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Background: Brain- and blood-derived protein analysis in the cerebro-spinal fluid (CSF) in various studies performed abroad found that some proteins and their isoforms were altered significantly in Guillain-Barre' syndrome (GBS) patients in comparison to controls. However, data are lacking in India with respect to the blood- or brain-derived proteins in patients of GBS. Objective: This study aimed to identify the role of apolipoprotein A IV (Apo A IV) and haptoglobin as potential protein markers in CSF of patients with GBS in our population. Materials and Methods: The study comprised 28 participants where 12 confirmed cases of GBS and 16 control subjects admitted for non-infectious neurological disorders were recruited after obtaining approval from the Institutional Ethics Committee. CSF glucose, protein, and adenosine deaminase were analyzed using an autoanalyzer. The concentrations of Apo A IV and haptoglobin were estimated with enzyme-linked immuno-sorbent assay (ELISA) kits. Results: The CSF protein concentrations of cases were higher as compared to controls. The concentrations of haptoglobin and Apo A IV were higher in the confirmed cases of GBS as compared to the control subjects, and this difference was found to be significant. The receiver operating characteristic curve analysis for haptoglobin revealed that the area under the curve (AUC) was 0.867 (95% CI: 0.732-1.001), with a sensitivity of 83.8% and a specificity of 63.3%. The AUC for Apo A IV was 0.883 (95% CI: 0.758-1.009), with a sensitivity of 91.7% and a specificity of 73.3%. Conclusions Haptoglobin along with Apo A IV can emerge as a potential biochemical marker in CSF for the diagnosis of GBS. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert. [ABSTRACT FROM AUTHOR]

Abstract Background Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. Methods In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. Results The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. Conclusions We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

Background: Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer's disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. Methods: In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. Results: The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. Conclusions: We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins' role in AD pathophysiology. [ABSTRACT FROM AUTHOR]

Objective: To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis (BM) from viral meningitis (VM) in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. Methods: Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. Results: At a cut‐off value of 3 mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between BM and VM, the area under the curve (AUC) for CSF lactate was 0.979. Conclusions: The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut‐off value of 3 mmol/L, CSF lactate has high diagnostic accuracy for BM, mean levels in VM remain essentially below 2 mmol/L.

Abstract Background The relative performance of semi-quantitative amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) markers in diagnosing Alzheimer’s disease (AD) and predicting the cognitive evolution of patients with mild cognitive impairment (MCI) is still debated. Methods Subjects from the Alzheimer’s Disease Neuroimaging Initiative 2 with complete baseline cognitive assessment (Mini Mental State Examination, Clinical Dementia Rating [CDR] and Alzheimer’s Disease Assessment Scale–Cognitive Subscale [ADAS-cog] scores), CSF collection (amyloid-β1–42 [Aβ], tau and phosphorylated tau) and 18F-florbetapir scans were included in our cross-sectional cohort. Among these, patients with MCI or substantial memory complaints constituted our longitudinal cohort and were followed for 30 ± 16 months. PET amyloid deposition was quantified using relative retention indices (standardised uptake value ratio [SUVr]) with respect to pontine, cerebellar and composite reference regions. Diagnostic and prognostic performance based on PET and CSF was evaluated using ROC analysis, multivariate linear regression and survival analysis with the Cox proportional hazards model. Results The cross-sectional study included 677 participants and revealed that pontine and composite SUVr values were better classifiers (AUC 0.88, diagnostic accuracy 85%) than CSF markers (AUC 0.83 and 0.85, accuracy 80% and 75%, for Aβ and tau, respectively). SUVr was a strong independent determinant of cognition in multivariate regression, whereas Aβ was not; tau was also a determinant, but to a lesser degree. Among the 396 patients from the longitudinal study, 82 (21%) converted to AD within 22 ± 13 months. Optimal SUVr thresholds to differentiate AD converters were quite similar to those of the cross-sectional study. Composite SUVr was the best AD classifier (AUC 0.86, sensitivity 88%, specificity 81%). In multivariate regression, baseline cognition (CDR and ADAS-cog) was the main predictor of subsequent cognitive decline. Pontine and composite SUVr were moderate but independent predictors of final status and CDR/ADAS-cog progression rate, whereas baseline CSF markers had a marginal influence. The adjusted HRs for AD conversion were 3.8 (p = 0.01) for PET profile, 1.2 (p = ns) for Aβ profile and 1.8 (p = 0.03) for tau profile. Conclusions Semi-quantitative amyloid PET appears more powerful than CSF markers for AD grading and MCI prognosis in terms of cognitive decline and AD conversion.

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Background: The relative performance of semi-quantitative amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) markers in diagnosing Alzheimer's disease (AD) and predicting the cognitive evolution of patients with mild cognitive impairment (MCI) is still debated. Methods: Subjects from the Alzheimer's Disease Neuroimaging Initiative 2 with complete baseline cognitive assessment (Mini Mental State Examination, Clinical Dementia Rating [CDR] and Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog] scores), CSF collection (amyloid-β1-42 [Aβ], tau and phosphorylated tau) and 18F-florbetapir scans were included in our cross-sectional cohort. Among these, patients with MCI or substantial memory complaints constituted our longitudinal cohort and were followed for 30 ± 16 months. PET amyloid deposition was quantified using relative retention indices (standardised uptake value ratio [SUVr]) with respect to pontine, cerebellar and composite reference regions. Diagnostic and prognostic performance based on PET and CSF was evaluated using ROC analysis, multivariate linear regression and survival analysis with the Cox proportional hazards model. Results: The cross-sectional study included 677 participants and revealed that pontine and composite SUVr values were better classifiers (AUC 0.88, diagnostic accuracy 85%) than CSF markers (AUC 0.83 and 0.85, accuracy 80% and 75%, for Aβ and tau, respectively). SUVr was a strong independent determinant of cognition in multivariate regression, whereas Aβ was not; tau was also a determinant, but to a lesser degree. Among the 396 patients from the longitudinal study, 82 (21%) converted to AD within 22 ± 13 months. Optimal SUVr thresholds to differentiate AD converters were quite similar to those of the cross-sectional study. Composite SUVr was the best AD classifier (AUC 0.86, sensitivity 88%, specificity 81%). In multivariate regression, baseline cognition (CDR and ADAS-cog) was the main predictor of subsequent cognitive decline. Pontine and composite SUVr were moderate but independent predictors of final status and CDR/ADAS-cog progression rate, whereas baseline CSF markers had a marginal influence. The adjusted HRs for AD conversion were 3.8 (p = 0.01) for PET profile, 1.2 (p=ns) for Aβ profile and 1.8 (p = 0.03) for tau profile. Conclusions: Semi-quantitative amyloid PET appears more powerful than CSF markers for AD grading and MCI prognosis in terms of cognitive decline and AD conversion. [ABSTRACT FROM AUTHOR]

Abstract: Biological markers would provide valuable tools for tracking disease activity, immunopathological processes or therapeutic efficacy in MS. In this study we analysed a panel of Th1/Th2 cytokines and the chemokine CCL2 in serum and CSF from MS patients and healthy controls. Increased levels of IL-6 (p <0.05) and decreased levels of CCL2 (p <0.001), with the lowest levels during acute relapses, was found in CSF from patients with relapsing–remitting MS. CSF levels of CCL2 correlated with indices for intrathecal IgG production and the CSF level of the neurofilament light protein, a marker for axonal damage, indicating a immunopathogenic role for CCL2. [Copyright &y& Elsevier]

Abstract: Predictive cerebrospinal fluid markers would provide valuable tools for tracking the development and progression of HIV CNS disease. In this study, expression of IL-6, MCP-1, and viral RNA in cerebrospinal fluid collected from SIV-inoculated macaques during acute, asymptomatic, and terminal stages of infection was quantitated to determine whether one or several of these parameters paralleled the severity of SIV encephalitis. Animals that developed moderate to severe SIV encephalitis had significantly elevated levels of CSF IL-6, MCP-1, and SIV RNA during asymptomatic infection and persisting through terminal disease as compared to animals developing mild or no CNS disease. [Copyright &y& Elsevier]

Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aβ peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract Objective: To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis from viral meningitis in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. Methods: Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. Results: At a cut-off value of 3 mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between bacterial and viral meningitis, the area under the curve for CSF lactate was 0.979. Conclusions: The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut-off value of 3 mmol/L, CSF lactate has high diagnostic accuracy for bacterial meningitis, mean levels in viral meningitis remain essentially below 2 mmol/L.

Background: The relative performance of semi-quantitative amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) markers in diagnosing Alzheimer's disease (AD) and predicting the cognitive evolution of patients with mild cognitive impairment (MCI) is still debated., Methods: Subjects from the Alzheimer's Disease Neuroimaging Initiative 2 with complete baseline cognitive assessment (Mini Mental State Examination, Clinical Dementia Rating [CDR] and Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog] scores), CSF collection (amyloid-β 1-42 [Aβ], tau and phosphorylated tau) and 18 F-florbetapir scans were included in our cross-sectional cohort. Among these, patients with MCI or substantial memory complaints constituted our longitudinal cohort and were followed for 30 ± 16 months. PET amyloid deposition was quantified using relative retention indices (standardised uptake value ratio [SUVr]) with respect to pontine, cerebellar and composite reference regions. Diagnostic and prognostic performance based on PET and CSF was evaluated using ROC analysis, multivariate linear regression and survival analysis with the Cox proportional hazards model., Results: The cross-sectional study included 677 participants and revealed that pontine and composite SUVr values were better classifiers (AUC 0.88, diagnostic accuracy 85%) than CSF markers (AUC 0.83 and 0.85, accuracy 80% and 75%, for Aβ and tau, respectively). SUVr was a strong independent determinant of cognition in multivariate regression, whereas Aβ was not; tau was also a determinant, but to a lesser degree. Among the 396 patients from the longitudinal study, 82 (21%) converted to AD within 22 ± 13 months. Optimal SUVr thresholds to differentiate AD converters were quite similar to those of the cross-sectional study. Composite SUVr was the best AD classifier (AUC 0.86, sensitivity 88%, specificity 81%). In multivariate regression, baseline cognition (CDR and ADAS-cog) was the main predictor of subsequent cognitive decline. Pontine and composite SUVr were moderate but independent predictors of final status and CDR/ADAS-cog progression rate, whereas baseline CSF markers had a marginal influence. The adjusted HRs for AD conversion were 3.8 (p = 0.01) for PET profile, 1.2 (p = ns) for Aβ profile and 1.8 (p = 0.03) for tau profile., Conclusions: Semi-quantitative amyloid PET appears more powerful than CSF markers for AD grading and MCI prognosis in terms of cognitive decline and AD conversion.

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to the subtle brain changes that occur in the preclinical stage of the disease. Reductions in the cerebral metabolic rate of glucose (CMRglc), a measure of neuronal function, have proven to be a promising tool in the early diagnosis of AD. In vivo brain 2-[(18)F]fluoro-2-Deoxy-D-glucose-positron emission tomography (FDG-PET) imaging demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. There is increasing evidence that hypometabolism appears during the preclinical stages of AD and can predict decline years before the onset of symptoms. This review will give an overview of FDG-PET results in individuals at risk for developing dementia, including: presymptomatic individuals carrying mutations responsible for early-onset familial AD; patients with Mild Cognitive Impairment (MCI), often a prodrome to late-onset sporadic AD; non-demented carriers of the Apolipoprotein E (ApoE) epsilon4 allele, a strong genetic risk factor for late-onset AD; cognitively normal subjects with a family history of AD; subjects with subjective memory complaints; and normal elderly followed longitudinally until they expressed the clinical symptoms and received post-mortem confirmation of AD. Finally, we will discuss the potential to combine different PET tracers and CSF markers of pathology to improve the early detection of AD.