Higher cerebrospinal fluid biomarkers of neuronal injury in HIV-associated neurocognitive impairment.

We evaluated whether biomarkers of age-related neuronal injury and amyloid metabolism are associated with neurocognitive impairment (NCI) in people with and without HIV (PWH, PWoH). This was a cross-sectional study of virally suppressed PWH and PWoH. NCI was assessed using a validated test battery; global deficit scores (GDS) quantified overall performance. Biomarkers in cerebrospinal fluid (CSF) were quantified by immunoassay: neurofilament light (NFL), total Tau (tTau), phosphorylated Tau 181 (pTau181), amyloid beta (Aß)42, and Aß40. Factor analysis was used to reduce biomarker dimensionality. Participants were 256 virally suppressed PWH and 42 PWoH, 20.2% female, 17.1% Black, 7.1% Hispanic, 60.2% non-Hispanic White, and 15.6% other race/ethnicities, mean (SD) age 56.7 (6.45) years. Among PWH, the best regression model for CSF showed that higher tTau (ß = 0.723, p = 3.79e-5) together with lower pTau181 (ß = -0.510, p = 0.0236) best-predicted poor neurocognitive performance. In univariable analysis, only higher tTau was significantly correlated with poor neurocognitive performance (tTau r = 0.214, p = 0.0006; pTau181 r = 0.00248, p = 0.969). Among PWoH, no CSF biomarkers were significantly associated with worse NCI. Predicted residual error sum of squares (PRESS) analysis showed no evidence of overfitting. Poorer neurocognitive performance in aging PWH was associated with higher CSF tTau, a marker of age-related neuronal injury, but not with biomarkers of amyloid metabolism. The findings suggest that HIV might interact with age-related neurodegeneration to contribute to cognitive decline in PWH.

Immunomodulatory lipid mediator profiling of cerebrospinal fluid following surgery in older adults.

Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation. Neuro-inflammation is thought to play a causal role in perioperative neurocognitive disorders, yet the role of these lipids in the human central nervous system in such disorders is unclear. Here we used liquid chromatography-mass spectrometry to quantify AA, DHA, and EPA derived lipid levels in non-centrifuged cerebrospinal fluid (CSF), centrifuged CSF pellets, and centrifuged CSF supernatants of older adults obtained before, 24 h and 6 weeks after surgery. GAGE analysis was used to determine AA, DHA and EPA metabolite pathway changes over time. Lipid mediators derived from AA, DHA and EPA were detected in all sample types. Postoperative lipid mediator changes were not significant in non-centrifuged CSF (p > 0.05 for all three pathways). The AA metabolite pathway showed significant changes in centrifuged CSF pellets and supernatants from before to 24 h after surgery (p = 0.0000247, p = 0.0155 respectively), from before to 6 weeks after surgery (p = 0.0000497, p = 0.0155, respectively), and from 24 h to 6 weeks after surgery (p = 0.0000499, p = 0.00363, respectively). These findings indicate that AA, DHA, and EPA derived lipids are detectable in human CSF, and the AA metabolite pathway shows postoperative changes in centrifuged CSF pellets and supernatants.

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.

BACKGROUND: One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated. METHODS: Cerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren's Children's Hospital were quantified and used for comparison. RESULTS: Children with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old. CONCLUSIONS: CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.

Elevated cerebrospinal fluid tumour necrosis factor is associated with acute and long-term neurocognitive impairment in cerebral malaria.

Systemic tumour necrosis factor-α (TNF-α) may contribute to the pathogenesis of cerebral malaria (CM) by promoting endothelial activation and parasite sequestration. However, less is known about the role of central nervous system (CNS) TNF-α in CM. We assessed plasma (n=249) and cerebrospinal fluid (CSF) (n=167) TNF-α levels in Ugandan children with CM, plasma TNF-α in Ugandan community control children (n=198) and CSF TNF-α in North American control children who had recovered from leukaemia (n=13). Plasma and CSF TNF-α were measured by magnetic bead assay. We compared plasma and CSF TNF-α levels in children with CM to mortality, acute and chronic neurologic deficits and long-term neurocognitive impairment. Plasma and CSF TNF-α levels were higher in CM than control children (P<.0001 for both). CSF TNF-α levels were higher in children who had neurologic deficits at discharge or 6-month follow-up (P≤.05 for both). Elevated CSF but not plasma TNF-α was associated with longer coma duration (Spearman's rho .18, P=.02) and deficits in overall cognition in children 5 years and older (ß coefficient -.74, 95% CI -1.35 to -0.13, P=.02). The study findings suggest that CNS TNF-α may be involved in the development of acute and chronic neurologic and cognitive sequelae in children with CM.

The relationship of CSF and plasma cytokine levels in HIV infected patients with neurocognitive impairment.

Although HAD is now rare due to HAART, the milder forms of HAND persist in HIV-infected patients. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. The levels of cytokines in CSF were associated with neurocognitive impairment in HIV infection. However, the changes of cytokines involved in cognition impairment in plasma have not been shown, and their relationships between CSF and plasma require to be addressed. We compared cytokine levels in paired CSF and plasma samples from HIV-infected individuals with or without neurocognitive impairment. Cytokine concentrations were measured by Luminex xMAP. In comparing the expression levels of cytokines in plasma and CSF, IFN-α2, IL-8, IP-10, and MCP-1 were significantly higher in CSF. Eotaxin was significantly higher in plasma, whereas G-CSF showed no difference between plasma and CSF. G-CSF (P = 0.0079), IL-8 (P = 0.0223), IP-10 (P = 0.0109), and MCP-1 (P = 0.0497) in CSF showed significant difference between HIV-CI and HIV-NC group, which may indicate their relationship to HIV associated neurocognitive impairment. In addition, G-CSF (P = 0.0191) and IP-10 (P = 0.0377) in plasma were significantly higher in HIV-CI than HIV-NC. The consistent changes of G-CSF and IP-10 in paired plasma and CSF samples might enhance their potential for predicting HAND.

Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy.

OBJECTIVE: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. METHODS: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. RESULTS: Tau form ratio was significantly reduced in patients with PSP (0.504 +/- 0.284) when compared to age-matched controls (0.989 +/- 0.343), and to patients with other neurodegenerative conditions (range = 0.899-1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p < 0.0001). VBM study showed that CSF tau form ratio decrease correlated significantly with brainstem atrophy. CONCLUSIONS: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness.

[Hashimoto encephalopathy. Analysis of four case reports]. / Encéphalopathie de Hashimoto. Analyse de quatre observations.

INTRODUCTION: Encephalopathy associated with Hashimoto's thyroiditis has been recognized for more than 30 years and is probably underestimated. EXEGESIS: We report four patients with Hashimoto's thyroiditis who presented neurological or psychiatric features. There were three women and one man, with a mean age of 68 years. Neurological presentations were various: seizures, psychotic episodes, altered consciousness, hallucinations without usual aetiological diseases (infectious, metabolic, neoplasic, vascular, etc.). Neurological investigations (EEG, brain CT, magnetic resonance imaging) were unspecific. In all cases, a moderately high CSF protein level without pleocytosis was found. Patients presented slight hypothyroidism with high titers of antithyroperoxidase antibodies. Despite hormone therapy replacement, neurological features persisted. Outcome was favorable under steroid therapy. CONCLUSION: Hashimoto's encephalopathy must be considered in the face of neuropsychiatric manifestations without obvious etiology. Pathogenic mechanisms are not clear but probably involve autoimmune cerebral vasculitis because of the efficacy of steroids.

Cerebrospinal fluid total protein in patients with affective disorders.

Cerebrospinal fluid (CSF) total protein was evaluated in 240 patients with affective disorders and compared with findings in 55 normal comparison subjects. Subtype diagnoses were as follows: bipolar I (n = 108, 47 men, 61 women); bipolar type II (n = 67, 26 men, 41 women); and unipolar (n = 65, 22 men, 43 women). Men had significantly elevated values compared with women. In men with bipolar I disorder, mean CSF protein levels were found to be significantly elevated over those in normal subjects, with 31.9% above the traditional normal range cutoff of 45 mg/dl. Moreover, CSF protein levels in male bipolar I patients were found to be positively correlated with severity of depression at the time of the lumbar puncture and with duration of illness. It thus appears that increased protein levels may be associated with illness severity or progression in male patients with bipolar I disorder. Although elevated CSF protein is a nonspecific marker of cerebral pathology, further search for the potential underlying pathophysiological mechanisms related to this finding would now appear to be warranted.

Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders.

The cerebrospinal fluid (CSF) of 47 children and adolescents with autism was analyzed for the contents of two astroglial proteins, the glial fibrillary acidic protein (GFA) and S 100. The results were contrasted with those obtained in similarly aged cases with other neuropsychiatric disorders (n = 25) and in normal children (n = 10). S-100 did not discriminate the groups from each other. However, GFA in autism and autistic-like conditions was at a level almost three times that in the normal group. The results could implicate gliosis and unspecific brain damage in autism. An alternative model would be increased synapse turnover regardless of underlying cause.

Cerebrospinal fluid and serum levels of neuron-specific enolase in patients with schizophrenia.

Some patients with schizophrenia appear to have brain abnormalities, including enlarged third and lateral ventricles and reduced volumes of temporal lobe structures. These abnormalities could be attributed to a developmental abnormality or a neurodegenerative process. Neuron-specific enolase (NSE), a protein that is found primarily in neurons and neuroendocrine cells, has been used as an index of neuronal damage or degeneration. Levels of NSE in cerebrospinal fluid (CSF) and serum from 50 patients with acute and chronic schizophrenia were compared with those in normal and neurological control subjects. A double-antibody, solid phase iodinated radioimmunoassay was used to determine NSE levels. There was no evidence of elevated levels in patients with schizophrenia, whereas control subjects with neurological illnesses had increased levels of NSE in CSF. Because NSE is rapidly cleared from CSF, however, elevated levels could have been missed. Unmedicated patients tended to have lower levels than medicated patients.

[Intracranial pressure in cases of non-traumatic cerebral hematoma-- personal observations and review of the literature]. / Cisnienie wewnatrzczaszkowe w przypadkach nieurazowych krwiaków sródmózgowych--obserwacje wlasne i analiza pismiennictwa.

The analysis of intracranial pressure records in 95 cases of non-traumatic intracerebral haematoma is presented. In 74 cases continuous recording was done. No correlation was found between the values of this pressure and consciousness disturbances. Three types of pressure change patterns were demonstrated: type A - low or normal values unchanging in 43 cases, type B - high initial values with normalization during conservative treatment, type C - very high initial values which decreased after operation in only some patients.

[Non-traumatic cerebral hematoma and the mechanisms of intracranial volume compensation]. / Nieurazowy krwiak sródmózgowy a mechanizmy wewnatrzczaszkowej kompensacji objetosciowej.

The results are presented of measurements of the intracranial pressure, pressure instability index and shifting of ventricular structures in 42 patients with non-traumatic intracerebral haematoma. Only the value of the instability index showed a correlation with the state of consciousness. For a more complete assessment of the state of sufficiency of the intracranial pressure compensation mechanism all these parameters should be analysed jointly.

Untreated neuroborreliosis: Bannwarth's syndrome evolving into acute schizophrenia-like psychosis. A case report.

In general, meningopolyradiculitis (Bannwarth's syndrome, stage 2 of neuroborreliosis) follows a predictable monophasic self-limiting course. In contrast, we report the case of a patient with an untreated meningopolyradiculitis which evolved into acute schizophrenia-like psychosis due to persistent infection with Borrelia burgdorferi. The psychosis resolved within 1 week of treatment with ceftriaxone. This case shows that the usually benign monophasic meningopolyradiculitis may progress to severe CNS complications, which may have implications on current pathophysiological beliefs.

Reduction of CSF monoamine metabolites in poststroke depression: a preliminary report.

Monoamine metabolites were measured in the cerebrospinal fluid (CSF) of depressed and nondepressed patients with acute stroke lesions and in nondepressed patients without stroke lesions. Depressed stroke patients had a significantly lower concentration of CSF 5-hydroxyindoleacetic acid (5-HIAA; a serotonin metabolite) than the other two groups. These findings suggest that poststroke depression may be mediated by serotonergic mechanisms.

User-friendly method for rapid brain and CSF volume calculation using transaxial MRI images.

A reliable computer method was developed for straightforward, rapid determination of whole brain and cerebrospinal fluid (CSF) volumes from a set of contiguous transaxial magnetic resonance images. The semiautomatic algorithm used a threshold-guided edge follower. Subtraction of proton-weighted from T2-weighted images was used to highlight CSF. Phantom studies were used for validity assessment. Interrater and intrarater reliability and correlation with manual measurement were excellent. Percent CSF and brain volumes were determined for small groups of Alzheimer's disease, HIV seropositive, obsessive-compulsive disorder, and schizophrenic patients as well as for young and elderly normal controls.

Decreased somatostatin-like immunoreactivity in the cerebrospinal fluid of chronic schizophrenic patients with cognitive impairment.

The level of cerebrospinal fluid somatostatin-like immunoreactivity (CSF SLI) was determined for 11 chronic schizophrenic patients with moderate cognitive impairment and for 8 controls. The CSF SLI was significantly reduced (37%) in schizophrenic patients, but this decrease did not correlate with the degree of cognitive decline measured by the Mini-Mental State Examination, with psychotic symptoms estimated by the Brief Psychiatric Rating Scale, or with the neuroleptic dose. Although a reducing effect of long-term neuroleptic treatment cannot be totally excluded, the present study suggests that the CSF SLI level is decreased in cognitively impaired schizophrenic patients, as in many other disorders with cognitive impairment.

Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid.

Concentrations of HVA, 5-HIAA, ascorbic acid, and uric acid in the lumbar and cisternal cerebrospinal fluid (CSF) were measured in psychiatric and neurologically impaired patients. The concentration of HVA is 6.1 times and of 5-HIAA 2.7 times higher in cisternal than in lumbar samples, the cisternal level of uric acid is half that of the lumbar region, but no significant differences were found in ascorbic acid concentrations. Correlation between lumbar and cisternal metabolite concentrations is high for 5-HIAA and ascorbic acid, and is less for HVA and uric acid. In cisternal CSF there is a significant correlation between levels of HVA-5-HIAA, 5-HIAA-ascorbic acid, and 5-HIAA-uric acid. These correlations disappear in lumbar CSF. These findings indicate that extrapolations to cisternal neurotransmitter metabolite concentration from lumbar measures are unwarranted for HVA, but not for 5-HIAA.