterogeneity and lack of precise diagnosis at the preclinical stage. Several cerebrospinal fluid (CSF) and blood biomarkers have been proposed to show excellent diagnosis ability by identifying tau pathology and cerebral amyloid beta (Aβ) for AD. Intense research endeavors are being made to develop ultrasensitive detection techniques and find potent biomarkers for early AD diagnosis. To mitigate AD worldwide, understanding various CSF biomarkers, blood biomarkers, and techniques that can be used for early diagnosis is imperative. This review attempts to provide information regarding AD pathophysiology, genetic and non-genetic factors associated with AD, several potential blood and CSF biomarkers, like neurofilament light, neurogranin, Aβ, and tau, along with biomarkers under development for AD detection. Besides, numerous techniques, such as neuroimaging, spectroscopic techniques, biosensors, and neuroproteomics, which are being explored to aid early AD detection, have been discussed. The insights thus gained would help in finding potential biomarkers and suitable techniques for the accurate diagnosis of early AD before cognitive dysfunction.

Thimet Oligopeptidase is a potential CSF biomarker for Alzheimer’s Disease

AbstractBackgroundUsing antibody‐based Olink proteomics, we recently established that Thimet Oligopeptidase (THOP1) is a potential cerebrospinal fluid (CSF) biomarker for Alzheimer’s Disease (AD). THOP1 is a neuropeptidase able to degradate Aβ peptides. Here, we aimed to develop specific THOP1 immunoassays for further clinical validation and to enable future implementation of this biomarker.MethodWe developed and compared novel immunoassays for CSF THOP1 analysis on automated Ella™ and Simoa™ platforms. After analytical validation, THOP1 levels were measured in a selection of CSF samples from the original discovery study (24 cognitively unimpaired controls, 24 AD and 24 dementia with Lewy bodies (DLB) patients) on both platforms. Passing bablok‐regression analysis showed that platforms were comparable and thus we selected the Ella platform for further validation in two independent cohorts (Amsterdam Dementia cohort (ADC) including 56 controls, 45 mild cognitive impairment with amyloid pathology (MCI‐Aβ+), 55 AD and 55 DLB patients; Sant Pau Initiative on Neurodegeneration (SPIN) cohort including 53 controls, 50 MCI‐Aβ+, 47 AD and 50 DLB patients). Differences in THOP1 levels between diagnostic groups and correlations to the AD CSF biomarkers were tested by ANCOVA (corrected for sex) and Spearman correlation analyses.ResultTHOP1 levels moderately correlated between proteomics analysis and the novel assays (Olink‐Ella: rho=0.720; Olink‐Simoa: rho=0.584; Ella‐Simoa rho=0.713; figure 1). Consistent with results obtained on the Olink proteomics platform, THOP1 levels were significantly increased in AD compared to DLB patients (Ella: 1.6‐fold; Simoa: 1.7‐fold) and controls (Ella: 1.8‐fold; Simoa: p&gt;0.05). We next showed increased THOP1 levels in both MCI‐Aβ+ (ADC: 1.2‐fold, p&lt;0.05; SPIN: 1.4‐fold, p&lt;0.001) and AD patients (ADC: 1.03‐fold, p&gt;0.05; SPIN: 1.4‐fold, p&lt;0.001) compared to controls (Figure 2). THOP1 levels correlated moderately with levels of t‐Tau (ADC: rho=0.644; SPIN: rho=0.721), p‐Tau (ADC: rho=0.480; SPIN: rho=0.712) and Aβ40 (ADC: not available; SPIN: rho=0.625) but not with Aβ42 (ADC: rho=0.110; SPIN: rho=‐0.09).ConclusionWe show increased CSF THOP1 levels in amyloid positive AD and MCI patients and correlation with CSF Aβ40, which together with literature showing colocalization of THOP1 with Aβ plaques suggests a relationship with Aβ‐production. The association of THOP1 to tau pathologies highlights the potential of this protein as a disease monitoring biomarker.

Identification of cerebrospinal fluid biomarkers for parkinsonism using a proteomics approach

The aim of our study was to investigate cerebrospinal fluid (CSF) tryptic peptide profiles as potential diagnostic biomarkers for the discrimination of parkinsonian disorders. CSF samples were collected from individuals with parkinsonism, who had an uncertain diagnosis at the time of inclusion and who were followed for up to 12 years in a longitudinal study. We performed shotgun proteomics to identify tryptic peptides in CSF of Parkinson’s disease (PD, n = 10), multiple system atrophy patients (MSA, n = 5) and non-neurological controls (n = 10). We validated tryptic peptides with differential levels between PD and MSA using a newly developed selected reaction monitoring (SRM) assay in CSF of PD (n = 46), atypical parkinsonism patients (AP; MSA, n = 17; Progressive supranuclear palsy; n = 8) and non-neurological controls (n = 39). We identified 191 tryptic peptides that differed significantly between PD and MSA, of which 34 met our criteria for SRM development. For 14/34 peptides we confirmed differences between PD and AP. These tryptic peptides discriminated PD from AP with moderate-to-high accuracy. Random forest modelling including tryptic peptides plus either clinical assessments or other CSF parameters (neurofilament light chain, phosphorylated tau protein) and age improved the discrimination of PD vs. AP. Our results show that the discovery of tryptic peptides by untargeted and subsequent validation by targeted proteomics is a suitable strategy to identify potential CSF biomarkers for PD versus AP. Furthermore, the tryptic peptides, and corresponding proteins, that we identified as differential biomarkers may increase our current knowledge about the disease-specific pathophysiological mechanisms of parkinsonism.

Diagnostic biomarkers from proteomic characterization of cerebrospinal fluid in patients with brain malignancies.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.

Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer's Disease.

Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer's disease (AD) and vascular dementia (VaD) compared with controls. The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC=0.83.0.93, p≤0.05) and as compared with the control group (AUC=0.79.0.87, p≤0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC=0.86.0.91, p≤0.05) and to controls (AUC=0.80.0.82, p≤0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC=0.64.80, p>0.05). No peptides differed between AD and controls. Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.

Cutibacterium acnes Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome.

Cutibacterium acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is likely underdiagnosed due to the difficulty in culturing this pathogen. Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. Currently, the gold standard for identifying CSF shunt infections is microbiologic culture. However, C. acnes infection often results in falsely negative cultures; therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a rat model of CSF catheter infection to C. acnes. We found elevated levels of interleukin-1β (IL-1β), IL-6, chemokine ligand 2, and IL-10 in the CSF and brain tissues of animals implanted with C. acnes-infected catheters compared to sterile controls at day 1 postinfection. This coincided with modest increases in neutrophils in the CSF and, to a greater extent, in the brain tissues of animals with C. acnes infection, which closely mirrors the clinical findings in patients with C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of disease, typified at day 1 postinfection by an acute-phase and pathogen neutralization response evolving to a response consistent with wound resolution at day 28 compared to a sterile catheter placement. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile postoperative inflammation and that CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.

Platelet‐derived growth factor receptor‐beta as a potential CSF biomarker for Alzheimer’s disease

AbstractBackgroundThere is a lack of biomarkers for the early detection of Alzheimer’s disease (AD). Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid‐β (Aβ) in the cerebral vasculature, is commonly found in AD. Platelet‐derived growth factor receptor‐β (PDGFRβ) is expressed by pericytes and since blood‐brain barrier (BBB) dysfunction is associated with pericyte degeneration, release of PDGFRβ protein may be a biomarker for BBB dysfunction, that is expected in CAA. Indeed, it has recently been described that PDGFRβ levels are elevated in cerebrospinal fluid (CSF) from patients with mild cognitive impairment (MCI) as compared to controls1. The aim of our study was to investigate the diagnostic and discriminative value of PDGFRβ in CSF in patients at various clinical stages of AD and in patients with CAA.MethodCSF PDGFRβ, Aβ42, total tau (t‐tau) and phosphorylated tau (p‐tau) levels were quantified by ELISA. Cohorts of controls (n=47), CAA patients (n=27) and AD patients (n=59; 19 patients with MCI (clinical dementia rating (CDR) = 0.5), 28 patients with CDR 1.0 and 12 patients with a CDR of ≥ 2.0) were studied.ResultCSF PDGFRβ levels were similar in controls, AD and CAA patients. Moreover, PDGFRβ levels were similar in patients at the various clinical stages of AD. PDGFRβ levels also did not correlate with blood‐CSF barrier dysfunction (i.e. elevated albumin ratio). We observed a strong correlation of CSF PDGFRβ levels with t‐tau and p‐tau levels, the degree of which was dependent on the CDR score. Interestingly, CSF PDGFRβ levels were significantly elevated in a selection of MCI/AD patients with an AD‐positive CSF biomarker profile (A+T+) as compared to controls with a completely normal profile of AD biomarkers (A‐T‐N‐).ConclusionWe could neither confirm previously reported elevated CSF PDGFRβ levels in MCI patients1, nor did we find elevated PDGFRβ levels in CAA patients. Our results suggest that CSF PDGFRβ levels are not useful as marker of BBB integrity, but instead may, as previously reported, be associated with AD (tau) pathology2.