Cerebrospinal Fluid Neopterin Research Articles

Persistent Intrathecal Immune Activation in HIV-1-Infected Individuals on Antiretroviral Therapy

Neopterin is a well-established marker of macrophage activation. The cerebrospinal fluid (CSF) neopterin levels are elevated in most HIV-1-infected individuals and decrease significantly after initiation of antiretroviral therapy (ART). Unexpectedly, CSF concentrations often remain mildly abnormal even in patients treated for a long time with suppressive ART. The aims of this study were to analyze if persistently elevated CSF neopterin levels were associated with the type of antiretroviral regimen or with low-level CSF HIV-1 concentrations and to evaluate if plasma HIV-1 RNA levels correlated to lingering CSF neopterin concentrations in patients with effective ART. One hundred fifty-seven chronically HIV-1-infected patients with stable ART for > or =6 months and no neurologic symptoms were included, and 193 HIV-1-infected patients without ART served as controls. Neopterin was analyzed with a radioimmunoassay or an enzyme-linked immunosorbent assay. HIV-1 RNA quantification was performed with the Roche Amplicor assay (version 1.5; Hoffman-La Roche, Basel, Switzerland). Two quantitative HIV-1 RNA assays with sensitivities < or =2.5 copies/mL were used in 40 samples. As anticipated, HIV-1 RNA and CSF neopterin levels were markedly lower in patients on ART compared with untreated controls. No significant difference in CSF neopterin concentrations was found between those treated with protease inhibitor- and nonnucleoside reverse transcriptase inhibitor-based regimens in combination with 2 nucleoside analogues. Subjects with CSF HIV-1 RNA loads <2.5 copies/mL had the lowest CSF neopterin levels. Plasma viral load had no impact on intrathecal immune activation in cases with CSF viral loads <50 copies/mL. The persistent intrathecal cell-mediated immune response was associated with CSF viral load but not with treatment regimen in individuals on ART.

Cerebrospinal Fluid Neopterin in Patients with Tumors and other Disorders

Abstract Increased urinary or serum concentrations of neopterin have been reported in cancer patients, but less is known about neopterin concentrations in cerebrospinal fluid (CSF). CSF neopterin was determined with radioimmunoassay in 64 patients. CSF neopterin concentrations in patients with tumors were significantly higher compared to patients with predominantly peripheral infections (Lyme borreliosis and herpes simplex infection) and no infectious, inflammatory or neoplastic disorder, and significantly lower compared to patients with meningitis or encephalitis. Among patients with tumors, CSF neopterin was significantly higher in patients with non- Hodgkin lymphoma (NHL) compared to other tumors. The difference between patients with tumors other than NHL and predominantly peripheral infections was of borderline significance, and a significant difference was observed between patients with tumors other than NHL and no disorder. CSF neopterin was significantly higher in patients with NHL compared to patients with predominantly peripheral infections, multiple sclerosis or polyneuropathy and no disorder, and no difference was evident compared to patients with meningitis or encephalitis. In conclusion, among patients with tumors, high CSF neopterin may suggest the diagnosis of NHL.

Elevated Cerebrospinal Fluid Neurofilament Light Protein Concentrations Predict the Development of AIDS Dementia Complex

The light subunit of neurofilament protein (NFL) is a sensitive indicator of central nervous system axonal injury. We retrospectively identified 9 subjects participating in a longitudinal cohort study who developed acquired immunodeficiency syndrome dementia complex (ADC) and who had had a lumbar puncture performed within 2 years before presentation. Elevated cerebrospinal fluid (CSF) NFL concentrations were found in 7 (78%) of the 9 case patients who later developed ADC, compared with 9 (33%) of 27 CD4 cell count-matched HIV-1-infected control subjects. By contrast, no differences were found in CSF HIV-1 RNA or neopterin concentrations between the 2 groups. CSF NFL may prove to be a useful predictive marker for ADC.

Diagnosis and treatment of neurotransmitter disorders

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.

Normalisation of cerebrospinal fluid biomarkers parallels improvement of neurological symptoms following HAART in HIV dementia – case report

BackgroundSince the introduction of HAART the incidence of HIV dementia has declined and HAART seems to improve neurocognitive function in patients with HIV dementia. Currently, HIV dementia develops mainly in patients without effective treatment, though it has also been described in patients on HAART and milder HIV-associated neuropsychological impairment is still frequent among HIV-1 infected patients regardless of HAART. Elevated cerebrospinal fluid (CSF) levels of markers of neural injury and immune activation have been found in HIV dementia, but neither of those, nor CSF HIV-1 RNA levels have been proven useful as diagnostic or prognostic pseudomarkers in HIV dementia.Case presentationWe report a case of HIV dementia (MSK stage 3) in a 57 year old antiretroviral naïve man who was introduced on zidovudine, lamivudine and ritonavir boosted indinavir, and followed with consecutive lumbar punctures before and after two and 15 months after initiation of HAART. Improvement of neurocognitive function was paralleled by normalisation of CSF neural markers (NFL, Tau and GFAP) levels and a decline in CSF and serum neopterin and CSF and plasma HIV-1 RNA levels.ConclusionThe value of these CSF markers as prognostic pseudomarkers of the effect of HAART on neurocognitive impairment in HIV dementia ought to be evaluated in longitudinal studies.

Defining and Evaluating HIV-Related Neurodegenerative Disease and Its Treatment Targets: A Combinatorial Approach to Use of Cerebrospinal Fluid Molecular Biomarkers

There are a number of reasons that the accomplishments of clinical trials related to HIV-related neurodegenerative disease (HRND) and the AIDS dementia complex (ADC) have had such limited impact on clinical practice. These include: rapid evolution and progress in the treatment of systemic HIV infection that has quickly outpaced neurological efforts and has markedly reduced disease incidence; ethical constraints that (rightly) demand neurologically compromised patients receive the best available treatment before experimental therapeutics; complicated backgrounds and comorbidities of patients now most susceptible to HRND; and reluctance of general AIDS clinicians and drug companies to look beyond systemic or pivotal outcomes. However, the field has also been slow to adopt methods that better exploit advances in understanding of the pathogenesis of central nervous system (CNS) infection and brain injury, and that might circumvent some of these constraints. Using a simple model of pathogenesis, we propose an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers. This model begins by using three markers related to cardinal components of HRND: CNS HIV infection (measurement of CSF HIV RNA), intrathecal immunoactivation (CSF neopterin), and brain injury [CSF light chain neurofilament (NFL)]. Careful analysis of this and other marker combinations promises more rational trial design and more rapid progress in managing CNS HIV infection and HRND using both antiviral and adjuvant treatment approaches.

Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study

BackgroundThe way various antiretroviral drugs and drug combinations affect HIV-1 infection in the central nervous system is still largely unknown. The aim of this study was to determine the cerebrospinal fluid (CSF) steady-state concentrations of saquinavir and nelfinavir in relation to plasma concentrations, and to study their effect in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) on CSF viral loads, intrathecal immunoactivation, and blood-brain barrier integrity.MethodsPaired CSF and plasma samples from 8 antiretroviral-naïve HIV-1 infected patients starting combination therapy with saquinavir, nelfinavir, and two nucleoside analogues were collected prior to treatment, and again after approximately 12 and 48 weeks of antiretroviral therapy. Additional plasma samples were taken at weeks 2, 4, 8, 24, and 36. The concentrations of protease inhibitors were analysed, as were levels of HIV-1 RNA, CD4+ T-cell count, β2-microglobulin, neopterin, albumin ratio, IgG index, and monocytic cell count.ResultsNone of the patients in the study presented with HIV-1 RNA < 50 copies/mL in CSF or plasma prior to treatment, compared to 5/7 at the end of the study. Signs of cell-mediated intrathecal immunoactivation, measured by neopterin and β2-microglobulin, decreased significantly in both CSF and serum, although only 1/7 reached normal CSF neopterin levels after 48 weeks of treatment. There was no significant reduction of albumin ratio, IgG index or CSF monocytic cell count. Saquinavir median (range) concentrations were < 2.5 (< 2.5–96.0) nM unbound in plasma, and < 2.5 (< 2.5–9.0) nM total in CSF. Nelfinavir median (range) concentrations were 10.0 (< 2.0–31.0) nM unbound in plasma, and < 2.0 (< 2.0–23.0) nM total in CSF. Saquinavir and nelfinavir were detectable in 7/15 and 9/15 CSF samples, respectively.ConclusionSaquinavir and nelfinavir, in combination with two NRTIs, decrease the CSF viral load and, to a lesser extent, intrathecal immunoactivation. We found reasonably high CSF concentrations of nelfinavir, but suboptimal concentrations of saquinavir.

Cerebrospinal Fluid and Serum Markers of Inflammation in Autism

Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased, and biopterin (P = 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.

Cerebrospinal fluid signs of neuronal damage after antiretroviral treatment interruption in HIV-1 infection

BackgroundThe neurofilament is a major structural component of myelinated axons. Increased cerebrospinal fluid (CSF) concentrations of the light chain of the neurofilament protein (NFL) can serve as a sensitive indicator of central nervous system (CNS) injury. To assess whether interrupting antiretroviral treatment of HIV infection might have a deleterious effect on the CNS, we measured NFL levels in HIV-infected subjects interrupting therapy.We identified subjects who had CSF HIV RNA concentrations below 50 copies/mL at the time combination antiretroviral therapy was interrupted, and for whom CSF samples were available before and after the interruption.ResultsA total of 8 subjects were studied. The median (range) CSF NFL level at baseline was <125 (<125–220) ng/L (normal <250 ng/L). All 8 subjects exhibited an increase in CSF and plasma HIV RNA after stopping therapy, accompanied by intrathecal immunoactivation as evidenced by CSF lymphocytic pleocytosis (7/8 patients) and increased CSF neopterin concentration (5/6 patients). Three subjects showed a consistent increase in CSF NFL, rising from <125 ng/L to a maximum of 880 (at day 148), 1,010 (day 58) and 10,930 ng/L (day 101). None exhibited new neurological symptoms or signs, or experienced functional deterioration during the period off treatment; of 5 who underwent brief quantitative neurological testing, none showed worsening performance.ConclusionThese findings suggest that resurgence of active HIV replication may result in measurable, albeit subclinical, CNS injury. Further studies are needed to define the frequency and pathobiological importance of the increase in CSF NFL.

Low T3 Syndrome in Head-Injured Patients is Associated with Prolonged Suppression of Markers of Cell-Mediated Immune Response

To clarify the association between disturbed thyroid hormone metabolism (low T3 syndrome) and release of cytokines and markers of cell-mediated immune response. Concentrations of cytokines as well as of thyroid hormones were determined in 32 patients suffering from severe traumatic brain injury: interleukin-( IL-)1, IL-6, IL-10, tumor necrosis factor, transforming growth factor-(TGF-)β, soluble interleukin-2 receptor (sIL-2R), neopterin, and β2-microglobulin (β2m) in serum and cerebrospinal fluid; triiodothyronine (T3), free T3, thyroxine (T4), free T4, thyrotropin, thyroxine-binding globulin, and albumin in serum. Additionally, clinical parameters were assessed: Glasgow Coma Score, CT scan, intracranial pressure, Glasgow Outcome Score, and occurrence of pneumonia. Among 31 patients with a low T3 syndrome, those with additional low serum T4 levels (n = 13) showed a prolonged suppression of serum β2m, neopterin, and sIL-2R, and a higher secondary increase of serum β2m, neopterin, and TGF-β, as well as lower T3 levels (all p < 0.05). These patients also had a longer stay in the intensive care unit (34 ± 6 days vs. 22 ± 12 days; p = 0.008). Increased levels of β2m correlated with a preceding decrease of thyrotropin (cerebrospinal fluid: r = –0.53; p = 0.004; serum: r = –0.41; p = 0.029). Associations of thyroid hormone metabolism with either other cytokines or with clinical parameters were not detected. These results show that low T3 syndrome is a very common pathophysiological feature after severe traumatic brain injury. The association of a low T3 syndrome in combination with low serum T4 levels, with an altered time course of markers of cell-mediated immunity led the authors to hypothesize that a disturbed thyroid hormone metabolism may be interrelated with a prolonged cellular immune dysfunction after traumatic brain injury.

Evidence of Cellular Immune Activation in Children With Opsoclonus-Myoclonus: Cerebrospinal Fluid Neopterin

To evaluate cellular immune activation in opsoclonus-myoclonus syndrome, we measured the inflammatory marker neopterin in the cerebrospinal fluid of 16 children with opsoclonus-myoclonus and neuroblastoma, 24 children with opsoclonus-myoclonus but no tumor, and 19 age-matched controls. The mean concentration in opsoclonus-myoclonus was 2.3-fold higher than in controls (P = .008). Neopterin was greatly elevated in four of the most neurologically severe cases, up to 8.3-fold above the highest control level. Thirteen of the 40 children with opsoclonus-myoclonus but no controls had a neopterin concentration >2 SD above the control mean (P = .005). In this high neopterin subgroup, neurologic severity was significantly greater and the duration of neurologic symptoms was less. In 16 children re-examined on immunotherapy, including adrenocorticotropic hormone (ACTH) combination therapy, treatment was associated with a significant reduction in both neopterin and neurologic severity. Neopterin did not differ significantly between the tumor and non-tumor opsoclonus-myoclonus etiologies. No abnormalities of tetrahydrobiopterin were found. Although cerebrospinal fluid neopterin lacked the sensitivity to be a biomarker of disease activity in opsoclonus-myoclonus, elevated concentrations do support a role for T-cell activation and cell-mediated immunity in its pathophysiology.

Clinical Application of Cerebrospinal Fluid Neopterin Concentrations in HIV Infection

Abstract HIV-1 infects the central nervous system (CNS) and may cause AIDS dementia complex (ADC) and other neurologic complications. The cerebrospinal fluid (CSF) virus load is usually 0,5 -1 log lower than in blood, but in some patients the CSF quantitative HIV-1 RNA values exceed the paired blood samples. CSF neopterin concentrations are increased in all stages of HIV-1 infection, with the highest concentrations in AIDS patients and patients with CNS opportunistic infections. CD4 cell count and quantitative HIV RNA PCR tests in peripheral blood are used in clinical practice to monitor the HIV-1 infection and the anti-retroviral treatment effect. In most patients the anti-retroviral treatment response is similar in the cerebrospinal fluid (CSF) compare to the peripheral blood and the CSF viral load and neopterin concentrations are markedly reduced following treatment. ADC has become a rare complication. In spite of virological effective treatment many patients have a low grade intrathecal immunoactivation, measured as CSF neopterin concentrations above the 95% confidence interval found in IIIV-1 negative controls, after such a long time as after 2 years of anti-retroviral treatment. The risk of long term intrathecal immunoactivation and which anti-retroviral combination treatment has the best effect on CSF parameters is not known. CSF neopterin concentrations are at present not used in clinical practice but may add valuable information.

Cerebrospinal fluid viral load, virus isolation, and intrathecal immunoactivation in HIV type 2 infection.

Four patients with HIV-2 infection were followed longitudinally with cerebrospinal fluid (CSF) analyses. Two patients had positive CSF HIV-2 isolations. These two patients had CD4 cell count below 200 x 10(6)/liter and maximum CSF HIV-2 RNA viral loads above 4000 copies/ml. Intrathecal immune activation was demonstrated by elevated CSF neopterin concentrations (14-18 nmol/liter). No opportunistic infections were diagnosed. After antiretroviral treatment CSF viral counts decreased to below 125 copies/ml and CSF neopterin concentrations decreased. In two other patients who had CD4 counts within the normal range CSF virus isolations were repeatedly negative and viral CSF loads were below 125 copies/ml. However, a slightly elevated CSF neopterin concentration in one sample and pleocytosis in another might also be caused by HIV-2 in these patients. Before antiretroviral treatment HIV-2 isolations from blood were positive in all four patients. Maximum HIV-2 RNA viral loads were higher in blood than in CSF. Treatment failure in one patient with increasing viral loads in blood did not result in viral rebound in CSF.

Neopterin and Macrophage Inflammatory Protein-1α in the Cerebrospinal Fluid of Schizophrenic Patients: No Evidence of Intrathecal Inflammation

Background: Numerous reports support the idea that inflammatory and/or immunological processes contribute to the etiopathogenesis of schizophrenia. Most of the data are, however, based on findings from body compartments outside the central nervous system (CNS). We measured the concentrations of the inflammatory marker neopterin and the chemokine macrophage inflammatory protein-α (MIP-1α) in the cerebrospinal fluid (CSF) of acutely psychotic schizophrenic patients and of healthy controls. Methods: The concentration of neopterin was measured in the CSF of 11 schizophrenic patients by radioimmunoassay, and of MIP-1α in the CSF from 8 patients using ELISA. Control CSF was collected from 10 and 8 healthy individuals. Results: No statistically significant differences in CSF neopterin or MIP-1α were detected between patients and controls or between the patient samples obtained on hospital admission and after the treatment period associated with clinical improvement. Conclusions: These findings argue against the hypothesis that active inflammatory processes are part of the pathophysiology of acute psychotic episodes in schizophrenia. The possible mechanisms explaining the previously reported aberrations of mononuclear cells and cytokines in schizophrenia are discussed.

Continuing intrathecal immunoactivation despite two years of effective antiretroviral therapy against HIV-1 infection.

To study the effect of antiretroviral combination treatment on intrathecal immunoactivation in HIV-1 infection. Lumbar punctures were performed at baseline, and after 4 months, 1 and 2 years on 30 neurologically asymptomatic, treatment-naive HIV-1-infected patients started on antiretroviral treatment with three or more drugs. Levels of neopterin, beta2-microglobulin and HIV-1 RNA were measured in cerebrospinal fluid (CSF) and blood. All patients continued the study until the 4-month follow-up, although seven discontinued before the 1-year control, and an additional five discontinued before the control after 2 years. Neopterin, beta2-microglobulin and HIV-1 RNA decreased significantly both in CSF and blood, but although 100% of the patients decreased their CSF concentrations of beta2-microglobulin and HIV-1 RNA to normal levels, only 55% had normal CSF neopterin concentrations after 2 years treatment. In addition to CSF viral load, antiretroviral combination therapy substantially decreases the intrathecal immunoactivation as reflected by CSF neopterin and beta2-microglobulin in neuroasymptomatic HIV-1-infected patients. However, almost half of the patients still have slightly increased CSF neopterin concentrations after 2 years of effective treatment, which might reflect an ongoing low-grade viral replication in brain tissue.

YKL-40 is elevated in cerebrospinal fluid from patients with purulent meningitis.

YKL-40, a member of the family 18 glycosyl hydrolases, is secreted by activated neutrophils and macrophages. It is a growth factor for connective tissue cells and a potent migration factor for endothelial cells and may function in inflammation and tissue remodeling. YKL-40 was determined in 134 cerebrospinal fluid (CSF) samples taken on admission from patients suspected of having meningitis (48 with purulent meningitis, 49 with lymphocytic meningitis, 5 with encephalitis, and 32 without evidence of meningitis). YKL-40 levels in CSF were significantly higher in patients with purulent meningitis (median, 663 microg/liter [range, 20 to 8,960]) and encephalitis (5,430 microg/liter [620 to 11,600]) than in patients with lymphocytic meningitis (137 microg/liter [41 to 1,865]) or patients without meningitis (167 microg/liter [24 to 630]) (Kruskal-Wallis and Dunn multiple comparison tests, P < 0.001). CSF YKL-40 levels were also determined for 26 patients with purulent meningitis having a repuncture, and patients who died (n = 5) had significantly higher YKL-40 levels than patients who survived (n = 21) (2,100 microg/liter [1,160 to 7,050] versus 885 microg/liter [192 to 15,400], respectively; Mann-Whitney test, P = 0.018). YKL-40 was most likely locally produced, since patients with infections of the central nervous system had CSF YKL-40 levels that were at least 10-fold higher than the corresponding levels in serum (2,033 microg/liter [470 to 11,600] versus 80 microg/liter [19 to 195]). The CSF neopterin level was the biochemical parameter in CSF and blood that correlated best with CSF YKL-40 levels, indicating that YKL-40 may be produced by activated macrophages within the central nervous system. In conclusion, high levels of YKL-40 in CSF are found in patients with purulent meningitis.

Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans

The mechanisms underlying cell death following traumatic brain injury (TBI) are not fully understood. Apoptosis is believed to be one mechanism contributing to a marked and prolonged neuronal cell loss following TBI. Recent data suggest a role for Fas (APO-1, CD95), a type I transmembrane receptor glycoprotein of the nerve growth factor/tumor necrosis factor superfamily, and its ligand (Fas ligand, FasL) in apoptotic events in the central nervous system. A truncated form of the Fas receptor, soluble Fas (sFas) may indicate activation of the Fas/FasL system and act as a negative feedback mechanism, thereby inhibiting Fas mediated apoptosis. Soluble Fas was measured in cerebrospinal fluid (CSF) and serum of 10 patients with severe TBI (GCS≤8) for up to 15 days post-trauma. No sFas was detected in CSF samples from patients without neurological pathologies. Conversely, after TBI 118 out of 120 CSF samples showed elevated sFas concentrations ranging from 56 to 4327 mU/ml. Paired serum samples showed above normal (8.5 U/ml) sFas concentrations in 5 of 10 patients. Serum levels of sFas were always higher than CSF levels. However, there was no correlation between concentrations measured in CSF and in serum ( r 2=0.078, p=0.02), suggesting that the concentrations in the two compartments are independently regulated. Also, no correlation was found between sFas in CSF and blood brain barrier (BBB) dysfunction as assessed by the albumin CSF/serum quotient ( Q A), and concentrations of the cytotoxic cytokine tumor necrosis factor-alpha in CSF, respectively. Furthermore, there was no correlation with two markers of immune activation (soluble interleukin-2 receptor and neopterin) in CSF. Maximal CSF levels of sFas correlated significantly ( r 2=0.8191, p<0.001) with the early peaks of neuron-specific enolase in CSF (a marker for neuronal cell destruction), indicating that activation of the Fas mediated pathway of apoptosis may be in part the direct result of the initial trauma. However, the prolonged elevation of sFas in CSF may be caused by the ongoing inflammatory response to trauma and delayed apoptotic cell death.

Increased blood-brain barrier permeability in neuro-asymptomatic HIV-1-infected individuals--correlation with cerebrospinal fluid HIV-1 RNA and neopterin levels.

The objective of this study was to assess the frequency of blood-brain barrier (BBB) impairment, as measured by the albumin ratio, in neuro-asymptomatic HIV-1-infected individuals without antiretroviral treatment and the correlation between BBB disruption and intrathecal immune activation and HIV-1 RNA levels. Serum and cerebrospinal fluid (CSF) albumin, neopterin, and HIV-1 RNA levels were analysed in 110 neuro-asymptomatic HIV-1-infected individuals at different stages of disease; 63 classified as CDC A, 25 as CDC B, and 22 as CDC C. Increased BBB permeability was found in 17 of 110 (15%) of HIV-1-infected individuals. This proportion was sustained throughout the CDC stages. The albumin ratio was correlated with the CSF neopterin levels (r(s) = 0.36, P < 0.001), the serum neopterin levels (r(s) = 0.37, P < 0.001), and the CSF HIV-1 RNA levels (r(s) = 0.26, P < 0.01), but not with the plasma HIV-1 RNA levels. The correlations between the albumin ratio and the CSF and serum neopterin concentrations and the CSF HIV-1 RNA levels indicate that immune activation and, possibly, intrathecal HIV-1 virus replication are important factors associated with increased BBB permeability in HIV-1 infection.

Neopterin and Cytokines in Non-pleocytotic Cerebrospinal Fluid in Child Patients

Abstract CSF and serum levels of neopterin and several kinds of CSF cytokines were measured in child patients with non-pleocytotic CSF. The CSF neopterin levels with febrile convulsions (FCs) were 27.4±33.0 nmol/1 and the CSF neopterinlserum neopterin ratio (C/S ratio) with FCs was 2.07±2.06. The longer the FCs patients' convulsions lasted, the higher their CSF neopterin levels tended to be come. The CSF neopterin levels with FCs were significantly higher than in those with pyrexia without convulsions (6.5±2.5 nmol/L) or convulsions without pyrexia, including epilepsy (4.9±2.9 nmol/L). The C/S ratio was also higher in patients with FCs than in those with pyrexia without convulsions (0.31±0.17) or convulsions without pyrexia (0.82±0.50).In addition, there was a tendency for CSF IFN-γ levels to be higher in patients with FCs than in those with pyrexia without convulsions or convulsions without pyrexia. However, TNF-α and IL-1α were under measurable levels in cases of non-pi eocytotic CSF. The CSF neopterin levels in patients with exanthem subitum with FCs were higher than in those without FCs. It has been reported that there is a possibility of neopterin production by microglial cells. Our finding that CSF neopterin levels were elevated in patients with FCs, whose CSF had no pleocytosis, are consistent with the possibility of neopterin production by microglia. Our results further suggest that immune activation of microgrial cells is one of the mechanisms involved in the onset of FCs.

Intrathecal immune activation is associated with cerebrospinal fluid markers of neuronal destruction in AIDS patients

We analysed the relationship between cerebrospinal fluid (CSF) concentrations of the light subunit of the neurofilament protein (NFL, a marker of neurons, mainly axons), neopterin (a marker of immune activation), and quantitative HIV RNA levels in 47 patients with HIV-1 infection, 25 of whom had AIDS. In the AIDS patients, the mean levels of CSF NFL were high indicating neuronal destruction. The CSF NFL and the CSF neopterin concentrations were correlated in the subgroup of patients without CNS opportunistic infection ( p<0.05). There was no significant correlation between NFL and HIV RNA levels in CSF. In HIV seropositive patients without AIDS, only 3/22 had CSF NFL concentrations above the upper normal reference value. The results suggest that CNS neuronal destruction occurs frequently in patients with AIDS but rarely in those without AIDS, and that immune activation rather than the HIV viral load is associated with neurochemical signs of axonal destruction.