Higher Cerebrospinal Fluid Soluble Urokinase-type Plasminogen Activator Receptor, But Not Interferon γ-inducible Protein 10, Correlate With Higher Working Memory Deficits.

BACKGROUND: We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S). METHODS: A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and ß2 microglobulin (ß2m) in the CSF and serum were quantified using different immunoassays. RESULTS: Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum ß2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and ß2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum ß2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024). DISCUSSION: We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

Biomarker profiles of Alzheimer's disease and dynamic of the association between cerebrospinal fluid levels of ß-amyloid peptide and tau.

OBJECTIVE: To investigate the relationship between cerebrospinal fluid (CSF) ß-amyloid peptide (Aß42) and CSF Tau in a large population of patients referred to memory clinics for investigation of cognitive dysfunction. METHODS: We analyzed Alzheimer's disease (AD) biomarkers in CSF taken from 3565 patients referred to 18 French memory clinics. Patients were classified into four profiles according to levels of CSF biomarkers (A: amyloidosis, N: neurodegeneration). The association between CSF Tau and CSF Aß42 were analyzed using general linear regression models, in the overall population and stratified by biomarkers profiles. We compared linear and quadratic models using Akaike information criterion. We also assessed change in biomarker profiles in a subset of patients who had 2 assessments of biomarkers. RESULTS: CSF Tau was negatively associated with CSF Aß42 in the overall population, following a non-linear quadratic model. However, the nature of this association was different in the 4 profiles: positive association in A-N- profile, negative association in A-N+ and A+N+ profiles, lack of association in A+N- patients. When considering patients with longitudinal data on profiles, 36% of those initially classified as A-N+ evolved to an A+N+ profile. CONCLUSIONS: The nature of the association between CSF Aß42 and CFS Tau depends on the A/N profiles of patients. These results suggest an increase in CSF Aß42 early in the disease before its decline while tau pathology progresses, this pattern is particularly observed in non-APOE4 subjects. This phenomenon may explain why some patients with neurodegeneration only markers convert to an AD profile (A+N+) over time.

Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety.

Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.

Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist.

For patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma, intrathecal (IT) methotrexate (MTX) significantly reduces the risk of relapse within the central nervous system, but is associated with neurotoxic sequelae. We established a rat model of MTX-induced cognitive deficits to further investigate the underlying pathophysiology and to develop protective therapeutic interventions. IT MTX 0.5 mg/kg was administered to 10-week old male Long Evans rats. Cerebrospinal fluid (CSF) was collected for measurement of folate, homocysteine, and excitotoxic glutamate analogs. Recognition and spatial memory were tested in the novel object recognition (NOR) task and the object placement (OP) task, respectively. Four doses of IT MTX in a two-week period induced cognitive deficits persisting at least three months after the final injection. CSF concentrations of the excitotoxic glutamate analogs homocysteic acid and homocysteine sulfinic acid were increased relative to baseline for the same three-month period. Dextromethorphan, a noncompetitive antagonist at the N-methyl-D-aspartate receptor, administered at a dose of 2 mg/kg intraperitoneally twice daily for a total of four doses, improved cognitive function among the MTX-treated rats, with no effect on control rats. Although this improvement was transient, each repeated treatment with dextromethorphan was followed by normalization of cognitive function. In conclusion, IT MTX induces persistent alterations in glutaminergic tone that may contribute to persistent cognitive deficits. Treatment with a glutamate receptor antagonist such as dextromethorphan may ameliorate the negative cognitive outcomes observed among patients with leukemia or lymphoma treated with repeated doses of prophylactic IT MTX.

Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjects infected with the human immunodeficiency virus.

Despite widespread use of antiretroviral therapies to control replication of the human immunodeficiency virus (HIV), dysfunctions of cognition that are collectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of those infected by the virus. Currently there is not a biomarker that can identify HIV-infected people who are at risk for the development of HAND. Previous studies have identified particular sphingolipid species that are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are not currently understood. To address this question, we compared cerebrospinal fluid (CSF) levels of sphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed to assess the function of multiple cognitive and motor domains in HIV-infected subjects. We found that sphingomyelin:ceramide ratios for acyl chain lengths of C16:0, C18:0, C22:0, and C24:0 were associated with worse performance on several indices of memory. The most striking finding was for the acyl chain of C18:0 that consistently associated with performance on multiple tests of memory. These findings suggest that the sphingomyelin:ceramide ratio for C18:0 may be a reasonable surrogate marker for memory dysfunction in HIV-infected subjects.

Intrathecal methotrexate induces focal cognitive deficits and increases cerebrospinal fluid homocysteine.

Although most children with acute lymphoblastic leukemia (ALL) can be cured, a significant subset of survivors manifests focal deficits in cognitive function, even when the treatment regimen does not include cranial radiation. Intrathecal administration of the folate antagonist methotrexate (MTX) is necessary to prevent leukemic relapse within the central nervous system, but is suspected to contribute to treatment-induced cognitive dysfunction. To better elucidate the underlying pathophysiology, we sought to establish a rodent model of the cognitive and neurotoxic effects resulting from direct administration of MTX into the cerebrospinal fluid (CSF). MTX or artificial CSF was injected via transcutaneous puncture at the level of the cisterna magna. Subsequent behavioral tests were designed to assess cognitive domains frequently impaired among children treated for ALL. MTX administration produced both recognition and spatial memory deficits, without altering general activity or motor coordination. In addition, MTX significantly reduced folate levels in both CSF and serum and increased CSF homocysteine. Thus, we have established an animal model that mimics the clinical effects of prophylactic intrathecal MTX on cognitive function. Using this model we can further study the pathophysiology of MTX-induced cognitive dysfunction and test protective interventions.

[Involvement of central nervous system disclosing Waldenstrom's disease: demonstration of intrathecal secretion of immunoglobulin M]. / Atteinte des fonctions supérieures révélant une maladie de Waldenström: mise en évidence d'une secrétion intrathécale d'immunoglobuline M.

We report the case of a 68-year old woman complaining of disorders of memory and persistent headaches in whom the diagnosis of Waldenström's macroglobulinaemia (WM) was made. Computerized tomography of the brain showed a butterfly-shaped hyperdensity in the splenium of the corpus callosum, with ventricular dilatation. Magnetic resonance imaging displayed high-intensity signals on T2-weighted sequences. Protein immunoelectrophoresis elicited an IgM kappa peak. The CSF was found to contain proteins and lymphocytes in excess, and immunohistochemical staining confirmed the predominance of anti-kappa and the presence of intrathecal IgM secretion. Chemotherapy was temporarily effective on the memory disorders, but the patient died 26 months after the beginning of treatment. Central nervous system manifestations are seldom observed in WM, and they are now grouped under the name of Bing-Neel syndrome. Psychic disorders are rarely reported. It is suggested that IgM secretion plays a predominant role in the pathogenesis of leucoencephalitis, and this is supported by the finding of intrathecal IgM synthesis.