Low Cerebrospinal Fluid Concentrations Research Articles

BSA nanoclusters-based sensor for detection of dopamine in schizophrenia from biofluids

Objective To develop nontoxic and stable fluorescent emission B-Cu nanoclusters (NCs) for the specific detection of dopamine at low concentrations in cerebrospinal fluid (CSF). Significance Fluorescent gold and copper NCs conjugated with proteins, such as bovine serum albumin (BSA), offer photostability and healthcare potential. This study focused on fabricating B-Cu NCs that exhibited superior characteristics for sensitive dopamine detection. Methods The study employed various instrumental techniques including attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), spectrofluorometry, and transmission electron microscopy (TEM) to characterize the formulated B-Cu NCs. The NCs were synthesized, resulting in particle size ∼300 nm. The highest observed fluorescence was recorded at 24542.81 relative fluorescence units (RFU). Results The introduction of dopamine at concentrations of 0.1, 0.2, 0.3, and 0.4 ng/mL led to decreased fluorescence in both B-Au and B-Cu NCs due to an electron transport system. This reduction in fluorescence allowed dopamine concentration analysis in phosphate buffer and biological fluids such as blood plasma and CSF. B-Cu NCs showed potential as a biosensing system for point-of-care (POC) applications, specifically for diagnosing schizophrenia. Conclusion The study successfully synthesized stable and nontoxic B-Cu NCs with enhanced fluorescent emission properties. These NCs exhibited the capacity to detect dopamine at low concentrations in CSF. The study’s findings hold promise for future applications, particularly in the development of a B-Cu NCs-based biosensing system for convenient POC detection of schizophrenia by both patients and clinicians. The potential impact of this technology on healthcare and biomedical fields is substantial.

Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial.

Niemann-Pick Disease Type C1 (NPC1) is a disorder of intracellular cholesterol and lipid trafficking that leads to the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment, resulting in systemic manifestations (including hepatosplenomegaly and lung infiltration) and neurodegeneration. Preclinical studies have demonstrated that systemically administered 2-hydroxypropyl-β-cyclodextrin (HPβCD; Trappsol® Cyclo™) restores cholesterol metabolism and homeostasis in peripheral organs and tissues and in the central nervous system (CNS). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of HPβCD in peripheral tissues and the CNS in adult subjects with NPC1. A Phase 1, randomized, double-blind, parallel group study enrolled 13 subjects with NPC1 who received either 1500 mg/kg or 2500 mg/kg HPβCD intravenously every 2 weeks for a total of 7 doses (14 weeks). Subjects were 18 years or older, with a confirmed diagnosis of NPC1 and evidence of systemic involvement on clinical assessment. Pharmacokinetic evaluations in plasma and cerebrospinal fluid (CSF) were performed at the first and seventh infusions. Pharmacodynamic assessments included biomarkers of systemic cholesterol synthesis (serum lathosterol) and degradation (serum 4β-hydroxycholesterol), secondary sphingomyelin storage (plasma lysosphingomyelin-509, now more accurately referred to as N-palmitoyl-O-phosphocholineserine [PPCS]), and CNS-specific biomarkers of neurodegeneration (CSF total Tau) and cholesterol metabolism (serum 24(S)-hydroxycholesterol [24(S)-HC]). Safety monitoring included assessments of liver and kidney function, infusion related adverse events, and hearing evaluations. Ten subjects completed the study, with 6 at the 1500 mg/kg dose and 4 at the 2500 mg/kg dose. One subject withdrew following the first infusion after experiencing hypersensitivity pneumonitis, and 2 subjects withdrew after meeting a stopping rule related to hearing loss. Overall, HPβCD had an acceptable safety profile. The observed pharmacokinetic profile of HPβCD was similar following the first and seventh infusions, with a plasma half-life of 2 h, a maximum concentration reached at 6 to 8 h, and no evidence of accumulation. Serum biomarkers of cholesterol metabolism showed reduced synthesis and increased degradation. Compared to Baseline, filipin staining of liver tissue showed significant reductions of trapped unesterified cholesterol at both dose levels at Week 14. Plasma PPCS levels were also reduced. HPβCD was detected at low concentrations in the CSF (maximum, 33 μM) at both dose levels and persisted longer in CSF than in plasma. Total Tau levels in CSF decreased in most subjects. Serum levels of 24(S)-HC, a cholesterol metabolite from the CNS that is exported across the blood-brain barrier and into the circulation, decreased after both the first and seventh doses. Hence, pharmacodynamic assessments in both peripheral and CNS-related tissue show target engagement. While not the aim of the study, subjects reported favorable impacts on their quality of life. The plasma pharmacokinetics and pharmacodynamics of HPβCD administered at two intravenous dose levels to subjects with NPC1 were comparable to those observed in preclinical models. HPβCD cleared cholesterol from the liver and improved peripheral biomarkers of cholesterol homeostasis. At low CSF concentrations, HPβCD appeared to be pharmacologically active in the CNS based on the increased efflux of 24(S)-HC and reduction in CSF total Tau, a biomarker of CNS neurodegeneration. These data support the initiation of longer-term clinical trials to evaluate the safety and efficacy of intravenous HPβCD in subjects with NPC1. (ClinicalTrials.gov numbers: present trial, NCT02939547; open-label extension of the present trial, NCT03893071; global pivotal trial, NCT04860960).

Measurement of D-dimer in cerebrospinal fluid using a luminescent oxygen channeling immunoassay.

Measurement of D-dimer in cerebrospinal fluid (CSF) allows insight into coagulation system activation in the central nervous system and can be utilized to monitor intracranial hemorrhage as well as acute phase processes beyond hemostasis in inflammatory and neoplastic diseases. So far, the measurability of D-dimer in low and very low concentrations in CSF was limited in conventional immunoassays. Novel high-sensitivity chemiluminescent immunoassays such as the luminescent oxygen channeling immunoassay (LOCI®) are getting increasingly available but have not been validated in CSF. The aim of this study was to investigate the accuracy and linearity of the LOCI® in assessing D-dimer in CSF. INNOVANCE LOCI hs D-dimer reagent cartridge was used for the measurement of D-dimer in CSF of patients with different neurological diseases. For the evaluation of linearity, dilution series were performed in a pooled CSF sample with the determination of intra-assay precision (CV, coefficient of variation) in 3 individual samples with 20 replicates. Furthermore, D-dimer concentrations measured by LOCI® were compared with the respective results of a routinely available clinical latex-enhanced immunoassay (HemosiIL D-Dimer HS 500). Linear regression analysis of the LOCI® method revealed a r 2 of 1.00 (p < 0.001) with a regression coefficient B of 1.012 ± 0.003 (CI: 1.005-1.019, p < 0.001) and an intercept of -1.475 ± 1.309 (CI: -4.493 to 1.543); the median intra-assay CV was 0.69% (range: 0.68-0.75). In total, 185 CSF samples were measured by LOCI® technology, showing a mean concentration of 204.84 ± 2,214.93 ng/ml. D-dimer concentration between LOCI and latex-enhanced immunoassay differed by a factor of 10.6 ± 13.6 on average with a maximum deviation by a factor of 61.3; the maximum deviation was found at low concentrations. D-dimer in CSF of patients with neurological disease can be reliably measured by the LOCI® method with high linearity and accuracy at low concentrations.

Quantification of endocannabinoids in human cerebrospinal fluid using a novel micro-flow liquid chromatography-mass spectrometry method

The endocannabinoid system (ECS) is implicated in various brain disorders. Changes in the composition of the cerebrospinal fluid (CSF) may be associated with ECS-related pathologies. Endocannabinoids (eCBs) and their analogues are present at low concentrations in human CSF, which hampered the investigation of the ECS in this body fluid. In this study, we developed a highly sensitive and selective micro-flow liquid chromatography-tandem mass spectrometry (micro-LC-MS/MS) method for the analysis of eCBs and eCB analogues in human CSF. The developed method allowed for the quantitative analysis of 16 eCBs and their analogues in human CSF. Micro-LC-MS/MS analyses were performed at a flow-rate of 4 μL min−1 with a 0.3-mm inner diameter column. A minor modification of a novel spray needle was carried out to improve the robustness of our method. By using an injection volume of 3 μL, our method reached limits of detection in the range from 0.6 to 1293.4 pM and limits of quantification in range from 2.0 to 4311.3 pM while intra- and interday precisions were below 13.7%. The developed workflow was successfully used for the determination of eCBs in 288 human CSF samples. It is anticipated that the proposed approach will contribute to a deeper understanding of the role of ECS in various brain disorders.

Routine cerebrospinal fluid parameters as biomarkers in first-episode psychosis: A prospective observational study

In recent years, multiple studies have investigated the role of biomarkers in first-episode psychosis (FEP) to facilitate early diagnosis, disease stratification, therapeutic choice and outcome prediction. Few studies have focused on cerebrospinal fluid (CSF) investigations. In this prospective observational study, 95 FEP inpatients were followed up for one year. A lumbar puncture was performed at index admission (baseline) to study the CSF parameters (glucose, total proteins, lactate dehydrogenase [LDH], and pleocytosis). At the baseline visit, the clinical assessment included prodromal (psychotic and non-psychotic) symptoms before the psychotic outbreak and psychopathology at admission. The SCID-I was administered to obtain a clinical diagnosis at baseline and at 12 months. The relationship between prodromal and psychopathology symptoms at the baseline visit was tested with multiple linear regression. Multinomial logistic regression was also used to explore the association between CSF biomarkers and longitudinal diagnoses at follow-up (schizophrenia/schizoaffective disorder vs unipolar/bipolar depression vs other psychoses). Higher CSF glucose was associated with depressive (Standardized beta = 0.27, p = 0.041) and disorganized/concrete symptoms (Standardized beta = 0.33, p = 0.023) and lower CSF LDH was associated with prodromal symptoms (Standardized beta = −0.25, p = 0.042). Lower LDH concentrations were also associated with social withdrawal (r = −0.342, p = 0.001). CSF glucose was a predictor of the long-term diagnosis (lower CSF concentrations were associated with schizophrenia or schizoaffective disorder diagnoses [OR = 0.88, CI95%: 0.77–0.99). Our study suggests that CSF biomarkers that involve bioenergetic systems are associated with prodromal symptoms and the phenotype of psychotic disorders during the early stages of the disease.

Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis

ObjectiveTo assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).DesignProspective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.SettingHasan Sadikin Hospital, Bandung,...

TDP-43 Is Elevated in Plasma Neuronal-Derived Exosomes of Patients With Alzheimer's Disease.

BackgroundRecently, TDP-43 has been recognized as a common proteinopathy in the “oldest old” and a neuropathological comorbidity in patients with Alzheimer’s disease (AD). However, since it has a low concentration in cerebrospinal fluid, the presence of TDP-43 in AD is rarely investigated in vivo.MethodsTwenty-four patients with amyloid PET confirmed AD and 15 healthy controls (HCs) were included in this study. TDP-43 level in plasma neuronal-derived exosomes (NDEs) was measured by enzyme-linked immunosorbent assay.ResultsTDP-43 level was elevated in patients with AD compared with HCs (median 1.08 ng/ml, IQR 0.72–1.37 ng/ml vs. median 0.66 ng/ml, IQR 0.48–0.76 ng/ml, P = 0.002). There was no correlation between TDP-43 level and cognitive function, neuropsychiatric symptoms or APOE genotype in patients with AD.ConclusionThis study demonstrated increased TDP-43 accumulation in AD patients by examining plasma NDEs, which may provide a window into the effects of TDP-43 on AD progression.

Amphotericin B Penetrates into the Central Nervous System Through Focal Disruption of the Blood Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis.

Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.

Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer\u2019s and Parkinson\u2019s disease

BackgroundIncreasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer’s disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson’s disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates.MethodsProteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68).ResultsA pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD.ConclusionIn summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.

Capacitive Micromachined Ultrasonic Transducer (CMUT)-based Biosensor for Detection of Low Concentration Neuropeptide.

Accurate detection of neuropeptides in cerebrospinal fluid (CSF) plays an important role in both indepth studies and early diagnosis of neurological diseases. Here, we report a biosensor based on Capacitive Micromachined Ultrasonic Transducer (CMUT) which is capable of detecting low concentrations (pg $\sim $ ng/ml) of a neuropeptide involved with the progression of Alzheimer's diseases, somatostatin (SST). A 10-MHz CMUT was fabricated and utilized as a physical resonant sensor which detects the change in the concentration of analyte through the mass-loading mechanism. The resonant plate was sequentially coated with protein G and antibodies to provide specificity to SST; Cysteine-tagged protein G layer enables controlled immobilization of antibodies in a welloriented manner. The change in the resonant frequency of the CMUT sensor was measured after incubating the sensor in various concentrations of SST. The significant shifts in the resonant frequency were observed for SST concentrations in the range of 10 pg/ml $\sim 1$ ng/ml. Compared to the previously reported biosensors developed for SST detection, our sensor shows discernable responses for SST that are $\sim 6$ orders of magnitude lower in concentration. Thus, this work demonstrates the potential of the CMUT resonant sensor as a promising biosensor platform for detection of neuropeptides involved with neurodegenerative diseases that often exist in low concentrations in CSF.

Biomarkers in Cerebrospinal Fluid: Analysis of Cell-Free Circulating Mitochondrial DNA by Digital PCR.

Cerebrospinal fluid (CSF) contains molecules directly linked with brain function because it permeates brain tissue. The analysis of protein biomarkers in CSF is currently recommended for the diagnosis of neurodegenerative disorders, but the clinical sensitivity and specificity are still being investigated. A major drawback is that most of the currently used biomarkers of neurodegenerative diseases are proteins that are found at very low concentrations in CSF and need to be measured by immunoassays that provide relative values, which sometimes are difficult to reproduce between laboratories. In contrast, the recent availability of digital PCR platforms allows the absolute quantification of nucleic acids at single-molecule resolution, but their presence in CSF has not been characterized. CSF contains cell-free mitochondrial DNA (mtDNA) and changes in the concentration of this nucleic acid are linked to neurodegeneration. Here we describe a method to measure the concentration of cell-free circulating mtDNA directly in unpurified CSF using droplet digital PCR with either hydrolysis probes or fluorescent DNA-binding dye methods. This protocol allows the detection and absolute quantification of mtDNA content in the CSF with high analytical sensitivity, specificity, and accuracy.

Biomarkers for the Early Detection and Progression of Alzheimer's Disease.

The recent failures of potential disease-modifying drugs for Alzheimer's disease (AD) may reflect the fact that the enrolled participants in clinical trials are already too advanced to derive a clinical benefit. Thus, well-validated biomarkers for the early detection and accurate diagnosis of the preclinical stages of AD will be crucial for therapeutic advancement. The combinatorial use of biomarkers derived from biological fluids, such as cerebrospinal fluid (CSF), with advanced molecular imaging and neuropsychological testing may eventually achieve the diagnostic sensitivity and specificity necessary to identify people in the earliest stages of the disease when drug modification is most likely possible. In this regard, positive amyloid or tau tracer retention on positron emission tomography imaging, low CSF concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau, mesial temporal lobe atrophy on magnetic resonance imaging, and temporoparietal/precuneus hypometabolism or hypoperfusion on 18F-fluorodeoxyglucose positron emission tomography have all emerged as biomarkers for the progression to AD. However, the ultimate AD biomarker panel will likely involve the inclusion of novel CSF and blood biomarkers more precisely associated with confirmed pathophysiologic mechanisms to improve its reliability for detecting preclinical AD. This review highlights advancements in biological fluid and imaging biomarkers that are moving the field towards achieving the goal of a preclinical detection of AD.

Mitochondrial DNA in CSF distinguishes LRRK2 from idiopathic Parkinson's disease

Mitochondrial DNA regulates mitochondrial function which is altered in both idiopathic and familial forms of Parkinson's disease. To investigate whether these two disease forms exhibit an altered regulation of mitochondrial DNA we measured cell free mitochondrial DNA content in cerebrospinal fluid (CSF) from idiopathic and LRRK2-related Parkinson's disease patients. The concentration of mitochondrial DNA was measured using a digital droplet polymerase chain reaction technique in a total of 98 CSF samples from a cohort of subjects including: 20 LRRK2G2019S mutation carriers with Parkinson's disease, 26 asymptomatic LRRK2G2019S mutation carriers, 31 patients with idiopathic Parkinson's disease and 21 first-degree relatives of LRRK2 Parkinson's disease patients without the mutation. Here we report that LRRK2G2019S mutation carriers with Parkinson's disease exhibit a high concentration of mitochondrial DNA in CSF compared with asymptomatic LRRK2G2019S mutation carriers and with idiopathic Parkinson's disease patients. In addition, idiopathic, but not LRRK2 Parkinson's disease is associated with low CSF concentration of α-synuclein. These results show that high mitochondrial DNA content in CSF distinguishes idiopathic from LRRK2-related Parkinson's disease suggesting that different biochemical pathways underlie neurodegeneration in these two disorders.

Study on Medicinal Chemistry of K203 in Wistar Rats and Beagle Dogs

K203 is an experimental bis-pyridinium mono-aldoxime type cholinesterase reactivator of potential use in organophosphate/ organophosphonate poisoning. Pharmacokinetics of K203 were examined in Wistar rats and beagle dogs using ion-pair HPLC. Serum and cerebrospinal fluid concentrations of K203 were determined using ion-pair reversedphase chromatography on octadecyl silica column. HPLC with ultraviolet detection was used for determination of serum concentration of K203 higher than 0.1 μg/mL while its low concentrations in cerebrospinal fluid required electrochemical detection (0.015 through 4 μg/mL range). In rats the serum levels of K203 followed zero order pharmacokinetics from 15 to 120 minutes post administration. Zero order pharmacokinetics was also observed in beagle dogs after low dose (15 μmol/kg) of K203 administration. High dose administration (250 μmol/kg) led to subsequent hindered elimination from both cerebrospinal fluid and serum.

Mechanism of action of vigabatrin: correcting misperceptions

Discovered more than three decades ago, vigabatrin is approved in more than 50 countries as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with infantile spasms. Contrary to a fairly common misperception, the compound's mechanism of action is very well-characterized in animal models and cell cultures. γ-Aminobutyric acid (GABA)-ergic synapses comprise approximately 30% of all synapses within the central nervous system, and therein underlies the primary mode of synaptic inhibition. Vigabatrin was rationally designed to have a specific effect on brain chemistry by inhibiting the GABA-degrading enzyme, GABA transaminase, resulting in a widespread increase in GABA concentrations in the brain. The increase in GABA functions as a brake on the excitatory processes that can initiate seizure activity. Despite the short half-life of vigabatrin in the body (5-7 h) and its relatively low concentration in cerebrospinal fluid (10% of the concentration observed in plasma), it has the profound effect of increasing GABA concentration in the brain for more than a week after a single dose in humans. This effect persists steadily over years of vigabatrin administration and results in significant and persistent decreases in seizure activity. Vigabatrin can be effective with once-daily dosing. Because of its specificity, vigabatrin has helped researchers explore the specific mechanisms within the brain that underlie seizure activity.

Thoracic Epidural Analgesia and Acute Pain Management

AIN continues to be a significant problem for many patients after major surgery. In addition to improving patient satisfaction and decreasing pain scores, enhanced perioperative pain control can improve clinical outcomes. Thoracic epidural analgesia (TEA) remains a critical tool for anesthesiologists to use in acute pain management. TEA is particularly effective for reducing pain after thoracic and upper abdominal surgery and likely permits major surgical procedures to be performed on patients with moderate to severe comorbid diseases, who several years ago may have been determined to be too great a risk for surgery. In the past 10 yr, peripheral nerve blockade has improved perioperative analgesia for patients undergoing extremity surgery. Although nerve blocks have reduced the use of continuous lumbar epidural analgesia, anesthesiologists must understand the indications, placement techniques, solutions administered, potential complications, and evidence-based outcomes for TEA in acute pain management. Indications

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

Neuropeptide Y (NPY), a peptide neurotransmitter that regulates stress and anxiety, has been proposed to be a stress resilience factor in humans. Posttraumatic stress disorder (PTSD) is a stress-related anxiety disorder. We hypothesized that central nervous system NPY is dysregulated in PTSD and sought to redress the absence of central NPY data in the disorder. We determined morning NPY concentrations in cerebrospinal fluid (CSF) from 10 male subjects with chronic combat-related PTSD and from 13 healthy men. Neuropeptide Y-like immunoreactivity was measured by enzyme immunoassay (EIA). As compared with the normal comparison subjects, PTSD patients had significantly lower concentrations of CSF neuropeptide Y (mean CSF NPY was 360.0 +/- 17.7 pg/mL in control subjects but only 233.6 +/- 28.7 pg/mL in PTSD patients [p = .0008]). Adjustments for age and body mass index (BMI) still revealed a highly significant reduction in CSF NPY in the PTSD group (p = .003). Men with combat-related PTSD have low CSF concentrations of the putative resiliency hormone NPY, possibly related to the disorder or to extreme stress exposure per se.

Disseminated Cryptococcal Infection and Anti-Tumor Necrosis Factor-α Treatment for Refractory Sarcoidosis: An Expected Association?

The use of anti-tumor necrosis factor-α(anti-TNF-α) agents is validated in refractory rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis. Although very effective in breaking down granulomatous inflammation typically involved in sarcoidosis, anti-TNF-α agents significantly reduce the host granulomatous defence mechanisms that normally contain pathogens such as mycobacteria and fungi. We describe a case of disseminated cryptococcosis in a patient with refractory systemic sarcoidosis, in whom complete resolution followed discontinuation of anti-TNF-α drug and antifungal therapy. A 42-year-old man was referred to our internal medicine department with a 2-year history of unexplained left-ear deafness and lymphocytic meningitis. Clinical examination was normal except for left-ear deafness. Gadolinium-enhanced magnetic resonance imaging (MRI) showed multiple solid enhancing lesions involving the left internal acoustic canal and the left frontal lobe. Cerebrospinal fluid (CSF) analysis revealed lymphocytosis (85/mm3), elevated CSF protein (1.24 g/l), and low glucose CSF concentrations (1.4 mmol/l). Viral, bacterial, and fungal cultures were negative. Thoracic computed tomography … Address reprint requests to Dr Sène; E-mail: damien.sene{at}psl.aphp.fr

Detection of Herpesvirus DNA in Cerebrospinal Fluid and Correlation with Clinical Symptoms

Novel PCR techniques can detect minute quantities of herpesvirus DNA in cerebrospinal fluid (CSF). The clinical significance of such findings is not always clear. (a) Investigation of clinical characteristics of 76 patients with herpesvirus DNA detection in CSF. (b) Screening for herpesvirus DNA in CSF samples of 208 patients without clinical signs of herpesvirus infection. (a) Eleven of 76 herpesvirus-DNA-positive patients did not show symptoms usually associated with the detected virus (HSV-1/2, n = 5; EBV, n = 6). (b) Two of 208 patients without hint for herpesvirus infection had HHV-6 DNA of low concentration in CSF. The detection of low-level herpesvirus replication in CSF by highly sensitive PCR assays requires critical evaluation.

P.2.e.013 The efficacy and tolerability of zotepine for mania: an observational study

A possible role for somatostatin in affective disorders is suggested by its low concentration in cerebrospinal fluid of patients with depression. Therefore, we studied the regional effects of antidepressant drugs and antimanic agents on somatostatin concentrations in rat brain. Repeated, but not acute, administration of clomipramine, a specific serotonin uptake inhibitor, caused a highly significant, widespread reduction in somatostatin levels. Somatostatin content was similarly reduced in the hypothalamus, and midbrain and thalamus following repeated administration of zimelidine, another specific serotonin uptake inhibitor. Repeated administration of either imipramine, maprotiline, mianserin, carbamazepine or zotepine were without effect on somatostatin levels. These results suggest that somatostatin in the brain might be involved in therapeutic effects of some of antidepressant drugs.