Enhanced Brain Clearance of Tau and Amyloid-ß in Alzheimer's Disease Patients by Transcranial Radiofrequency Wave Treatment: A Central Role of Vascular Endothelial Growth Factor (VEGF).

Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered-meningeal lymphatic vessels (mLVs)-which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-ß (Aß) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aß1-40, Aß1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aß from the brain, likely through VEGF's actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aß clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels.

Astrocytic-derived vascular remodeling factors are independently associated with blood brain barrier permeability in Alzheimer's disease.

Astrocytes in Alzheimer's disease (AD) exert a pivotal role in the maintenance of blood-brain barrier (BBB) integrity essentially through structural support and release of soluble factors. This study provides new insights into the vascular remodeling processes occurring in AD, and reveals, in vivo, a pathological profile of astrocytic secretion involving Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinases (MMP)-9, MMP-2 and Endothelin-1 (ET-1). Cerebrospinal fluid (CSF) levels of VEGF, MMP-2/-9 were lower in patients belonging to the AD continuum, compared to aged-matched controls. CSF levels of VEGF and ET-1 positively correlated with MMP-9 but negatively with MMP-2, suggesting a complex vascular remodeling process occurring in AD. Only MMP-2 levels were significantly associated with CSF AD biomarkers. Conversely, higher MMP-2 (ß = 0.411, p < 0.001), ET-1 levels (ß = 0.344, p < 0.001) and VEGF (ß = 0.221, p = 0.022), were associated with higher BBB permeability. Astrocytic-derived vascular remodeling factors are altered in AD, disclosing the failure of important protective mechanisms which proceed independently alongside AD pathology.

Association of Vascular Endothelial Growth Factor Levels with Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss. Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the association of CSF and serum VEGF concentrations with the risk of Alzheimer's disease was investigated using systematic review and meta-analysis. METHODS: A systematic literature search was carried out using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. The meta-analysis was performed using the random-effects model and only case-control publications describing VEGF concentrations in Alzheimer's patients were considered for calculating the pooled effect size. RESULTS: In the systematic literature search, 6 and 13 studies met the inclusion criteria to evaluate CSF and serum VEGF concentrations of Alzheimer's patients, respectively. This meta-analysis retrieved a total number of 2380 Alzheimer's patients and 5368 healthy controls. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer's patients were -0.13 (95%CI,-0.42-0.16) and 0.23 (95%CI,-0.27-0.73), respectively. Results of meta-regression analysis showed that the quality scores of papers and female sex ratios of participants did not affect the associations of VEGF concentrations with the risk of Alzheimer's disease. However, the age average of patients significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer's disease (P=0.051). There was a statistically significant subgroup effect for the disease severity of Alzheimer's patients which modifies the associations of serum VEGF concentrations with the risk of Alzheimer's disease (P<0.01) and subgroup analysis shows that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer's disease (P<0.01). CONCLUSION: The results show that the serum VEGF concentrations increased for Alzheimer's patients in accordance with the increased expression of VEGF and the VEGF levels of Alzheimer's patients decreased by increasing their disease severities. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.

Distribution of Bevacizumab into the Cerebrospinal Fluid of Children and Adolescents with Recurrent Brain Tumors.

BACKGROUND: To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). OBJECTIVE: This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. PATIENTS AND METHODS: Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. RESULTS: Apart from in serum (minimum concentration/maximum concentration [Cmin/Cmax] 77.0-305/267-612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01-2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). CONCLUSIONS: This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.

A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.

Cerebrospinal fluid cytokine levels are associated with macrophage infiltration into tumor tissues of glioma patients.

BACKGROUND: Diffuse gliomas are the most common malignant tumors of the central nervous system with poor treatment efficacy. Infiltration of immune cells into tumors during immunosurveillance is observed in multiple tumor entities and often associated with a favorable outcome. The aim of this study was to evaluate the infiltration of immune cells in gliomas and their association with cerebrospinal fluid (CSF) cytokine concentrations. METHODS: We applied immunohistochemistry in tumor tissue sections of 18 high-grade glioma (HGG) patients (4 anaplastic astrocytoma, IDH-wildtype WHO-III; 14 glioblastomas (GBM), IDH-wildtype WHO-IV) in order to assess and quantify leucocytes (CD45) and macrophages (CD68, CD163) within the tumor core, infiltration zone and perivascular spaces. In addition, we quantified the concentrations of 30 cytokines in the same patients' CSF and in 14 non-inflammatory controls. RESULTS: We observed a significantly higher percentage of CD68+ macrophages (21-27%) in all examined tumor areas when compared to CD45+ leucocytes (ca. 3-7%); CD163+ cell infiltration was between 5 and 15%. Compared to the tumor core, significantly more macrophages and leucocytes were detectable within the perivascular area. The brain parenchyma showing a lower tumor cell density seems to be less infiltrated by macrophages. Interleukin (IL)-7 was significantly downregulated in CSF of GBM patients compared to controls. Additionally, CD68+ macrophage infiltrates showed significant correlations with the expression of eotaxin, interferon-γ, IL-1ß, IL-2, IL-10, IL-13, IL-16 and vascular endothelial growth factor. CONCLUSIONS: Our findings suggest that the infiltration of lymphocytes is generally low in HGG, and does not correlate with cytokine concentrations in the CSF. In contrast, macrophage infiltrates in HGG are associated with CSF cytokine changes that possibly shape the tumor microenvironment. Although results point towards an escape from immunosurveillance or even exploitation of immune cells by HGG, further studies are necessary to decipher the exact role of the immune system in these tumors.

Regional relationships between CSF VEGF levels and Alzheimer's disease brain biomarkers and cognition.

Vascular endothelial growth factor (VEGF) is a complex signaling protein that supports vascular and neuronal function. Alzheimer's disease (AD) -neuropathological hallmarks interfere with VEGF signaling and modify previously detected positive associations between cerebral spinal fluid (CSF) VEGF and cognition and hippocampal volume. However, it remains unknown 1) whether regional relationships between VEGF and glucose metabolism and cortical thinning exist, and 2) whether AD-neuropathological hallmarks (CSF Aß, t-tau, p-tau) also modify these relationships. We addressed this in 310 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (92 cognitively normal, 149 mild cognitive impairment, 69 AD; 215 CSF Aß+, 95 CSF Aß-) with regional cortical thickness and cognition measurements and 158 participants with FDG-PET. In Aß + participants (CSF Aß42 ≤ 192 pg/mL), higher CSF VEGF levels were associated with greater FDG-PET signal in the inferior parietal, and middle and inferior temporal cortices. Abnormal CSF amyloid and tau levels strengthened the positive association between VEGF and regional FDG-PET indices. VEGF also had both direct associations with semantic memory, as well as indirect associations mediated by regional FDG-PET signal to cognition.

Inflammatory Markers in Cerebrospinal Fluid from Patients with Hydrocephalus: A Systematic Literature Review.

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 3rd 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-1ß, 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-1ß, 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.

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects.

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.

Beta-amyloid peptides(1-42) and (1-40) in the cerebrospinal fluid during pregnancy: a prospective observational study.

To evaluate changes in concentrations of selected biomarkers, neurotrophic factors, and growth factors in the cerebrospinal fluid during pregnancy. A prospective observational study was conducted in 32 pregnant women undergoing gynecological and obstetrical surgery under spinal anesthesia in a university hospital. Beta-amyloid(1-42) and beta-amyloid(1-40) peptides, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor were analyzed in cerebrospinal fluid using an enzyme-linked immunosorbent assay. Eight women in second trimester pregnancy who underwent spinal anesthesia for gynecological or obstetrical surgery were compared with 24 matched women in third trimester pregnancies. CSF concentrations of beta-amyloid(1-42) were significantly higher in third trimester pregnancies (p = 0.025). During third trimester, the beta-amyloid ratio correlated with the vascular endothelial growth factor (rs = 0.657; p = 0.008). Higher concentrations of beta-amyloid(1-42) in cerebrospinal fluid of third trimester pregnancies and correlations between the beta-amyloid ratio and the vascular endothelial growth factor support the hypothesis that beta-amyloid peptides are involved in complex adaptive brain alterations during pregnancy.

Identifying putative cerebrospinal fluid biomarkers of amyotrophic lateral sclerosis in a north Indian population.

INTRODUCTION: Evidence-based information about cerebrospinal fluid (CSF) levels of biomarkers in patients with amyotrophic lateral sclerosis (ALS) is limited. METHODS: Vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2), optineurin (OPTN), monocyte chemoattractant protein-1 (MCP-1), angiogenin (ANG), and TAR DNA-binding protein (TDP-43) were quantified by enzyme-linked immunoassay in the CSF of 54 patients with sporadic ALS and 32 controls in a case-control study design. RESULTS: CSF levels of VEGF (P = .014) and ANG (P = .009) were decreased, whereas VEGFR2 was higher (P = .002) in patients with ALS than in controls. TDP-43 positively correlated with MCP-1 (P = .003), VEGF (P < .001), and VEGFR2 (P < .001) in patients with ALS. DISCUSSION: Our findings suggest possible utility of VEGF, VEGFR2, and ANG as biomarkers for use in ALS treatment trials.

Cerebrospinal fluid VEGF levels and angiogenic capacity as potential prognostic markers in patients with gliomas: a pilot study.

INTRODUCTION: Gliomas are tumors of the central nervous system. Despite new classifications, they are still divided in low and high-grade gliomas, being the latter of greater malignancy. The degree of malignancy is directly related with the angiogenic activity in tumoral tissues. We measured VEGF concentrations and angiogenic capacity in cerebrospinal fluid (CSF) from patients with high and low-grade gliomas. The purpose of this study was to find a biomarker that contributes in the differential diagnosis and prognosis of gliomas. METHODS: CSF was obtained from 19 individuals: 8 with low-grade gliomas, 6 with high-grade gliomas and 5 controls. VEGF concentration in CSF was measured by ELISA and the angiogenic capacity was measured by chick chorioallantoic membrane (CAM) test. RESULTS: The VEGF concentration was higher in patients with high-grade gliomas, compared to patients with low-grade gliomas and controls (2860 pg/mL ± 975 vs. 182.6 ± 37.1 and 47.4 ± 0.4, respectively). On the other hand, CSF from patients with high-grade gliomas generated a higher microvascular density (MVD) than patients with low-grade gliomas and controls (13.23 ± 0.6 vessels/9000µm2 vs. 9.3 ± 0.3 and 7.92 ± 0.2, respectively). Interestingly, there was not statistical differences in both VEGF levels and angiogenic capacity in patients with low-grade gliomas and controls. CONCLUSION: Together VEGF levels and angiogenic capacity in CSF can be used as a biological marker of gliomas malignancy.

Reduced vascular endothelial growth factor levels in the cerebrospinal fluid in patients with treatment resistant major depression and the effects of electroconvulsive therapy-A pilot study.

BACKGROUND: Several lines of evidence are pointing towards an involvement of the vascular endothelial growth factor (VEGF) in the pathophysiology of depression. There are studies analyzing blood levels of VEGF in patients with depression compared to controls, but a data on cerebrospinal fluid (CSF) levels of VEGF in patients with depression are lacking. METHOD: CSF VEGF levels were measured in patients (n = 12) with a severe, treatment-resistant depressive episode before and after the antidepressant treatment by a course of electroconvulsive therapy (ECT) and compared to age- and sex-matched controls (n = 20). RESULTS: The patients with depression showed lower mean VEGF levels in the CSF prior to ECT than the controls (p = 0.041). Regarding the patients, CSF VEGF concentration at baseline and after the complete ECT treatment did not differ from each other (p = 0.78). LIMITATIONS: Major limitations of this study are the small sample size and that data from corresponding serum levels cannot be provided. Another limitation is that the controls were not completely healthy, as they were recruited from a memory clinic with subjective complaints. The timing of the second sample might have been suboptimal, when taking into account that there might be an on-going phase of re-equilibrating after ECT. CONCLUSIONS: CSF VEGF concentrations were lower in a clinical sample of patients with treatment-resistant depression compared with matched controls. Additionally, no change in CSF VEGF levels during a course of ECT could be detected.

CSF inflammatory markers differ in gram-positive versus gram-negative shunt infections.

BACKGROUND: Cerebrospinal fluid (CSF) shunt placement is frequently complicated by bacterial infection. Shunt infection diagnosis relies on bacterial culture of CSF which can often produce false-negative results. Negative cultures present a conundrum for physicians as they are left to rely on other CSF indices, which can be unremarkable. New methods are needed to swiftly and accurately diagnose shunt infections. CSF chemokines and cytokines may prove useful as diagnostic biomarkers. The objective of this study was to evaluate the potential of systemic and CSF biomarkers for identification of CSF shunt infection. METHODS: We conducted a retrospective chart review of children with culture-confirmed CSF shunt infection at Children's Hospital and Medical Center from July 2013 to December 2015. CSF cytokine analysis was performed for those patients with CSF in frozen storage from the same sample that was used for diagnostic culture. RESULTS: A total of 12 infections were included in this study. Patients with shunt infection had a median C-reactive protein (CRP) of 18.25 mg/dL. Median peripheral white blood cell count was 15.53 × 103 cells/mL. Those with shunt infection had a median CSF WBC of 332 cells/mL, median CSF protein level of 406 mg/dL, and median CSF glucose of 35.5 mg/dL. An interesting trend was observed with gram-positive infections having higher levels of the anti-inflammatory cytokine interleukin (IL)-10 as well as IL-17A and vascular endothelial growth factor (VEGF) compared to gram-negative infections, although these differences did not reach statistical significance. Conversely, gram-negative infections displayed higher levels of the pro-inflammatory cytokines IL-1ß, fractalkine (CX3CL1), chemokine ligand 2 (CCL2), and chemokine ligand 3 (CCL3), although again these were not significantly different. CSF from gram-positive and gram-negative shunt infections had similar levels of interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8. CONCLUSIONS: This pilot study is the first to characterize the CSF cytokine profile in patients with CSF shunt infection and supports the distinction of chemokine and cytokine profiles between gram-negative and gram-positive infections. Additionally, it demonstrates the potential of CSF chemokines and cytokines as biomarkers for the diagnosis of shunt infection.

Association of vascular endothelial growth factor levels in CSF and cerebral glucose metabolism across the Alzheimer's disease spectrum.

The association of vascular endothelial growth factor (VEGF) levels in CSF and cerebral glucose metabolism across the Alzheimer's disease (AD) spectrum is unclear. CSF VEGF levels were cross-sectionally related to cerebral glucose metabolism, as measured by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), using linear regression models. We found that VEGF levels were associated with cerebral glucose metabolism in patients with mild cognitive impairment (MCI) and AD, but not in cognitively normal older adults. Our data indicated that VEGF may play an important role in cerebral glucose metabolism.

Cerebrospinal Fluid Inflammatory Cytokine Aberrations in Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

It has been suggested that cytokine-mediated inflammation plays a key role for the onset and/or development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). However, clinical studies have yielded inconsistent results for the aberrant cytokine levels in circulation of patients with AD, PD, and ALS. Previous studies have used meta-analysis to address the inconsistent data for blood cytokine levels in the patients with AD, PD, and ALS. Here, we performed a systemic review of cerebrospinal fluid inflammatory cytokine data in patients with AD, PD and ALS, and sought to quantitatively summarize the CSF inflammatory cytokine data with a meta-analytical technique. The systematic search from Pubmed and Web of Science identified 71 articles with 2629 patients and 2049 controls for the meta-analysis. Random-effects meta-analysis demonstrated that CSF TGF-ß, MCP-1, and YKL-40 levels were significantly elevated in AD patients when compared with controls. In addition, patients with PD had heightened levels of TGF-ß1, IL-6, and IL-1ß in CSF. Furthermore, G-CSF, IL-2, IL-15, IL-17, MCP-1, MIP-1α, TNF-α, and VEGF levels were significantly increased in patients with ALS as compared with controls. Taken together, these results not only strengthen the clinical evidence that neurodegenerative diseases are accompanied by the increased inflammatory response, but also reveal the unique inflammatory response profile in the central nervous system of patients with AD, PD and ALS. Given the robust associations between some cytokines and neurodegenerative diseases found in this meta-analysis, CSF inflammatory cytokines may be used as biomarkers for these diseases in the future.

Vascular Endothelial Growth Factor remains unchanged in cerebrospinal fluid of patients with Alzheimer's disease and vascular dementia.

BACKGROUND: Increasing evidence suggests that cerebral vascular dysfunction is associated with the early stages of Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF) is one of the key players involved in the development and maintenance of the vasculature. Here, we hypothesized that VEGF levels in cerebrospinal fluid (CSF) may be altered in AD patients with vascular involvement, characterized by the presence of microbleeds (MB), and in vascular dementia (VaD) patients compared to controls. METHODS: VEGF levels were determined by electrochemilumiscence Meso Scale Discovery (MULTI-SPOT Assay System) in CSF from age-matched groups of controls with subjective cognitive decline (n = 21), AD without MB (n = 25), AD with MB (n = 25), and VaD (n = 21) patients. RESULTS: The average level of VEGF in the different groups was 2.8 ± 1 pg/ml CSF. Adjusted for age and gender, no significant differences were detected between groups (p > 0.5). However, we detected a significant correlation between the concentration of VEGF in the CSF and age (r = 0.22, p = 0.03). In addition, males (n = 54) revealed higher VEGF levels in their CSF compared to females (n = 38) (males = 3.08 ± 0.769 pg/ml (mean ± SD), females = 2.6 ± 0.59; p = 0.006), indicating a gender-related regulation. CONCLUSION: Our study suggests that VEGF levels in the CSF do not reflect the cerebral vascular alterations in either AD or VaD patients. The observed associations of VEGF with age and gender may indicate that VEGF reflects normal aging and that males and females may differ in their aging process.

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer's disease.

BACKGROUND: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD. METHODS: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time. RESULTS: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories. CONCLUSIONS: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

Effects of surgery and propofol-remifentanil total intravenous anesthesia on cerebrospinal fluid biomarkers of inflammation, Alzheimer's disease, and neuronal injury in humans: a cohort study.

BACKGROUND: Surgery and anesthesia have been linked to postoperative cognitive disturbance and increased risk of Alzheimer's disease. It is not clear by which mechanisms this increased risk for cognitive disease is mediated. Further, amyloid ß production has been suggested to depend on the sleep-wake cycle and neuronal activity. The aim of the present study was to examine if cerebrospinal fluid (CSF) concentrations of a number of biomarkers for Alzheimer's disease-related processes, including amyloid ß, neuronal injury, and inflammation, changed over time during intravenous anesthesia in surgical patients. METHODS: We included patients scheduled for hysterectomy via laparotomy during general anesthesia with intravenous propofol and remifentanil. CSF samples were obtained before, during, and after surgery (5 h after induction) and tested for 27 biomarkers. Changes over time were tested with linear mixed effects models. RESULTS: A total of 22 patients, all females, were included. The mean age was 50 years (± 9 SD). The mean duration of the anesthesia was 145 min (± 40 SD). Interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, and vascular endothelial growth factor A increased over time. IL-15 and IL-7 decreased slightly over time. Macrophage inflammatory protein 1ß and placental growth factor also changed significantly. There were no significant effects on amyloid ß (Aß) or tau biomarkers. CONCLUSIONS: Surgery and general anesthesia with intravenous propofol and remifentanil induce, during and in the short term after the procedure, a neuroinflammatory response which is dominated by monocyte attractants, without biomarker signs of the effects on Alzheimer's disease pathology or neuronal injury.

Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype.

Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF biomarkers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage.