Cerebrospinal Fluid Concentrations Research Articles

Metals in Alzheimer's Disease.

The role of metals in the pathogenesis of Alzheimer's disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies that (1) compared the metal concentrations between AD patients and healthy controls, (2) correlated concentrations of AD cerebrospinal fluid (CSF) biomarkers with metal concentrations, and (3) used Mendelian randomization (MR) to assess the potential metal contributions to AD risk. Although many studies have examined various metals in dementia patients, understanding the dynamics of metals in these patients remains difficult due to considerable inconsistencies among the results of individual studies. The most consistent findings were for Zn and Cu, with most studies observing a decrease in Zn levels and an increase in Cu levels in AD patients. However, several studies found no such relation. Because few studies have compared metal levels with biomarker levels in the CSF of AD patients, more research of this type is required. Given that MR is revolutionizing epidemiologic research, additional MR studies that include participants from diverse ethnic backgrounds to assess the causal relationship between metals and AD risk are critical.

Abstract 3581: Differentiation of niraparib and olaparib brain penetration in healthy rhesus macaque monkeys

Abstract Purpose: There remains an unmet need to provide effective treatment therapy for patients with primary and metastatic brain tumors; lack of drug penetration across the blood brain barrier (BBB) is a key factor. Synthetic lethality is an attractive mechanism in treating brain tumors post radiotherapy. Here we investigate the brain penetration of niraparib and olaparib in healthy monkeys to understand the potential of each to cross the intact BBB. Experimental Procedures: Four healthy male Rhesus macaque monkeys were dosed daily via oral gavage for five days with either niraparib (n=2; 6 mg/kg) or olaparib (n=2; 10 mg/kg). Pre-dose blood was collected daily and terminal blood, cerebrospinal fluid (CSF), and brain tissue was collected at necropsy. Coronal brain sections were analyzed by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to quantitatively assess the tissue distribution of the dosed compounds. Blood, CSF, and bulk homogenate of brain tissue were analyzed by LC-MS bioanalysis. Summary of Data: Greater brain penetration was observed for niraparib when compared to olaparib in healthy Rhesus macaque monkeys following five days oral administration. The unbound brain-to-plasma partition coefficient (Kp,uu,brain) was 15x higher for niraparib compared to olaparib. Quantitative MALDI IMS of coronal brain sections from monkeys administered niraparib showed consistent concentrations distributed throughout the brain parenchyma. Olaparib was not detected by MALDI IMS in any of the coronal brain sections collected from the monkeys administered olaparib. Similar plasma and CSF concentrations were observed between the monkey’s administered niraparib vs olaparib, highlighting the unique ability of niraparib to cross the intact BBB of monkeys and distribute throughout the brain. Conclusions: Niraparib showed markedly higher brain penetration than olaparib in healthy Rhesus macaque monkeys demonstrating enhanced ability to cross intact BBB. Summary of Quantification Results Displayed as Total Conc. with Adjusted Free Conc. in Parentheses Compound Animal LC-MS Pre-Dose Plasma Days 1-5 (ng/mL) LC-MS Pre-Dose Plasma Days 1-5 (ng/mL) LC-MS Terminal CSF (ng/mL) LC-MS Bulk Brain Homogenate (ng/g) MALDI IMS Brain Section Average (ng/g) Kp,uu Brain/Plasma Mean Kp, uu Brain/Plasma Niraparib Monkey 1 BLQ, 28 (10), 49 (18), 59 (22), 72 (26) 84 (31) 9 378 (14) 283 (10) 0.45 0.30 Niraparib Monkey 2 BLQ, 58 (21), 87 (32), 74 (27), 66 (24) 436 (160) 25 797 (29) 684 (25) 0.16 Olaparib Monkey 3 BLQ, 27 (8), 26 (8), 33 (10), 33 (10) 322 (99) 13 12 (2) BLQ 0.02 0.02 Olaparib Monkey 4 BLQ, 51 (16), 17 (5), 53 (16), 45 (14) 254 (78) 6 11 (2) BLQ 0.03 Citation Format: Mark Reid Groseclose, Jeremy Barry, Yongle Pang, Jennifer Deutsch, Shannon Berry, Elaina McCormick, David K. Lim, Hoang Tran, Sean Maguire, Hasan Alsaid, Amine Aziez, Elaine Paul, Keyur Gada. Differentiation of niraparib and olaparib brain penetration in healthy rhesus macaque monkeys. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3581.

Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study.

The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC=0.93, 95% CI 0.9-0.95) and its concentrations were significantly higher in progressors vs non-progressors (p<0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials. AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit.

Determination of olverembatinib in human plasma and cerebrospinal fluid by an LC-MS/MS method: Validation and clinical application

A sensitive and robust LC-MS/MS method has been developed and validated for olverembatinib quantification in human plasma and cerebrospinal fluid (CSF). The method involved liquid-liquid extraction with methyl tertiary butyl ether for plasma pretreatment and precipitation enrichment with methanol for CSF pretreatment. Separation was achieved on the C18 column with gradient elutions of 10 mM ammonium formate in water and methanol-acetonitrile (50:50,v/v). Analyte detection was conducted by electrospray ionization (ESI) in a positive ion mode using multiple reaction monitoring (MRM). The m/z transitions were 533.4→433.2 for olverembatinib and m/z 502.4→394.2 for the internal standard (IS, Imatinib-d8). Calibration curves ranged from 0.500 to 50.0 ng/mL for plasma and from 0.0100 to 1.00 ng/mL for CSF. The intra- and inter-day precision and accuracy were < 15% for both plasma and CSF with four different quality control concentrations. The relative matrix effect was < 10% in plasma and artificial CSF. This method was successfully utilized for the measurement of olverembatinib concentrations in plasma and CSF from chronic myeloid leukemia patients.

Metal concentrations in cerebrospinal fluid, blood, serum, plasma, hair, and nails in amyotrophic lateral sclerosis: A systematic review and meta-analysis

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive muscle wasting, paralysis, and respiratory failure. Whereas approximately 10–15 % of ALS cases are familial, the etiology of the remaining, sporadic ALS cases remains largely unknown. Environmental exposures have been suggested as causative factors for decades, and previous studies have found elevated concentrations of metals in ALS patients. PurposeThis meta-analysis aims to assess metal concentrations in body fluids and tissues of ALS patients. MethodsWe searched the MEDLINE and EMBASE databases on December 7th, 2022 for cross-sectional, case-control, and cohort studies which measure metal concentrations in whole blood, blood plasma, blood serum, cerebrospinal fluid (CSF), urine, erythrocytes, nail, and hair samples of ALS patients. Meta-analysis was then performed when three or more articles existed for a comparison. FindingsTwenty-nine studies measuring 23 metals were included and 13 meta-analyses were performed from 4234 screened entries. The meta-analysis results showed elevated concentrations of lead and selenium. Lead, measured in whole blood in 6 studies, was significantly elevated by 2.88 µg/L (95 % CI: 0.83–4.93, p = 0.006) and lead, measured in CSF in 4 studies, was significantly elevated by 0.21 µg/L (95 % CI: 0.01 – 0.41, p = 0.04) in ALS patients when compared to controls. Selenium, measured in serum/plasma in 4 studies, was significantly elevated by 4.26 µg/L (95% CI: 0.73 – 7.79, p = 0.02) when compared to controls.Analyses of other metal concentrations showed no statistically significant difference between the groups. ConclusionLead has been discussed as a possible causative agent in ALS since 1850. Lead has been found in the spinal cord of ALS patients, and occupational exposure to lead is more common in ALS patients than in controls. Selenium in the form of neurotoxic selenite has been shown to geochemically correlate to ALS occurrence in Italy. Although no causal relationship can be established from the results of this meta-analysis, the findings suggest an involvement of lead and selenium in the pathophysiology of ALS. After a thorough meta-analysis of published studies on metal concentrations in ALS it can only be concluded that lead and selenium are elevated in ALS.

Metal ratios as possible biomarkers for amyotrophic lateral sclerosis

Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown aetiology. Metals have been suspected to contribute to ALS pathogenesis since mid-19th century, yet studies on measured metal concentrations in ALS patients have often yielded conflicting results, with large individual variation in measured values. Calculating metal concentration ratios can unveil possible synergistic effects of neurotoxic metals in ALS pathogenesis. The aim of this study was to investigate if ratios of different metal concentrations in cerebrospinal fluid (CSF) and blood plasma, respectively, differ between ALS patients and healthy controls. MethodsCerebrospinal fluid and blood plasma were collected from 17 ALS patients and 10 controls. Samples were analysed for 22 metals by high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS), and all possible 231 metal ratios calculated in each body fluid. ResultsFifty-three metal ratios were significantly elevated in ALS cases as compared to controls (p < 0.05); five in blood plasma, and 48 in CSF. The finding of fewer elevated ratios in blood plasma may indicate specific transport of metals into the central nervous system. The elevated metal ratios in CSF include Cd/Se (p = 0.031), and 16 ratios with magnesium, such as Mn/Mg (p = 0.005) and Al/Mg (p = 0.014). ConclusionMetal ratios may be used as biomarkers in ALS diagnosis and as guidelines for preventive measures.

Relationships between cause of death and concentrations of seven steroids obtained from the serum and cerebrospinal fluid of cadavers

In this study, we assessed 80 autopsy samples to investigate the relationships between cause of death and the concentrations of multiple steroids in serum and cerebrospinal fluid (CSF). First, we developed and validated analytical methods to quantify seven steroids (cortisol, cortisone, corticosterone, 11-deoxycortisol, 11-deoxycortiocosterone, progesterone, and testosterone) by using liquid chromatography coupled with electrospray ionization–tandem mass spectrometry. Next, we statistically evaluated the levels of each steroid for six causes of death: hypothermia, traumatic injury, fire fatality, asphyxia, intoxication, and internal disease. We observed that cortisol concentrations in serum and CSF obtained from cadavers who died from hypothermia were significantly higher than those in samples obtained from cadavers who died from the remaining causes of death (P < 0.05). Similarly, corticosterone concentrations obtained from cadavers who died from hypothermia were significantly higher than those in samples from several other causes of death. However, concentrations of the remaining steroids analyzed did not differ significantly among the causes of death. We further elucidated the correlations between steroid concentrations in serum and CSF. Except for 11-deoxycorticosterone and progesterone, steroid concentrations were significantly positively correlated in serum and CSF. Although data on cadaveric steroid concentrations are limited—especially in CSF—values obtained were in the approximate range of the living human data reported to date.

SCRN1: A cerebrospinal fluid biomarker correlating with tau in Alzheimer's disease.

Secernin-1 (SCRN1) is a neuronal protein that co-localizes with neurofibrillary tangles in Alzheimer's disease (AD), but not with tau inclusions in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or Pick's disease. We measured SCRN1 concentration in cerebrospinal fluid (CSF) using a novel mass spectrometric parallel reaction monitoring method in three clinical cohorts comprising patients with neurochemically characterized AD (n=25) and controls (n=28), clinically diagnosed Parkinson's disease (PD; n=38), multiple system atrophy (MSA; n=31), PSP (n=20), CBD (n=8), healthy controls (n=37), and neuropathology-confirmed AD (n=47). CSF SCRN1 was significantly increased in AD (P<0.01, fold change=1.4) compared to controls (receiver operating characteristic area under the curve=0.78) but not in CBD, PSP, PD, or MSA. CSF SCRN1 positively correlated with CSF total tau (R=0.78, P=1.1×10-13 ), phosphorylated tau181 (R=0.64, P=3.2×10-8 ), and Braak stage and negatively correlated with Mini-Mental State Examination score. CSF SCRN1 is a candidate biomarker of AD, reflecting tau pathology. We developed a parallel reaction monitoring assay to measure secernin-1 (SCRN1) in cerebrospinal fluid (CSF). CSF SCRN1 was increased in Alzheimer's disease compared to healthy controls. CSF SCRN1 remained unchanged in Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration compared to controls. CSF SCRN1 correlated strongly with CSF phosphorylated tau and total tau. CSF SCRN1 increased across Braak stages and negatively correlated with Mini-Mental State Examination score.

Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies

Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To assess the pharmacokinetics of increased doses (8 to 15 mg/kg/day) of micafungin in preterm and term neonates with invasive candidiasis and to complete previously presented results, we analyzed the pharmacokinetic data on a total of 53 newborns treated with micafungin, whereby 3 of them had Candida meningitis and hydrocephalus. Methods: Fifty-three neonates with systemic candidiasis, three of them with meningitis, were treated for at least 14 days with intravenous micafungin (Mycamine®) at a dosage ranging from 8 to 15 mg/kg/day. Plasma and cerebrospinal fluid (CSF) concentrations of micafungin were measured before the drug administration and at 1, 2, and 8 h after the end of the infusion using high-performance liquid chromatography (HPLC). Systemic exposure was assessed according to AUC0-24, plasma clearance (CL), and half-life measured in 52/53 patients, divided by chronological age. Results and conclusions: The mean micafungin clearance is higher in neonates than in older infants (0.036 L/h/kg before 28 days of life versus 0.028 L/h/kg after 120 days). The drug half-life is shorter in neonates than in older patients (13.5 h before 28 days of life versus 14.4 h after 120 days). With doses ranging between 8 and 15 mg/kg/day, micafungin crosses the blood-brain barrier reaching therapeutic levels in CSF.

Cerebrospinal fluid cytokines and chemokines exhibit distinct profiles in bacterial meningitis and viral meningitis.

Differential diagnosis of bacterial meningitis (BM) and viral meningitis (VM) is a critical clinical challenge, as the early and accurate identification of the causative agent determines the appropriate treatment regimen and markedly improves patient outcomes. Clinical and experimental studies have demonstrated that the pathogen and the host immune response contribute to mortality and neurological sequelae. As BM is associated with the activation of an inflammatory cascade, the patterns of pro- and anti-inflammatory cytokines/chemokines (CTs/CKs) present in the cerebrospinal fluid (CSF) in response to the immune assault may be useful as sensitive markers for differentiating BM from VM. In the present study, the ability of CTs/CKs in the CSF to differentiate between BM and VM was investigated. For this, biochemical markers and CT/CK profiles were analysed in 145 CSF samples, divided into three groups: BM (n=61), VM (n=58) and the control group (C; n=26) comprising patients with meningism. The CSF concentrations of monocyte chemoattractant protein-1, interleukin (IL)-8, IL-1β, IL-6, macrophage inflammatory protein-1α (MIP-1α), epithelial-neutrophil activating peptide, IL-10, tumour necrosis factor-α (TNF-α), proteins and white blood cells were significantly higher and the CSF glucose level was significantly lower in the BM group compared with the VM and C groups (P<0.01). Correlation analysis identified 28 significant correlations between various CTs/CKs in the BM group (P<0.01), with the strongest positive correlations being for TNF-α/IL-6 (r=0.75), TNF-α/MIP-1α (r=0.69), TNF-α/IL-1β (r=0.64) and IL-1β/MIP-1α (r=0.64). To identify the optimum CT/CK patterns for predicting and classifying BM and VM, a dataset of 119 BM and VM samples was divided into training (n=90) and testing (n=29) subsets for use as input for a Random Forest (RF) machine learning algorithm. For the 29 test samples (15 BM and 14 VM), the RF algorithm correctly classified 28 samples, with 92% sensitivity and 93% specificity. The results show that the patterns of CT/CK levels in the CSF can be used to aid discrimination of BM and VM.

Cerebrospinal Fluid Panel of Synaptic Proteins in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. We therefore aimed to investigate synaptic dysfunction in CAA. Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n = 6) were similar to AD patients, while levels in CAA/ATN- (n = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

Determining plasma and cerebrospinal fluid concentrations of EGFR-TKI in lung cancer patients

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used to treat advanced non-small cell lung cancer (NSCLC). A rapid and reliable method for measuring plasma and cerebrospinal fluid (CSF) concentrations of EGFR-TKIs is needed for therapeutic drug monitoring. By using UHPLC‒MS/MS with multiple reaction monitoring mode, we developed a method for rapidly determining the plasma and CSF concentrations of gefitinib, erlotinib, afatinib, and osimertinib. Protein precipitation was employed to remove protein interference for plasma and CSF matrix. The LC‒MS/MS assay was validated to be satisfactory in terms of linearity, precision, and accuracy. This method was successfully applied to measure plasma (n = 44) and CSF (n = 6) concentrations of EGFR-TKIs in NSCLC patients. The chromatographic separation was achieved by a Hypersil Gold aQ column within 3 min. The median plasma concentrations were 325.76, 1981.50, 42.62, 40.27, and 340.92 ng/ml for gefitinib erlotinib, afatinib 30 mg/day, afatinib 40 mg/day, and osimertinib, respectively. The CSF penetration rates were 2.15% for the patients receiving erlotinib therapy, 0.59% for afatinib, 0.08–1.12% for osimertinib 80 mg/day, and 2.18% for those receiving osimertinib 160 mg/day. This assay helps to predict the effectiveness and toxicities of EGFR-TKIs in the pursuit of precision medicine for lung cancer patients.

Soluble TREM2 in body fluid in Alzheimer's disease and Parkinson's disease.

Previous studies showed conflicting results regarding soluble triggering receptor expressed on myeloid cells 2 (sTREM2) level alteration in body fluid in Alzheimer's disease (AD) and Parkinson's disease (PD). We applied the STATA 12.0 software to compute standard mean difference (SMD) and 95% confidence interval (CI). The study showed elevated sTREM2 level in cerebrospinal fluid (CSF) in AD, mild cognitive impairment (MCI), and preclinical AD (pre-AD) patients, compared to healthy controls (HCs) with random effects models (AD: SMD 0.28, 95% CI 0.12 to 0.44, I2 = 77.6%, p < 0.001; MCI: SMD 0.29, 95% CI 0.09 to 0.48, I2 = 89.7%, p < 0.001; pre-AD: SMD 0.24, 95% CI 0.00 to 0.48, I2 = 80.8%, p < 0.001). The study showed no significant difference in sTREM2 level in plasma between AD patients and HCs with a random effects model (SMD 0.06, 95% CI - 0.16 to 0.28, I2 = 65.6%, p = 0.008). The study showed no significant difference in sTREM2 level in CSF or plasma between PD patients and HCs with random effects models (CSF: SMD 0.33, 95% CI - 0.02 to 0.67, I2 = 85.6%, p < 0.001; plasma: SMD 0.37, 95% CI - 0.17 to 0.92, I2 = 77.8%, p = 0.011). In conclusion, the study highlighted the CSF sTREM2 as a promising biomarker in the different clinical stages of AD. More studies were essential to explore the CSF and plasmatic concentrations of sTREM2 alteration in PD.

Efficacy and safety of lenalidomide in HIV-associated cryptococcal meningitis patients with persistent intracranial inflammation: an open-label, single-arm, prospective interventional study

BackgroundPatients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined.MethodsWe identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide.ResultsOf 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7–3.2) g/L at baseline to 0.9 (0.6–1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4–149.8) mg/L at baseline to 55.3 (38.3–89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed.ConclusionLenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

Glial fibrillary acidic protein is a robust biomarker in cerebrospinal fluid and peripheral blood after traumatic spinal cord injury: a prospective pilot study.

Biochemical biomarkers to determine the injury severity and the potential for functional recovery of traumatic spinal cord injury (TSCI) are highly warranted; however, it remains to be clarified whether cerebrospinal fluid (CSF) or peripheral blood (PB) is the ideal sample media. This study aims to measure and compare biomarker concentrations in CSF and PB and to explore associations between biomarker concentrations and injury severity, i.e., American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, and biomarker concentrations and clinical outcome, i.e., AIS grade improvement and Spinal Cord Independent Measure version III (SCIM-III) score. From 2018 to 2020, we conducted a single-center prospective pilot study of TSCI patients (n=15) and healthy controls (n=15). Sample collection and clinical outcome assessment were performed at median 13 h [IQR: 19], 9 days [IQR: 2], and 148 days [IQR: 49] after TSCI. Concentrations of neuron-specific enolase (NSE); glial fibrillary acid protein (GFAP); neurofilament light chain (NfL); interferon-γ (IFN-γ); interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13; and tumor necrosis factor α (TNF-α) were measured and associated to clinical outcomes. The biomarker concentrations were higher in CSF than PB. CSF concentrations of GFAP, NSE, IFN-y, TNF-a, IL-2, IL-12p70, IL-4, IL-10, and IL-13 and PB concentrations of GFAP and IFN-y were significantly associated with AIS grade, but not with AIS grade improvement or SCIM-III score. Our results support GFAP as a potential diagnostic biomarker that may be measured in CSF as well as PB.

Insomnia Symptoms and Biomarkers of Alzheimer's Disease in the Community.

Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer's disease remains equivocal. We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer's disease biomarkers in a cognitively unimpaired middle-aged community sample. A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia's core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOEɛ4 genotype. Higher ISI score was associated with greater average levels of CSF Aβ42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55-192, p < 0.001). Difficulty initiating sleep was not associated with CSF Aβ42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels. Insomnia symptoms were associated with higher CSF Aβ42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.

Screening of pesticides in serum, urine and cerebrospinal fluid collected from an urban population in China

Human exposure to pesticides is a topic of public health concern for decades. Pesticide exposures have been assessed through the analysis of urine or blood matrices, but little is known on the accumulation of these chemicals in cerebrospinal fluid (CSF). CSF plays an important role in maintaining physical and chemical balance of the brain and central nervous system and any perturbation can have adverse effects on health. In this study, we investigated the occurrence of 222 pesticides in CSF from 91 individuals using gas chromatography-tandem mass spectrometry (GC-MS/MS). Measured pesticide concentrations in CSF were compared with those in 100 serum and urine specimens from individuals living in the same urban location. Twenty pesticides were found in CSF, serum and urine, at levels above the limit of detection. Three most frequently detected pesticides in CSF were biphenyl (100%), diphenylamine (75%), and hexachlorobenzene (63%). Median concentrations of biphenyl in CSF, serum and urine were 1.11, 10.6, and 1.10 ng/mL, respectively. Six triazole fungicides were found only in CSF, but not in other matrices. To our knowledge, this is the first study to report pesticide concentrations in CSF in a general urban population.

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

BackgroundPotential biomarkers for neuropsychiatric disorders are cerebrospinal fluid (CSF) monoamines and their corresponding precursors and metabolites. During CSF sampling, CSF flows towards the lumbar sampling site from more cranial regions. To compare the results of studies in which different CSF volumes were acquired, it is important to know if ventricular-lumbar concentration gradients exist. This has only been addressed for a few biogenic amines, and almost exclusively in neurologically unwell patients due to the burden of a lumbar puncture (necessary to obtain CSF). The aim of our study was to determine if concentration gradients exist for routinely measured CSF constituents and biogenic amines in neurologically healthy patients. We applied a novel ultrasensitive liquid chromatography mass spectrometry (LC–MS/MS) method for the simultaneous quantification of multiple monoamines, precursors and metabolites in CSF and plasma.MethodsCSF and blood samples were collected from twenty neurologically healthy patients undergoing spinal anaesthesia. Ten mL of lumbar CSF was collected in five consecutive two mL fractions. We determined leucocyte and erythrocyte counts, glucose, albumin and protein concentrations and quantified monoamines, precursors and metabolites on each of the fractions using LC–MS/MS.ResultsIn twenty patients (60% male; median age: 46 years), dopamine, DOPAC, 3-MT, HVA, noradrenaline, normetanephrine and 5-HIAA concentrations increased from the first to the last CSF fraction (all p < 0.001). CSF adrenaline concentrations were below the detection limit, whereas serotonin measurements were regarded as unreliable. Albumin and total protein levels decreased significantly across CSF fractions.ConclusionsA ventricular-lumbar CSF concentration gradient existed for most of the investigated analytes. This is a novel finding for dopamine, noradrenaline, 3-MT and normetanephrine. These results contribute to the understanding of the neurobiology and underline the importance of standardized procedures for CSF handling to allow comparisons between studies.

Is seminal nerve growth factor-induced luteinizing hormone release in camelids mediated at the hypothalamus?

Seminal nerve growth factor induces ovulation in camelids by influencing the secretion of gonadotrophin-releasing hormone (GnRH) into the portal vessels of the pituitary gland. We show that the nerve growth factor-induced release of GnRH is not mediated directly through interaction with hypothalamic neurons. Ovulation in camelids is triggered by seminal nerve growth factor (NGF). The mechanism of action of NGF appears to occur via the central nervous system. In this study, we tested the hypothesis that NGF acts in the hypothalamus to induce GnRH release. To determine if NGF-induced ovulation is associated with a rise in NGF concentrations in the cerebrospinal fluid (CSF), llamas were i) mated with an urethrostomized male, ii) mated with intact male, or given intrauterine iii) seminal plasma or i.v.) saline (Experiment 1). To characterize the luteinizing hormone (LH) response after central vs peripheral administration, llamas were treated with saline (negative control) or NGF either by i.v. or intracerebroventricular (ICV) administration (Experiment 2). To determine the role of kisspeptin, the effect of ICV infusion of a kisspeptin receptor antagonist on NGF-induced LH secretion and ovulation was tested in llamas (Experiment 3). In Experiment 1, a surge in circulating concentrations of LH was detected only in llamas mated with an intact male and those given intrauterine seminal plasma, but no changes in CSF concentrations of NGF were detected. In Experiment 2, peripheral administration (i.v.) of NGF induced an LH surge and ovulation, whereas no response was detected after central (ICV) administration. In Experiment 3, the kisspeptin receptor antagonist had no effect on the LH response to NGF. In conclusion, results did not support the hypothesis that NGF-induced ovulation is mediated via a trans-synaptic pathway within the hypothalamus, but rather through a releasing effect on tanycytes at the median eminence.

Residual Central Nervous System Immune Activation Is Not Prevented by Antiretroviral Therapy Initiated During Early Chronic HIV Infection.

Antiretroviral therapy (ART) initiated during acute infection can potentially impact the central nervous system (CNS) reservoir, but the differential long-term effects of ART initiation during early or late chronic infection are unknown. We included neuroasymptomatic people with human immunodeficiency virus (HIV) with suppressive ART initiated during chronic (>1 year since transmission) HIV with archived cerebrospinal fluid (CSF) and serum samples after 1 and/or ≥3 years of ART from a cohort study. CSF and serum neopterin was measured using a commercial immunoassay (BRAHMS, Germany). In total, 185 people with HIV (median, 79 [interquartile range, 55-128] months on ART) were included. A significant inverse correlation was found between CD4+ T-cell count and CSF neopterin only at baseline (r = -0.28, P = .002), but not after 1 (r = -0.026, P = .8) or ≥3 (r -0.063, P = .5) years of ART. No significant differences were seen in CSF or serum neopterin concentrations between different pretreatment CD4+ T-cell strata after 1 or ≥3 (median, 6.6) years of ART. In people with HIV initiating ART during chronic infection, occurrence of residual CNS immune activation was not correlated with pretreatment immune status, even when treatment was initiated at high CD4+ T-cell counts, suggesting that the CNS reservoir, once established, is not differentially affected by the timing of ART initiation during chronic infection.