Changes In CSF Levels Research Articles

Neuronal and glial CSF biomarkers in multiple sclerosis: a systematic review and meta-analysis.

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.

Localization, Occurrence, and CSF Changes of SP-G, a New Surface Active Protein with Assumable Immunoregulatory Functions in the CNS.

Conventional surfactant proteins (A, B, C, and D) are important players of the innate immunity in the central nervous system and serve as effective regulators of cerebrospinal fluid rheology, probably being involved in clearance of detrimental metabolites like beta-amyloid and phospho-tau. Recently, a novel surfactant protein, SP-G, was described in kidneys and peripheral endocrine and exocrine glands. So far, its presence and possible functions in the central nervous system are unknown. Therefore, our study aimed to elucidate the presence of SP-G in the brain and its concentration in normal and pathologic samples of cerebrospinal fluid in order to gain first insight into its regulation and possible functions. A total of 121 samples of human cerebrospinal fluid (30 controls, 60 hydrocephalus patients, 7 central nervous system infections, and 24 brain hemorrhage patients) and 21 rat brains were included in our study. CSF samples were quantified using a commercially available ELISA system. Results were analyzed statistically using SPSS 22, performing Spearman Rho correlation and ANOVA with Dunnett's post hoc analysis. Rat brains were investigated via immunofluorescence to determine SP-G presence and colocalization with common markers like aquaporin-4, glial fibrillary acidic protein, platelet endothelial adhesion molecule 1, and neuronal nuclear antigen. SP-G occurs associated with brain vessels, comparable to other conventional SPs, and is present in a set of cortical neurons. SP-G is furthermore actively produced by ependymal and choroid plexus epithelium and secreted into the cerebrospinal fluid. Its concentrations are low in control subjects and patients suffering from aqueductal stenosis, higher in normal pressure hydrocephalus (p < 0.01), and highest in infections of the central nervous system and brain hemorrhage (p < 0.001). Interestingly, SP-G did correlate with total CSF protein in patients with CNS infections and hemorrhage, but not with cell count. Based on the changes in CSF levels of SP-G in hydrocephalus, brain hemorrhage, and CNS infections as well as its abundance at CSF flow-related anatomical structures closely associated with immunological barrier systems, importance for CSF rheology, brain waste clearance, and host defense is assumable. Thus, SP-G is a potential new CSF biomarker, possibly not only reflecting aspects of CNS innate immune responses, but also rheo-dynamically relevant changes of CSF composition, associated with CSF malabsorbtion. However, further studies are warranted to validate our findings and increase insight into the physiological importance of SP-G in the CNS.

A Specific Reduction in Aβ1-42 vs. a Universal Loss of Aβ Peptides in CSF Differentiates Alzheimer's Disease From Meningitis and Multiple Sclerosis.

A reduced concentration of Aβ1−42 in CSF is one of the established biomarkers of Alzheimer's disease. Reduced CSF concentrations of Aβ1−42 have also been shown in multiple sclerosis, viral encephalitis and bacterial meningitis. As neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease, an infectious origin of the disease has been proposed. According to this hypothesis, amyloid pathology is a consequence of a microbial infection and the resulting immune defense. Accordingly, changes in CSF levels of amyloid-β peptides should be similar in AD and inflammatory brain diseases. Aβ1−42 and Aβ1−40 levels were measured in cerebrospinal fluid by ELISA and Western blotting in 34 patients with bacterial meningitis (n = 9), multiple sclerosis (n = 5) or Alzheimer's disease (n = 9) and in suitable controls (n = 11). Reduced concentrations of Aβ1−42 were detected in patients with bacterial meningitis, multiple sclerosis and Alzheimer's disease. However, due to a concurrent reduction in Aβ1−40 in multiple sclerosis and meningitis patients, the ratio of Aβ1−42/Aβ1−40 was reduced only in the CSF of Alzheimer's disease patients. Urea-SDS-PAGE followed by Western blotting revealed that all Aβ peptide variants are reduced in bacterial meningitis, whereas in Alzheimer's disease, only Aβ1−42 is reduced. These results have two implications. First, they confirm the discriminatory diagnostic power of the Aβ1−42/Aβ1−40 ratio. Second, the differential pattern of Aβ peptide reductions suggests that the amyloid pathology in meningitis and multiple sclerosis differs from that in AD and does not support the notion of AD as an infection-triggered immunopathology.

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

Several studies report associations between the particularly interesting new cysteine histidine-rich (PINCH) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients, and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy or before and after a change in the treatment regimen. The intervals were approximately 1 (T2) and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4 T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold changes in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm(3) at T2 compared to those with CD4 counts <200 cells/mm(3) at T2. This trend persisted irrespective of plasma or CSF viral burden or antiretroviral therapy CPE scores. The fold changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation coefficient = 0.69, p < 0.001; correlation coefficient = 0.83, p < 0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, WBC, or antiretroviral regimen CPE.

Mother–infant interactions in free-ranging rhesus macaques: Relationships between physiological and behavioral variables

Studies of mother–infant relationships in nonhuman primates have increasingly attempted to understand the neuroendocrine bases of interindividual variation in mothering styles and the mechanisms through which early exposure to variable mothering styles affects infant behavioral development. In this study of free-ranging rhesus macaques on Cayo Santiago, Puerto Rico, we aimed to: 1) compare lactating and nonlactating females to investigate whether lactation is associated with changes in plasma cortisol, prolactin and oxytocin, as well as changes in CSF levels of serotonin and dopamine metabolites (5-HIAA and HVA); 2) examine the extent to which interindividual variation in maternal physiology is associated with variation in maternal behavior; 3) examine the extent to which interindividual variation in infant physiology and behavior is accounted for by variation in maternal physiology and behavior. Lactating females had higher plasma concentrations of cortisol, prolactin, and oxytocin but lower CSF concentrations of HVA than nonlactating females. Variation in maternal rejection behavior was positively correlated with variation in maternal plasma cortisol levels and in CSF 5-HIAA levels while variation in the time spent nursing and grooming was associated with maternal plasma oxytocin levels. Infants who were protected more by their mothers had higher cortisol levels than those who were protected less, while infants who were rejected more had lower CSF 5-HIAA than infants who were rejected less. Since exposure to high levels of maternal protectiveness and rejection is known to affect the offspring's behavior and responsiveness to the environment later in life, our results are consistent with the hypothesis that these effects are mediated by long-term changes in the activity of the offspring's HPA axis and brain serotonergic system.

O2-04-07: Treatment with donepezil in Korean Alzheimer patients with and without cerebrovascular factors: One-year follow-up study

randomized to receive either Vitamin E 800 IU vitamin C 200 mg alpha lipoic acid 600 mg/day; coenzyme Q 2400 mg per day (800mg 3 times per day), or placebo, for 16 weeks. CSF and plasma were obtained at baseline and after 16 weeks of treatment. Physical examination, blood tests and adverse event reports were used to monitor safety. The MMSE and ADCS-ADL were administered at baseline and week 16. CSF levels of A-beta42, tau and P-tau181 were measured by multiplex assays. F2-isoprostanes are measured by LC-MS methods. Clinical and CSF data were compared between groups using ANCOVA models. Results: 78 subjects with AD (50% women) were randomized. Study medications were well-tolerated, without differences in adverse events between groups. 74 subjects completed treatment and had successful serial lumbar punctures. At baseline, means (SD) were: age 72.8 (9.1), MMSE 22.9 (3.7); these did not differ between treatment arms. CSF levels of A-beta42, tau and P-tau-181 did not differ between treatment arms at baseline. Changes in CSF levels of A-beta42, tau and P-tau181 from baseline to week 16 did not differ between either treatment arm and placebo. Measurements of F2-isoprostanes are in progress. Conclusions: Treatment with a cytosolic antioxidant combination or with CoQ did not alter CSF biomarkers related to A-beta or tau in AD. The supplements, at the doses used, did not appear to influence AD pathologic processes in the brain sufficiently to alter CSF biomarkers. Supported by NIA grant AG10483.

Neuron-specific enolase as an aid to outcome prediction in head injury.

A statistically significant elevation was observed in serum and CSF neuron-specific enolase (NSE) levels in patients with major head injury, relative to control individuals. No correlation was noted between serum NSE and either APACHE II, Injury Severity Score (ISS), Glasgow Outcome Score (GOS) or Glasgow Coma Scale (GCS). A significant correlation was noted between CSF NSE levels and GCS, but not between CSF NSE and APACHE II, ISS or GOS. Of the patients with major head injury, 100% had NSE CSF levels above the normal level, while 47% had elevated serum NSE levels. In nine patients with major head injury, changes in CSF levels reflected changes in serum NSE levels. In all nine patients, serum NSE decreased to reach normal values, regardless of the outcome as predicted by the GOS. Therefore, while NSE would appear to be a marker of neuronal cell damage, other markers are also essential.

Effect of vigabatrin (gamma-vinyl GABA) on amino acid levels in CSF of epileptic patients.

Vigabatrin (gamma-vinyl GABA) is a new anticonvulsive drug that irreversibly inhibits the activity of GABA transaminase. The effect of vigabatrin on neurotransmission-related amino acids in CSF of 28 epileptic patients was studied and the relationship between the amino acid pattern and clinical response during 7 months of administration of vigabatrin. Of this study population, 46% had more than 50% decrease in seizure frequency (responders). In 54% the seizures decreased less than 50% (nonresponders). In the whole study group, the levels of total GABA during vigabatrin treatment were 283%, free GABA 197%, homocarnosine 310% and glycine 128% that of the levels at baseline in the same patients. Glutamate, glutamine, aspartate, asparagine, and taurine concentrations did not change. The amino acid pattern in CSF during administration of vigabatrin did not differ significantly in responders and nonresponders. The study suggests that both GABAergic and glycinergic neurotransmission are affected by vigabatrin. The changes in CSF levels of neurotransmitter amino acids are, however, not necessarily related to the clinical response.

Effects of microbial flora on levels of colonay stimulating factor in serums of irradiated CFW mice.

SummaryGermfree, specifically mono-associated with bacteria, and conventional CFW mice were evaluated for changes in serum CSF levels following 850 R whole-body X-irradiation. Gram-negative E. coli-monoassociated mice showed elevations of CSF levels similar to that in conventional mice. However, CSF levels in mice mono-associated with S. faecalis remained unchanged, as in germfree mice. In mice with bone marrow transplantations following X-irradiation, serum CSF levels were maintained at the level of untreated mice, which indicates that CSF levels are regulated by functioning bone marrow cells. The data also indicates that the changes in CSF levels that are associated with gram-negative bacteria may be due to the production of endotoxin, which is involved in levels of serum CSF; which, in turn, may play a role in regulating granulopoiesis.We express our thanks to Dr. Donald Metcalf for his valuable advice in implementation of this project.