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Sample records for ad csf biomarkers

  1. Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification.

    PubMed

    Davatzikos, Christos; Bhatt, Priyanka; Shaw, Leslie M; Batmanghelich, Kayhan N; Trojanowski, John Q

    2011-12-01

    Magnetic resonance imaging (MRI) patterns were examined together with cerebrospinal fluid (CSF) biomarkers in serial scans of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with mild cognitive impairment (MCI). The SPARE-AD score, summarizing brain atrophy patterns, was tested as a predictor of short-term conversion to Alzheimer's disease (AD). MCI individuals that converted to AD (MCI-C) had mostly positive baseline SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD) and atrophy in temporal lobe gray matter (GM) and white matter (WM), posterior cingulate/precuneous, and insula. MCI individuals that converted to AD had mostly AD-like baseline CSF biomarkers. MCI nonconverters (MCI-NC) had mixed baseline SPARE-AD and CSF values, suggesting that some MCI-NC subjects may later convert. Those MCI-NC with most negative baseline SPARE-AD scores (normal brain structure) had significantly higher baseline Mini Mental State Examination (MMSE) scores (28.67) than others, and relatively low annual rate of Mini Mental State Examination decrease (-0.25). MCI-NC with midlevel baseline SPARE-AD displayed faster annual rates of SPARE-AD increase (indicating progressing atrophy). SPARE-AD and CSF combination improved prediction over individual values. In summary, both SPARE-AD and CSF biomarkers showed high baseline sensitivity, however, many MCI-NC had abnormal baseline SPARE-AD and CSF biomarkers. Longer follow-up will elucidate the specificity of baseline measurements.

  2. Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia.

    PubMed

    Simonsen, Anja Hviid; Herukka, Sanna-Kaisa; Andreasen, Niels; Baldeiras, Ines; Bjerke, Maria; Blennow, Kaj; Engelborghs, Sebastiaan; Frisoni, Giovanni B; Gabryelewicz, Tomasz; Galluzzi, Samantha; Handels, Ron; Kramberger, Milica G; Kulczyńska, Agnieszka; Molinuevo, Jose Luis; Mroczko, Barbara; Nordberg, Agneta; Oliveira, Catarina Resende; Otto, Markus; Rinne, Juha O; Rot, Uroš; Saka, Esen; Soininen, Hilkka; Struyfs, Hanne; Suardi, Silvia; Visser, Pieter Jelle; Winblad, Bengt; Zetterberg, Henrik; Waldemar, Gunhild

    2017-03-01

    This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

  3. Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers.

    PubMed

    Da, Xiao; Toledo, Jon B; Zee, Jarcy; Wolk, David A; Xie, Sharon X; Ou, Yangming; Shacklett, Amanda; Parmpi, Paraskevi; Shaw, Leslie; Trojanowski, John Q; Davatzikos, Christos

    2014-01-01

    This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1-42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.

  4. Age and diagnostic performance of Alzheimer disease CSF biomarkers

    PubMed Central

    Rosén, E.; Hansson, O.; Andreasen, N.; Parnetti, L.; Jonsson, M.; Herukka, S.-K.; van der Flier, W.M.; Blankenstein, M.A.; Ewers, M.; Rich, K.; Kaiser, E.; Verbeek, M.M.; Olde Rikkert, M.; Tsolaki, M.; Mulugeta, E.; Aarsland, D.; Visser, P.J.; Schröder, J.; Marcusson, J.; de Leon, M.; Hampel, H.; Scheltens, P.; Wallin, A.; Eriksdotter-Jönhagen, M.; Minthon, L.; Winblad, B.; Blennow, K.; Zetterberg, H.

    2012-01-01

    Objectives: Core CSF changes in Alzheimer disease (AD) are decreased amyloid β1–42, increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. Methods: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43–89 years) and 304 controls (67, 44–91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43–89 years) followed for at least 2 years, or until dementia diagnosis. Results: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. Conclusion: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations. PMID:22302554

  5. Using CSF biomarkers to replicate genetic associations in Alzheimer's disease.

    PubMed

    Schott, Jonathan M

    2012-07-01

    Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies.

  6. CSF biomarkers cutoffs: the importance of coincident neuropathological diseases

    PubMed Central

    Toledo, Jon B.; Brettschneider, Johannes; Grossman, Murray; Arnold, Steven E.; Hu, William T.; Xie, Sharon X.; Lee, Virginia M.-Y.; Shaw, Leslie M.

    2012-01-01

    The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients [71 Alzheimer’s disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses] were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Aβ42, total, and phosphorylated tau181 were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14–17 % underestimation of the biomarker accuracy. These results show that while CSF Aβ and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses. PMID:22526019

  7. CSF biomarkers in different phenotypes of Parkinson disease.

    PubMed

    Jellinger, Kurt A

    2012-04-01

    CSF biomarker studies were performed in 6 patients each with tremor-dominant (TD) and non-tremor-dominant (NT) Parkinson disease (PD) patients, 27 Alzheimer disease (AD) and 17 age-matched controls. In both NT-PD and AD patients total tau levels and the cortex tau/Aβ-42 were significantly increased compared to both TD-PD patients and controls (p < 0.01). These data in a small cohort confirm previous studies, corroborating the opinion that CSF levels of tau protein and the index total-tau/Aβ-42 may be potential markers of the severity of neurodegeneration in PD.

  8. T1rho MRI and CSF biomarkers in diagnosis of Alzheimer's disease.

    PubMed

    Haris, Mohammad; Yadav, Santosh K; Rizwan, Arshi; Singh, Anup; Cai, Kejia; Kaura, Deepak; Wang, Ena; Davatzikos, Christos; Trojanowski, John Q; Melhem, Elias R; Marincola, Francesco M; Borthakur, Arijitt

    2015-01-01

    In the current study, we have evaluated the performance of magnetic resonance (MR) T1rho (T1ρ) imaging and CSF biomarkers (T-tau, P-tau and Aβ-42) in characterization of Alzheimer's disease (AD) patients from mild cognitive impairment (MCI) and control subjects. With informed consent, AD (n = 27), MCI (n = 17) and control (n = 17) subjects underwent a standardized clinical assessment and brain MRI on a 1.5-T clinical-scanner. T1ρ images were obtained at four different spin-lock pulse duration (10, 20, 30 and 40 ms). T1ρ maps were generated by pixel-wise fitting of signal intensity as a function of the spin-lock pulse duration. T1ρ values from gray matter (GM) and white matter (WM) of medial temporal lobe were calculated. The binary logistic regression using T1ρ and CSF biomarkers as variables was performed to classify each group. T1ρ was able to predict 77.3% controls and 40.0% MCI while CSF biomarkers predicted 81.8% controls and 46.7% MCI. T1ρ and CSF biomarkers in combination predicted 86.4% controls and 66.7% MCI. When comparing controls with AD, T1ρ predicted 68.2% controls and 73.9% AD, while CSF biomarkers predicted 77.3% controls and 78.3% for AD. Combination of T1ρ and CSF biomarkers improved the prediction rate to 81.8% for controls and 82.6% for AD. Similarly, on comparing MCI with AD, T1ρ predicted 35.3% MCI and 81.9% AD, whereas CSF biomarkers predicted 53.3% MCI and 83.0% AD. Collectively CSF biomarkers and T1ρ were able to predict 59.3% MCI and 84.6% AD. On receiver operating characteristic analysis T1ρ showed higher sensitivity while CSF biomarkers showed greater specificity in delineating MCI and AD from controls. No significant correlation between T1ρ and CSF biomarkers, between T1ρ and age, and between CSF biomarkers and age was observed. The combined use of T1ρ and CSF biomarkers have promise to improve the early and specific diagnosis of AD. Furthermore, disease progression form MCI to AD might be easily tracked using

  9. CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease.

    PubMed

    Fjell, Anders M; Walhovd, Kristine B; Fennema-Notestine, Christine; McEvoy, Linda K; Hagler, Donald J; Holland, Dominic; Brewer, James B; Dale, Anders M

    2010-02-10

    Brain atrophy and altered CSF levels of amyloid beta (Abeta(42)) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's disease (AD)-related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions. (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change [clinical dementia rating sum of boxes (CDR-sb)]? Three hundred seventy participants (105 NC, 175 MCI, 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for 1 year and 176 for 2 years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest. Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Abeta(42) comparable with controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes and that the two types of biomarkers yield complementary information.

  10. Mapping CSF biomarker profiles onto NIA-AA guidelines for Alzheimer's disease.

    PubMed

    Alexopoulos, Panagiotis; Roesler, Jennifer; Thierjung, Nathalie; Werle, Lukas; Buck, Dorothea; Yakushev, Igor; Gleixner, Lena; Kagerbauer, Simone; Ortner, Marion; Grimmer, Timo; Kübler, Hubert; Martin, Jan; Laskaris, Nikolaos; Kurz, Alexander; Perneczky, Robert

    2016-10-01

    The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers β-amyloid 1-42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3-52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA-AA guidelines, and more than 40 % of participants could not be classified into the NIA-AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA-AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile.

  11. Predicting MCI outcome with clinically available MRI and CSF biomarkers

    PubMed Central

    Heister, D.; Brewer, J.B.; Magda, S.; Blennow, K.

    2011-01-01

    Objective: To determine the ability of clinically available volumetric MRI (vMRI) and CSF biomarkers, alone or in combination with a quantitative learning measure, to predict conversion to Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). Methods: We stratified 192 MCI participants into positive and negative risk groups on the basis of 1) degree of learning impairment on the Rey Auditory Verbal Learning Test; 2) medial temporal atrophy, quantified from Food and Drug Administration–approved software for automated vMRI analysis; and 3) CSF biomarker levels. We also stratified participants based on combinations of risk factors. We computed Cox proportional hazards models, controlling for age, to assess 3-year risk of converting to AD as a function of risk group and used Kaplan-Meier analyses to determine median survival times. Results: When risk factors were examined separately, individuals testing positive showed significantly higher risk of converting to AD than individuals testing negative (hazard ratios [HR] 1.8–4.1). The joint presence of any 2 risk factors substantially increased risk, with the combination of greater learning impairment and increased atrophy associated with highest risk (HR 29.0): 85% of patients with both risk factors converted to AD within 3 years, vs 5% of those with neither. The presence of medial temporal atrophy was associated with shortest median dementia-free survival (15 months). Conclusions: Incorporating quantitative assessment of learning ability along with vMRI or CSF biomarkers in the clinical workup of MCI can provide critical information on risk of imminent conversion to AD. PMID:21998317

  12. Beneficial effect of bilingualism on Alzheimer's disease CSF biomarkers and cognition.

    PubMed

    Estanga, Ainara; Ecay-Torres, Mirian; Ibañez, Almudena; Izagirre, Andrea; Villanua, Jorge; Garcia-Sebastian, Maite; Iglesias Gaspar, M Teresa; Otaegui-Arrazola, Ane; Iriondo, Ane; Clerigue, Monserrat; Martinez-Lage, Pablo

    2017-02-01

    Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer's disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n = 100, nCSF = 59), early (n = 81, nCSF = 55) and late bilinguals (n = 97, nCSF = 52) were evaluated. Models adjusted for confounders showed that bilinguals performed better than monolinguals on digits backwards (early-bilinguals p = 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p = 0.018; late-bilinguals p = 0.004), and Trail Making Test-B (late-bilinguals p = 0.047). Early bilingualism was associated with lower CSF total-tau (p = 0.019) and lower prevalence of preclinical AD (NIA-AA classification) (p = 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile.

  13. Alliance for aging research AD biomarkers work group: structural MRI.

    PubMed

    Jack, Clifford R

    2011-12-01

    Biomarkers of Alzheimer's disease (AD) are increasingly important. All modern AD therapeutic trials employ AD biomarkers in some capacity. In addition, AD biomarkers are an essential component of recently updated diagnostic criteria for AD from the National Institute on Aging--Alzheimer's Association. Biomarkers serve as proxies for specific pathophysiological features of disease. The 5 most well established AD biomarkers include both brain imaging and cerebrospinal fluid (CSF) measures--cerebrospinal fluid Abeta and tau, amyloid positron emission tomography (PET), fluorodeoxyglucose (FDG) positron emission tomography, and structural magnetic resonance imaging (MRI). This article reviews evidence supporting the position that MRI is a biomarker of neurodegenerative atrophy. Topics covered include methods of extracting quantitative and semiquantitative information from structural MRI; imaging-autopsy correlation; and evidence supporting diagnostic and prognostic value of MRI measures. Finally, the place of MRI in a hypothetical model of temporal ordering of AD biomarkers is reviewed.

  14. Biobanking of CSF: international standardization to optimize biomarker development.

    PubMed

    Teunissen, Charlotte E; Tumani, Hayrettin; Engelborghs, Sebastiaan; Mollenhauer, Brit

    2014-03-01

    Cerebrospinal fluid (CSF) reflects pathophysiological aspects of neurological diseases, where neuroprotective strategies and biomarkers are urgently needed. Therefore, biobanking is very relevant for biomarker discovery and evaluation of neurological diseases. Important and unique features of CSF biobanking are intensive collaboration in international networks and the tight application of standardized protocols. The current adoption of standardized protocols for CSF and blood collection as presented in this review enables biomarker studies in large cohorts of patients and controls. Another topic of this review is the selection of control groups, which influences the outcome of biomarker investigations. Control groups in CSF biobanks mainly consist of different disease controls. This is in part due to the fact that lumbar punctures are mostly performed for clinical indications and rarely for research purposes only, as it is a relatively invasive procedure. Moreover, there is a lack of homogenous criteria and definition of control groups. We therefore propose uniform consensus definitions for such control groups in biomarker research, i.e. Healthy controls (HC), Spinal anesthesia subjects (SAS), Symptomatic controls (SC), Inflammatory Neurological Disease Controls (CINDC), Peripheral Inflammatory Neurological Disease Controls (PINDC) and Non-inflammatory Neurological Disease Controls (NINDC). Another important aspect of CSF biobanking is quality control. Systematic studies to address effects of pre-analytical and storage variation on a broad range of CSF proteins are needed. In conclusion, biomarker research in neurodegenerative diseases has entered a new era due to the collaborative and multicenter efforts of many groups. The streamlining of biobanking procedures, including quality control, and the selection of optimal control groups for investigating biomarkers are important improvements to perform high quality biomarker studies.

  15. A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology

    PubMed Central

    Paterson, R W; Heywood, W E; Heslegrave, A J; Magdalinou, N K; Andreasson, U; Sirka, E; Bliss, E; Slattery, C F; Toombs, J; Svensson, J; Johansson, P; Fox, N C; Zetterberg, H; Mills, K; Schott, J M

    2016-01-01

    Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as ‘AD' or ‘non-AD' on the basis of their CSF T-tau and amyloid Aβ1–42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF Aβ1–42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical

  16. Visual ratings of atrophy in MCI: prediction of conversion and relationship with CSF biomarkers.

    PubMed

    Lehmann, Manja; Koedam, Esther L; Barnes, Josephine; Bartlett, Jonathan W; Barkhof, Frederik; Wattjes, Mike P; Schott, Jonathan M; Scheltens, Philip; Fox, Nick C

    2013-01-01

    Medial temporal lobe atrophy (MTA) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) pathology may aid the early detection of AD in mild cognitive impairment (MCI). However, the relationship between structural and pathological markers is not well understood. Furthermore, while posterior atrophy (PA) is well recognized in AD, its value in predicting conversion from late-onset amnestic MCI to AD is unclear. In this study we used visual ratings of MTA and PA to assess their value in predicting conversion to AD in 394 MCI patients. The relationship of atrophy patterns with CSF Aβ1-42, tau, and p-tau(181) was further investigated in 114 controls, 192 MCI, and 99 AD patients. There was a strong association of MTA ratings with conversion to AD (p < 0.001), with a weaker association for PA ratings (p = 0.047). Specific associations between visual ratings and CSF biomarkers were found; MTA was associated with lower levels of Aβ1-42 in MCI, while PA was associated with elevated levels of tau in MCI and AD, which may reflect widespread neuronal loss including posterior regions. These findings suggest both that posterior atrophy may predict conversion to AD in late-onset MCI, and that there may be differential relationships between CSF biomarkers and regional atrophy patterns.

  17. Could clinical profile influence CSF biomarkers in early-onset Alzheimer disease?

    PubMed

    Koric, Lejla; Felician, Olivier; Guedj, Eric; Hubert, Anne Michele; Mancini, Julien; Boucraut, Jose; Ceccaldi, Mathieu

    2010-01-01

    In common forms of Alzheimer disease (AD), anterograde memory impairment is the first deficit to occur. However, the disease, especially in its presenile forms, may also manifest itself through initial deficits that are predominantly of a nonmemory type. These distinct clinical profiles, which reflect the distinct topography of the underlying pathologic processes, may also differ in terms of their cerebrospinal fluid (CSF) markers. The aim of this study was to assess the levels of total tau, phosphorylated tau, and amyloid-beta 42 peptide in the CSF of "atypical" (nonmemory) early-onset AD patients. CSF biomarkers were evaluated in 22 atypical patients, and compared with those from a group of 13 "typical" patients, with a memory onset form of the disease. Our results show that independently of age, disease duration, education level, and clinical severity indices, patients with an atypical onset have significantly higher levels of total tau in the CSF (P=0.023). These findings indicate that an assessment of CSF biomarkers may be of particular use in the clinical diagnosis of "atypical-onset" forms of early-onset AD in which the initial symptoms involve language and visuospatial abilities rather than memory. In addition, they highlight the heterogeneity of pathologic processes in AD, suggesting more intense degeneration in the forms of the disease that primarily involve neocortical structures.

  18. Mining the secrets of the CSF: developing biomarkers of neurodegeneration.

    PubMed

    Potter, William Z

    2012-09-01

    Our ability to track the progression of neurological disorders like Parkinson's disease (PD) is hampered by a lack of biomarkers, rendering the neuronal changes that underlie clinical symptoms largely a mystery. In this issue of the JCI, Fanara et al. report the development of an innovative approach to biomarker development. They describe a method to measure axonal microtubule function via cerebrospinal fluid (CSF) sampling and use this technique to provide evidence of deficiencies in this process in PD patients. This both sheds light on the pathophysiology of PD and has implications for the more general problem of developing biomarkers for any brain process.

  19. Relationship between CSF biomarkers of Alzheimer's disease and rates of regional cortical thinning in ADNI data.

    PubMed

    Tosun, Duygu; Schuff, Norbert; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W

    2011-01-01

    Previously it was reported that Alzheimer's disease (AD) patients have reduced amyloid (Aβ 1-42) and elevated total tau (t-tau) and phosphorylated tau (p-tau 181p) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Aβ 1-42, t-tau, and p-tau 181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Aβ 1-42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Aβ 1-42 levels and higher p-tau levels supports the hypothesis that CSF Aβ 1-42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific.

  20. Increased CSF biomarkers of angiogenesis in Parkinson disease

    PubMed Central

    Janelidze, Shorena; Francardo, Veronica; Hall, Sara; Zetterberg, Henrik; Blennow, Kaj; Adler, Charles H.; Beach, Thomas G.; Serrano, Geidy E.; van Westen, Danielle; Londos, Elisabet; Cenci, M. Angela; Hansson, Oskar

    2015-01-01

    Objective: To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood–brain barrier (BBB) permeability, and cerebrovascular disease. Methods: In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia. Results: Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein–1 (a marker of glial activation). The main results were validated in the 2 additional cohorts. Conclusions: CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms. PMID:26511451

  1. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI.

    PubMed

    Shaw, Leslie M; Vanderstichele, Hugo; Knapik-Czajka, Malgorzata; Figurski, Michal; Coart, Els; Blennow, Kaj; Soares, Holly; Simon, Adam J; Lewczuk, Piotr; Dean, Robert A; Siemers, Eric; Potter, William; Lee, Virginia M-Y; Trojanowski, John Q

    2011-05-01

    The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau(181)) and Aβ(1-42) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0-6.0% (5.3%) for CSF Aβ(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p-tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Aβ(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aβ(1-42) and for the ratio t-tau/Aβ(1-42) were determined in an ADNI independent, autopsy-confirmed AD cohort from whom

  2. Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team

    PubMed Central

    Arnerić, Stephen P.; Batrla-Utermann, Richard; Beckett, Laurel; Bittner, Tobias; Blennow, Kaj; Carter, Leslie; Dean, Robert; Engelborghs, Sebastiaan; Genius, Just; Gordon, Mark Forrest; Hitchcock, Janice; Kaplow, June; Luthman, Johan; Meibach, Richard; Raunig, David; Romero, Klaus; Samtani, Mahesh N.; Savage, Mary; Shaw, Leslie; Stephenson, Diane; Umek, Robert M.; Vanderstichele, Hugo; Willis, Brian; Yule, Susan

    2016-01-01

    Abstract Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development. PMID:27662307

  3. Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria

    PubMed Central

    Ferreira, Daniel; Perestelo-Pérez, Lilisbeth; Westman, Eric; Wahlund, Lars-Olof; Sarría, Antonio; Serrano-Aguilar, Pedro

    2014-01-01

    Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable. Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD. Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker. Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia. Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics. Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development. PMID:24715863

  4. Do CSF Biomarkers Predict Progression to Cognitive Impairment in Parkinson's disease patients? A Systematic Review.

    PubMed

    Leaver, Katherine; Poston, Kathleen L

    2015-12-01

    Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the cerebrospinal fluid (CSF) of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis. Recent studies suggest that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients. However, the strength of this evidence and difference between specific CSF biomarkers is not well delineated. We therefore performed a systematic review to assess if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment. Nine articles were identified that met inclusion criteria for the review. Findings from the review suggest a convergence of evidence that a low baseline Aβ42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time. Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker. There are mixed results for other CSF biomarkers such as α-synuclein, Neurofilament light chain, and Heart fatty acid-binding protein. Overall the results of this review show that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment. Given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more efficacious.

  5. Value of neuropsychological testing, imaging, and CSF biomarkers for the differential diagnosis and prognosis of clinically ambiguous dementia.

    PubMed

    Boutoleau-Bretonnière, Claire; Lebouvier, Thibaud; Delaroche, Odile; Lamy, Estelle; Evrard, Christelle; Charriau, Tiphaine; Bretonnière, Cédric; Damier, Philippe; Derkinderen, Pascal; Vercelletto, Martine

    2012-01-01

    The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis.

  6. Relations between brain tissue loss, CSF biomarkers and the ApoE genetic profile: A longitudinal MRI study

    PubMed Central

    Tosun, Duygu; Schuff, Norbert; Truran-Sacrey, Diana; Shaw, Leslie M.; Trojanowski, John Q.; Aisen, Paul; Peterson, Ronald; Weiner, Michael W.

    2010-01-01

    Previously it was reported that Alzheimer's disease (AD) patients have reduced amyloid (Aβ1-42) and elevated total tau (t-tau) and phosphorylated tau (p-tau181p) in the cerebrospinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Aβ1-42, t-tau, and p-tau181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Aβ1-42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Aβ1-42 levels and higher p-tau levels supports the hypothesis that CSF Aβ1-42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific. PMID:20570401

  7. Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection

    SciTech Connect

    Price, Richard W.; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E.; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena S.; Smith, Richard D.; Jacobs, Jon M.; Brown, Joseph N.; Gisslen, Magnus

    2013-12-13

    Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previouslydefined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

  8. Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

    PubMed Central

    Vilar-Bergua, A; Riba-Llena, I; Nafría, C; Bustamante, A; Llombart, V; Delgado, P

    2016-01-01

    Vascular dementia is the second most common type of dementia after Alzheimer’s disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral small-vessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies. PMID:25899297

  9. CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment.

    PubMed

    Rolstad, Sindre; Jakobsson, Joel; Sellgren, Carl; Isgren, Anniella; Ekman, Carl Johan; Bjerke, Maria; Blennow, Kaj; Zetterberg, Henrik; Pålsson, Erik; Landén, Mikael

    2015-08-01

    Persistent cognitive impairment in the euthymic state of bipolar disorder is increasingly recognized. Mounting evidence also suggests an association between neuroinflammation and cognitive dysfunction. The purpose of this study was to test if cerebrospinal fluid (CSF) markers of neuroinflammation could account for cognitive impairment in bipolar disorder. Hierarchical linear regression models were applied to account for performance in five cognitive domains using CSF neuroinflammatory biomarkers as predictors in patients with bipolar disorder type I and II (N=78). The associations between these biomarkers and cognition were further tested in healthy age- and sex-matched controls (N=86). In patients with bipolar disorder, the CSF biomarkers accounted for a significant proportion of the variance in executive functions (42.8%, p=<.0005) independently of age, medication, disease status, and bipolar subtype. The microglial marker YKL-40 had a high impact (beta=-.99), and was the only biomarker that contributed individually. CSF biomarkers were not associated with cognitive performance in healthy controls. The CSF neuroinflammation biomarker YKL-40 is associated with executive performance in euthymic bipolar disorder, but not in healthy controls.

  10. Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection.

    PubMed

    Price, Richard W; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena; Smith, Richard D; Jacobs, Jon M; Brown, Joseph N; Gisslen, Magnus

    2013-12-01

    Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

  11. Do CSF biomarkers help clinicians predict the progression of mild cognitive impairment to dementia?

    PubMed

    Mitchell, Alex J; Monge-Argilés, J A; Sánchez-Paya, J

    2010-08-01

    There is increasing interest in the value of CSF biomarkers to predict those individuals with mild cognitive impairment who will progress to dementia. However, lumbar puncture is not routine in these patients and biomarker assays are not universally available. To change clinical practice there must be very good evidence that biomarkers are helpful over and above clinical impression. Here we discuss the merits of CSF biomarkers compared with clinicians using simple bedside cognitive tests. Although every biomarker has a superior positive predictive value, most have inferior negative predictive values. When predicting the progression of mild cognitive impairment, the overall misclassification rate by clinicians using bedside cognitive tests is approximately 38% but this could be reduced to approximately 30% by using Abeta1-42 and to 24% with phosphorylated tau or total tau (or a combination of CSF biomarkers). Clinicians and patients together should decide whether this is sufficient to warrant the additional burden of a lumbar puncture, and the cost of the test, or whether further studies are needed before useful and clinically practical conclusions can be reached.

  12. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease.

    PubMed

    Forner, Sven A; Takada, Leonel T; Bettcher, Brianne M; Lobach, Iryna V; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L; Rosen, Howard J; Geschwind, Michael D

    2015-04-01

    We assessed the diagnostic utility of 3 CSF biomarkers-14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)-from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92-1.00) and a diagnostic accuracy of 97% (CI 90%-100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03).

  13. IL-17 production by CSF lymphocytes as a biomarker for cerebral vasculitis

    PubMed Central

    Thom, Vivien; Schmid, Sabrina; Gelderblom, Mathias; Hackbusch, Romy; Kolster, Manuela; Schuster, Simon; Thomalla, Götz; Keminer, Oliver; Pleß, Ole; Bernreuther, Christian; Glatzel, Markus; Wegscheider, Karl; Gerloff, Christian

    2016-01-01

    Objective: To explore the possibility of using interleukin-17 (IL-17) production by CD4+ T cells in the CSF as a potential biomarker for cerebral vasculitis in stroke patients. Methods: In this consecutive case study, we performed prospective analysis of CSF and blood in patients admitted to a university medical center with symptoms of stroke and suspected cerebral vasculitis. Flow cytometry was performed for intracellular detection of inflammatory cytokines in peripheral blood lymphocytes and expanded T cells from CSF. Results: CSF CD4+ lymphocytes from patients with cerebral vasculitis showed significantly higher levels of the proinflammatory cytokine IL-17 compared to patients with stroke not due to vasculitis or with other, noninflammatory neurologic diseases. There was no difference in the production of interferon-γ in the CSF and no overall differences in the relative frequencies of peripheral immune cells. Conclusions: Intracellular IL-17 in CSF cells is potentially useful in discriminating cerebral vasculitis as a rare cause in patients presenting with ischemic stroke. Classification of evidence: This study provides Class II evidence that an increased proportion of IL-17-producing CD4+ cells in CSF of patients presenting with stroke symptoms is indicative of cerebral vasculitis (sensitivity 73%, 95% confidence interval [CI] 39–94%; specificity 100%, 95% CI 74%–100%). PMID:27144213

  14. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis

    PubMed Central

    Bergman, Petra; Piket, Eliane; Khademi, Mohsen; James, Tojo; Brundin, Lou; Olsson, Tomas; Piehl, Fredrik

    2016-01-01

    Objective: To explore circulating microRNAs (miRNAs) in cell-free CSF as novel biomarkers for multiple sclerosis (MS). Methods: Profiling of miRNAs in CSF of pooled patients with clinically isolated syndrome (CIS), patients with relapsing-remitting MS, and inflammatory and noninflammatory neurologic disease controls was performed using TaqMan miRNA arrays. Two independent patient cohorts (n = 142 and n = 430) were used for validation with real-time PCR. Results: We reliably detected 88 CSF miRNAs in the exploratory cohort. Subsequent validation in 2 cohorts demonstrated significantly higher levels of miR-150 in patients with MS. Higher miR-150 levels were also observed in patients with CIS who converted to MS compared to nonconverters, and in patients initiating natalizumab treatment. Levels of miR-150 correlated with immunologic parameters including CSF cell count, immunoglobulin G index, and presence of oligoclonal bands, and with candidate protein biomarkers C-X-C motif chemokine 13, matrix metallopeptidase 9, and osteopontin. Correlation with neurofilament light chain (NFL) was observed only when NFL was adjusted for age using a method that requires further validation. Additionally, miR-150 discriminated MS from controls and CIS converters from nonconverters equally well as the most informative protein biomarkers. Following treatment with natalizumab, but not fingolimod, CSF levels of miR-150 decreased, while plasma levels increased with natalizumab and decreased with fingolimod, suggesting immune cells as a source of miR-150. Conclusions: Our findings demonstrate miR-150 as a putative novel biomarker of inflammatory active disease with the potential to be used for early diagnosis of MS. Classification of evidence: This study provides Class II evidence that CSF miR-150 distinguishes patients with MS from patients with other neurologic conditions. PMID:27144214

  15. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Forner, Sven A.; Takada, Leonel T.; Bettcher, Brianne M.; Lobach, Iryna V.; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L.; Rosen, Howard J.

    2015-01-01

    Summary We assessed the diagnostic utility of 3 CSF biomarkers—14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)—from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92–1.00) and a diagnostic accuracy of 97% (CI 90%–100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03). PMID:26137420

  16. CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

    PubMed

    Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S; Toledo, Jon B; Weintraub, Daniel; Galasko, Douglas R; Irwin, David J; Van Deerlin, Vivianna; Chen-Plotkin, Alice S; Caspell-Garcia, Chelsea; Waligórska, Teresa; Taylor, Peggy; Shah, Nirali; Pan, Sarah; Zero, Pawel; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Tanner, Caroline M; Simuni, Tanya; Singleton, Andrew; Toga, Arthur W; Chowdhury, Sohini; Trojanowski, John Q; Shaw, Leslie M

    2016-06-01

    The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.

  17. Monitoring concussion in a knocked-out boxer by CSF biomarker analysis.

    PubMed

    Neselius, Sanna; Brisby, Helena; Granholm, Fredrik; Zetterberg, Henrik; Blennow, Kaj

    2015-09-01

    Concussion is common in many sports, and the incidence is increasing. The medical consequences after a sport-related concussion have received increased attention in recent years since it is known that concussions cause axonal and glial damage, which disturbs the cerebral physiology and makes the brain more vulnerable for additional concussions. This study reports on a knocked-out amateur boxer in whom cerebrospinal fluid (CSF) neurofilament light (NFL) protein, reflecting axonal damage, was used to identify and monitor brain damage. CSF NFL was markedly increased during 36 weeks, suggesting that neuronal injury persists longer than expected after a concussion. CSF biomarker analysis may be valuable in the medical counselling of concussed athletes and in return-to-play considerations.

  18. An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

    PubMed Central

    Sheline, Yvette I.; West, Tim; Yarasheski, Kevin; Swarm, Robert; Jasielec, Mateusz S.; Fisher, Jonathan R.; Ficker, Whitney D.; Yan, Ping; Xiong, Chengjie; Frederiksen, Christine; Grzelak, Monica V.; Chott, Robert; Bateman, Randall J.; Morris, John C.; Mintun, Mark A.; Lee, Jin-Moo; Cirrito, John R.

    2014-01-01

    Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased Aβ in brain interstitial fluid (ISF) in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable-isotope labeling kinetics (SILK), with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials. PMID:24828079

  19. Altered Prion Protein Expression Pattern in CSF as a Biomarker for Creutzfeldt-Jakob Disease

    PubMed Central

    Torres, Mauricio; Cartier, Luis; Matamala, José Manuel; Hernández, Nancy; Woehlbier, Ute; Hetz, Claudio

    2012-01-01

    Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression

  20. Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease

    PubMed Central

    Vinther-Jensen, Tua; Börnsen, Lars; Budtz-Jørgensen, Esben; Ammitzbøll, Cecilie; Larsen, Ida U.; Hjermind, Lena E.; Sellebjerg, Finn

    2016-01-01

    Objective: To investigate CSF biomarkers of neuroinflammation and neurodegeneration in Huntington disease (HD) gene-expansion carriers compared to controls and to investigate these biomarkers in association with clinical HD rating scales and disease burden score. Methods: We collected CSF from 32 premanifest and 48 manifest HD gene-expansion carriers and 24 gene-expansion negative at-risk controls. We examined biomarkers of neuroinflammation (matrix metalloproteinase 9, C-X-C motif chemokine 13, terminal complement complex, chitinase-3-like-protein 1 [CHI3L1], and osteopontin [OPN]) and neurodegeneration (microtubule-associated protein tau, neurofilament light polypeptide [NFL], and myelin basic protein [MBP]). The study was approved by the Ethics Committee of the Capital Region of Denmark (H2-2011-085) and written informed consent was obtained from each participant before enrollment. Results: NFL was the only biomarker that increased in premanifest stages and no evidence of early involvement of neuroinflammation in HD was found. However, we found that the biomarkers for neurodegeneration, MBP and tau, increased during the disease course in manifest HD gene-expansion carriers and were associated with an increase of the neuroinflammation biomarkers CHI3L1 and OPN. Tau was also increased in all gene-expansion carriers with psychiatric symptoms compared to gene-expansion carriers without psychiatric symptoms. Conclusions: Neuroinflammation, which seems not to be an early event in our cohort, may be secondary to neurodegeneration in late HD. NFL is a possible disease burden correlate in HD, reflecting neuronal loss even before motor symptom onset, and may be useful as a dynamic biomarker in intervention studies. PMID:27734023

  1. Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

    PubMed

    de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

    2017-02-28

    Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

  2. α-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies

    PubMed Central

    Kasuga, Kensaku; Nishizawa, Masatoyo; Ikeuchi, Takeshi

    2012-01-01

    Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. Although α-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids. α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB and α-synuclein-related disorders, because α-synuclein is characteristically accumulated in the brain of patients with these disorders. The α-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSF α-synuclein level in DLB and α-synuclein-related disorders. Discrepant findings of studies of plasma α-synuclein level in patients with DLB have been reported. Because the level of α-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of α-synuclein. Here, the recent progress in the studies of α-synuclein as a biomarker of DLB and their potential clinical applications are reviewed. PMID:23056991

  3. 3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects

    PubMed Central

    Apostolova, Liana G.; Hwang, Kristy S.; Andrawis, John P.; Green, Amity E.; Babakchanian, Sona; Morra, Jonathan H.; Cummings, Jeffrey L.; Toga, Arthur W.; Trojanowski, John Q.; Shaw, Leslie M.; Jack, Clifford R.; Petersen, Ronald C.; Aisen, Paul S.; Jagust, William J.; Koeppe, Robert A.; Mathis, Chester A.; Weiner, Michael W.; Thompson, Paul M.

    2011-01-01

    Cerebrospinal fluid (CSF) measures of Ab and tau, Pittsburgh Compound B (PIB) imaging and hippocampal atrophy are promising Alzheimer’s disease biomarkers yet the associations between them are not known. We applied a validated, automated hippocampal labeling method and 3D radial distance mapping to the 1.5T structural magnetic resonance imaging (MRI) data of 388 ADNI subjects with baseline CSF Ab42, total tau (t-tau) and phosphorylated tau (p-tau181) and 98 subjects with positron emission tomography (PET) imaging using PIB. We used linear regression to investigate associations between hippocampal atrophy and average cortical, parietal and precuneal PIB standardized uptake value ratio (SUVR) and CSF Ab42, t-tau, p-tau181, t-tau/Ab42 and p-tau181/Ab42. All CSF measures showed significant associations with hippocampal volume and radial distance in the pooled sample. Strongest correlations were seen for p-tau181, followed by p-tau181/Ab42 ratio, t-tau/Ab42 ratio, t-tau and Ab42. p-tau181 showed stronger correlation in ApoE4 carriers, while t-tau showed stronger correlation in ApoE4 noncarriers. Of the 3 PIB measures the precuneal SUVR showed strongest associations with hippocampal atrophy. PMID:20538372

  4. CSF xanthine, homovanillic acid, and their ratio as biomarkers of Parkinson's disease.

    PubMed

    LeWitt, Peter; Schultz, Lonni; Auinger, Peggy; Lu, Mei

    2011-08-23

    Diminished nigrostriatal dopaminergic neurotransmission is a biochemical hallmark of Parkinson's disease. Despite this, a reliable trait biomarker of sporadic Parkinson's disease has not emerged from measurements of cerebrospinal fluid dopamine metabolites. Previous studies have highlighted strong neurochemical relationships between dopamine and various purine compounds. In this study, we analyzed cerebrospinal fluid concentrations of homovanillic acid (the major catabolite of dopamine) and the purine compound xanthine for a comparison of 217 unmedicated Parkinson's disease subjects and 26 healthy controls. These compounds were highly correlated for both the Parkinson's disease subjects (r=0.68) and for controls (r=0.73; both groups, p<0.001). While neither homovanillic acid nor xanthine concentrations differentiated Parkinson's disease from controls, their ratio did. For controls, the mean [xanthine]/[homovanillic acid] quotient was 13.1±5.5 as compared to the Parkinson's disease value of 17.4±6.7 at an initial lumbar CSF collection (p=0.0017), and 19.7±8.7 (p<0.001) at a second CSF collection up to 24 months later. The [xanthine]/[homovanillic acid] ratio in the Parkinson's disease subjects differed as a function of disease severity, as measured by the sum of Unified Parkinson's Disease Rating Scale Activities of Daily Living and Motor Exam ratings. The [xanthine]/[homovanillic acid] ratio also increased between the first and second CSF collections, suggesting that this quotient provides both a state and trait biomarker of Parkinson's disease. These observations add to other neurochemical evidence that links purine metabolism to Parkinson's disease.

  5. Improved discrimination of autopsy-confirmed Alzheimer's disease (AD) from non-AD dementias using CSF P-tau(181P).

    PubMed

    Koopman, Karen; Le Bastard, Nathalie; Martin, Jean-Jacques; Nagels, Guy; De Deyn, Peter P; Engelborghs, Sebastiaan

    2009-09-01

    To establish diagnostic accuracy (acc) and optimal cut-off levels of CSF tau phosphorylated at threonine 181 (P-tau(181P)) for discriminating Alzheimer's disease (AD) from non-AD dementias in autopsy-confirmed dementia patients, CSF levels of beta-amyloid peptide (Abeta(1-42)), total tau protein (T-tau) and P-tau(181P) from patients with definite AD (n=95) and non-AD dementias (n=50) were determined with single-parameter ELISA kits. Optimal P-tau(181P) cut-off levels for differentiating AD from pooled non-AD dementias, dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) were 50.4pg/mL (acc=0.73), 52.8pg/mL (acc=0.73) and 35.3pg/mL (acc=0.90), respectively. The optimal CSF P-tau(181P) cut-off level for discriminating AD from non-AD dementias was 50.4pg/mL. Optimal CSF P-tau(181P) cut-off levels differed between non-AD diagnostic dementia categories.

  6. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.

    PubMed

    Kothur, Kavitha; Wienholt, Louise; Brilot, Fabienne; Dale, Russell C

    2016-01-01

    Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment.

  7. Mapping correlations between ventricular expansion and CSF amyloid and tau biomarkers in 240 subjects with Alzheimer’s disease, mild cognitive impairment and elderly controls

    PubMed Central

    Chou, Yi-Yu; Leporé, Natasha; Avedissian, Christina; Madsen, Sarah K.; Parikshak, Neelroop; Hua, Xue; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Toga, Arthur W.; Thompson, Paul M.

    2009-01-01

    Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer’s disease, NeuroImage 40(2): 615–630); with this method, we calculated minimal numbers of subjects needed to detect correlations between clinical scores and ventricular maps. We also assessed correlations between emerging CSF biomarkers of Alzheimer’s disease pathology and localizable deficits in the brain, in 80 AD, 80 mild cognitive impairment (MCI), and 80 healthy controls from the Alzheimer’s Disease Neuroimaging Initiative. Six expertly segmented images and their embedded parametric mesh surfaces were fluidly registered to each brain; segmentations were averaged within subjects to reduce errors. Surface-based statistical maps revealed powerful correlations between surface morphology and 4 variables: (1) diagnosis, (2) depression severity, (3) cognitive function at baseline, and (4) future cognitive decline over the following year. Cognitive function was assessed using the mini-mental state exam (MMSE), global and sum-of-boxes clinical dementia rating (CDR) scores, at baseline and 1-year follow-up. Lower CSF Aβ1–42 protein levels, a biomarker of AD pathology assessed in 138 of the 240 subjects, were correlated with lateral ventricular expansion. Using false discovery rate (FDR) methods, 40 and 120 subjects, respectively, were needed to discriminate AD and MCI from normal groups. 120 subjects were required to detect correlations between ventricular enlargement and MMSE, global CDR, sum-of-boxes CDR and clinical depression scores. Ventricular expansion maps correlate with pathological and cognitive measures in AD, and may be useful in future imaging-based clinical trials. PMID:19236926

  8. CSF clearance in Alzheimer Disease measured with dynamic PET.

    PubMed

    de Leon, Mony J; Li, Yi; Okamura, Nobuyuki; Tsui, Wai H; Saint Louis, Les A; Glodzik, Lidia; Osorio, Ricardo S; Fortea, Juan; Butler, Tracy; Pirraglia, Elizabeth; Fossati, Silvia; Kim, Hee-Jin; Carare, Roxana O; Nedergaard, Maiken; Benveniste, Helene; Rusinek, Henry

    2017-03-16

    Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with (18)F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with (18)F-THK5117. 10 subjects additionally received (11)C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of (18)F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

  9. CSF Biomarkers of Monocyte Activation and Chemotaxis correlate with Magnetic Resonance Spectroscopy Metabolites during Chronic HIV Disease

    PubMed Central

    Anderson, Albert M.; Fennema-Notestine, Christine; Umlauf, Anya; Taylor, Michael J.; Clifford, David B.; Marra, Christina M.; Collier, Ann C.; Gelman, Benjamin B.; McArthur, Justin C.; McCutchan, J. Allen; Simpson, David M.; Morgello, Susan; Grant, Igor; Letendre, Scott L.

    2015-01-01

    Background HIV-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. Methods A multicenter cross-sectional study involving five sites in the United States was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein 1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM) and frontal gray matter (FGM): N-acetyl-aspartate (NAA), Myo-inositol (MI), Choline (Cho), and Creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Results 83 HIV-infected individuals were included, 78% on cART and 37% with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R2 0.179, p<0.001) as well as MCP-1 and MI in FWM (R2 0.137, p=0.002). Higher Cr levels in FWM were associated with MCP-1 (R2 0. 075, p=0.01) and IP-10 (R2 0.106, p=0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R2 0.224, p<0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. Conclusion These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals. PMID:26069183

  10. CSF Biomarkers and Its Associations with 18F-AV133 Cerebral VMAT2 Binding in Parkinson’s Disease—A Preliminary Report

    PubMed Central

    Gao, Rui; Zhang, Guangjian; Chen, Xueqi; Yang, Aimin; Smith, Gwenn; Wong, Dean F.; Zhou, Yun

    2016-01-01

    Objective Cerebrospinal fluid (CSF) biomarkers, such as α-synuclein (α-syn), amyloid beta peptide 1–42 (Aβ1–42), phosphorylated tau (181P) (p-tau), and total tau (t-tau), have long been associated with the development of Parkinson disease (PD) and other neurodegenerative diseases. In this investigation, we reported the assessment of CSF biomarkers and their correlations with vesicular monoamine transporter 2 (VMAT2) bindings measured with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV133) that is being developed as a biomarker for PD. We test the hypothesis that monoaminergic degeneration was correlated with CSF biomarker levels in untreated PD patients. Methods The available online data from the Parkinson’s Progression Markers Initiative study (PPMI) project were collected and analyzed, which include demographic information, clinical evaluations, CSF biomarkers (α-syn, Aβ1–42, p-tau, and t-tau), 18F-AV133 brain PET, and T1 weighted MRIs. Region of interest (ROI) and voxel-wise Pearson correlation between standardized uptake value ratio (SUVR) and CSF biomarkers were calculated. Results Our major findings are: 1) Compared with controls, CSF α-syn and tau levels decreased significantly in PD; 2) α-syn was closely correlated with Aβ1–42 and tau in PD, especially in early-onset patients; and 3) hypothesis-driven ROI analysis found a significant negative correlation between CSF Aβ1–42 levels and VMAT2 densities in post cingulate, left caudate, left anterior putamen, and left ventral striatum in PDs. CSF t-tau and p-tau levels were significantly negatively related to VMAT2 SUVRs in substantia nigra and left ventral striatum, respectively. Voxel-wise analysis showed that left caudate, parahippocampal gyrus, insula and temporal lobe were negatively correlated with Aβ1–42. In addition, superior frontal gyrus and transverse temporal gyrus were negatively correlated with CSF p-tau levels. Conclusion These results suggest that monoaminergic

  11. Oligomeric Neuronal Protein Aggregates as Biomarkers for Traumatic Brain Injury (TBI) and Alzheimer Disease (AD)

    DTIC Science & Technology

    2013-10-01

    as Biomarkers for Traumatic Brain Injury (TBI) and Alzheimer Disease (AD) PRINCIPAL INVESTIGATOR: Michael Sierks CONTRACTING...Oligomeric Neuronal Protein Aggregates as Biomarkers for Traumatic Brain Injury (TBI) and Alzheimer Disease (AD) 5b. GRANT NUMBER 12109023 5c

  12. Alteration of regional homogeneity and white matter hyperintensities in amnestic mild cognitive impairment subtypes are related to cognition and CSF biomarkers.

    PubMed

    Luo, Xiao; Jiaerken, Yerfan; Huang, Peiyu; Xu, Xiao Jun; Qiu, Tiantian; Jia, Yunlu; Shen, Zhujing; Guan, Xiaojun; Zhou, Jiong; Zhang, Minming

    2017-02-24

    Amnestic mild cognitive impairment can be further classified as single-domain aMCI (SD-aMCI) with isolated memory deficit, or multi-domain aMCI (MD-aMCI) if memory deficit is combined with impairment in other cognitive domains. Prior studies reported these clinical subtypes presumably differ in etiology. Thus, we aimed to explore the possible mechanisms between different aMCI subtypes by assessing alteration in brain activity and brain vasculature, and their relations with CSF AD biomarkers. 49 healthy controls, 32 SD-aMCI, and 32 MD-aMCI, who had undergone structural scans, resting-state functional MRI (rsfMRI) scans and neuropsychological evaluations, were identified. Regional homogeneity (ReHo) was employed to analyze regional synchronization. Periventricular white matter hyperintensities (PWMH) and deep WMH (DWMH) volume of each participant was quantitatively assessed. AD biomarkers from CSF were also measured. SD-aMCI showed decreased ReHo in medial temporal gyrus (MTG), and increased ReHo in lingual gyrus (LG) and superior temporal gyrus (STG) relative to controls. MD-aMCI showed decreased ReHo, mostly located in precuneus (PCu), LG and postcentral gyrus (PCG), relative to SD-aMCI and controls. As for microvascular disease, MD-aMCI patients had more PWMH burden than SD-aMCI and controls. Correlation analyses indicated mean ReHo in differenced regions were related with memory, language, and executive function in aMCI patients. However, no significant associations between PWMH and behavioral data were found. The Aβ level was related with the ReHo value of STG in SD-aMCI. MD-aMCI displayed different patterns of abnormal regional synchronization and more severe PWMH burden compared with SD-aMCI. Therefore aMCI is not a uniform disease entity, and MD-aMCI group may show more complicated pathologies than SD-aMCI group.

  13. [Biomarkers in Alzheimer's disease].

    PubMed

    García-Ribas, G; López-Sendón Moreno, J L; García-Caldentey, J

    2014-04-01

    The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.

  14. Altered protein phosphorylation as a resource for potential AD biomarkers

    PubMed Central

    Henriques, Ana Gabriela; Müller, Thorsten; Oliveira, Joana Machado; Cova, Marta; da Cruz e Silva, Cristóvão B.; da Cruz e Silva, Odete A. B.

    2016-01-01

    The amyloidogenic peptide, Aβ, provokes a series of events affecting distinct cellular pathways regulated by protein phosphorylation. Aβ inhibits protein phosphatases in a dose-dependent manner, thus it is expected that the phosphorylation state of specific proteins would be altered in response to Aβ. In fact several Alzheimer’s disease related proteins, such as APP and TAU, exhibit pathology associated hyperphosphorylated states. A systems biology approach was adopted and the phosphoproteome, of primary cortical neuronal cells exposed to Aβ, was evaluated. Phosphorylated proteins were recovered and those whose recovery increased or decreased, upon Aβ exposure across experimental sets, were identified. Significant differences were evident for 141 proteins and investigation of their interactors revealed key protein clusters responsive to Aβ treatment. Of these, 73 phosphorylated proteins increased and 68 decreased upon Aβ addition. These phosphorylated proteins represent an important resource of potential AD phospho biomarkers that should be further pursued. PMID:27466139

  15. Altered protein phosphorylation as a resource for potential AD biomarkers.

    PubMed

    Henriques, Ana Gabriela; Müller, Thorsten; Oliveira, Joana Machado; Cova, Marta; da Cruz E Silva, Cristóvão B; da Cruz E Silva, Odete A B

    2016-07-28

    The amyloidogenic peptide, Aβ, provokes a series of events affecting distinct cellular pathways regulated by protein phosphorylation. Aβ inhibits protein phosphatases in a dose-dependent manner, thus it is expected that the phosphorylation state of specific proteins would be altered in response to Aβ. In fact several Alzheimer's disease related proteins, such as APP and TAU, exhibit pathology associated hyperphosphorylated states. A systems biology approach was adopted and the phosphoproteome, of primary cortical neuronal cells exposed to Aβ, was evaluated. Phosphorylated proteins were recovered and those whose recovery increased or decreased, upon Aβ exposure across experimental sets, were identified. Significant differences were evident for 141 proteins and investigation of their interactors revealed key protein clusters responsive to Aβ treatment. Of these, 73 phosphorylated proteins increased and 68 decreased upon Aβ addition. These phosphorylated proteins represent an important resource of potential AD phospho biomarkers that should be further pursued.

  16. Abnormalities of CSF flow patterns in the cerebral aqueduct in treatment-resistant late-life depression: a potential biomarker of microvascular angiopathy.

    PubMed

    Naish, Josephine H; Baldwin, Robert C; Patankar, Tufail; Jeffries, Suzanne; Burns, Alistair S; Taylor, Christopher J; Waterton, John C; Jackson, Alan

    2006-09-01

    There is growing evidence that microvascular angiopathy (MVA) plays an important role in the development of dementia and affective disorders in older people. At currently available image resolutions it is not possible to image directly the vascular changes associated with MVA, but the effects on blood and cerebrospinal fluid (CSF) flow may be detectable. The aim of this study was to investigate a potential biomarker for MVA based on MRI of abnormalities in CSF flow. Since there is considerable indirect evidence that treatment resistance in late-onset depressive disorder is related to MVA, we assessed the method in a group of 22 normal volunteers and 29 patients with responsive (N=21) or treatment-resistant (N=8) late-onset depressive disorder. Single-slice quantified phase-contrast (PC) images of cerebral blood and CSF flow were collected at 15 points over a cardiac cycle, and the resulting flow curves were parameterized. Significant differences in the CSF flow (width of systolic flow peak and diastolic flow volume, both P<0.01) through the cerebral aqueduct were observed for the group of treatment-resistant patients when compared to age matched controls. No significant difference was observed for a group of 21 patients with treatment-responsive depression. The findings support the hypothesis that MR measurement of CSF flow abnormalities provides a biomarker of MVA, and thus could have application in a wide range of age-related diseases.

  17. Are CSF Biomarkers Useful as Prognostic Indicators in Diagnostically Unresolved Cognitively Impaired Patients in a Normal Clinical Setting

    PubMed Central

    Schjønning Nielsen, Malene; Simonsen, Anja Hviid; Siersma, Volkert; Hasselbalch, Steen Gregers; Høgh, Peter

    2016-01-01

    Background Despite an extensive evaluation program, patients may remain diagnostically unresolved with regard to the etiology of their cognitive dysfunction. Cerebrospinal fluid neuroinflammation and Alzheimer disease (AD) biomarkers may act as indicators of neurodegenerative disorders in diagnostically unresolved patients. Methods Data on 348 patients were retrospectively evaluated. All participants had a standardized diagnostic workup and follow-up in a memory clinic. Results Aβ42 levels and Aβ42/p-tau ratios were reduced and levels of t-tau and p-tau as well as the t-tau × p-tau/Aβ42 ratio were elevated in diagnostically unresolved patients who clinically progressed, compared to a stable group. No differences in neuroinflammatory parameters were found. Conclusion AD biomarkers - in particular the Aβ42/p-tau ratio, but not neuroinflammatory parameters - predicted clinical progression, regardless of etiology. PMID:27843444

  18. The Glycan Role in the Glycopeptide Immunogenicity Revealed by Atomistic Simulations and Spectroscopic Experiments on the Multiple Sclerosis Biomarker CSF114(Glc)

    NASA Astrophysics Data System (ADS)

    Bruno, Agostino; Scrima, Mario; Novellino, Ettore; D'Errico, Gerardino; D'Ursi, Anna Maria; Limongelli, Vittorio

    2015-03-01

    Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most valid protocol to investigate other systems where the environment effect is determinant for the biological activity.

  19. The Glycan Role in the Glycopeptide Immunogenicity Revealed by Atomistic Simulations and Spectroscopic Experiments on the Multiple Sclerosis Biomarker CSF114(Glc)

    PubMed Central

    Bruno, Agostino; Scrima, Mario; Novellino, Ettore; D'Errico, Gerardino; D'Ursi, Anna Maria; Limongelli, Vittorio

    2015-01-01

    Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most valid protocol to investigate other systems where the environment effect is determinant for the biological activity. PMID:25776265

  20. Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease.

    PubMed

    Ewers, Michael; Schmitz, Susanne; Hansson, Oskar; Walsh, Cathal; Fitzpatrick, Annette; Bennett, David; Minthon, Lennart; Trojanowski, John Q; Shaw, Leslie M; Faluyi, Yetunde O; Vellas, Bruno; Dubois, Bruno; Blennow, Kaj; Buerger, Katharina; Teipel, Stefan J; Weiner, Michael; Hampel, Harald

    2012-08-01

    Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects.

  1. Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges.

    PubMed

    Kim, Dana; Kim, Young Sam; Shin, Dong Wun; Park, Chang Shin; Kang, Ju Hee

    2016-10-01

    No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

  2. CSF tau markers are correlated with hippocampal volume in Alzheimer's disease.

    PubMed

    de Souza, Leonardo C; Chupin, Marie; Lamari, Foudil; Jardel, Claude; Leclercq, Delphine; Colliot, Olivier; Lehéricy, Stéphane; Dubois, Bruno; Sarazin, Marie

    2012-07-01

    Hippocampal atrophy as assessed by magnetic resonance imaging (MRI) and abnormal cerebrospinal fluid (CSF) biomarkers are supportive features for the diagnosis of Alzheimer's disease (AD) and are assumed to be indirect pathological markers of the disease. In AD patients, antemortem MRI hippocampal volumes (HVs) correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy suggesting that HVs may better correlate with CSF tau and hyperphosphorylated tau (P-tau) levels than CSF amyloid beta protein (Aβ)(42) level. Here, we tested this hypothesis in a well-defined AD group. Patients were selected according to the New Research Criteria for AD, including specific episodic memory deficit and CSF AD profile (defined as abnormal ratio of Aβ(42):tau). MRI was performed within 6 months of lumbar puncture. HVs were obtained using automated segmentation software. Thirty-six patients were included. Left HV correlated with CSF tau (R = -0.53) and P-tau (R = -0.56) levels. Mean HVs correlated with the CSF P-tau level (R = -0.52). No correlation was found between any brain measurement and CSF Aβ(42) level. The CSF tau and P-tau levels, but not the CSF Aβ(42) level, correlated with HV, suggesting that CSF tau markers reflect the neuronal loss associated with the physiopathological process of AD.

  3. Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease.

    PubMed

    Babić, Mirjana; Svob Štrac, Dubravka; Mück-Šeler, Dorotea; Pivac, Nela; Stanić, Gabrijela; Hof, Patrick R; Simić, Goran

    2014-08-28

    Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.

  4. Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease

    PubMed Central

    Babić, Mirjana; Švob Štrac, Dubravka; Mück-Šeler, Dorotea; Pivac, Nela; Stanić, Gabrijela; Hof, Patrick R.; Šimić, Goran

    2014-01-01

    Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed. PMID:25165049

  5. Increased CSF neurogranin concentration is specific to Alzheimer disease

    PubMed Central

    Paterson, Ross W.; Portelius, Erik; Törnqvist, Ulrika; Magdalinou, Nadia; Fox, Nick C.; Blennow, Kaj; Schott, Jonathan M.; Zetterberg, Henrik

    2016-01-01

    Objective: To assess the specificity of the dendritic protein neurogranin (Ng) in CSF from patients with a broad range of neurodegenerative diseases including a variety of dementias, tauopathies, and synucleinopathies. Method: An optimized immunoassay was used to analyze CSF Ng in a retrospective cohort of 331 participants with different neurodegenerative diseases, including healthy controls (n = 19), biomarker-proven Alzheimer disease (AD) (n = 100), genetic AD (n = 2), behavioral variant frontotemporal dementia (n = 20), speech variant frontotemporal dementia (n = 21), Lewy body dementia (n = 13), Parkinson disease (n = 31), progressive supranuclear palsy (n = 46), multiple system atrophy (n = 29), as well as a heterogeneous group with non-neurodegenerative cognitive impairment (n = 50). CSF Ng concentrations and correlations of CSF Ng with total tau, phosphorylated tau, and β-amyloid 42 concentrations, Mini-Mental State Examination score, and disease duration in the different groups were investigated. Results: Median CSF Ng concentration was higher in patients with AD compared to both controls (p < 0.001) and all other disease groups (all p < 0.001) except speech variant frontotemporal dementia. There were no significant differences in CSF Ng concentrations between any other neurodegenerative groups and controls. In addition, we found strong correlations between Ng and total tau (p < 0.001) and phosphorylated tau (p < 0.001). Conclusions: These results confirm an increase in CSF Ng concentration in patients with AD as previously reported and show that this is specific to AD and not seen in a range of other neurodegenerative diseases. PMID:26826204

  6. A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In s...

  7. Cerebrospinal Fluid Biomarkers in Diagnosing Alzheimer's Disease in Clinical Practice: An Illustration with 3 Case Reports

    PubMed Central

    Slats, Diane; Spies, Petra E.; Sjögren, Magnus J.C.; Verhey, Frans R.J.; Verbeek, Marcel M.; Olde Rikkert, Marcel G.M.

    2010-01-01

    Analysis of the brain specific biomarkers amyloid β42 (Aβ42) and total tau (t-tau) protein in cerebrospinal fluid (CSF) has a sensitivity and specificity of more than 85% for differentiating Alzheimer's Disease (AD) from non-demented controls. International guidelines are contradictory in their advice on the use of CSF biomarkers in AD diagnostics, resulting in a lack of consistency in clinical practice. We present three case reports that illustrate clinical practice according to the Dutch and European guidelines and portray the value of CSF biomarker analysis as an add-on diagnostic to the standard diagnostic workup for AD. PMID:20689628

  8. CSF amyloid-β peptides in neuropathologically diagnosed dementia with Lewy bodies and Alzheimer's disease.

    PubMed

    Mollenhauer, Brit; Esselmann, Herrmann; Trenkwalder, Claudia; Schulz-Schaeffer, Walter; Kretzschmar, Hans; Otto, Markus; Wiltfang, Jens; Bibl, Mirko

    2011-01-01

    Appropriate treatment of dementia requires biomarkers that provide an exact and differential diagnosis. We recently presented differentially expressed amyloid-β (Aβ) peptide patterns in cerebrospinal fluid (CSF) as biomarker candidates for neurochemical diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The objective of the present study was to investigate CSF Aβ peptide patterns in both neuropathologically and clinically defined diagnostic groups of AD and DLB. Using the quantitative Aβ-SDS-PAGE/immunoblot, we analyzed CSF samples of neuropathologically defined patients with AD (definite AD, dAD; n = 11) and DLB (definite, dDLB; n = 12). We compared absolute and relative quantities of CSF Aβ-peptides with a larger cohort of clinically diagnosed patients with probable AD (pAD; n = 71), probable DLB (pDLB; n = 32), and non-demented controls (NDC; n = 71). Each neuropathologically and clinically defined diagnostic group showed a similar relative distribution of CSF Aβ-peptides (Aβ(1-X%)). Aβ(1-42%) was lowered in dAD compared to NDC (p = 1.6 × 10⁻⁷, but did not differ between dAD and pAD. Aβ(1-40ox%) was elevated in dDLB as compared to NDC (p = 1.8 × 10⁻⁵, but did not differ between dDLB and pDLB. Thus, we were able to confirm previous results on Aβ peptide patterns in neuropathologically characterized patients with AD and DLB. Our results underline the usefulness of the CSF Aβ(1-42%) and Aβ(1-40ox%) as diagnostic biomarkers for AD and DLB, respectively.

  9. Recommendations to standardize preanalytical confounding factors in Alzheimer's and Parkinson's disease cerebrospinal fluid biomarkers: an update.

    PubMed

    del Campo, Marta; Mollenhauer, Brit; Bertolotto, Antonio; Engelborghs, Sebastiaan; Hampel, Harald; Simonsen, Anja Hviid; Kapaki, Elisabeth; Kruse, Niels; Le Bastard, Nathalie; Lehmann, Sylvain; Molinuevo, Jose L; Parnetti, Lucilla; Perret-Liaudet, Armand; Sáez-Valero, Javier; Saka, Esen; Urbani, Andrea; Vanmechelen, Eugeen; Verbeek, Marcel; Visser, Pieter Jelle; Teunissen, Charlotte

    2012-08-01

    Early diagnosis of neurodegenerative disorders such as Alzheimer's (AD) or Parkinson's disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (Aβ42, total tau and phosphorylated tau) and PD CSF biomarker (α-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for Aβ42, total tau and phosphorylated tau, and α-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders.

  10. Reference measurement procedures for Alzheimer's disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid β42.

    PubMed

    Mattsson, Niklas; Zegers, Ingrid; Andreasson, Ulf; Bjerke, Maria; Blankenstein, Marinus A; Bowser, Robert; Carrillo, Maria C; Gobom, Johan; Heath, Theresa; Jenkins, Rand; Jeromin, Andreas; Kaplow, June; Kidd, Daniel; Laterza, Omar F; Lockhart, Andrew; Lunn, Michael P; Martone, Robert L; Mills, Kevin; Pannee, Josef; Ratcliffe, Marianne; Shaw, Leslie M; Simon, Adam J; Soares, Holly; Teunissen, Charlotte E; Verbeek, Marcel M; Umek, Robert M; Vanderstichele, Hugo; Zetterberg, Henrik; Blennow, Kaj; Portelius, Erik

    2012-08-01

    Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a candidate reference method for quantification of CSF amyloid β42.

  11. The application of cerebrospinal fluid biomarkers in early diagnosis of Alzheimer disease.

    PubMed

    Blennow, Kaj; Zetterberg, Henrik

    2013-05-01

    This article gives an updated account of the clinical application of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD). The clinically most relevant biomarkers, total tau, phospho-tau and Aβ42 are discussed, and how they may be used, together with other diagnostic investigations, to make a predementia diagnosis of AD. Recent findings in sporadic and genetic preclinical AD are also discussed and, more specifically, what the biomarkers have taught us on the sequence of events in the pathogenic process underlying AD.

  12. CSF analysis

    MedlinePlus

    Cerebrospinal fluid analysis ... Analysis of CSF can help detect certain conditions and diseases. All of the following can be, but ... An abnormal CSF analysis result may be due to many different causes, ... Encephalitis (such as West Nile and Eastern Equine) Hepatic ...

  13. Increased neurogranin concentrations in cerebrospinal fluid of Alzheimer's disease and in mild cognitive impairment due to AD.

    PubMed

    Sanfilippo, Cristina; Forlenza, Orestes; Zetterberg, Henrik; Blennow, Kaj

    2016-12-01

    Synaptic dysfunction is linked to both major depressive disorder (MDD) and Alzheimer's disease (AD). Synapse protein concentrations in cerebrospinal fluid (CSF) may be useful biomarkers to monitor synaptic dysfunction and degeneration that lead to depressive symptoms and AD, respectively. CSF neurogranin (Ng), a post-synaptic protein, has emerged as a promising tool to measure synaptic dysfunction and/or loss in AD. The aim of this study was to test the specific hypothesis that CSF neurogranin (Ng) is able to differentiate AD from MDD and cognitively normal controls. CSF samples from 44 healthy control individuals (CTRL), 86 patients with mild cognitive impairment (MCI), 36 of whom had prodromal AD as defined by a positive CSF AD biomarker signature, 25 AD dementia and 6 patients with MDD were analysed using an in house enzyme-linked immunosorbent assay for Ng. CSF Ng levels were significantly higher in AD patients and in prodromal AD (MCI patients with an "AD-like" CSF tau and Aβ42 profile) compared with CTRL individuals (p < 0.0001 for both groups) and MDD patients (p < 0.001 and p < 0.01, respectively). Significantly higher CSF Ng concentration was also seen in prodromal AD patients as compared to MCI patients without biomarker evidence of underlying AD pathology (p < 0.0001). CSF Ng correlated positively with the classical axonal injury markers CSF T-tau and P-tau (p < 0.0001), whereas correlation to plaque pathology as reflected by CSF Aβ42 was less clear. Negative correlations of CSF Ng with cognitive evaluation scores (MMSE and CAMCOG) were observed. This study strengthens the clinical utility of CSF Ng as a CSF biomarker for AD. AD patients in both MCI and dementia stages of the disease had increased CSF Ng concentrations compared with cognitively normal control individuals, patients with non-AD MCI and patients with MDD. The lowest CSF Ng concentrations were seen in patients with MDD, a finding that warrants validation in further studies.

  14. Diagnostic Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer’s Disease

    PubMed Central

    Niemantsverdriet, Ellis; Goossens, Joery; Struyfs, Hanne; Martin, Jean-Jacques; Goeman, Johan; De Deyn, Peter Paul; Vanderstichele, Hugo; Engelborghs, Sebastiaan

    2016-01-01

    Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer’s disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau181P >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between –20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria. PMID:26836187

  15. Diagnostic Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer's Disease.

    PubMed

    Niemantsverdriet, Ellis; Goossens, Joery; Struyfs, Hanne; Martin, Jean-Jacques; Goeman, Johan; De Deyn, Peter Paul; Vanderstichele, Hugo; Engelborghs, Sebastiaan

    2016-01-01

    Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer's disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.

  16. Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease

    PubMed Central

    Mattsson, Niklas; Insel, Philip S; Landau, Susan; Jagust, William; Donohue, Michael; Shaw, Leslie M; Trojanowski, John Q; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael

    2014-01-01

    Background Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance. Methods We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard. Results CSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] −6.7 to 1.5). CSF Aβ42 and global PET florbetapir did not differ in sensitivity, but PET had greater specificity than CSF in most comparisons. Sixteen CN progressed to MCI and AD (six Aβ negative, seven Aβ positive, and three PET positive but CSF negative). Interpretation The overall diagnostic accuracies of CSF Aβ42 and PET florbetapir were similar, but PET had greater specificity. This was because some CN and sMCI subjects appear pathological using CSF but not using PET, suggesting that low CSF Aβ42 not always translates to cognitive decline or brain Aβ accumulation. Other factors, including costs and side effects, may also be considered when determining the optimal modality for different applications. PMID:25356425

  17. The added value of biomarker analysis to the genesis of Plaggic Anthrosols.

    NASA Astrophysics Data System (ADS)

    van Mourik, Jan; Jansen, Boris

    2015-04-01

    degradation, resulting in the second extension of sand drifting. To improve our knowledge about the evolution of plaggen soils we can combine data of pollen and biomarker spectra of samples of plaggic deposits. Species, present in pollen spectra of plaggic deposits, can have three sources: 1. Pollen, already present in sods, used in the stable to produce manure. 2. Pollen, originating from flowering crop species. 3. Pollen, originating from flowering species in the surroundings. Species, present in biomarker spectra, can have three sources: 1. Biomarkers from tissues, present in sods, used for manure production. 2. Biomarkers from decomposed roots of crop species. 3. Biomarkers from straw of crop species, used in the stable for manure production. Comparison pollen and biomarker spectra of samples of a regular Anthrosol (Posteles, NE-Netherlands) and a Buried (Nabbegat, SE-Netherlands, buried around 1800 AD) Plaggic Anthrosol yielded some interesting features: a. The biomarker spectra of the 2Ap horizons (agricultural layer below the plaggic deposits) are dominated by biomarkers of deciduous trees (dominated by Quercus), indicating the use of organic litter from the forests. These trees are also present in the pollen spectra. b. The biomarker spectra of the plaggic deposits are dominated by crop species (Avena, Secale, Fagpyrum), Calluna is absent in most of the spectra. This is different from pollen spectra where Calluna is present, together with crop species and transported pollen of other species. Only the biomarker spectra of the upper 10 cm of the plaggic horizons are dominated by Calluna. c. Comparison of the spectra of the buried and regular Plaggic Anthrosols show the contribution of biomarkers of roots of Zea mais (introduced around 1950 AD), suppressing the other species. The negligible percentages of Calluna in biomarker spectra of plaggic deposits suggest an overestimating of the use of heath sods in the traditional interpretation of the genesis of plaggic horizons

  18. Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

    PubMed Central

    Kim, Dana; Kim, Young-Sam; Shin, Dong Wun; Park, Chang-Shin

    2016-01-01

    No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era. PMID:27819412

  19. High-Dimensional Medial Lobe Morphometry: An Automated MRI Biomarker for the New AD Diagnostic Criteria

    PubMed Central

    Valdivia, Fernando

    2014-01-01

    Introduction. Medial temporal lobe atrophy assessment via magnetic resonance imaging (MRI) has been proposed in recent criteria as an in vivo diagnostic biomarker of Alzheimer's disease (AD). However, practical application of these criteria in a clinical setting will require automated MRI analysis techniques. To this end, we wished to validate our automated, high-dimensional morphometry technique to the hypothetical prediction of future clinical status from baseline data in a cohort of subjects in a large, multicentric setting, compared to currently known clinical status for these subjects. Materials and Methods. The study group consisted of 214 controls, 371 mild cognitive impairment (147 having progressed to probable AD and 224 stable), and 181 probable AD from the Alzheimer's Disease Neuroimaging Initiative, with data acquired on 58 different 1.5 T scanners. We measured the sensitivity and specificity of our technique in a hierarchical fashion, first testing the effect of intensity standardization, then between different volumes of interest, and finally its generalizability for a large, multicentric cohort. Results. We obtained 73.2% prediction accuracy with 79.5% sensitivity for the prediction of MCI progression to clinically probable AD. The positive predictive value was 81.6% for MCI progressing on average within 1.5 (0.3 s.d.) year. Conclusion. With high accuracy, the technique's ability to identify discriminant medial temporal lobe atrophy has been demonstrated in a large, multicentric environment. It is suitable as an aid for clinical diagnostic of AD. PMID:25254139

  20. MRI and CSF studies in the early diagnosis of Alzheimer's disease.

    PubMed

    de Leon, M J; DeSanti, S; Zinkowski, R; Mehta, P D; Pratico, D; Segal, S; Clark, C; Kerkman, D; DeBernardis, J; Li, J; Lair, L; Reisberg, B; Tsui, W; Rusinek, H

    2004-09-01

    The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the

  1. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.

    PubMed

    Blennow, Kaj; Hampel, Harald; Weiner, Michael; Zetterberg, Henrik

    2010-03-01

    Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-beta immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-beta. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.

  2. CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease.

    PubMed

    Bendlin, Barbara B; Carlsson, Cynthia M; Johnson, Sterling C; Zetterberg, Henrik; Blennow, Kaj; Willette, Auriel A; Okonkwo, Ozioma C; Sodhi, Aparna; Ries, Michele L; Birdsill, Alex C; Alexander, Andrew L; Rowley, Howard A; Puglielli, Luigi; Asthana, Sanjay; Sager, Mark A

    2012-01-01

    Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.

  3. Global standardization measurement of cerebral spinal fluid for Alzheimer's disease: an update from the Alzheimer's Association Global Biomarkers Consortium.

    PubMed

    Carrillo, Maria C; Blennow, Kaj; Soares, Holly; Lewczuk, Piotr; Mattsson, Niklas; Oberoi, Pankaj; Umek, Robert; Vandijck, Manu; Salamone, Salvatore; Bittner, Tobias; Shaw, Leslie M; Stephenson, Diane; Bain, Lisa; Zetterberg, Henrik

    2013-03-01

    Recognizing that international collaboration is critical for the acceleration of biomarker standardization efforts and the efficient development of improved diagnosis and therapy, the Alzheimer's Association created the Global Biomarkers Standardization Consortium (GBSC) in 2010. The consortium brings together representatives of academic centers, industry, and the regulatory community with the common goal of developing internationally accepted common reference standards and reference methods for the assessment of cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and tau biomarkers. Such standards are essential to ensure that analytical measurements are reproducible and consistent across multiple laboratories and across multiple kit manufacturers. Analytical harmonization for CSF Aβ42 and tau will help reduce confusion in the AD community regarding the absolute values associated with the clinical interpretation of CSF biomarker results and enable worldwide comparison of CSF biomarker results across AD clinical studies.

  4. Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis.

    PubMed

    Wang, Hua-Long; Wang, Yan-Yong; Liu, Xin-Gang; Kuo, Sheng-Han; Liu, Na; Song, Qiao-Yun; Wang, Ming-Wei

    2016-01-01

    Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

  5. Additional value of CSF amyloid-beta 40 levels in the differentiation between FTLD and control subjects.

    PubMed

    Verwey, Nicolaas A; Kester, Maartje I; van der Flier, Wiesje M; Veerhuis, Robert; Berkhof, Hans; Twaalfhoven, Harry; Blankenstein, Marinus A; Scheltens And, Philip; Pijnenburg, Yolande A L

    2010-01-01

    To determine the additional value of cerebrospinal fluid (CSF)amyloid-beta1-40 (Abeta40) next to amyloid-beta1-42 (beta42), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls, we measured CSF levels of Abeta40, Abeta42, pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost=test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. Logistic regression showed that Abeta42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Abeta42, Tau, and Abeta40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Abeta42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau(cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step,Abeta40 (cut-off 10 ng/ml) was used to differentiate controls (PPV68%). Applying CSF Abeta40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Abeta42 and Tau were used. CSF Abeta40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Abeta40 in differential diagnosis between FTLD, AD, and control subjects.

  6. Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer’s disease

    PubMed Central

    Majbour, Nour K.; Chiasserini, Davide; Vaikath, Nishant N.; Eusebi, Paolo; Tokuda, Takahiko; van de Berg, Wilma; Parnetti, Lucilla; Calabresi, Paolo; El-Agnaf , Omar M. A.

    2017-01-01

    Several studies reported an association between CSF alpha-synuclein (α-syn) and tau in Alzheimer’s disease (AD), and demonstrated the significance of α-syn in improving the diagnostic sensitivity/specificity of classical AD CSF biomarkers. In the current study, we measured CSF levels of different α-syn species in a cohort of AD patients (n = 225) who showed a CSF profile typical of AD at baseline as well as in cognitively intact controls (n = 68). CSF total α-syn (t-α-syn) significantly increased in the AD group (p < 0.0001) compared to controls, while oligomeric- and phosphorylated-Ser129-α-syn did not change significantly. ROC analysis showed a sensitivity of 85% and a specificity of 84% (AUC = 0.88) in distinguishing AD from controls. T-α-syn levels correlated positively with tau species in AD group and negatively with baseline MMSE score. Our data support the added value of measurement of CSF α-syn species for further characterization of the CSF AD profile. PMID:28071698

  7. Clinical Utility and Analytical Challenges in Measurement of Cerebrospinal Fluid Amyloid-β1–42 and τ Proteins as Alzheimer Disease Biomarkers

    PubMed Central

    Kang, Ju-Hee; Korecka, Magdalena; Toledo, Jon B.; Trojanowski, John Q.; Shaw, Leslie M.

    2014-01-01

    BACKGROUND Over the past 2 decades, clinical studies have provided evidence that cerebrospinal fluid (CSF) amyloid β1–42 (Aβ1–42), total τ(t-τ), and τ phosphorylated at Thr181 (p-τ181) are reliable biochemical markers of Alzheimer disease (AD) neuropathology. CONTENT In this review, we summarize the clinical performance and describe the major challenges for the analytical performance of the most widely used immunoassay platforms [based on ELISA or microbead-based multianalyte profiling (xMAP) technology] for the measurement of CSF AD biomarkers (Aβ1–42, t-τ, and p-τ181). With foundational immunoassay data providing the diagnostic and prognostic values of CSF AD biomarkers, the newly revised criteria for the diagnosis of AD include CSF AD biomarkers for use in research settings. In addition, it has been suggested that the selection of AD patients at the predementia stage by use of CSF AD biomarkers can improve the statistical power of clinical trial design. Owing to the lack of a replenishable and commutable human CSF-based standardized reference material (SRM) and significant differences across different immunoassay platforms, the diagnostic–prognostic cutpoints of CSF AD biomarker concentrations are not universal at this time. These challenges can be effectively met in the future, however, through collaborative ongoing standardization efforts to minimize the sources of analytical variability and to develop reference methods and SRMs. SUMMARY Measurements of CSF Aβ1–42, t-τ, and p-τ181 with analytically qualified immunoassays reliably reflect the neuropathologic hallmarks of AD in patients at the early predementia stage of the disease and even in presymptomatic patients. Thus these CSF biomarker tests are useful for early diagnosis of AD, prediction of disease progression, and efficient design of drug intervention clinical trials. PMID:23519967

  8. CSF leak

    MedlinePlus

    ... PA: Elsevier Saunders; 2012:chap 138. Rosenberg GA. Brain edema and disorders of cerebrospinal fluid circulation. In: Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL, eds. Bradley's Neurology in Clinical Practice . 7th ed. Philadelphia, PA: Elsevier; ... Cerebral spinal fluid (CSF) collection Review Date 5/30/ ...

  9. Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and Progressive Supranuclear Palsy

    PubMed Central

    Wagshal, Dana; Sankaranarayanan, Sethu; Guss, Valerie; Hall, Tracey; Berisha, Flora; Lobach, Iryna; Karydas, Anna; Voltarelli, Lisa; Scherling, Carole; Heuer, Hilary; Tartaglia, Maria Carmela; Miller, Zachary; Coppola, Giovanni; Ahlijanian, Michael; Soares, Holly; Kramer, Joel H; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Meredith, Jere; Boxer, Adam L

    2014-01-01

    Background Elevated CSF tau is considered a biomarker of neuronal injury in newly developed Alzheimer’s disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of tau species in other primary tauopathies. We assessed CSF tau protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterized by deposition of four microtubule binding repeat (4R) tau with minimal Aβ pathology. Methods 26 normal control (NC), 37 AD, and 24 PSP patients participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total tau, and ptau181. Additional, novel ELISAs targeting different N-terminal and central tau epitopes were developed to examine CSF tau components and to investigate interactions between diagnostic group, demographics, and genetic variables. Results PSP had lower CSF N-terminal and C-terminal tau concentrations than NC and AD measured with both the novel tau ELISAs and the standard AlzBio3 tau and ptau assays. AD had higher total tau and ptau levels than NC and PSP. There was a gender by diagnosis interaction in both AD and PSP for most tau species, with lower concentrations for male compared to female patients. Conclusions CSF tau fragment concentrations are different in PSP compared with AD despite the presence of severe tau pathology and neuronal injury in both disorders. CSF tau concentration likely reflects multiple factors in addition to the degree of neuronal injury. PMID:24899730

  10. Chronic Inflammation: Synergistic Interactions of Recruiting Macrophages (TAMs) and Eosinophils (Eos) with Host Mast Cells (MCs) and Tumorigenesis in CALTs. M-CSF, Suitable Biomarker for Cancer Diagnosis!

    PubMed Central

    Khatami, Mahin

    2014-01-01

    dysfunction in the direction of tumorigenesis. Activated MFs (TAMs or M2) and Eos that are recruited by tissues (e.g., conjunctiva or perhaps lung airways) whose principal resident immune cells are MCs and lymphocytes are suggested to play crucial synergistic roles in enhancing growth promoting capacities of host toward tumorigenesis. Under oxidative stress, M-CSF may produce signals that are cumulative/synergistic with host mediators (e.g., low levels of histamine), facilitating tumor-directed expression of decoy receptors and immune suppressive factors (e.g., dTNFR, IL-5, IL-10, TGF-β, PGE2). M-CSF, possessing superior sensitivity and specificity, compared with conventional markers (e.g., CA-125, CA-19-9) is potentially a suitable biomarker for cancer diagnosis and technology development. Systematic monitoring of interactions between resident and recruited cells should provide key information not only about early events in loss of immune surveillance, but it would help making informed decisions for balancing the inherent tumoricidal (Yin) and tumorigenic (Yang) properties of immune system and effective preventive and therapeutic approaches and accurate risk assessment toward improvement of public health. PMID:24473090

  11. Detection of Soluble Amyloid-β Oligomers and Insoluble High-Molecular-Weight Particles in CSF: Development of Methods with Potential for Diagnosis and Therapy Monitoring of Alzheimer's Disease.

    PubMed

    Funke, Susanne Aileen

    2011-01-01

    The diagnosis of probable Alzheimer's disease (AD) can be established premortem based on clinical criteria like neuropsychological tests. Post mortem, specific neuropathological changes like amyloid plaques define AD. However, the standard criteria based on medical history and mental status examinations do not take into account the long preclinical features of the disease, and a biomarker for improved diagnosis of AD is urgently needed. In a large number of studies, amyloid-β (Aβ) monomer concentrations in CSF of AD patients are consistently and significantly reduced when compared to healthy controls. Therefore, monomeric Aβ in CSF was suggested to be a helpful biomarker for the diagnosis of preclinical AD. However, not the monomeric form, but Aβ oligomers have been shown to be the toxic species in AD pathology, and their quantification and characterization could facilitate AD diagnosis and therapy monitoring. Here, we review the current status of assay development to reliably and routinely detect Aβ oligomers and high-molecular-weight particles in CSF.

  12. Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease in South Korea

    PubMed Central

    Chae, Won Seok; Kim, Hyeong Jun; Shin, Ho Sik; Kim, Saeromi; Im, Ji Young; Ahn, Sang Il; Min, Kyoung Dae; Yim, Soo Jae; Ye, Byoung Seok; Seo, Sang Won; Jeong, Jee Hyang; Park, Kyung Won; Choi, Seong Hye; Na, Duk L.

    2017-01-01

    Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P<0.001 for all), and between the ADD and OND groups (P<0.001 for all). The areas under the curve in differentiation of ADD from control subjects were 0.97 for Aβ42, 0.93 for total tau (tTau), 0.86 for pTau, and 0.99 for both tTau/Aβ42 and pTau/Aβ42 ratios. Our revised cutoff value for Aβ42 was higher than our previous one, whereas the values for the Tau proteins were similar. The tTau/Aβ42 ratio had the highest accuracy, 97%. Our findings highlight the usefulness of CSF AD biomarkers in South Korea, and the necessity of continually testing the reliability of cutoff values. PMID:28030437

  13. Identification of longitudinally dynamic biomarkers in Alzheimer’s disease cerebrospinal fluid by targeted proteomics

    PubMed Central

    2014-01-01

    Background Alzheimer’s disease (AD) is the leading cause of dementia affecting greater than 26 million people worldwide. Although cerebrospinal fluid (CSF) levels of Aβ42, tau, and p-tau181 are well established as diagnostic biomarkers of AD, there is a need for additional CSF biomarkers of neuronal function that continue to change during disease progression and could be used as pharmacodynamic measures in clinical trials. Multiple proteomic discovery experiments have reported a range of CSF biomarkers that differ between AD and control subjects. These potential biomarkers represent multiple aspects of the disease pathology. The performance of these markers has not been compared with each other, and their performance has not been evaluated longitudinally. Results We developed a targeted-proteomic, multiple reaction monitoring (MRM) assay for the absolute quantitation of 39 peptides corresponding to 30 proteins. We evaluated the candidate biomarkers in longitudinal CSF samples collected from aged, cognitively-normal control (n = 10), MCI (n = 5), and AD (n = 45) individuals (age > 60 years). We evaluated each biomarker for diagnostic sensitivity, longitudinal consistency, and compared with CSF Aβ42, tau, and p-tau181. Four of 28 quantifiable CSF proteins were significantly different between aged, cognitively-normal controls and AD subjects including chitinase-3-like protein 1, reproducing published results. Four CSF markers demonstrated significant longitudinal change in AD: Amyloid precursor protein, Neuronal pentraxin receptor, NrCAM and Chromogranin A. Robust correlations were observed within some subgroups of proteins including the potential disease progression markers. Conclusion Using a targeted proteomics approach, we confirmed previous findings for a subset of markers, defined longitudinal performance of our panel of markers, and established a flexible proteomics method for robust multiplexed analyses. PMID:24902845

  14. Cerebrospinal Fluid Biomarker Signature in Alzheimer’s Disease Neuroimaging Initiative Subjects

    PubMed Central

    Shaw, Leslie M.; Vanderstichele, Hugo; Knapik-Czajka, Malgorzata; Clark, Christopher M.; Aisen, Paul S.; Petersen, Ronald C.; Blennow, Kaj; Soares, Holly; Simon, Adam; Lewczuk, Piotr; Dean, Robert; Siemers, Eric; Potter, William; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2009-01-01

    Objective Develop a cerebrospinal fluid biomarker signature for mild Alzheimer’s disease (AD) in Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects. Methods Amyloid-β 1 to 42 peptide (Aβ1-42), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and Aβ1-42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. Results CSF Aβ1-42 was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for Aβ1-42, t-tau, and APOε4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/Aβ1-42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. Interpretation The CSF biomarker signature of AD defined by Aβ1-42 and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD. PMID:19296504

  15. Biomarkers in Alzheimer's Disease-Recent Update.

    PubMed

    Sharma, Sushil; Lipincott, Walter

    2017-02-20

    Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized by loss of memory and cognitive function. It is the common cause of dementia in elderly and is a global health concern as the population of people aged 85 and older, is growing alarmingly. Although pharmacotherapy for the treatment of AD has improved, lot of work remains to treat this devastating disease. AD pathology begins even before the onset of clinical symptoms. Because therapies could be more effective if implemented early in the disease progression, it is highly prudent to discover reliable biomarkers, to detect its exact pathophysiology during pre-symptomatic stage. Biomarker(s) with high sensitivity and specificity would facilitate AD diagnosis at early stages. Currently, CSF amyloid β 1-42, total tau, and phosphorylated tau181 are used as AD biomarkers. This report describes conventional and potential in-vitro and in-vivo biomarkers of AD. Particularly, in-vitro transcriptomic, proteomic, lipidomic, and metabolomic; body fluid biomarkers (C-reactive proteins, homocysteine, α-sunuclein index, and dehydroepiandrosterone sulphate) from blood, serum, plasma, CSF, and saliva; and neuronal, platelets, and lymphocyte microRNA, mtDNA, and Charnoly body are detected. In-vivo physiological and neurobehavioral biomarkers are evaluated by analyzing computerized EEG, event-related potentials, circadian rhythm, and multimodality fusion imaging including: CT, MRI, SPECT, and PET. More specifically, PET imaging biomarkers representing reduced fronto-temporal 18FdG uptake, increased 11C or 18F-PIB uptake, 11C-PBR28 to measure 18 kDa translocator protein (TSPO), a biomarker for inflammation; and 3-D MRI (ventriculomegaly)/MRS are performed for early and effective clinical management of AD.

  16. Biomarkers in Alzheimer's Disease: A Review

    PubMed Central

    Chintamaneni, Meena; Bhaskar, Manju

    2012-01-01

    Alzheimer's disease is the most common form of dementia affecting millions of individuals worldwide. It is currently diagnosed only via clinical assessments and confirmed by postmortem brain pathology. The development of validated biomarkers for Alzheimer's disease is essential to improve diagnosis and accelerate the development of new therapies. Biochemical and neuroimaging markers could facilitate diagnosis, predict AD progression from a pre-AD state of mild cognitive impairment (MCI), and be used to monitor efficacies of disease-modifying therapies. Cerebrospinal fluid (CSF) levels of Aβ40, Aβ42, total tau, and phosphorylated tau have diagnostic values in AD. Measurements of the above CSF markers in combination are useful in predicting the risk of progression from MCI to AD. New potential biomarkers are emerging, and CSF or plasma marker profiles may eventually become part of the clinician's toolkit for accurate AD diagnosis and management. These biomarkers along with clinical assessment, neuropsychological testing, and neuroimaging could achieve a much higher diagnostic accuracy for AD and related disorders in the future. PMID:22811931

  17. What is the Clinical Significance of Cerebrospinal Fluid Biomarkers in Parkinson's disease? Is the Significance Diagnostic or Prognostic?

    PubMed

    Kim, Dana; Paik, Jin Hui; Shin, Dong-Woon; Kim, Hak-Su; Park, Chang-Shin; Kang, Ju-Hee

    2014-12-01

    The clinical diagnostic criteria of Parkinson's disease (PD) have limitations in detecting the disease at early stage and in differentiating heterogeneous clinical progression. The lack of reliable biomarker(s) for early diagnosis and prediction of prognosis is a major hurdle to achieve optimal clinical care of patients and efficient design of clinical trials for disease-modifying therapeutics. Numerous efforts to discover PD biomarkers in CSF were conducted. In this review, we describe the molecular pathogenesis of PD and discuss its implication to develop PD biomarkers in CSF. Next, we summarize the clinical utility of CSF biomarkers including alpha-synuclein for early and differential diagnosis, and prediction of PD progression. Given the heterogeneity in the clinical features of PD and none of the CSF biomarkers for an early diagnosis have been developed, research efforts to develop biomarkers to predict heterogeneous disease progression is on-going. Notably, a rapid cognitive decline followed by the development of dementia is a risk factor of poor prognosis in PD. In connection to this, CSF levels of Alzheimer's disease (AD) biomarkers have received considerable attention. However, we still need long-term longitudinal observational studies employing large cohorts to evaluate the clinical utility of CSF biomarkers reflecting Lewy body pathology and AD pathology in the brain. We believe that current research efforts including the Parkinson's Progression Markers Initiative will resolve the current needs of early diagnosis and/or prediction of disease progression using CSF biomarkers, and which will further accelerate the development of disease-modifying therapeutics and optimize the clinical management of PD patients.

  18. What is the Clinical Significance of Cerebrospinal Fluid Biomarkers in Parkinson's disease? Is the Significance Diagnostic or Prognostic?

    PubMed Central

    Kim, Dana; Paik, Jin Hui; Shin, Dong-Woon; Kim, Hak-Su; Park, Chang-Shin

    2014-01-01

    The clinical diagnostic criteria of Parkinson's disease (PD) have limitations in detecting the disease at early stage and in differentiating heterogeneous clinical progression. The lack of reliable biomarker(s) for early diagnosis and prediction of prognosis is a major hurdle to achieve optimal clinical care of patients and efficient design of clinical trials for disease-modifying therapeutics. Numerous efforts to discover PD biomarkers in CSF were conducted. In this review, we describe the molecular pathogenesis of PD and discuss its implication to develop PD biomarkers in CSF. Next, we summarize the clinical utility of CSF biomarkers including alpha-synuclein for early and differential diagnosis, and prediction of PD progression. Given the heterogeneity in the clinical features of PD and none of the CSF biomarkers for an early diagnosis have been developed, research efforts to develop biomarkers to predict heterogeneous disease progression is on-going. Notably, a rapid cognitive decline followed by the development of dementia is a risk factor of poor prognosis in PD. In connection to this, CSF levels of Alzheimer's disease (AD) biomarkers have received considerable attention. However, we still need long-term longitudinal observational studies employing large cohorts to evaluate the clinical utility of CSF biomarkers reflecting Lewy body pathology and AD pathology in the brain. We believe that current research efforts including the Parkinson's Progression Markers Initiative will resolve the current needs of early diagnosis and/or prediction of disease progression using CSF biomarkers, and which will further accelerate the development of disease-modifying therapeutics and optimize the clinical management of PD patients. PMID:25548535

  19. Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus

    PubMed Central

    Leinonen, Ville; Menon, Lata G.; Carroll, Rona S.; Dello Iacono, Donna; Grevet, Jeremy; Jääskeläinen, Juha E.; Black, Peter M.

    2011-01-01

    The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau181, Aβ42, NFL, TNF-α, TGFβ1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result—that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-α concentration was low in iNPH patients. PMID:21660204

  20. Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia.

    PubMed

    Rostgaard, Nina; Waldemar, Gunhild; Nielsen, Jørgen Erik; Simonsen, Anja Hviid

    2015-01-01

    As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

  1. Rethinking on the concept of biomarkers in preclinical Alzheimer's disease.

    PubMed

    Berti, Valentina; Polito, Cristina; Lombardi, Gemma; Ferrari, Camilla; Sorbi, Sandro; Pupi, Alberto

    2016-05-01

    The neuropathological processes eventually leading to Alzheimer's disease (AD) are thought to start decades before the appearance of clinical symptoms and the clinical diagnosis of AD dementia. The term "preclinical AD" has been recently introduced to identify this "silent stage" of AD, when the disease is already present, but symptoms are not yet clinically evident. Advances in AD biomarkers have dramatically improved the ability to detect AD pathological processes in vivo in cognitively intact subjects, thus demonstrating the presence of AD pathology in the preclinical phase. This review focuses on the recent advances in the field of neuroimaging and CSF AD biomarkers specifically in the preclinical phase of AD, and aims to discuss the significance that such biomarkers could have in cognitively intact subjects. Even though the use of such biomarkers in AD preclinical phase has contributed to improve our understanding of AD early pathological processes, it raised also a number of new challenges that still remain to be overcome, such as a better definition of the clinical and individual significance of currently known biomarkers in preclinical stages and the development of novel biomarkers of different early AD-related events.

  2. Differentiated effective connectivity patterns of the executive control network in progressive MCI: a potential biomarker for predicting AD.

    PubMed

    Cai, Suping; Peng, Yanlin; Chong, Tao; Zhang, Yun; von Deneen, Karen M; Huang, Liyu; Aibl Research Group

    2017-03-09

    Mild cognitive impairment (MCI) is often a transitional state between normal aging and Alzheimer's disease (AD). When observed longitudinally, some MCI patients convert to AD, while a considerable portion either remain MCI or revert to a normal functioning state. This divergence has provided some enlightenment on a potential biomarker be represented in the resting state brain activities of MCI patients with different post-hoc labels. Recent studies have shown impaired executive functions, other than typically explicated memory impairment with AD/MCI patients. This observation raises the question that whether or not the executive control network (ECN) was impaired, as which pivotally supports the central executive functions. Given the fact that effective connectivity is a sufficient index in detecting resting brain abnormalities in AD/MCI, the current study specifically asks a question whether the effective connectivity patterns are differentiated in MCI patients with different post-hoc labels. We divided the MCI subjects into three groups depending on their progressive state obtained longitudinally: 1) 15 MCI-R subjects: MCI reverted to the normal functioning state and stabilized to the normal state in 24 months; 2) 35 MCI-S subjects: MCI patients maintained this disease in a stable state for 24 months; 3) 22 MCI-P subjects: MCI progressed to AD and stabilized to AD in 24 months, and 4) 39 age-matched normal control subjects (NC). We conducted a Granger causality analysis after identifying the core nodes of ECN in all of the subjects using Independent Component Analysis. Our findings revealed that different MCI groups presented different effective connectivity patterns within the ECN compared to the NC group. Specifically, (1) dorsolateral prefrontal cortex (dLPFC) and medial prefrontal cortex (mPFC) were the core nodes in the ECN network that exhibited different connecting patterns; (2) an effective connection circuit "R.dLPFC right caudate Left thalamus

  3. Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

    PubMed Central

    Ryoo, Na-Young; Shin, Dong Wun; Trojanowski, John Q

    2014-01-01

    Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the PMID:25598657

  4. The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans

    PubMed Central

    Kang, Ju-Hee; Korecka, Magdalena; Figurski, Michal J.; Toledo, Jon B.; Blennow, Kaj; Zetterberg, Henrik; Waligorska, Teresa; Brylska, Magdalena; Fields, Leona; Shah, Nirali; Soares, Holly; Dean, Robert A.; Vanderstichele, Hugo; Petersen, Ronald C.; Aisen, Paul S.; Saykin, Andrew J.; Weiner, Michael W.; Trojanowski, John Q.; Shaw, Leslie M.

    2016-01-01

    Introduction We describe Alzheimer’s Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1–42), t-tau, and p-tau181 analytical performance, definition of Alzheimer’s disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1–42, t-tau, and p-tau181 data. Results CSFAD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. Discussion Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials. PMID:26194312

  5. CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters.

    PubMed

    Malm, J; Kristensen, B; Ekstedt, J; Adolfsson, R; Wester, P

    1991-03-01

    Monoamine metabolites, cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS, n = 15), Alzheimer's disease (AD, n = 14), multi-infarct dementia (MID, n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography, cholinesterases and lactate were determined photometrically. In the AHS patients, CSF monoamine concentrations were not significantly different compared with controls, AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid, CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is, resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion.

  6. CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters.

    PubMed Central

    Malm, J; Kristensen, B; Ekstedt, J; Adolfsson, R; Wester, P

    1991-01-01

    Monoamine metabolites, cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS, n = 15), Alzheimer's disease (AD, n = 14), multi-infarct dementia (MID, n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography, cholinesterases and lactate were determined photometrically. In the AHS patients, CSF monoamine concentrations were not significantly different compared with controls, AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid, CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is, resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion. PMID:1709421

  7. VENTRICULAR MAPS IN 804 SUBJECTS CORRELATE WITH COGNITIVE DECLINE, CSF PATHOLOGY, AND IMMINENT ALZHEIMER’S DISEASE

    PubMed Central

    Chou, Yi-Yu; Leporé, Natasha; Madsen, Sarah K.; Saharan, Priya; Hua, Xue; Jack, Clifford R.; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Toga, Arthur W.; Thompson, Paul M.

    2017-01-01

    There is an urgent need for neuroimaging biomarkers of Alzheimer’s disease (AD) that correlate with cognitive decline, and with accepted measures of pathology detectable in cerebrospinal fluid (CSF). Ideal biomarkers should also be able to predict future decline, and should be computable automatically from hundreds to thousands of images without user intervention. Here we used our multi-atlas fluid image alignment method (MAFIA [1]), to automatically segment parametric 3D surface models of the lateral ventricles in brain MRI scans from 184 AD, 391 MCI, and 229 healthy elderly controls. Radial expansion of the ventricles, computed pointwise, was correlated with measures of (1) clinical decline, (2) pathology from CSF, and (3) future deterioration. Surface–based correlation maps were assessed using a cumulative distribution function method to rank influential covariates according to their effect sizes. The resulting approach is highly automated, and boosts the power of fluid image registration by integrating multiple independent registrations to reduce segmentation errors.

  8. Biomarkers in translational research of Alzheimer's disease.

    PubMed

    Tarawneh, Rawan; Holtzman, David M

    2010-01-01

    The identification and characterization of amyloid-beta (Abeta) and tau as the main pathological substrates of Alzheimer's disease (AD) have driven many efforts in search for suitable biomarkers for AD. In the last decade, research in this area has focused on developing a better understanding of the principles that govern protein deposition, mechanisms that link aggregation to toxicity and neuronal death, and a better understanding of protein dynamics in brain tissue, interstitial fluid and CSF. While Abeta and tau represent the two key pathological mediators of disease, other aspects of this multifaceted disease (e.g. oxidative stress, calcium-mediated toxicity, and neuroinflammation) are being unraveled, with the hope to develop a more comprehensive approach in exploring disease mechanisms. This has not only expanded possible areas for disease-modifying therapies, but has also allowed the introduction of novel, and potentially useful, fluid and radiological markers for the presence and progression of AD pathology. There is no doubt that the identification of several fluid and imaging biomarkers that can reliably detect the early stages of AD will have great implications in the design of clinical trials, in the selection of homogenous research populations, and in the assessment of disease outcomes. Markers with good diagnostic specificity will aid researchers in differentiating individuals with preclinical and probable AD from individuals who do not have AD pathology or have other dementing disorders. Markers that change with disease progression may offer utility in assessing the rates of disease progression and the efficacy of potential therapeutic agents on AD pathology. For both of these purposes, CSF Abeta42, amyloid imaging, and CSF tau appear to be very good markers of the presence of AD pathology as well as predictive of who will progress from MCI to AD. Volumetric MRI is also good at separating individuals with MCI and AD from controls and is predictive of

  9. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer's Disease: Potential Pools of New Biomarkers

    PubMed Central

    Mietelska-Porowska, Anna

    2017-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers. PMID:28293644

  10. In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings.

    PubMed

    Formaglio, Maïté; Costes, Nicolas; Seguin, Jérémie; Tholance, Yannick; Le Bars, Didier; Roullet-Solignac, Isabelle; Mercier, Bernadette; Krolak-Salmon, Pierre; Vighetto, Alain

    2011-10-01

    Our objective was to evaluate amyloid deposition in posterior cortical atrophy (PCA), using both cerebrospinal fluid (CSF) biomarker analysis and amyloid imaging. Five PCA patients, selected based on their neuropsychological profile and atrophic changes in posterior regions on MRI, underwent CSF analysis. CSF amyloid-beta 1-42, total tau, and phosphorylated tau at threonine 181 levels were determined. They also had positron emission tomography (PET) with Pittsburgh Compound B ([(11)C]PIB). [(11)C]PIB ratio images were assessed with visual, regional and voxel-based analyses and compared to eight typical Alzheimer's disease (AD) patients and eight controls. The biological profile in the five PCA patients, resulting from CSF and [(11)C]PIB images analysis, was consistent with AD. Individual comparisons of PCA patients' [(11)C]PIB images with the AD group with Statistical Parametric Mapping (SPM) revealed a distinctive posterior uptake in four out of the five patients showing increased amyloid deposition in occipital, temporal, and/or parietal regions. ROI group analysis showed a tendency for higher amyloid deposition in occipital and temporal regions. However, this pattern was not found with SPM group analysis when the global level of [(11)C]PIB uptake was used as a covariate. Our results indicate that amyloid burden can be demonstrated in vivo in PCA suggesting a diagnosis of AD. PCA patients may present a higher global amyloid load than AD that was not related to age at onset, disease severity, disease duration, or educational level in our study. Combined CSF and PET biomarkers seem helpful for in vivo diagnosis of this focal syndrome with underlying AD pathology.

  11. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers

    PubMed Central

    Bennett, David A.; Blennow, Kaj; Carrillo, Maria C.; Feldman, Howard H.; Frisoni, Giovanni B.; Hampel, Harald; Jagust, William J.; Johnson, Keith A.; Knopman, David S.; Petersen, Ronald C.; Scheltens, Philip; Sperling, Reisa A.; Dubois, Bruno

    2016-01-01

    Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the “A/T/N” system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. “A” refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); “T,” the value of a tau biomarker (CSF phospho tau, or tau PET); and “N,” biomarkers of neurodegeneration or neuronal injury ([18F]-fluorodeoxyglucose–PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N−, or A+/T−/N−, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme. PMID:27371494

  12. CSF and clinical hallmarks of subcortical dementias: focus on DLB and PDD.

    PubMed

    Stefani, Alessandro; Brusa, Livia; Olivola, Enrica; Pierantozzi, Mariangela; Martorana, Alessandro

    2012-07-01

    Dementia has become a relevant problem associated with the elderly in our countries. Increased interest in the field has yielded a copious literature, so far mostly centered on Alzheimer's dementia. Cerebrospinal fluid (CSF) analysis combined with neuropsychology, even in absence of neuroimaging, represents the gold standard to reach a diagnosis when cortical cognitive impairment prevails. In view of this, low levels of CSF amyloid peptides β (Aβ) and high tau/Aβ protein ratio, despite prominent impairment of executive functions or concomitant vascular burden, facilitate the diagnosis of Alzheimer's disease. Conversely, an early cognitive impairment occurring in patients suffering from Parkinson's disease (PD) or Lewy body disorders (LBDs), both diagnoses posed on pure clinical grounds, remains quite elusive in term of biomarkers or neuropsychological assessment. Whether PD with dementia (PDD) and dementia with Lewy bodies (DLB) represent further steps along with a continuum of the same progressive degeneration due to Lewy bodies deposition, rather then the association of Lewy bodies and Aβ pathology, remains a challenging issue. Aim of this work is to set a state-of-the-art on the neuropsychological profiles of both or DLB. Then, we will focus on the ongoing controversies about the specificity of the standard CSF biomarkers if applied to extrapyramidal disorders. Our conclusions are that the CSF pattern, in PDD and DLB, can certainly be distinct from that in AD, though mechanisms leading to dementia could be shared among them. It is possible that, by combining imaging tracers, neuropsychologically careful assessment and renewed CSF biomarkers, DLB can be better distinguished in subgroups, depending on the presence or absence of a relevant amyloid burden. However, more complete data, possibly collected in fieri during the progressive derangement of cognitive abilities, are needed to improve our ability to decipher and treat these entities.

  13. The use of PIB-PET as a dual pathological and functional biomarker in AD.

    PubMed

    Forsberg, Anton; Engler, Henry; Blomquist, Gunnar; Långström, Bengt; Nordberg, Agneta

    2012-03-01

    Amyloid imaging with positron emission tomography (PET) is presently used in Alzheimer's disease (AD) research. In this study we investigated the possibility to use early frames (ePIB) of the PIB scans as a rough index of CBF by comparing normalised early PIB values with cerebral glucose metabolism (rCMRglc). PIB-PET and FDG-PET were performed in 37 AD patients, 21 subjects with mild cognitive impairment (MCI) and 6 healthy controls (HC). The patients were divided based on their PIB retention (amyloid load) as either PIB positive (PIB+) or PIB negative (PIB-). Data of the unidirectional influx K(1) from a subset of the subjects including 7 AD patients and 3 HC was used for correlative analysis. Data was analysed using regions of interest (ROI) analysis. A strong, positive correlation was observed across brain regions between K(1) and ePIB (r=0.70; p≤0.001). The ePIB values were significantly lower in the posterior cingulate (p≤0.001) and the parietal cortices (p=0.002) in PIB+ subjects compared to PIB-, although the group difference were stronger for rCMRglc in cortical areas (p≤0.001). Strong positive correlations between ePIB and rCMRglc were observed in all cortical regions analysed, especially in the posterior cingulate and parietal cortices (p≤0.001). A single dynamic PIB-PET scan may provide information about pathological and functional changes (amyloidosis and impaired blood flow). This might be important for diagnosis of AD, enrichment of patients in clinical trials and evaluation of treatment effects. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

  14. CSF cortisol in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Popp, Julius; Schaper, Karsten; Kölsch, Heike; Cvetanovska, Gabriela; Rommel, Fatima; Klingmüller, Dietrich; Dodel, Richard; Wüllner, Ullrich; Jessen, Frank

    2009-03-01

    Hypercortisolaemia occurs in Alzheimer's disease (AD) and may be involved in the AD related neurodegenerative process. In order to determine whether brain structures are exposed to high cortisol concentrations early in AD, we measured cerebrospinal fluid (CSF) cortisol in 66 subjects with AD, 33 subjects with mild cognitive impairment (MCI) and 34 control subjects. CSF cortisol concentrations were higher in AD subjects compared to controls (p<0.001) and to MCI subjects (p=0.002). There was no significant increase of cortisol in MCI subjects compared with controls suggesting that the increase of CSF cortisol is not an early event in the course of AD.

  15. Impact of the 2008-2012 French Alzheimer Plan on the use of cerebrospinal fluid biomarkers in research memory center: the PLM Study.

    PubMed

    Gabelle, Audrey; Dumurgier, Julien; Vercruysse, Olivier; Paquet, Claire; Bombois, Stéphanie; Laplanche, Jean-Louis; Peoc'h, Katell; Schraen, Susanna; Buée, Luc; Pasquier, Florence; Hugon, Jacques; Touchon, Jacques; Lehmann, Sylvain

    2013-01-01

    The French Alzheimer's Disease Plan aims, in an unprecedented national effort, to develop research, promote optimal diagnosis, and take better care of patients. In order to evaluate the clinical interest and use of cerebrospinal fluid (CSF) biomarkers, a data-sharing project, the PLM (Paris-North, Lille and Montpellier) study has emerged through collaboration between these memory centers, already involved in this field. The revised Alzheimer's disease (AD) diagnosis criteria include CSF biomarkers, but little is known about their use in routine clinical practice. To evaluate their interest and diagnostic accuracy in routine AD diagnosis, a cohort of 677 patients from Montpellier was first analyzed. The results were then validated through the analysis of a second cohort of 638 patients from Lille and Paris-Nord. Diagnoses of AD and other dementias were established by multidisciplinary expert teams, based on neuropsychological exams and structural brain imaging, blinded from CSF results. CSF amyloid-β, tau, and p-tau concentrations were measured for all patients. Receiver-operating characteristic curves were used to define cut-offs and evaluate the ability of each biomarker to discriminate AD from other diagnoses. We showed that p-tau outperformed other biomarkers for discriminating AD from non-AD patients and presents a clear clinical interest. The other biomarkers also showed relevant variations especially when the differential AD diagnoses were taken into account. Altogether we could demonstrate in both mono-centric and multi-centric cohorts from memory clinics the capacity of CSF biomarkers to discriminate AD from non-AD patients in clinical routine with a high sensitivity and specificity.

  16. d-serine levels in Alzheimer's disease: implications for novel biomarker development

    PubMed Central

    Madeira, C; Lourenco, M V; Vargas-Lopes, C; Suemoto, C K; Brandão, C O; Reis, T; Leite, R E P; Laks, J; Jacob-Filho, W; Pasqualucci, C A; Grinberg, L T; Ferreira, S T; Panizzutti, R

    2015-01-01

    Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis. PMID:25942042

  17. Preanalytical Confounding Factors in the Analysis of Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: The Issue of Diurnal Variation

    PubMed Central

    Cicognola, Claudia; Chiasserini, Davide; Parnetti, Lucilla

    2015-01-01

    Given the growing use of cerebrospinal fluid (CSF) beta-amyloid (Aβ) and tau as biomarkers for early diagnosis of Alzheimer’s disease (AD), it is essential that the diagnostic procedures are standardized and the results comparable across different laboratories. Preanalytical factors are reported to be the cause of at least 50% of the total variability. Among them, diurnal variability is a key issue and may have an impact on the comparability of the values obtained. The available studies on this issue are not conclusive so far. Fluctuations of CSF biomarkers in young healthy volunteers have been previously reported, while subsequent studies have not confirmed those observations in older subjects, the ones most likely to receive this test. The observed differences in circadian rhythms need to be further assessed not only in classical CSF biomarkers but also in novel forthcoming biomarkers. In this review, the existing data on the issue of diurnal variations of CSF classical biomarkers for AD will be analyzed, also evaluating the available data on new possible biomarkers. PMID:26175714

  18. Predicting missing biomarker data in a longitudinal study of Alzheimer disease

    PubMed Central

    Jagust, William J.; Aisen, Paul; Jack, Clifford R.; Toga, Arthur W.; Beckett, Laurel; Gamst, Anthony; Soares, Holly; C. Green, Robert; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Bandy, Dan; Chen, Kewei; Morris, John; Lee, Virginia M.-Y.; Korecka, Magdalena; Crawford, Karen; Neu, Scott; Harvey, Danielle; Kornak, John; Saykin, Andrew J.; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Buckholtz, Neil; Kaye, Jeffrey; Dolen, Sara; Quinn, Joseph; Schneider, Lon; Pawluczyk, Sonia; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Petersen, Ronald; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Tang, Cheuk; Marzloff, George; Toledo-Morrell, Leylade; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn S.; Pedroso, Julia; Toroney, Jaimie; Rusinek, Henry; de Leon, Mony J; De Santi, Susan M; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Aiello, Marilyn; Clark, Christopher M.; Pham, Cassie; Nunez, Jessica; Smith, Charles D.; Given, Curtis A.; Hardy, Peter; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Ismail, M. Saleem; Brand, Connie; Richard, Jennifer; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Diaz-Arrastia, Ramon; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Laubinger, Mary M.; Bartzokis, George; Silverman, Daniel H.S.; Lu, Po H.; Graff-Radford MBBCH, Neill R; Parfitt, Francine; Johnson, Heather; Farlow, Martin; Herring, Scott; Hake, Ann M.; van Dyck, Christopher H.; MacAvoy, Martha G.; Benincasa, Amanda L.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Graham, Simon; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Wu, Chuang-Kuo; Johnson, Nancy; Mesulam, Marsel; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Scott; Johnson, Kathleen B.; Behan, Kelly E.; Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.; Rosen, Allyson; Tinklenberg, Jared; Ashford, Wes; Sabbagh, Marwan; Connor, Donald; Jacobson, Sandra; Killiany, Ronald; Norbash, Alexander; Nair, Anil; Obisesan, Thomas O.; Jayam-Trouth, Annapurni; Wang, Paul; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; DeCarli, Charles; Fletcher, Evan; Carmichael, Owen; Kittur, Smita; Mirje, Seema; Borrie, Michael; Lee, T-Y; Bartha, Dr Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Hendin, Barry A.; Scharre, Douglas W.; Kataki, Maria; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Gandy, Sam; Marenberg, Marjorie E.; Rovner, Barry W.; Pearlson, Godfrey; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Englert, Jessica; Williamson, Jeff D.; Sink, Kaycee M.; Watkins, Franklin; Ott, Brian R.; Wu, Chuang-Kuo; Cohen, Ronald; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo

    2012-01-01

    Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). Methods: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. Results: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. Conclusion: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD. PMID:22491869

  19. CSF glucose test

    MedlinePlus

    Glucose test - CSF; Cerebrospinal fluid glucose test ... The glucose level in the CSF should be 50 to 80 mg/100 mL (or greater than 2/3 ... Abnormal results include higher and lower glucose levels. Abnormal ... or fungus) Inflammation of the central nervous system Tumor

  20. CSF total protein

    MedlinePlus

    CSF total protein is a test to determine the amount of protein in your spinal fluid, also called cerebrospinal fluid (CSF). ... The normal protein range varies from lab to lab, but is typically about 15 to 60 milligrams per deciliter (mg/dL) ...

  1. Exploring Biomarkers for Alzheimer’s Disease

    PubMed Central

    Singh, Anshika Nikita

    2016-01-01

    Alzheimer’s Disease (AD) is one of the most common form of dementia occurring in elderly population worldwide. Currently Aβ42, tau and p-tau in the cerebrospinal fluid is estimated for confirmation of AD. CSF which is being used as the potent source for biomarker screening is obtained by invasive lumbar punctures. Thus, there is an urgent need of minimal invasive methods for identification of diagnostic markers for early detection of AD. Blood serum and plasma serves as an appropriate source, due to minimal discomfort to the patients, promoting frequent testing, better follow-up and better consent to clinical trials. Hence, the need of the hour demands discovery of diagnostic and prognostic patient specific signature biomarkers by using emerging technologies of mass spectrometry, microarrays and peptidomics. In this review we summarize the present scenario of AD biomarkers such as circulatory biomarkers, blood based amyloid markers, inflammatory markers and oxidative stress markers being investigated and also some of the potent biomarkers which might be able to predict early onset of Alzheimer’s and delay cognitive impairment. PMID:27630867

  2. The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

    PubMed

    Bocchetta, Martina; Galluzzi, Samantha; Kehoe, Patrick Gavin; Aguera, Eduardo; Bernabei, Roberto; Bullock, Roger; Ceccaldi, Mathieu; Dartigues, Jean-François; de Mendonça, Alexandre; Didic, Mira; Eriksdotter, Maria; Félician, Olivier; Frölich, Lutz; Gertz, Hermann-Josef; Hallikainen, Merja; Hasselbalch, Steen G; Hausner, Lucrezia; Heuser, Isabell; Jessen, Frank; Jones, Roy W; Kurz, Alexander; Lawlor, Brian; Lleo, Alberto; Martinez-Lage, Pablo; Mecocci, Patrizia; Mehrabian, Shima; Monsch, Andreas; Nobili, Flavio; Nordberg, Agneta; Rikkert, Marcel Olde; Orgogozo, Jean-Marc; Pasquier, Florence; Peters, Oliver; Salmon, Eric; Sánchez-Castellano, Carmen; Santana, Isabel; Sarazin, Marie; Traykov, Latchezar; Tsolaki, Magda; Visser, Pieter Jelle; Wallin, Åsa K; Wilcock, Gordon; Wilkinson, David; Wolf, Henrike; Yener, Görsev; Zekry, Dina; Frisoni, Giovanni B

    2015-02-01

    We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

  3. Papilloedema, CSF pressure, and CSF flow in cerebral tumours.

    PubMed Central

    van Crevel, H

    1979-01-01

    The presence or absence of papilloedema and the cisternal CSF pressure were compared with the RIHSA cisternograms in 24 patients with supratenotorial tumours. It was found that severe subarachnoid obstruction of CSF flow, leading to impaired CSF absorption at the superior sagittal sinus, was the main cause of raised CSF pressure and papilloedema associated with supratentorial tumours. Images PMID:469556

  4. Potential fluid biomarkers for pathological brain changes in Alzheimer's disease: Implication for the screening of cognitive frailty

    PubMed Central

    Ruan, Qingwei; D'Onofrio, Grazia; Sancarlo, Daniele; Greco, Antonio; Yu, Zhuowei

    2016-01-01

    Cognitive frailty (CF) overlaps with early neuropathological alterations associated with aging-related major neurocognitive disorders, including Alzheimer's disease (AD). Fluid biomarkers for these pathological brain alterations allow for early diagnosis in the preclinical stages of AD, and for objective prognostic assessments in clinical intervention trials. These biomarkers may also be helpful in the screening of CF. The present study reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. The selection criteria for potentially suitable fluid biomarkers included: i) Frequent use in studies of fluid-derived markers and ii) evidence of novel measurement techniques for fluid-derived markers. The present study focused on studies that assessed these biomarkers in AD, mild cognitive impairment and non-AD demented subjects. At present, widely used fluid biomarkers include cerebrospinal fluid (CSF), total tau, phosphorylated tau and amyloid-β levels. With the development of novel measurement techniques and improvements in understanding regarding the mechanisms underlying aging-related major neurocognitive disorders, numerous novel biomarkers associated with various aspects of AD neuropathology are being explored. These include specific measurements of Aβ oligomer or monomer forms, tau proteins in the peripheral plasma and CSF, and novel markers of synaptic dysfunction, neuronal damage and apoptosis, neuronal activity alteration, neuroinflammation, blood brain barrier dysfunction, oxidative stress, metabolites, mitochondrial function and aberrant lipid metabolism. The proposed panels of fluid biomarkers may be useful in the early diagnosis of AD, prediction of the progression of AD from preclinical stages to the dementia stage, and the differentiation of AD from non-AD dementia. In combination with physical frailty, the present study surmised that these biomarkers may also be used as biomarkers for CF, thus contribute

  5. Cerebrospinal Fluid Biomarker and Brain Biopsy Findings in Idiopathic Normal Pressure Hydrocephalus

    PubMed Central

    Pyykkö, Okko T.; Lumela, Miikka; Rummukainen, Jaana; Nerg, Ossi; Seppälä, Toni T.; Herukka, Sanna-Kaisa; Koivisto, Anne M.; Alafuzoff, Irina; Puli, Lakshman; Savolainen, Sakari; Soininen, Hilkka; Jääskeläinen, Juha E.; Hiltunen, Mikko; Zetterberg, Henrik; Leinonen, Ville

    2014-01-01

    Background The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown. Objective To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings. Methods The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE. Results Lumbar CSF levels of sAPPα were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPPβ showed a similar trend (p = 0.06). CSF sAPP isoform levels showed no association to Aβ or HPτ in the brain biopsy. Quantified Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ42 in ventricular (r = −0.295, p = 0.003) and lumbar (r = −0.356, p = 0.01) samples, while the levels of Aβ38 and Aβ40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure

  6. Brain ventricular volume and cerebrospinal fluid biomarkers of Alzheimer’s disease

    PubMed Central

    Ott, Brian R.; Cohen, Ronald A.; Gongvatana, Assawin; Okonkwo, Ozioma C.; Johanson, Conrad E.; Stopa, Edward G.; Donahue, John E.; Silverberg, Gerald D.

    2010-01-01

    The frequent co-occurrence of Alzheimer disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid beta peptide (Aβ) in CSF in preclinical and early AD. CSF biomarker data (Aβ, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Aβ in APOE ε4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Aβ in ε4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Aβ in preclinical AD. The basis for the apparent effect of APOE ε4 genotype on the relationship of ventricular volume to Aβ and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease. PMID:20182051

  7. CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease.

    PubMed

    Chiasserini, Davide; Parnetti, Lucilla; Andreasson, Ulf; Zetterberg, Henrik; Giannandrea, David; Calabresi, Paolo; Blennow, Kaj

    2010-01-01

    Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.

  8. CSF tau levels influence cortical plasticity in Alzheimer's disease patients.

    PubMed

    Koch, Giacomo; Esposito, Zaira; Kusayanagi, Hajime; Monteleone, Fabrizia; Codecá, Claudia; Di Lorenzo, Francesco; Caltagirone, Carlo; Bernardi, Giorgio; Martorana, Alessandro

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative process characterized by progressive neuronal degeneration, reduced levels of neurotransmitters, and altered forms of synaptic plasticity. In animal models of AD, amyloid-β (Aβ) and tau proteins are supposed to interfere with synaptic transmission. In the current study, we investigated the correlation between motor cortical plasticity, measured with 1 Hz repetitive transcranial magnetic stimulation (rTMS), and the levels of Aβ₁₋₄₂, total tau (t-Tau), and phosphorylated tau (p-Tau) detected in cerebrospinal fluid (CSF) of AD patients. We found that the overall rTMS after effects were milder in AD patients in comparison with controls. In AD patients the amount of rTMS-induced inhibition correlated with CSF t-Tau, but not with Aβ₁₋₄₂ CSF levels. Surprisingly, higher CSF t-Tau levels were associated to a stronger inhibition of the motor evoked potentials, implying that the expected effects of the 1 Hz rTMS protocol were more evident in patients with more pathological t-Tau CSF levels. These data could be interpreted as the consequence of CSF t-Tau mediated abnormal excitatory activity and could suggest that CSF t-Tau may impact mechanisms of cortical plasticity.

  9. Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults

    PubMed Central

    Hoscheidt, Siobhan M.; Starks, Erika J.; Oh, Jennifer M.; Zetterberg, Henrik; Blennow, Kaj; Krause, Rachel A.; Gleason, Carey E.; Puglielli, Luigi; Atwood, Craig S.; Carlsson, Cynthia M.; Asthana, Sanjay; Johnson, Sterling C.; Bendlin, Barbara B.

    2016-01-01

    Background Type 2 diabetes is associated with an increased risk for Alzheimer disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. Objective We examined associations between IR as indexed by HOMA-IR, cerebral spinal fluid (CSF) biomarkers of AD pathology and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOE ε4 carriage would be associated with greater CSF AD pathology and poor memory performance. Methods Cognitively asymptomatic middle-aged adults (N=70, mean age=57.7 years) from the Wisconsin Alzheimer’s Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw and neuropsychological testing. CSF AD biomarkers including soluble amyloid precursor protein β (sAPP-β), β–amyloid42 (Aβ42) and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOE ε4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers and APOE ε4 status. Results Higher HOMA-IR was associated with higher sAPP-β and Aβ42. APOE ε4 carriers had significantly higher levels of sAPP-α, sAPP-β and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. Conclusion Overall, the findings suggest that IR and APOE ε4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD. PMID:27079723

  10. Cerebrospinal Fluid Biomarkers for Huntington's Disease.

    PubMed

    Byrne, Lauren M; Wild, Edward J

    2016-01-01

    Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.

  11. Cingulum fiber diffusivity and CSF T-tau in patients with subjective and mild cognitive impairment.

    PubMed

    Stenset, Vidar; Bjørnerud, Atle; Fjell, Anders M; Walhovd, Kristine B; Hofoss, Dag; Due-Tønnessen, Paulina; Gjerstad, Leif; Fladby, Tormod

    2011-04-01

    Diffusion tensor imaging (DTI) and CSF biomarkers are useful diagnostic tools to differentiate patients with mild cognitive impairment (MCI) from normal controls, and may help predict conversion to dementia. Total Tau protein (T-tau) and DTI parameters are both markers for axonal damage, thus it is of interest to determine if DTI parameters are associated with elevated CSF T-tau levels in patients with cognitive impairment. For this purpose, patients with subjective cognitive impairment (SCI) and MCI were recruited from a university based memory clinic. Regions of interest were used to determine fractional anisotropy (FA), radial diffusivity (DR) and axial diffusivity (DA) in known white matter tracts in patients with MCI (n=39) and SCI (n=8) and 26 cognitively healthy controls. Significant lower FA and higher DR values were observed in patients with pathological vs. patients with normal CSF T-tau levels and vs. controls in left posterior cingulum fibers. T-tau values were negatively correlated with FA and positively correlated with DR values in the posterior cingulum fibers. Cingulum fiber diffusivity was related to T-tau pathology in SCI/MCI patients and altered DR may suggest that loss of myelin contributes to early white matter changes in patients at risk of developing Alzheimer's disease (AD).

  12. Alzheimer Disease Biomarkers, Attentional Control and Semantic Memory Retrieval: Synergistic and Mediational Effects of Biomarkers on a Sensitive Cognitive Measure

    PubMed Central

    Aschenbrenner, Andrew J.; Balota, David A.; Tse, Chi-Shing; Fagan, Anne M.; Holtzman, David M.; Benzinger, Tammie L.S.; Morris, John C.

    2014-01-01

    Objective Past studies have shown that measures of attentional control and semantic memory are sensitive markers of Alzheimer disease (AD). The effects of established biomarkers of AD (cerebrospinal fluid tau and amyloid-beta42, PET-PIB, and APOE genotype) on concurrent cognitive performance in cognitively normal individuals have been mixed. The present study examined the utility of combining attentional control with semantic retrieval as a sensitive correlate of AD biomarkers and used mediation analyses to examine possible mechanisms by which the biomarkers influence cognition. Method 363 participants completed a category verification task (CVT) and 113 of them concurrently underwent biomarker assessments. On each trial, participants viewed a category (e.g. “unit of time”) and verified whether a subsequent target item was an exemplar of the category (“hour”) or not (“clock”). Importantly, the nonmembers of the category were associatively related to the category (e.g., “clock” is not “a unit of time”, but is highly related), and demanded attentional control to reject. Results Accuracy to the foil items was the strongest discriminator between healthy aging and very mild symptomatic AD. CSF biomarkers had independent yet synergistic influence on CVT performance in cognitively healthy older adults. Furthermore, the influence of the biomarkers and APOE genotype was mediated primarily through increased levels of PIB. Conclusion The combined influence of attentional control with semantic retrieval is a marker of symptomatic AD and a sensitive correlate of established biomarkers for AD risk in cognitively healthy participants. The biomarkers influenced cognition primarily through increased levels of amyloid in the brain. PMID:25222200

  13. Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases.

    PubMed

    Boll, Marie-Catherine; Alcaraz-Zubeldia, Mireya; Montes, Sergio; Rios, Camilo

    2008-09-01

    The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.

  14. CSF N-glycoproteomics for early diagnosis in Alzheimer's disease.

    PubMed

    Palmigiano, Angelo; Barone, Rita; Sturiale, Luisa; Sanfilippo, Cristina; Bua, Rosaria Ornella; Romeo, Donata Agata; Messina, Angela; Capuana, Maria Luisa; Maci, Tiziana; Le Pira, Francesco; Zappia, Mario; Garozzo, Domenico

    2016-01-10

    This work aims at exploring the human CSF (Cerebrospinal fluid) N-glycome by MALDI MS techniques, in order to assess specific glycosylation pattern(s) in patients with Alzheimer's disease (n:24) and in subjects with mild cognitive impairment (MCI) (n:11), these last as potential AD patients at a pre-dementia stage. For comparison, 21 healthy controls were studied. We identified a group of AD and MCI subjects (about 40-50% of the studied sample) showing significant alteration of CSF N-glycome profiling, consisting of a decrease in the overall sialylation degree and an increase in species bearing bisecting GlcNAc. Noteworthy, all the MCI patients that converted to AD within the clinical follow-up, had an abnormal CSF glycosylation profile. Based on the studied cohort, CSF glycosylation changes may occur before an AD clinical onset. Previous studies specifically focused on the key role of glycosyltransferase GnT-III on AD-pathogenesis, addressing the patho-mechanism to specific sugar modification of BACE-1 glycoprotein with bisecting GlcNAc. Our patients addressed protein N-glycosylation changes at an early phase of the whole biomolecular misregulation on AD, pointing to CSF N-glycome analyses as promising tool to enhance early detection of AD and also suggesting alternative therapeutics target molecules, such as specific glyco-enzymes.

  15. Biochemical studies in Normal Pressure Hydrocephalus (NPH) patients: change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Aβ) peptide and phospho-tau.

    PubMed

    Ray, Balmiki; Reyes, Patricio F; Lahiri, Debomoy K

    2011-04-01

    Normal Pressure Hydrocephalus (NPH) is one of the causes of dementia of the elderly characterized by impaired mental function, gait difficulties and urinary incontinence. Previously, it was proposed that some of the NPH patients may develop Alzheimer's disease (AD) like pathology. Aim of this study was to compare levels of different CSF biomarkers, including total secreted β-amyloid precursor protein (sAPP), sAPP-alpha form (sAPPα), amyloid-beta (Aβ) peptide, total-tau protein and hyperphosphorylated-tau protein in subjects from NPH and Non-NPH Control (NNC). CSF was collected from 23 NPH patients and 13 Non-NPH controls by lumber puncture. Western blot analysis was performed to measure levels of sAPP-total. ELISA was used separately to determine levels of sAPPα, Aβ peptide, total-tau and phospho-tau proteins. We found a significant decrease in levels of total secreted APP, sAPPα and Aβ (1-42) in the CSF sample of NPH patients vs. NNC. We did not observe any change in levels of total-tau or phospho-tau in NPH vs. NNC subjects. Notably, phospho-tau level was significantly increased in the NPH patients, who were suffering from the disease for more than one year, vs. NNC. Among five biomarkers studied, decreased sAPP, sAPPα and Aβ (1-42) levels in CSF can be molecular markers to distinguish NPH cases from NNC. Disease severity can also be assessed by increased levels of CSF phospho-tau protein and the ratio of phospho-tau to Aβ (1-42), which might be a useful tool for predicting conversion of NPH individuals to other neurodegenerative disorders including Alzheimer's disease (AD).

  16. Florbetapir positron emission tomography and cerebrospinal fluid biomarkers

    PubMed Central

    Hake, Ann; Trzepacz, Paula T.; Wang, Shufang; Yu, Peng; Case, Michael; Hochstetler, Helen; Witte, Michael M.; Degenhardt, Elisabeth K.; Dean, Robert A.

    2015-01-01

    Background We evaluated the relationship between florbetapir-F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers. Methods Alzheimer’s Disease Neuroimaging Initiative (ADNI)-GO/2 healthy control (HC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) dementia subjects with clinical measures and CSF collected ±90 days of FBP PET data were analyzed using correlation and logistic regression. Results In HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Aβ1-42) and tau/Aβ1-42 ratios. Using logistic regression, Aβ1-42, total tau (t-tau), phosphorylated tau181P (p-tau), and FBP PET composite each differentiated HC versus AD. Aβ1-42 and t-tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p-tau added discriminative power to FBP PET when classifying HC versus AD. Conclusion Based on cross-sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed. PMID:25916563

  17. Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease

    PubMed Central

    Henneman, W J.P.; Vrenken, H; Barnes, J; Sluimer, I C.; Verwey, N A.; Blankenstein, M A.; Klein, M; Fox, N C.; Scheltens, P; Barkhof, F; van der Flier, W M.

    2009-01-01

    Objective: To investigate whether baseline CSF biomarkers are associated with hippocampal atrophy rate as a measure of disease progression in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls, controlling for baseline neuropsychological and MRI findings. Methods: We assessed data from 31 patients with AD, 25 patients with MCI, and 19 controls (mean age 68 ± 8 years; 39 [52%] female) who visited our memory clinic and had received serial MRI scanning (scan interval 1.7 ± 0.7 years). At baseline, CSF biomarkers (amyloid β 1-42, tau, and tau phosphorylated at threonine 181 [p-tau]) were obtained, as well as neuropsychological data. Baseline MRI scans were assessed using visual rating scales for medial temporal lobe atrophy (MTA), global cortical atrophy, and white matter hyperintensities. Hippocampal atrophy rates were estimated using regional nonlinear “fluid” registration of follow-up scan to baseline scan. Results: Stepwise multiple linear regression, adjusted for age and sex, showed that increased CSF p-tau levels (β [standard error]: −0.79 [0.35]) at baseline was independently associated with higher subsequent hippocampal atrophy rates (p < 0.05), together with poorer memory performance (0.09 [0.04]) and more severe MTA (−0.60 [0.21]). The association of memory function with hippocampal atrophy rate was explained by the link with diagnosis, because it disappeared from the model after we additionally corrected for diagnosis. Conclusions: Baseline CSF levels of tau phosphorylated at threonine 181 are independently associated with subsequent disease progression, as reflected by hippocampal atrophy rate. This effect is independent of baseline neuropsychological and MRI predictors. Our results imply that predicting disease progression can best be achieved by combining information from different modalities. GLOSSARY Aβ1-42 = amyloid β 1-42; AD = Alzheimer disease; FOV = field of view; GCA = global cortical

  18. Homovanillic acid and 5-hydroxyindole acetic acid as biomarkers for dementia with Lewy bodies and coincident Alzheimer’s disease: An autopsy-confirmed study

    PubMed Central

    Takao, Masaki; Hatsuta, Hiroyuki; Nishina, Yasushi; Komiya, Tadashi; Sengoku, Renpei; Nakano, Yuta; Uchino, Akiko; Sumikura, Hiroyuki; Saito, Yuko; Kanemaru, Kazutomi; Murayama, Shigeo

    2017-01-01

    Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are the two most common causes of dementia. Both pathologies often coexist, and AD patients with concomitant neocortical LB pathology (referred to as the Lewy body variant of AD) generally show faster cognitive decline and accelerated mortality relative to patients with pure AD. Thus, discriminating among patients with DLB, AD, and coincident DLB and AD is important in clinical practice. We examined levels of homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), tau, phosphorylated tau (p-tau), and beta-amyloid (Aβ) 1–42 in cerebrospinal fluid (CSF) to evaluate their viability as biomarkers to discriminate among different forms of dementia. We obtained a total of 3498 CSF samples from patients admitted to our hospital during the period from 1996 to 2015. Of these patients, we were able to carry out a brain autopsy in 94 cases. Finally, 78 neuropathologically diagnosed cases (10 AD, six DLB, five DLB with AD, five controls without neurological diseases, and 52 cases with other neurological diseases) were studied. CSF levels of HVA and 5-HIAA were consistently decreased in pathologically advanced Lewy body disorder (LBD; Braak LB stages >3) compared with pathologically incipient LBD (Braak LB stages <2). These results suggest that if an individual has LB pathology in the central nervous system, CSF levels of HVA and 5-HIAA may decrease after the onset of clinical symptoms. In addition, CSF levels of HVA and 5-HIAA decreased with LB pathology, and were especially low in cases of DLB and DLB with AD. Furthermore, the combination of HVA, 5-HIAA, and brain specific proteins t-tau, p-tau, and Aβ 1–42 in CSF were useful for discriminating among DLB, DLB with AD, and AD with high diagnostic accuracy. PMID:28166276

  19. Aβ40 Oligomers Identified as a Potential Biomarker for the Diagnosis of Alzheimer's Disease

    PubMed Central

    Wang, Xuemei; Magdangal, Erika; Salisbury, Cleo; Peretz, David; Zuckermann, Ronald N.; Connolly, Michael D.; Hansson, Oskar; Minthon, Lennart; Zetterberg, Henrik; Blennow, Kaj; Fedynyshyn, Joseph P.; Allauzen, Sophie

    2010-01-01

    Alzheimer's Disease (AD) is the most prevalent form of dementia worldwide, yet the development of therapeutics has been hampered by the absence of suitable biomarkers to diagnose the disease in its early stages prior to the formation of amyloid plaques and the occurrence of irreversible neuronal damage. Since oligomeric Aβ species have been implicated in the pathophysiology of AD, we reasoned that they may correlate with the onset of disease. As such, we have developed a novel misfolded protein assay for the detection of soluble oligomers composed of Aβ x-40 and x-42 peptide (hereafter Aβ40 and Aβ42) from cerebrospinal fluid (CSF). Preliminary validation of this assay with 36 clinical samples demonstrated the presence of aggregated Aβ40 in the CSF of AD patients. Together with measurements of total Aβ42, diagnostic sensitivity and specificity greater than 95% and 90%, respectively, were achieved. Although larger sample populations will be needed to confirm this diagnostic sensitivity, our studies demonstrate a sensitive method of detecting circulating Aβ40 oligomers from AD CSF and suggest that these oligomers could be a powerful new biomarker for the early detection of AD. PMID:21209907

  20. Alzheimer’s disease biomarkers in animal models: closing the translational gap

    PubMed Central

    Sabbagh, Jonathan J; Kinney, Jefferson W; Cummings, Jeffrey L

    2013-01-01

    The rising prevalence of Alzheimer’s disease (AD) is rapidly becoming one of the largest health and economic challenges in the world. There is a growing need for the development and implementation of reliable biomarkers for AD that can be used to assist in diagnosis, inform disease progression, and monitor therapeutic efficacy. Preclinical models permit the evaluation of candidate biomarkers and assessment of pipeline agents before clinical trials are initiated and provide a translational opportunity to advance biomarker discovery. Fast and inexpensive data can be obtained from examination of peripheral markers, though they currently lack the sensitivity and consistency of imaging techniques such as MRI or PET. Plasma and cerebrospinal fluid (CSF) biomarkers in animal models can assist in development and implementation of similar approaches in clinical populations. These biomarkers may also be invaluable in decisions to advance a treatment to human testing. Longitudinal studies in AD models can determine initial presentation and progression of biomarkers that may also be used to evaluate disease-modifying efficacy of drugs. The refinement of biomarker approaches in preclinical systems will not only aid in drug development, but may facilitate diagnosis and disease monitoring in AD patients. PMID:23844335

  1. Alzheimer's disease dementia as the diagnosis best supported by the cerebrospinal fluid biomarkers: difference in cut-off levels from thai experience.

    PubMed

    Senanarong, V; Siwasariyanon, N; Washirutmangkur, L; Poungvarin, N; Ratanabunakit, C; Aoonkaew, N; Udomphanthurak, S

    2012-01-01

    Objectives. To determine how beta-amyloid 1-42 (Aβ 1-42), total tau (tTau), and phosphorylated tau (pTau) levels in CSF behave in a cohort of Thai patients from the Memory Clinic in Bangkok, Thailand. Methods. During 2009-2011, twenty eight subjects from the memory clinic at Siriraj Hospital had CSF analysis for AD biomarkers. Aβ 1-42, tTau, and pTau (at amino acid 181) were measured in CSF by ELISA technique. Results. Mean of Thai mental state examination (TMSE) of 28 Thai cohort was 16.48 (6.63). Fourteen had AD, ten had non-AD dementia, and four non-cases were those with subjective memory complaint (SMC) without dementia. Mean CSF Aβ 1-42, tTau, ptau (181), and pTau/Aβ 1-42 in the AD group were 241.36 (60.14) pg/mL, 222.79 (212.24) pg/mL, 40.79 (27.84) pg/mL, and 0.18 (0.12) accordingly. Mean CSF Aβ 1-42, tTau, pTau (181), and pTau/Aβ 1-42 in the non-AD dementia group were 430.40 (125.18) pg/mL, 349.30 (692.16) pg/mL, 36.80 (14.90) pg/mL, and 0.09 (0.04) accordingly. Mean CSF Aβ 1-42, tTau, pTau (181), and pTau/Aβ 1-42 in the non-cases with SMC without dementia were 499.75 (93.44) pg/mL, 137.25 (62.74) pg/mL, 31.75 (17.48) pg/mL, and 0.06 (0.02). There is significant difference (P < 0.05) among the 3 groups in CSF Aβ 1-42 and pTau/Aβ 1-42. We propose mean + 1.5 SD of CSF Aβ 1-42 in AD group (331.57 pg/mL) to be the cut-off point in Thai subjects. Conclusion. There are significant different in CSF Aβ 1-42 and CSF p-tau/Aβ 1-42 among those with AD, non-AD dementia and non cases with SMC without dementia in Thai cohort. Cut-off point of CSF Aβ 1-42 of 331.57 pg/mL is suggested in Thai study.

  2. G-CSF and GM-CSF in clinical trials.

    PubMed Central

    Antman, K. H.

    1990-01-01

    Hematopoietic growth factors have now been purified, cloned, and produced in bacteria and yeast. Those that are currently in clinical study include erythropoietin, GM-CSF, G-CSF, M-CSF (also called CSF-1), and multi-CSF (also called interleukin 3). Growth factor appear likely to enhance the recovery and function of circulating white cells after standard-dose cancer therapy and high-bone-dose cancer therapy with marrow transplant and to restore leukocyte numbers and competence in the acquired immune deficiency syndromes and myelodysplastic syndromes. Phase I, II trials in AIDS, in cancer patients receiving chemotherapy, in cases of myeloproliferative disease, and after bone marrow transplant have been published. The results of phase III studies are just becoming available. PMID:1705737

  3. Alzheimer's disease biomarkers as outcome measures for clinical trials in MCI

    PubMed Central

    Caroli, Anna; Prestia, Annapaola; Wade, Sara; Chen, Kewei; Ayutyanont, Napatkamon; Landau, Susan M.; Madison, Cindee M.; Haense, Cathleen; Herholz, Karl; Reiman, Eric M.; Jagust, William J.; Frisoni, Giovanni B.

    2014-01-01

    Background Aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Methods MRI, FDG-PET markers, and ADAS-COG were compared in terms of effect size and statistical power over different followup periods in two MCI groups, selected from ADNI dataset based on CSF (abnormal CSF Aβ1-42 concentration - ABETA+) or MRI evidence of Alzheimer's Disease (AD) (positivity to hippocampal atrophy - HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. Results Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. Conclusions These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials. PMID:25437302

  4. The mediational effects of FDG hypometabolism on the association between cerebrospinal fluid biomarkers and neurocognitive function.

    PubMed

    Dowling, N Maritza; Johnson, Sterling C; Gleason, Carey E; Jagust, William J

    2015-01-15

    Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described. Using a statistical mediation model, we examined relationships between cerebrospinal fluid (CSF) analytes (hyperphosphorylated tau (p-Tau(181p)), β-amyloid peptides 1-42 (Aβ(1-42)), total tau (t-Tau), and their ratios); change in cognitive function; and change in [18F]fluorodeoxyglucose (FDG) uptake using positron emission tomography (PET). We hypothesized that a) abnormal CSF protein values at baseline, result in cognitive declines by decreasing neuronal glucose metabolism across time, and b) the role of altered glucose metabolism in the assumed causal chain varies by brain region and the nature of CSF protein alteration. Data from 412 individuals participating in Alzheimer's Disease Neuroimaging (ADNI) cohort studies were included in analyses. At baseline, individuals were cognitively normal (N = 82), or impaired: 241 with mild cognitive impairment, and 89 with Alzheimer's disease. A parallel-process latent growth curve model was used to test mediational effects of changes in regional FDG-PET uptake over time in relation to baseline CSF biomarkers and changes in cognition, measured with the 13-item Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog). Findings suggested a causal sequence of events; specifically, FDG hypometabolism acted as a mediator between antecedent CSF biomarker alterations and subsequent cognitive impairment. Higher baseline concentrations of t-Tau, and p-Tau(181p) were more predictive of decline in cerebral glucose metabolism than lower baseline concentrations of Aβ(1-42). FDG-PET changes appeared to mediate t-Tau or t-Tau/Aβ(1-42)-associated cognitive change across all brain

  5. Alzheimer's disease biomarker discovery using in silico literature mining and clinical validation

    PubMed Central

    2012-01-01

    Background Alzheimer’s Disease (AD) is the most widespread form of dementia in the elderly but despite progress made in recent years towards a mechanistic understanding, there is still an urgent need for disease modification therapy and for early diagnostic tests. Substantial international efforts are being made to discover and validate biomarkers for AD using candidate analytes and various data-driven 'omics' approaches. Cerebrospinal fluid is in many ways the tissue of choice for biomarkers of brain disease but is limited by patient and clinician acceptability, and increasing attention is being paid to the search for blood-based biomarkers. The aim of this study was to use a novel in silico approach to discover a set of candidate biomarkers for AD. Methods We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of assertional metadata derived from relevant legacy information. We then assessed the validity of this approach using direct assays of the identified biomarkers in plasma by immunodetection methods. Results Using this in silico approach, we identified 25 biomarker candidates, at least three of which have subsequently been reported to be altered in blood or CSF from AD patients. Two further candidate biomarkers, indicated from the in silico approach, were choline acetyltransferase and urokinase-type plasminogen activator receptor. Using immunodetection, we showed that, in a large sample set, these markers are either altered in disease or correlate with MRI markers of atrophy. Conclusions These data support as a proof of concept the use of data mining and in silico analyses to derive valid biomarker candidates for AD and, by extension, for other disorders. PMID:23113945

  6. Super-Resolution Microscopy of Cerebrospinal Fluid Biomarkers as a Tool for Alzheimer's Disease Diagnostics.

    PubMed

    Zhang, William I; Antonios, Gregory; Rabano, Alberto; Bayer, Thomas A; Schneider, Anja; Rizzoli, Silvio O

    2015-01-01

    Alzheimer's disease (AD) is neuropathologically characterized by aggregates of amyloid-β peptides (Aβ) and tau proteins. The consensus in the AD field is that Aβ and tau should serve as diagnostic biomarkers for AD. However, their aggregates have been difficult to investigate by conventional fluorescence microscopy, since their size is below the diffraction limit (∼200 nm). To solve this, we turned to a super-resolution imaging technique, stimulated emission depletion (STED) microscopy, which has a high enough precision to allow the discrimination of low- and high-molecular weight aggregates prepared in vitro. We used STED to analyze the structural organization of Aβ and tau in cerebrospinal fluid (CSF) from 36 AD patients, 11 patients with mild cognitive impairment (MCI), and 21 controls. We measured the numbers of aggregates in the CSF samples, and the aggregate sizes and intensities. These parameters enabled us to distinguish AD patients from controls with a specificity of ∼87% and a sensitivity of ∼79% . In addition, the aggregate parameters determined with STED microscopy correlated with the severity of cognitive impairment in AD patients. Finally, these parameters may be useful as predictive tools for MCI cases. The STED parameters of two MCI patients who developed AD during the course of the study, as well as of MCI patients whose Aβ ELISA values fall within the accepted range for AD, placed them close to the AD averages. We suggest that super-resolution imaging is a promising tool for AD diagnostics.

  7. Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred A Cross-sectional Study

    PubMed Central

    Fleisher, Adam S.; Chen, Kewei; Quiroz, Yakeel T.; Jakimovich, Laura J.; Gomez, Madelyn Gutierrez; Langois, Carolyn M.; Langbaum, Jessica B. S.; Roontiva, Auttawut; Thiyyagura, Pradeep; Lee, Wendy; Ayutyanont, Napatkamon; Lopez, Liliana; Moreno, Sonia; Muñoz, Claudia; Tirado, Victoria; Acosta-Baena, Natalia; Fagan, Anne M.; Giraldo, Margarita; Garcia, Gloria; Huentelman, Matthew J.; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

    2015-01-01

    IMPORTANCE Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and noncarriers from the world’s largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau

  8. Anti-Aβ Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    DiFrancesco, Jacopo C.; Longoni, Martina; Piazza, Fabrizio

    2015-01-01

    Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (Aβ) immunotherapy for Alzheimer’s disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-Aβ autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-Aβ autoantibody as a promising candidate biomarker for ARIA in clinical trials. PMID:26441825

  9. A Genetics-based Biomarker Risk Algorithm for Predicting Risk of Alzheimer’s Disease

    PubMed Central

    Lutz, Michael W.; Sundseth, Scott S.; Burns, Daniel K.; Saunders, Ann M.; Hayden, Kathleen M.; Burke, James R.; Welsh-Bohmer, Kathleen A.; Roses, Allen D.

    2016-01-01

    Background A straightforward, reproducible blood-based test that predicts age dependent risk of Alzheimer’s disease (AD) could be used as an enrichment tool for clinical development of therapies. This study evaluated the prognostic performance of a genetics-based biomarker risk algorithm (GBRA) established on a combination of Apolipoprotein E (APOE)/Translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes and age, then compare it to cerebrospinal fluid (CSF) biomarkers, neuroimaging and neurocognitive tests using data from two independent AD cohorts. Methods The GBRA was developed using data from the prospective Bryan-ADRC study (n=407; 86 conversion events (mild cognitive impairment (MCI) or late onset Alzheimer’s disease (LOAD)). The performance of the algorithm was tested using data from the ADNI study (n=660; 457 individuals categorized as MCI or LOAD). Results The positive predictive values (PPV) and negative predictive values (NPV) of the GBRA are in the range of 70–80%. The relatively high odds ratio (approximately 3–5) and significant net reclassification index (NRI) scores comparing the GBRA to a version based on APOE and age alone support the value of the GBRA in risk prediction for MCI due to LOAD. Performance of the GBRA compares favorably with CSF and imaging (fMRI) biomarkers. In addition, the GBRA “high” and “low” AD-risk categorizations correlated well with pathological CSF biomarker levels, PET amyloid burden and neurocognitive scores. Conclusions Unlike dynamic markers (i.e., imaging, protein or lipid markers) that may be influenced by factors unrelated to disease, genomic DNA is easily collected, stable, and the technical methods for measurement are robust, inexpensive, and widely available. The performance characteristics of the GBRA support its use as a pharmacogenetic enrichment tool for LOAD delay of onset clinical trials, and merits further evaluation for its clinical utility in evaluating therapeutic

  10. Quantitative appraisal of ventricular cerebrospinal fluid biomarkers in neuropathologically diagnosed Parkinson's disease cases lacking Alzheimer's disease pathology.

    PubMed

    Maarouf, Chera L; Beach, Thomas G; Adler, Charles H; Malek-Ahmadi, Michael; Kokjohn, Tyler A; Dugger, Brittany N; Walker, Douglas G; Shill, Holly A; Jacobson, Sandra A; Sabbagh, Marwan N; Roher, Alex E

    2013-01-01

    Identifying biomarkers that distinguish Parkinson's disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer's disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau(181), Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau(181)/Aβ42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau(181)/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12-1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest coexistent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.

  11. Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease.

    PubMed

    Mandecka, Monika; Budziszewska, Magdalena; Barczak, Anna; Pepłońska, Beata; Chodakowska-Żebrowska, Małgorzata; Filipek-Gliszczyńska, Anna; Nesteruk, Marta; Styczyńska, Maria; Barcikowska, Maria; Gabryelewicz, Tomasz

    2016-07-29

    In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aβ1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aβ1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aβ1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

  12. Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer's disease.

    PubMed

    Popp, Julius; Meichsner, Sabrina; Kölsch, Heike; Lewczuk, Piotr; Maier, Wolfgang; Kornhuber, Johannes; Jessen, Frank; Lütjohann, Dieter

    2013-07-01

    The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans. We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEε4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group. The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau.

  13. Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases.

    PubMed

    Tumani, Hayrettin; Teunissen, Charlotte; Süssmuth, Sigurd; Otto, Markus; Ludolph, Albert C; Brettschneider, Johannes

    2008-07-01

    Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.

  14. GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice.

    PubMed

    Boyd, Tim D; Bennett, Steven P; Mori, Takashi; Governatori, Nicholas; Runfeldt, Melissa; Norden, Michelle; Padmanabhan, Jaya; Neame, Peter; Wefes, Inge; Sanchez-Ramos, Juan; Arendash, Gary W; Potter, Huntington

    2010-01-01

    Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer's disease (AD). While it has been commonly assumed that RA patients' usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. To determine whether intrinsic factors within RA pathogenesis itself may underlie RA's protective effect, we investigated the activity of colony-stimulating factors, upregulated in RA, on the pathology and behavior of transgenic AD mice. 5 microg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factors (M-CSF, G-CSF, or GM-CSF) were administered unilaterally into the hippocampus of aged cognitively-impaired AD mice and the resulting amyloid load reductions determined one week later, using the artificial cerebrospinal fluid-injected contralateral sides as controls. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. 20 daily subcutaneous injections of 5 microg of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) were administered to balanced cohorts of AD mice after assessment in a battery of cognitive tests. Reductions in amyloid load and improvements in cognitive function were assessed. Subcutaneous GM-CSF administration significantly reduced brain amyloidosis and completely reversed the cognitive impairment, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, recombinant human GMCSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.

  15. Crystallization of M-CSF.alpha.

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    1999-01-01

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor (M-CSF) and to a crystalline M-CSF produced thereby. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  16. Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease.

    PubMed

    Kauwe, John S K; Cruchaga, Carlos; Karch, Celeste M; Sadler, Brooke; Lee, Mo; Mayo, Kevin; Latu, Wayne; Su'a, Manti; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

    2011-02-09

    Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aβ(42)) and tau phosphorylated at threonine 181 (ptau(181)), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aβ(42) or ptau(181) levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aβ(42) or ptau(181).

  17. Adding Recognition Discriminability Index to the Delayed Recall Is Useful to Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative.

    PubMed

    Russo, María J; Campos, Jorge; Vázquez, Silvia; Sevlever, Gustavo; Allegri, Ricardo F

    2017-01-01

    Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Aβ1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (χ(2) = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI.

  18. Adding Recognition Discriminability Index to the Delayed Recall Is Useful to Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative

    PubMed Central

    Russo, María J.; Campos, Jorge; Vázquez, Silvia; Sevlever, Gustavo; Allegri, Ricardo F.; Weiner, Michael W.

    2017-01-01

    Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Aβ1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (χ2 = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI. PMID:28344552

  19. Diagnosis and biomarkers of predementia in Alzheimer's disease

    PubMed Central

    2010-01-01

    In view of the growing prevalence of Alzheimer's disease (AD) worldwide, there is an urgent need for the development of better diagnostic tools and more effective therapeutic interventions. At the earliest stages of AD, no significant cognitive or functional impairment is detected by conventional clinical methods. However, new technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid (CSF) may reveal correlates of intracerebral pathology in individuals with mild, predementia symptoms. These putative correlates are commonly referred to as AD-related biomarkers. The relevance of the early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Here we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and point out the challenges and perspectives for the translation of research data into clinical practice. PMID:21176189

  20. Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies

    PubMed Central

    Shalaby, Tarek; Grotzer, Michael A.

    2015-01-01

    Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations. PMID:26690130

  1. Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease

    PubMed Central

    Steinacker, Petra; Blennow, Kaj; Halbgebauer, Steffen; Shi, Song; Ruf, Viktoria; Oeckl, Patrick; Giese, Armin; Kuhle, Jens; Slivarichova, Dana; Zetterberg, Henrik; Otto, Markus

    2016-01-01

    While cerebrospinal fluid (CSF) biomarkers for Creutzfeldt-Jakob disease (CJD) are established and partly included in the diagnostic criteria, no blood biomarkers are available. Here, we assessed the utility of serum neurofilament light chain (NF-L) and tau protein in comparison to CSF markers (NF-L and phosphorylated NF heavy chain (pNF-H), tau, S100B, 14-3-3) and prion conversion assay (real-time quaking induced conversion (RT-QuIC)) for sporadic and genetic CJD. Importantly, a Gerstmann-Sträussler-Scheinker mutation carrier in the asymptomatic phase and at disease onset was included as well. Both NF-L and tau were markedly increased in CJD serum, reaching similar or even better performance as in CSF (sensitivity and specificity for serum NF-L 100% and 85.5%, and for serum tau 84.6% and 96.2%, respectively). Serum S100B showed high sensitivity as well (84.2%), but lower specificity (63%). CSF neurofilaments were increased before symptom onset, while prion seeding assay was negative. Just before a clinical diagnosis could be made, all CSF markers and NF-L in the serum were increased and CSF prion conversion assay was positive. The data suggest that neurofilaments are sensitive and specific blood markers for the diagnosis of genetic and sporadic CJD and might represent promising tools to predict disease onset. PMID:27929120

  2. Alzheimer's disease neuroimaging initiative: a one-year follow up study using tensor-based morphometry correlating degenerative rates, biomarkers and cognition.

    PubMed

    Leow, Alex D; Yanovsky, Igor; Parikshak, Neelroop; Hua, Xue; Lee, Suh; Toga, Arthur W; Jack, Clifford R; Bernstein, Matt A; Britson, Paula J; Gunter, Jeffrey L; Ward, Chadwick P; Borowski, Bret; Shaw, Leslie M; Trojanowski, John Q; Fleisher, Adam S; Harvey, Danielle; Kornak, John; Schuff, Norbert; Alexander, Gene E; Weiner, Michael W; Thompson, Paul M

    2009-04-15

    Tensor-based morphometry can recover three-dimensional longitudinal brain changes over time by nonlinearly registering baseline to follow-up MRI scans of the same subject. Here, we compared the anatomical distribution of longitudinal brain structural changes, over 12 months, using a subset of the ADNI dataset consisting of 20 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with mild cognitive impairment (MCI). Each individual longitudinal change map (Jacobian map) was created using an unbiased registration technique, and spatially normalized to a geometrically-centered average image based on healthy controls. Voxelwise statistical analyses revealed regional differences in atrophy rates, and these differences were correlated with clinical measures and biomarkers. Consistent with prior studies, we detected widespread cerebral atrophy in AD, and a more restricted atrophic pattern in MCI. In MCI, temporal lobe atrophy rates were correlated with changes in mini-mental state exam (MMSE) scores, clinical dementia rating (CDR), and logical/verbal learning memory scores. In AD, temporal atrophy rates were correlated with several biomarker indices, including a higher CSF level of p-tau protein, and a greater CSF tau/beta amyloid 1-42 (ABeta42) ratio. Temporal lobe atrophy was significantly faster in MCI subjects who converted to AD than in non-converters. Serial MRI scans can therefore be analyzed with nonlinear image registration to relate ongoing neurodegeneration to a variety of pathological biomarkers, cognitive changes, and conversion from MCI to AD, tracking disease progression in 3-dimensional detail.

  3. Pathological Fingerprints, Systems Biology and Biomarkers of Blast Brain Injury

    DTIC Science & Technology

    2010-06-01

    stressors,including sheqar stress and blast wave. sICAM was measured in CSF and serum using SW ELISA and significantly accumulated in CSF and serum 24...metalloproteinases after different forms of blast. MMPs were measured using Quantibody arrays (Ray Biotech) and expressed as % of sham values (set as 100 %). Data...Neuron-Glia cell damage pathways. We measured CSF and serum levels of GFAP and UCHL-1, biomarkers of glia and neuron activation, respectively, after

  4. CSF alpha-synuclein levels in dementia with Lewy bodies and Alzheimer's disease.

    PubMed

    Noguchi-Shinohara, Moeko; Tokuda, Takahiko; Yoshita, Mitsuhiro; Kasai, Takashi; Ono, Kenjiro; Nakagawa, Masanori; El-Agnaf, Omar M A; Yamada, Masahito

    2009-01-28

    Dementia with Lewy bodies (DLB) is characterized by widespread depositions of alpha-synuclein, which are described as Lewy bodies. Recently, it was shown that neuronal cells in culture constitutively release alpha-synuclein into the culture medium and that alpha-synuclein is normally present in human cerebrospinal fluid (CSF). The aim of the present study was to evaluate the diagnostic value of CSF alpha-synuclein levels in discriminating DLB from Alzheimer's disease (AD). Alpha-synuclein was measured in CSF from 16 patients with DLB and 21 patients with AD. Iodine-123 metaiodobenzylguanidine cardiac scintigraphy was also performed to assess Lewy body pathology. CSF alpha-synuclein levels did not differ significantly between DLB and AD patients. However, the duration of illness was associated with lower alpha-synuclein levels (p<0.05) in DLB, while no such association was found in AD. The present data show CSF alpha-synuclein levels are not sensitive diagnostic markers to discriminate DLB from AD. However, the lower alpha-synuclein levels in DLB patients with longer duration suggest a reduction in CSF alpha-synuclein in association with increased severity of alpha-synucleinopathy in the brain.

  5. Oligomeric α-synuclein and β-amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases.

    PubMed

    Williams, Stephanie M; Schulz, Philip; Sierks, Michael R

    2016-01-01

    Oligomeric forms of α-synuclein and β-amyloid are toxic protein variants that are thought to contribute to the onset and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. The detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise for facilitating early and accurate diagnoses of these devastating diseases. Two hurdles that have impeded the use of these protein variants as biomarkers are the availability of reagents that can bind the different variants and a sensitive assay to detect their very low concentrations. We previously isolated antibody-based reagents that selectively bind two different oligomeric variants of α-synuclein and two of β-amyloid, and developed a phage-based capture enzyme-linked immunosorbent assay (ELISA) with subfemtomolar sensitivity to quantify their presence. Here, we used these reagents to show that these oligomeric α-synuclein variants are preferentially present in PD brain tissue, CSF and serum, and that the oligomeric β-amyloid variants are preferentially present in AD brain tissue, CSF, and serum. Some AD samples also had α-synuclein pathology and some PD samples also had β-amyloid pathology, and, very intriguingly, these PD cases also had a history of dementia. Detection of different oligomeric α-synuclein and β-amyloid species is an effective method for identifying tissue, CSF and sera from PD and AD samples, respectively, and samples that also contained early stages of other protein pathologies, indicating their potential value as blood-based biomarkers for neurodegenerative diseases.

  6. Reassessing cerebrospinal fluid (CSF) hydrodynamics: a literature review presenting a novel hypothesis for CSF physiology.

    PubMed

    Chikly, Bruno; Quaghebeur, Jörgen

    2013-07-01

    The traditional model of cerebrospinal fluid (CSF) hydrodynamics is being increasingly challenged in view of recent scientific evidences. The established model presumes that CSF is primarily produced in the choroid plexuses (CP), then flows from the ventricles to the subarachnoid spaces, and is mainly reabsorbed into arachnoid villi (AV). This model is seemingly based on faulty research and misinterpretations. This literature review presents numerous evidence for a new hypothesis of CSF physiology, namely, CSF is produced and reabsorbed throughout the entire CSF-Interstitial fluid (IF) functional unit. IF and CSF are mainly formed and reabsorbed across the walls of CNS blood capillaries. CP, AV and lymphatics become minor sites for CSF hydrodynamics. The lymphatics may play a more significant role in CSF absorption when CSF-IF pressure increases. The consequences of this complete reformulation of CSF hydrodynamics may influence applications in research, publications, including osteopathic manual treatments.

  7. γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ.

    PubMed

    Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R; Rose, Gregory M; Cai, Huaibin; Struble, Robert G; Cai, Yan; Yan, Xiao-Xin

    2013-05-01

    Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD.

  8. The Combined Performance of ADC, CSF CXCL-13, and CSF IL-10 in the Diagnosis of Central Nervous System Lymphoma

    PubMed Central

    Mabray, Marc C.; Barajas, Ramon F.; Villanueva-Meyer, Javier E.; Zhang, Chiyuan A.; Valles, Francisco E.; Rubenstein, James L.; Cha, Soonmee

    2015-01-01

    Background and Purpose CXC chemokine ligand 13 (CXCL-13) and interleukin 10 (IL-10) have emerged as CSF biomarkers for the diagnosis of CNS Lymphoma (CNSL). Our hypothesis is that the combined use of ADC, CXCL-13, and IL-10 will result in increased diagnostic performance as compared to the use of ADC values alone. Materials and Methods 87 patients were included in this HIPAA and IRB compliant study including 43 with CNSL and 44 without CNSL (21 metastases, 14 high-grade gliomas, 9 tumefactive demyelinating lesions) who had undergone CSF proteomic analysis and had a new enhancing mass on brain MRI. Average ADC (ADCavg) was derived by contouring the contrast enhancing tumor volume. Group means were compared via t-tests for ADCavg, CXCL-13, and IL-10. Receiver operating characteristic (ROC) analysis was performed for each individual variable. Multiple variable logistic regression with ROC was performed and the multiple variable ROC was compared to single variable ROCs. Results ADCavg was lower and CSF CXCL-13 and IL-10 values higher in CNSL (p<0.001). Areas under the curve (AUC) ranged from 0.739-0.832 for single variable ROC. Multiple variable logistic regression yielded statistically significant individual effects for all three variables in a combined model. Multiple variable ROC (AUC 0.928) demonstrated statistically significantly superior diagnostic performance as compared to the use of single variables alone. Conclusion The combined use of ADC, CSF CXCL-13, and IL-10 results in increased diagnostic performance for the diagnosis of CNSL. This highlights the importance of CSF analysis when the diagnosis of CNSL is considered based on MRI. PMID:26381553

  9. Ischemic cardiac complications following G-CSF.

    PubMed

    Eckman, Peter M; Bertog, Stefan C; Wilson, Robert F; Henry, Timothy D

    2010-07-01

    Granulocyte-colony stimulating factor (G-CSF) is commonly used in bone marrow transplant donors to increase the number of circulating progenitor cells. G-CSF has also been studied following myocardial infarction, but concern has been raised about the risks of G-CSF administration in patients with coronary artery disease. We present two cases of ischemic cardiac complications that are likely to be related to administration of G-CSF and provide a contemporary overview of the literature on the cardiovascular risks of G-CSF.

  10. Distinct cerebral perfusion patterns in FTLD and AD

    PubMed Central

    Hu, W.T.; Wang, Z.; Lee, V.M.-Y.; Trojanowski, J.Q.; Detre, J.A.; Grossman, M.

    2010-01-01

    Objective: We examined the utility of distinguishing between patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) using quantitative cerebral blood flow (CBF) imaging with arterial spin labeled (ASL) perfusion MRI. Methods: Forty-two patients with FTLD and 18 patients with AD, defined by autopsy or CSF-derived biomarkers for AD, and 23 matched controls were imaged with a continuous ASL method to quantify CBF maps covering the entire brain. Results: Patients with FTLD and AD showed distinct patterns of hypoperfusion and hyperperfusion. Compared with controls, patients with FTLD showed significant hypoperfusion in regions of the frontal lobe bilaterally, and hyperperfusion in posterior cingulate and medial parietal/precuneus regions. Compared with controls, patients with AD showed significant hypoperfusion in the medial parietal/precuneus and lateral parietal cortex, and hyperperfusion in regions of the frontal lobe. Direct comparison of patient groups showed significant inferior, medial, and dorsolateral frontal hypoperfusion in FTLD, and significant hypoperfusion in bilateral lateral temporal-parietal and medial parietal/precuneus regions in AD. Conclusions: Doubly dissociated areas of hypoperfusion in FTLD and AD are consistent with areas of significant histopathologic burden in these groups. ASL is a potentially useful biomarker for distinguishing patients with these neurodegenerative diseases. GLOSSARY Aβ42 = β-amyloid1-42; AD = Alzheimer disease; ASL = arterial spin labeling; bvFTD = behavioral-variant frontotemporal dementia; cASL = continuous arterial spin labeling; CBS = corticobasal syndrome; CBF = cerebral blood flow; dACC = dorsal anterior cingulate cortex; dlPFC = dorsolateral prefrontal cortex; FDR = false detection rate; FTLD = frontotemporal lobar degeneration; GM = gray matter; iFC = inferior frontal cortex; MCI = mild cognitive impairment; MNI = Montreal Neurological Institute; mTC = middle temporal cortex; OFC

  11. The added value of biomarker analysis to the genesis of plaggic Anthrosols; the identification of stable fillings used for the production of plaggic manure

    NASA Astrophysics Data System (ADS)

    van Mourik, Jan M.; Wagner, Thomas V.; Geert de Boer, J.; Jansen, Boris

    2016-07-01

    Plaggic Anthrosols are the result of historical forms of land management in cultural landscapes on chemically poor sandy substrates. Application of plaggic manure was responsible for the development of the plaggic horizons of these agricultural soils. Pollen diagrams reflect aspects of the environmental development but the interpretation of the pollen spectra is complicated due to the mix of the aeolian pollen influx of crop species and species in the surroundings, and of pollen occurring in the used stable fillings. Pollen diagrams and radiocarbon dates of plaggic Anthrosols suggested a development period of more than a millennium. Calluna is present in almost all the pollen spectra, indicating the presence of heath in the landscape during the whole period of soil development. Optically stimulated luminescence dating of the plaggic horizon made clear that the deposition of plaggic covers started in the 16th century and accelerated in the 18th century. The stable fillings, used for the production of plaggic manure and responsible for the rise of the soil surface, cannot be identified with pollen diagrams alone. Biomarker analyses provide more evidence about the sources of stable fillings. The oldest biomarker spectra of the plaggic horizons of three typical plaggic Anthrosols examined in this study were dominated by biomarkers of forest species such as Quercus and Betula while the spectra of middle part of the plaggic horizons were dominated by biomarkers of stem tissue of crop species such as Secale and Avena. Only the youngest spectra of the plaggic horizons were dominated by biomarkers of Calluna. This indicates that the use of heath sods as stable filling was most likely introduced very late in the development of the Anthrosols. Before the 19th century the mineral component in plaggic manure cannot be explained by the use of heath sods. We conclude that other sources of materials, containing mineral grains must have been responsible for the raise of the plaggic

  12. The added value of biomarker analysis to the genesis of Plaggic Anthrosols; the identification of stable fillings used for the production of plaggic manure.

    NASA Astrophysics Data System (ADS)

    van Mourik, Jan; Wagner, Thomas; de Boer, Geert; Jansen, Boris

    2016-04-01

    Plaggic Anthrosols are the result of historical forms of land management in cultural landscapes on chemically poor sandy substrates. Application of plaggic manure was responsible for the development of the plaggic horizons of these agricultural soils. Pollen diagrams reflect aspects of the environmental development but the interpretation of the pollen spectra is complicated due to the mix of the aeolian pollen influx of crop species and species in the surroundings, and of pollen occurring in the used stable fillings. Pollen diagrams and radiocarbon dates of plaggic Anthrosols suggested a development period of more than a millennium. Calluna is present in almost all the pollen spectra, indicating the presence of heath in the landscape during the whole period of soil development. Optically stimulated luminescence dating of the plaggic horizon made clear that the deposition of plaggic covers started in the 16th century and accelerated in the 18th century. The stable fillings, used for the production of plaggic manure and responsible for the rise of the soil surface, cannot be identified with pollen diagrams alone. Biomarker analyses provide more evidence about the sources of stable fillings. The oldest biomarker spectra of the plaggic horizons of three typical plaggic Anthrosols examined in this study, were dominated by biomarkers of forests species as Quercus and Betula while the spectra of middle part of the plaggic horizons were dominated by biomarkers of stem tissue of crop species as Secale and Avena. Only the youngest spectra of the plaggic horizons were dominated by biomarkers of Calluna. This indicates that the use of heath sods as stable filling was most likely introduced late in the development of the Anthrosols. Before the 18th century the mineral component in plaggic manure cannot be explained by the use of (dry) heath sods. We conclude that other sources of materials, containing mineral grains must have been responsible for the raise of the plaggic

  13. Biomarkers in dementia: clinical utility and new directions

    PubMed Central

    Ahmed, R M; Paterson, R W; Warren, J D; Zetterberg, H; O'Brien, J T; Fox, N C; Halliday, G M; Schott, J M

    2014-01-01

    Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic. PMID:25261571

  14. Amyloid-β Peptides and Tau Protein as Biomarkers in Cerebrospinal and Interstitial Fluid Following Traumatic Brain Injury: A Review of Experimental and Clinical Studies

    PubMed Central

    Tsitsopoulos, Parmenion P.; Marklund, Niklas

    2013-01-01

    Traumatic brain injury (TBI) survivors frequently suffer from life-long deficits in cognitive functions and a reduced quality of life. Axonal injury, observed in many severe TBI patients, results in accumulation of amyloid precursor protein (APP). Post-injury enzymatic cleavage of APP can generate amyloid-β (Aβ) peptides, a hallmark finding in Alzheimer’s disease (AD). At autopsy, brains of AD and a subset of TBI victims display some similarities including accumulation of Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins. Most epidemiological evidence suggests a link between TBI and AD, implying that TBI has neurodegenerative sequelae. Aβ peptides and tau may be used as biomarkers in interstitial fluid (ISF) using cerebral microdialysis and/or cerebrospinal fluid (CSF) following clinical TBI. In the present review, the available clinical and experimental literature on Aβ peptides and tau as potential biomarkers following TBI is comprehensively analyzed. Elevated CSF and ISF tau protein levels have been observed following severe TBI and suggested to correlate with clinical outcome. Although Aβ peptides are produced by normal neuronal metabolism, high levels of long and/or fibrillary Aβ peptides may be neurotoxic. Increased CSF and/or ISF Aβ levels post-injury may be related to neuronal activity and/or the presence of axonal injury. The heterogeneity of animal models, clinical cohorts, analytical techniques, and the complexity of TBI in the available studies make the clinical value of tau and Aβ as biomarkers uncertain at present. Additionally, the link between early post-injury changes in tau and Aβ peptides and the future risk of developing AD remains unclear. Future studies using methods such as rapid biomarker sampling combined with enhanced analytical techniques and/or novel pharmacological tools could provide additional information on the importance of Aβ peptides and tau protein in both the acute pathophysiology and long

  15. A Surgical Method to Improve the Homeostasis of CSF for the Treatment of Alzheimer’s Disease

    PubMed Central

    Qin, Yang; Gu, Jian W.

    2016-01-01

    Reduced cerebrospinal fluid (CSF) production and increased resistance to CSF outflow are considered to be associated with aging, and are also characteristics of Alzheimer’s disease (AD). These changes probably result in a decrease in the efficiency of the mechanism by which CSF removes toxic molecules such as amyloid-β (Aβ) and tau from the interstitial fluid space. Soluble Aβ is potently neurotoxic and dysfunctional in CSF circulation and can accelerate the progression of AD. Current therapies for AD exhibit poor efficiency; therefore, a surgical method to improve the homeostasis of CSF is worthy of investigation. To achieve this, we conceived a novel device, which consists of a ventriculo-peritoneal shunt, an injection port and a portable infusion pump. Artificial CSF (ACSF) is pumped into the ventricles and the ACSF composition, infusion modes and pressure threshold of shunting can be adjusted according to the intracranial pressure and CSF contents. We hypothesize that this active treatment for CSF circulation dysfunction will significantly retard the progression of AD. PMID:27853433

  16. Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

    PubMed Central

    Malone, James P.; Shah, Aarti R.; Gilmore, Petra; Davis, Alan E.; Roe, Catherine M.; Peskind, Elaine R.; Li, Ge; Galasko, Douglas R.; Clark, Christopher M.; Quinn, Joseph F.; Kaye, Jeffrey A.; Morris, John C.; Holtzman, David M.; Townsend, R. Reid; Fagan, Anne M.

    2011-01-01

    Background Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the ‘preclinical’ stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome. Methods and Findings CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85–0.94 95% confidence interval [CI]) and 0.88 (0.81–0.94 CI), respectively. Conclusions Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel

  17. Qualification opinion of novel methodologies in the predementia stage of Alzheimer's disease: cerebro-spinal-fluid related biomarkers for drugs affecting amyloid burden--regulatory considerations by European Medicines Agency focusing in improving benefit/risk in regulatory trials.

    PubMed

    Isaac, Maria; Vamvakas, Spiros; Abadie, Eric; Jonsson, Bertil; Gispen, Christine; Pani, Luca

    2011-11-01

    The European Medicines Agency (EMA) in London is responsible for the Regulatory review of new medicinal products for Marketing Authorisation, through which pharmaceutical companies may obtain first Marketing Authorisation and subsequent Variations valid throughout the EU and EFTA. The qualification opinion of novel methodologies is a new procedure where applicants can obtain scientific advice on new methodologies for regulatory clinical trials of efficacy of new compounds. It will help benefit/risk assessment of the CHMP. The definition of prodromal AD is acceptable. The "Dubois Criteria" as criteria to define the population must be validated in full at the time of the submission of the dossiers. Including a positive CSF biomarker profile is considered predictive for the evaluation of the AD-dementia type. However, although high CSF tau and low CSF Aβ42 are predictive of Alzheimer's disease, the criterion "positive CSF tau/Aβ42 ratio" is not well defined. The qualification of biomarkers in the pre-dementia stage of Alzheimer's disease will allow better inclusion criteria of patients in pre-dementia trials in which the benefit/risk is higher for treatment with these novel compounds.

  18. Biomarkers for neuromyelitis optica.

    PubMed

    Chang, Kuo-Hsuan; Ro, Long-Sun; Lyu, Rong-Kuo; Chen, Chiung-Mei

    2015-02-02

    Neuromyelitis optica (NMO) is an acquired, heterogeneous inflammatory disorder, which is characterized by recurrent optic neuritis and longitudinally extensive spinal cord lesions. The discovery of the serum autoantibody marker, anti-aquaporin 4 (anti-AQP4) antibody, revolutionizes our understanding of pathogenesis of NMO. In addition to anti-AQP4 antibody, other biomarkers for NMO are also reported. These candidate biomarkers are particularly involved in T helper (Th)17 and astrocytic damages, which play a critical role in the development of NMO lesions. Among them, IL-6 in the peripheral blood is associated with anti-AQP4 antibody production. Glial fibrillary acidic protein (GFAP) in CSF demonstrates good correlations with clinical severity of NMO relapses. Detecting these useful biomarkers may be useful in the diagnosis and evaluation of disease activity of NMO. Development of compounds targeting these biomarkers may provide novel therapeutic strategies for NMO. This article will review the related biomarker studies in NMO and discuss the potential therapeutics targeting these biomarkers.

  19. CSF hydrodynamic studies in man. 2 . Normal hydrodynamic variables related to CSF pressure and flow.

    PubMed Central

    Ekstedt, J

    1978-01-01

    With the patient in the supine position, the subarachnoidal space was infused with artificial CSF at several constant pressure levels. The resulting flow of liquid was recorded. By draining CSF at a low pressure the CSF production rate was determined. Normal values are given and discussed for (1) the resting pressure, (2) the conductance of the CSF outflow pathways, (3) the formation rate of CSF, (4) the pressure difference across the CSF outflow pathways, and (5) the sagittal sinus pressure. None of the variables showed any age dependence, nor was there any sex difference. PMID:650242

  20. P50: A candidate ERP biomarker of prodromal Alzheimer’s disease

    PubMed Central

    Payne, Lisa; Polikar, Robi; Moberg, Paul J.; Wolk, David A.; Kounios, John

    2015-01-01

    INTRODUCTION Reductions of cerebrospinal fluid (CSF) amyloid-beta (Aβ42) and elevated phosphorylated-tau (p-Tau) reflect in vivo Alzheimer’s disease (AD) pathology and show utility in predicting conversion from mild cognitive impairment (MCI) to dementia. We investigated the P50 event-related potential component as a noninvasive biomarker of AD pathology in non-demented elderly. METHODS 36 MCI patients were stratified into amyloid positive (MCI-AD, n=17) and negative (MCI-Other, n=19) groups using CSF levels of Aβ42. All amyloid positive patients were also p-Tau positive. P50s were elicited with an auditory oddball paradigm. RESULTS MCI-AD patients yielded larger P50s than MCI-Other. The best amyloid-status predictor model showed 94.7% sensitivity, 94.1% specificity and 94.4% total accuracy. DISCUSSION P50 predicted amyloid status in MCI patients, thereby showing a relationship with AD pathology versus MCI from another etiology. The P50 may have clinical utility for inexpensive pre-screening and assessment of Alzheimer’s pathology. PMID:26256251

  1. Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment.

    PubMed

    Malpas, Charles B; Saling, Michael M; Velakoulis, Dennis; Desmond, Patricia; O'Brien, Terence J

    2015-01-01

    Alzheimer's disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials.

  2. Current application of neurochemical biomarkers in the prediction and differential diagnosis of Alzheimer's disease and other neurodegenerative dementias.

    PubMed

    Genius, J; Klafki, H; Benninghoff, J; Esselmann, H; Wiltfang, J

    2012-11-01

    In light of the dramatically increasing prevalence of Alzheimer's disease (AD) to be expected in the future, the development of novel therapeutics, improved differential and early diagnostics, and means for the identification of individuals at risk are urgently needed. At present, instruments for a reliable differential diagnosis in clinical dementia, mild cognitive impairment, or prodromal stages have direct practical implications for differentiating secondary dementias from neurodegenerative conditions and for treatment decisions. It may also be reasonable to enforce the incorporation of biomarkers into clinical studies as surrogate outcome parameters and as an attempt to optimize recruitment criteria. Recently, revised research criteria increasingly rely on the interpretation of biomarker patterns, including neuroimaging and CSF-based neurochemical dementia diagnosis (NDD) in supporting the clinical diagnosis. Here, we review the performance of current core CSF biomarkers (Aβ(42) peptide, total tau protein and phosphorylated tau species) and try to define objectives for prospective markers, also considering blood-based tests, which would increase the acceptance and wide application of NDD. Moreover, we evaluate the role and the limitations of genotyping in the predictive diagnosis of AD.

  3. The PREVENT study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease

    PubMed Central

    Ritchie, Craig W; Ritchie, Karen

    2012-01-01

    Introduction Epidemiological studies indicate that significant decreases in the incidence of Alzheimer's disease (AD) may be obtained by targeting multiple middle-age risk factors. However, as dementia is unlikely to be diagnosed for decades, short-term outcome measures are required. AD biomarker changes precede clinical symptoms by many years, but their sensitivity to mid-life change remains unknown. Methods and analysis PREVENT is a prospective cohort study examining biomarker status at mid-life in at least 150 individuals genetically at high, medium or low risk of late-onset AD. Participants are children of individuals with or without a diagnosed AD allocated to high, medium and low-risk groups according to parental clinical status and ApoE genotype. The biomarkers examined over 2 years are plasma and CSF Aβ42 amyloid, Tau and pTau, proinflammatory cytokines, acute-phase proteins, medial temporal-lobe atrophy, white matter lesion volume, cognitive performance related to transentorhinal and hippocampal functioning and hypothalamic−pituitary−adrenal and sympathetic axes regulation. Ethics and dissemination Detected pathologies are communicated to the participant's general practitioner with their permission. Risk status by genotype would not be revealed. The results of the study would be published in peer-reviewed journals and validated biomarkers used to construct a randomised controlled intervention study. PMID:23166135

  4. The interaction between sleep-disordered breathing and ApoE genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly

    PubMed Central

    Osorio, Ricardo S.; Ayappa, Indu; Mantua, Janna; Gumb, Tyler; Varga, Andrew; Mooney, Anne M.; Burschtin, Omar E.; Taxin, Zachary; During, Emmanuel; Spector, Nicole; Biagioni, Milton; Pirraglia, Elizabeth; Lau, Hiuyan; Zetterberg, Henrik; Blennow, Kaj; Lu, Shou-En; Mosconi, Lisa; Glodzik, Lidia; Rapoport, David M.; de Leon, Mony J.

    2014-01-01

    Background Previous studies have suggested a link between Sleep Disordered Breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers, and the ApoE alleles. Methods 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (P-Tau), total-tau (T-Tau), and amyloid beta 42 (Aβ42), as well as ApoE allele status. Findings In ApoE3+ subjects, significant differences were found between sleep groups for P-Tau (F[df2]=4.3, p=0.017), and T-Tau (F[df2]=3.3, p=0.043). Additionally, among ApoE3+ subjects, the apnea/hypopnea with 4% O2-desaturation index (AHI4%) was positively correlated with P-Tau (r=0.30, p=0.023), T-Tau (r=0.31, p=0.021), and Aβ42 (r=0.31, p=0.021). In ApoE2+ subjects, AHI4% was correlated with lower levels of CSF Aβ42 (r=−0.71, p=0.004), similarly to ApoE4+ subjects where there was also a trend towards lower CSF Aβ42 levels Interpretation Our observations suggest that there is an association between SDB and CSF AD- biomarkers in cognitively normal elderly. Existing therapies for SDB such as CPAP could delay the onset to mild cognitive impairment or dementia in normal elderly. PMID:24439479

  5. Immune blood biomarkers of Alzheimer disease patients.

    PubMed

    Avagyan, Hripsime; Goldenson, Ben; Tse, Eric; Masoumi, Ava; Porter, Verna; Wiedau-Pazos, Martina; Sayre, James; Ong, Reno; Mahanian, Michelle; Koo, Patrick; Bae, Susan; Micic, Miodrag; Liu, Philip T; Rosenthal, Mark J; Fiala, Milan

    2009-05-29

    Alzheimer disease (AD) patients have an impairment of anti-amyloid-beta (Abeta) innate immunity and a defect in immune gene transcription [Fiala, M., Liu, P.T., Espinosa-Jeffrey, A., Rosenthal, M.J., Bernard, G., Ringman, J.M., Sayre, J., Zhang, L., Zaghi, J., Dejbakhsh, S., Chiang, B., Hui, J., Mahanian, M., Baghaee, A., Hong, P., Cashman, J., 2007b. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proc. Natl. Acad. Sci. U. S. A. 104, 12849-12854]. Early diagnosis is a cornerstone of preventive approaches to AD. Phospho-tau and Abeta CSF levels are useful markers of neurodegeneration but not of a process leading to neurodegeneration. To detect an early biomarker of AD, we developed a flow cytometric test of Abeta phagocytosis, which was 94% positive (<400 MFI units) in AD patients (mean age+/-SEM 77+2.2 years; mean score+/-SEM 198.6+/-25.5 MFI units) and 60% positive in MCI patients (77+/-5.6 years; 301+/-106 MFI units). Control subjects, active senior university professors, were 100% negative (74.2+/-4.2 years; 1348+/-174 MFI units). The test had a low specificity in older caregivers and older amyotrophic lateral sclerosis (ALS) patients. We also tested transcriptional regulation of the genes MGAT-III and Toll-like receptor-3 in macrophages. Macrophages of "Type I" patients (a majority of patients) showed gene down regulation at baseline and up regulation by curcuminoids; macrophages of "Type II" patients showed opposite responses. The results of flow cytometric testing suggest that normal Abeta phagocytosis is associated with healthy cognition and lesser risk of AD. The significance of abnormal results in aged persons should be investigated by prospective studies to determine the risk of AD.

  6. Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis

    PubMed Central

    2013-01-01

    Background Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease. Results Quantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia. Conclusion Elevated CHIT-1 levels in the ALS-CSF suggest a definitive role for the enzyme in the disease pathogenesis. Its synthesis and release from microglia into the CSF may be an aligned event of neurodegeneration. Thus, high levels of CHIT-1 signify enhanced microglial activity which may exacerbate the process of neurodegeneration. In view of the multifold increase observed in ALS-CSF, it can serve as a potential CSF biomarker for the diagnosis of SALS. PMID:24295388

  7. Elevation of CSF albumin in old sheep: relations to CSF turnover and albumin extraction at blood-CSF barrier.

    PubMed

    Chen, Ruo-Li; Chen, Carl Pai-Chu; Preston, Jane Elizabeth

    2010-06-01

    Albumin is the most abundant protein in both CSF and plasma, and albumin quotient is often used to assess the functions of brain barriers especially that of the blood-CSF barrier [i.e. the choroid plexus (CP) which also secretes CSF]. In this study, we took albumin as a model molecule to investigate ageing-related alterations in the CSF-CP system in sheep. We found significant ageing-related increases in the weight of lateral CP [122.4 +/- 14.0 mg in the young, 198.6 +/- 35.4 mg in the middle aged, 286.1 +/- 25.1 mg in the old (p < 0.05)], in the CSF albumin as well as the albumin quotient. Albumin protein spots in old CSF displayed wider on 2D western immunoblotting images, and had higher densities on images of 2D large gels stained with Pro-Q Emerald 488 compared to the young samples, suggesting ageing-related post-translational modification in the albumin. CSF secretion was reduced with age: 0.148 +/- 0.013 mL/min/g in the young, 0.092 +/- 0.02 mL/min/g in the middle aged, 0.070 +/- 0.013 mL/min/g in the old (p < 0.05). The (125)I-BSA extraction was not different among the sheep groups, nor was altered by temperature reduction, monensin, nocodazole, anti-transforming growth factor beta receptor II antibody, as well as unlabelled albumins. In conclusion, elevation of albumin in old CSF is associated with reduced CSF secretion by the CP, which size increases with age. (125)I-BSA extract, reflecting the extracellular space rather than the active albumin uptake in the CP, is not different between ages. These early changes in health ageing may result in the accumulation and modifications of CSF proteins leading to neurotoxicity.

  8. CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer's disease

    PubMed Central

    Remnestål, Julia; Just, David; Mitsios, Nicholas; Fredolini, Claudia; Mulder, Jan; Schwenk, Jochen M; Uhlén, Mathias; Kultima, Kim; Ingelsson, Martin; Kilander, Lena; Lannfelt, Lars; Svenningsson, Per; Nellgård, Bengt; Zetterberg, Henrik; Blennow, Kaj; Häggmark‐Månberg, Anna

    2016-01-01

    1 Purpose This study is part of a larger effort aiming to expand the knowledge of brain‐enriched proteins in human cerebrospinal fluid (CSF) and to provide novel insight into the relation between such proteins and different neurodegenerative diseases. 2 Experimental design Here 280 brain‐enriched proteins in CSF from patients with Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are profiled. In total, 441 human samples of ventricular CSF collected post mortem and lumbar CSF collected ante mortem are analyzed using 376 antibodies in a suspension bead array setup, utilizing a direct labelling approach. 3 Results Among several proteins displaying differentiated profiles between sample groups, we focus here on two synaptic proteins, neuromodulin (GAP43) and neurogranin (NRGN). They are both found at elevated levels in CSF from AD patients in two independent cohorts, providing disease‐associated profiles in addition to verifying and strengthening previously observed patterns. Increased levels are also observed for patients for whom the AD diagnosis was not established at the time of sampling. 4 Conclusions and clinical relevance These findings indicate that analyzing the brain‐enriched proteins in CSF is of particular interest to increase the understanding of the CSF proteome and its relation to neurodegenerative disorders. In addition, this study lends support to the notion that measurements of these synaptic proteins could potentially be of great relevance in future diagnostic tests for AD. PMID:27604409

  9. Utility of CSF in translational neuroscience.

    PubMed

    de Lange, Elizabeth C M

    2013-06-01

    Human cerebrospinal fluid (CSF) sampling is of high value as the only general applicable methodology to obtain information on free drug concentrations in individual human brain. As the ultimate interest is in the free drug concentration at the CNS target site, the question is what CSF concentrations may tell us in that respect. Studies have been performed in rats and other animals for which concentrations in brain extracellular fluid (brain ECF) as a target site for many drugs, have been compared to (cisterna magna) CSF concentrations, at presumed steady state conditions,. The data indicated that CSF drug concentrations provided a rather good indication of, but not a reliable measure for predicting brain ECF concentrations. Furthermore, comparing rat with human CSF concentrations, human CSF concentrations tend to be higher and display much more variability. However, this comparison of CSF concentrations cannot be a direct one, as humans probably had a disease for which CSF was collected in the first place, while the rats were healthy. In order to be able to more accurately predict human brain ECF concentrations, understanding of the complexity of the CNS in terms of intrabrain pharmacokinetic relationships and the influence of CNS disorders on brain pharmacokinetics needs to be increased. This can be achieved by expanding a currently existing preclinically derived physiologically based pharmacokinetic model for brain distribution. This model has been shown to successfully predict data obtained for human lumbar CSF concentrations of acetaminophen which renders trust in the model prediction of human brain ECF concentrations. This model should further evolute by inclusion of influences of drug properties, fluid flows, transporter functionalities and different disease conditions. Finally the model should include measures of target site engagement and CNS effects, to ultimately learn about concentrations that best predict particular target site concentrations, via human

  10. In-depth Characterization of the Cerebrospinal Fluid (CSF) Proteome Displayed Through the CSF Proteome Resource (CSF-PR)*

    PubMed Central

    Guldbrandsen, Astrid; Vethe, Heidrun; Farag, Yehia; Oveland, Eystein; Garberg, Hilde; Berle, Magnus; Myhr, Kjell-Morten; Opsahl, Jill A.; Barsnes, Harald; Berven, Frode S.

    2014-01-01

    In this study, the human cerebrospinal fluid (CSF) proteome was mapped using three different strategies prior to Orbitrap LC-MS/MS analysis: SDS-PAGE and mixed mode reversed phase-anion exchange for mapping the global CSF proteome, and hydrazide-based glycopeptide capture for mapping glycopeptides. A maximal protein set of 3081 proteins (28,811 peptide sequences) was identified, of which 520 were identified as glycoproteins from the glycopeptide enrichment strategy, including 1121 glycopeptides and their glycosylation sites. To our knowledge, this is the largest number of identified proteins and glycopeptides reported for CSF, including 417 glycosylation sites not previously reported. From parallel plasma samples, we identified 1050 proteins (9739 peptide sequences). An overlap of 877 proteins was found between the two body fluids, whereas 2204 proteins were identified only in CSF and 173 only in plasma. All mapping results are freely available via the new CSF Proteome Resource (http://probe.uib.no/csf-pr), which can be used to navigate the CSF proteome and help guide the selection of signature peptides in targeted quantitative proteomics. PMID:25038066

  11. Lower CSF Aβ is Associated with HAND in HIV-Infected Adults with a Family History of Dementia

    PubMed Central

    Fazeli, Pariya. L.; Moore, David J.; Franklin, Donald R.; Umlauf, Anya; Heaton, Robert K.; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; Sacktor, Ned C.; Morgello, Susan; Simpson, David M.; McCutchan, John A.; Grant, Igor; Letendre, Scott L.

    2015-01-01

    Background Both family history of dementia (FHD) and lower levels of Aβ-42 are indepentently associated with worse neurocognitive functioning in HIV-infected patients. Objective To examine the relationships between cerebrospinal fluid (CSF) Aβ-42 and FHD with HIV-associated neurocognitive disorders (HAND). Methods One hundred eighty-three HIV+ adults underwent neuropsychological and neuromedical assessments, and determination of CSF Aβ-42 concentration and FHD (defined as a self-reported first or second-degree relative with a dementia diagnosis). Univariate analyses and multivariable logistic regressions were used. Results FHD was not associated with HAND (p = 0.24); however, CSF Aβ-42 levels were lower (p = 0.03) in the HAND group, but were not associated with FHD (p = 0.89). Multivariable models showed a main effect of CSF Aβ-42 (p = 0.03) and a trend-level (p = 0.06) interaction between FHD and CSF Aβ-42, such that lower CSF Aβ-42 was associated with HAND in those with FHD (p < 0.01) compared to those without FHD (p = 0.83). An analysis in those with follow-up data showed that higher baseline CSF Aβ-42 was associated with lower risk of neurocognitive decline (p = 0.02). While we did not find an FHD X CSF Aβ-42 interaction (p = 0.83), when analyses were stratified by FHD, lower CSF Aβ-42 was associated at the trend-level with neurocognitive decline in the FHD group (p = 0.08) compared to the no FHD group (p = 0.15). Conclusions FHD moderates the relationship between of CSF Aβ-42 and HAND. The findings highlight the complexities in interpreting the relationships between biomarkers of age-related neurodegeneration and HAND. PMID:26673902

  12. The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function.

    PubMed

    Overgaard, Christian E; Schlingmann, Barbara; Dorsainvil White, StevenClaude; Ward, Christina; Fan, Xian; Swarnakar, Snehasikta; Brown, Lou Ann S; Guidot, David M; Koval, Michael

    2015-06-15

    Lung barrier dysfunction is a cardinal feature of the acute respiratory distress syndrome (ARDS). Alcohol abuse, which increases the risk of ARDS two- to fourfold, induces transforming growth factor (TGF)-β1, which increases epithelial permeability and impairs granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent barrier integrity in experimental models. We hypothesized that the relative balance of GM-CSF and TGF-β1 signaling regulates lung epithelial barrier function. GM-CSF and TGF-β1 were tested separately and simultaneously for their effects on lung epithelial cell barrier function in vitro. TGF-β1 alone caused an ∼ 25% decrease in transepithelial resistance (TER), increased paracellular flux, and was associated with projections perpendicular to tight junctions ("spikes") containing claudin-18 that colocalized with F-actin. In contrast, GM-CSF treatment induced an ∼ 20% increase in TER, decreased paracellular flux, and showed decreased colocalization of spike-associated claudin-18 with F-actin. When simultaneously administered to lung epithelial cells, GM-CSF antagonized the effects of TGF-β1 on epithelial barrier function in cultured cells. Given this, GM-CSF and TGF-β1 levels were measured in bronchoalveolar lavage (BAL) fluid from patients with ventilator-associated pneumonia and correlated with markers for pulmonary edema and patient outcome. In patient BAL fluid, protein markers of lung barrier dysfunction, serum α2-macroglobulin, and IgM levels were increased at lower ratios of GM-CSF/TGF-β1. Critically, patients who survived had significantly higher GM-CSF/TGF-β1 ratios than nonsurviving patients. This study provides experimental and clinical evidence that the relative balance between GM-CSF and TGF-β1 signaling is a key regulator of lung epithelial barrier function. The GM-CSF/TGF-β1 ratio in BAL fluid may provide a concentration-independent biomarker that can predict patient outcomes in ARDS.

  13. CSF-1 Receptor Signaling in Myeloid Cells

    PubMed Central

    Stanley, E. Richard; Chitu, Violeta

    2014-01-01

    The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We review, the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R. PMID:24890514

  14. Etravirine in CSF is highly protein bound

    PubMed Central

    Nguyen, Anh; Rossi, Steven; Croteau, David; Best, Brookie M.; Clifford, David; Collier, Ann C.; Gelman, Benjamin; Marra, Christina; McArthur, Justin; McCutchan, J. Allen; Morgello, Susan; Simpson, David; Ellis, Ronald J.; Grant, Igor; Capparelli, Edmund; Letendre, Scott; Ellis, Ronald J.; Letendre, Scott; Abramson, Ian; Al-Lozi, Muhammad; Atkinson, J. Hampton; Capparelli, Edmund; Clifford, David; Collier, Ann C.; Fennema-Notestine, Christine; Gamst, Anthony C.; Gelman, Benjamin; Heaton, Robert K.; Marcotte, Thomas D.; Marra, Christina; McCutchan, J. Allen; McArthur, Justin; Morgello, Susan; Simpson, David; Smith, Davey M.; Taylor, Michael J.; Theilmann, Rebecca; Vaida, Florin; Paul Woods, Steven; Cushman, Clint; Dawson, Matthew; Franklin, Donald; Jones, Trudy; Lewis, Kristen; Mintz, Letty; Teshome, Mengesha; Toperoff, Will

    2013-01-01

    Objectives Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL). Methods Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL. Results Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens. Conclusions Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS. PMID:23335197

  15. Identification of CSF fistulas by radionuclide counting

    SciTech Connect

    Yamamoto, Y.; Kunishio, K.; Sunami, N.; Yamamoto, Y.; Satoh, T.; Suga, M.; Asari, S. )

    1990-07-01

    A radionuclide counting method, performed with the patient prone and the neck flexed, was used successfully to diagnose CSF rhinorrhea in two patients. A normal radionuclide ratio (radionuclide counts in pledget/radionuclide counts in 1-ml blood sample) was obtained in 11 normal control subjects. Significance was determined to be a ratio greater than 0.37. Use of radionuclide counting method of determining CSF rhinorrhea is recommended when other methods have failed to locate a site of leakage or when posttraumatic meningitis suggests subclinical CSF rhinorrhea.

  16. Advances in Biomarker Research in Parkinson's Disease.

    PubMed

    Mehta, Shyamal H; Adler, Charles H

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease, and the numbers are projected to double in the next two decades with the increase in the aging population. An important focus of current research is to develop interventions to slow the progression of the disease. However, prerequisites to it include the development of reliable biomarkers for early diagnosis which would identify at-risk groups and disease progression. In this review, we present updated evidence of already known clinical biomarkers (such as hyposmia and rapid eye movement (REM) sleep behavior disorder (RBD)) and neuroimaging biomarkers, as well as newer possible markers in the blood, CSF, and other tissues. While several promising candidates and methods to assess these biomarkers are on the horizon, it is becoming increasingly clear that no one candidate will clearly fulfill all the roles as a single biomarker. A multimodal and combinatorial approach to develop a battery of biomarkers will likely be necessary in the future.

  17. Antibody-free quantification of seven tau peptides in human CSF using targeted mass spectrometry.

    PubMed

    Bros, Pauline; Vialaret, Jérôme; Barthelemy, Nicolas; Delatour, Vincent; Gabelle, Audrey; Lehmann, Sylvain; Hirtz, Christophe

    2015-01-01

    Tau protein concentration in cerebrospinal fluid (CSF) is currently used as a sensitive and specific biomarker for Alzheimer's disease. Its detection currently relies on ELISA but the perspective of using mass spectrometry (MS) to detect its different proteoforms represents an interesting alternative. This is however an analytical challenge because of its low concentration in the CSF, a biological fluid collected in small volume by lumbar puncture, and with a high structural heterogeneity. To overcome these issues, instead of using immunocapture as previously done, we rather relied on an original two steps pre-fractionation technique of CSF: perchloric acid (PCA) followed by micro solid phase extraction (μSPE). We could then measure seven tau trypsic peptides by Multiple Reaction Monitoring (MRM) on a triple quadrupole mass spectrometer. Quantification was performed using isotopically labeled (15)N- recombinant tau protein as internal standard and validated using CSF pools with low, medium, or high tau concentrations (HTCs). Repeatability, intermediate precision, linearity, limit of quantification (LOQ), and recovery were calculated for the different peptides. This new MRM assay, which allowed for the first time CSF tau protein quantification without immunocapture, has important potential application to follow tau metabolism in both diagnostic and therapeutic research.

  18. CSF 5-HIAA and DST non-suppression--orthogonal biologic risk factors for suicide in male mood disorder inpatients.

    PubMed

    Jokinen, Jussi; Nordström, Anna-Lena; Nordström, Peter

    2009-01-30

    Two biomarkers of suicide risk; non-suppression in the dexamethasone suppression test (DST) and low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been reported to be predictors of suicide in mood disorders. The interrelation of the two systems seems to be different in suicide attempters compared with depressed inpatients who have not made a suicide attempt, indicating that the two biomarkers may be seen as independent. This investigation examined the interrelation of low CSF 5-HIAA and DST non-suppression in suicide victims with mood disorder. Fifty-eight mood disorder inpatients not receiving any treatment with antidepressants underwent lumbar puncture and the DST. Plasma cortisol levels at 8:00 a.m., 4:00 p.m. and 11:00 p.m. were analysed in relation to CSF 5-HIAA. All patients were followed up for causes of death and suicides were verified with death certificates. During follow-up (mean 21 years), 11 (19%) patients had committed suicide. In male suicide victims (n=6), the serum cortisol level at 4:00 p.m. showed a significant positive correlation with CSF 5-HIAA. Low CSF 5-HIAA predicted all early suicides (within 1 year), whereas all males who committed suicide after 1 year were DST non-suppressors. In female suicide victims (n=5), the post-DST serum cortisol did not correlate with CSF 5-HIAA. Low CSF 5-HIAA and DST non-suppression are orthogonal biologic risk factors for suicide in male mood disorder inpatients. CSF 5-HIAA is associated with short-term suicide risk; dysregulation of the hypothalamic-pituitary-adrenal axis seems to be a long-term suicide predictor.

  19. CSF and Blood Levels of GFAP in Alexander Disease

    PubMed Central

    Jany, Paige L.; Agosta, Guillermo E.; Benko, William S.; Eickhoff, Jens C.; Keller, Stephanie R.; Köehler, Wolfgang; Mar, Soe; Naidu, Sakkubai; Marie Ness, Jayne; Renaud, Deborah L.; Salsano, Ettore; Schiffmann, Raphael; Simon, Julie; Vanderver, Adeline; Eichler, Florian; van der Knaap, Marjo S.

    2015-01-01

    Abstract Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment. PMID:26478912

  20. An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients.

    PubMed

    Sun, Ying; Bresell, Anders; Rantalainen, Mattias; Höglund, Kina; Lebouvier, Thibaud; Salter, Hugh

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia, with no disease-modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181, and with the two ratios t-tau/Aβ1-42 and p-tau181/Aβ1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF biomarker p-tau181/Aβ1-42 ratio with consideration of APOE ε4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome-wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181/Aβ1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients.

  1. CSF hydrodynamic studies in man. 1. Method of constant pressure CSF infusion.

    PubMed Central

    Ekstedt, J

    1977-01-01

    The constant pressure method for the study of the hydrodynamics of CSF is presented. By infusing artificial CSF at constant pressures and recording the resultant flow, it is possible to obtain information about the hydrodynamic conductance of the CSF outflow pathways. By lowering the infusion pressure below the pressure of the sagittal sinus all CSF produced can be collected and the CSF formation rate may thus be calculated. There is a rectilinear relationship between CSF pressure and the flow necessary to maintain the pressure. It is thus concluded that the arachnoidal villi, when once opened, are not further distended by pressure. This method makes possible indirect calculation of the pressure of the sagittal sinus and the pressure difference between the subarachnoid space and the sagittal sinus. Images PMID:864474

  2. CSF concentration gradients of monoamine metabolites in patients with hydrocephalus.

    PubMed

    Malm, J; Kristensen, B; Ekstedt, J; Wester, P

    1994-09-01

    Concentration gradients of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed in 762 successive CSF fractions (2 ml lumbar CSF) from 15 patients with the adult hydrocephalus syndrome (AHS) and 11 patients with hydrocephalus of other causes (mixed group). A mean volume of 49.6 (SD 11.8) ml CSF was removed in the AHS group and 56.4 (10.2) ml in the mixed group. The CSF was collected with a specially designed carousel fraction collector and the corresponding CSF dynamics were continuously registered by a constant pressure CSF infusion method. Pronounced gradients in CSF HVA and CSF 5-HIAA were seen in both patient groups in the first 25 ml of CSF removed. The concentration curves levelled off, despite the removal of larger amounts of CSF and stabilised at about twice the initial concentrations. This phenomenon has not been described before. Concentrations of HVA and 5-HIAA in the first CSF fraction correlated strongly with concentrations in fractions up to about 40 ml. A positive correlation between the first fraction of CSF HVA and CSF 5-HIAA concentrations and CSF outflow conductance was found in the AHS group. There was no gradient in MHPG. It is suggested that the rostrocaudal gradients in CSF HVA and 5-HIAA may be explained by a downward flow of CSF along the spinal cord with absorption of metabolites occurring during passage. Mixing of CSF from different CSF compartments, extraventricular production sites of CSF, clearance of metabolites to venous blood or extracellular fluid, and CSF outflow conductance are probably important determinants of the plateau phase in patients with hydrocephalus. It is concluded that lumbar CSF does not exclusively reflect the concentrations of HVA, 5-HIAA, or MHPG in the ventricles. It should be noted that these results obtained in patients with hydrocephalus may not be applicable to other groups of patients or normal subjects.

  3. CSF concentration gradients of monoamine metabolites in patients with hydrocephalus.

    PubMed Central

    Malm, J; Kristensen, B; Ekstedt, J; Wester, P

    1994-01-01

    Concentration gradients of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed in 762 successive CSF fractions (2 ml lumbar CSF) from 15 patients with the adult hydrocephalus syndrome (AHS) and 11 patients with hydrocephalus of other causes (mixed group). A mean volume of 49.6 (SD 11.8) ml CSF was removed in the AHS group and 56.4 (10.2) ml in the mixed group. The CSF was collected with a specially designed carousel fraction collector and the corresponding CSF dynamics were continuously registered by a constant pressure CSF infusion method. Pronounced gradients in CSF HVA and CSF 5-HIAA were seen in both patient groups in the first 25 ml of CSF removed. The concentration curves levelled off, despite the removal of larger amounts of CSF and stabilised at about twice the initial concentrations. This phenomenon has not been described before. Concentrations of HVA and 5-HIAA in the first CSF fraction correlated strongly with concentrations in fractions up to about 40 ml. A positive correlation between the first fraction of CSF HVA and CSF 5-HIAA concentrations and CSF outflow conductance was found in the AHS group. There was no gradient in MHPG. It is suggested that the rostrocaudal gradients in CSF HVA and 5-HIAA may be explained by a downward flow of CSF along the spinal cord with absorption of metabolites occurring during passage. Mixing of CSF from different CSF compartments, extraventricular production sites of CSF, clearance of metabolites to venous blood or extracellular fluid, and CSF outflow conductance are probably important determinants of the plateau phase in patients with hydrocephalus. It is concluded that lumbar CSF does not exclusively reflect the concentrations of HVA, 5-HIAA, or MHPG in the ventricles. It should be noted that these results obtained in patients with hydrocephalus may not be applicable to other groups of patients or normal subjects. PMID:7522267

  4. Impact of APOE4-CSF Aβ interaction on hippocampal volume loss over 1 year in MCI

    PubMed Central

    Chiang, G.C.; Insel, P.S.; Tosun, D.; Schuff, N.; Truran-Sacrey, D.; Raptentsetsang, S.T.; Thompson, P.M.; Reiman, E.M.; Jack, C.R.; Fox, N.C.; Jagust, W.J.; Harvey, D.J.; Beckett, L.A.; Gamst, A.; Aisen, P.S.; Petersen, R.C.; Weiner, M.W.

    2011-01-01

    Background The majority of studies relating amyloid pathology with brain volumes have been cross-sectional. Apolipoprotein E4 (APOE4), a genetic risk factor for Alzheimer’s disease (AD), is also associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE4 together on longitudinal volume loss. Methods We evaluated whether an abnormal level of cerebrospinal fluid beta-amyloid (CSF Aβ) and APOE4 carrier status were independently associated with greater hippocampal volume loss over 1 year. We then assessed whether APOE4 status and CSF Aβ acted synergistically, testing the significance of an interaction term in the regression analysis. We included 297 participants: 77 cognitively normal (NC), 144 with mild cognitive impairment (MCI), and 76 with AD. Results An abnormal CSF Aβ level was found to be associated with greater hippocampal volume loss over 1 year in each group. APOE4 was associated with hippocampal volume loss only in the NC and MCI groups. APOE4 carriers with abnormal CSF Aβ in the MCI group acted synergistically to produce disproportionately greater volume loss than noncarriers. Conclusion Baseline CSF Aβ predicts progression of hippocampal volume loss. APOE4 carrier status amplifies the degree of neurodegeneration in MCI. Understanding the effect of interactions between genetic risk and amyloid pathology will be important in clinical trials and our understanding of the disease process. PMID:21889115

  5. Addition of sargramostim (GM-CSF) to imatinib results in major cytogenetic response in a patient with chronic myeloid leukemia.

    PubMed

    Connor, Rebecca F; Hurd, David; Pettenati, Mark J; Koty, Patrick; Molnár, István

    2006-10-01

    Imatinib mesylate, an inhibitor of BCR/ABL tyrosine kinase, has remarkable activity in chronic myeloid leukemia resulting in an 87% major cytogenetic response. We describe a woman who failed to achieve any cytogenetic response after 2.5 years of imatinib, 400mg daily. When daily sargramostim (GM-CSF) 100 microg/m2 was added, cytogenetic studies revealed a gradual increase in percentage of normal cells from start, 4, 9, and 15 months at 0%, 10%, 55%, and 85%, respectively. She became transfusion independent after starting GM-CSF. The addition of GM-CSF to imatinib resulted in a clinical benefit and a major cytogenetic response in this patient.

  6. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases.

    PubMed

    Bacioglu, Mehtap; Maia, Luis F; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Pilotto, Andrea; Shimshek, Derya R; Neumann, Ulf; Kahle, Philipp J; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

    2016-07-06

    A majority of current disease-modifying therapeutic approaches for age-related neurodegenerative diseases target their characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are crucial. We found robust increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and β-amyloidosis. Blood and CSF NfL levels were strongly correlated, and NfL increases coincided with the onset and progression of the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions increased CSF and blood NfL levels, while blocking Aβ lesions attenuated the NfL increase. Consistently, we also found NfL increases in CSF and blood of human α-synucleinopathies, tauopathies, and Alzheimer's disease. Our results suggest that CSF and particularly blood NfL can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially in human proteopathic neurodegenerative diseases.

  7. European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease—the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow

    PubMed Central

    Meulenbroek, Olga; O'Dwyer, Sarah; de Jong, Daan; van Spijker, Gerrita; Kennelly, Sean; Cregg, Fiona; Olde Rikkert, Marcel; Abdullah, Laila; Wallin, Anders; Walsh, Cathal; Coen, Robert; Kenny, Rose Anne; Daly, Leslie; Segurado, Ricardo; Borjesson-Hanson, Anne; Crawford, Fiona; Mullan, Michael; Lucca, Ugo; Banzi, Rita; Pasquier, Florence; Breuilh, Laetitia; Riepe, Matthias; Kalman, Janos; Tsolaki, Magda; Howard, Robert; Adams, Jessica; Gaynor, Siobhan; Lawlor, Brian

    2016-01-01

    Introduction In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers. Methods and analysis All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30 mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10 mL CSF is collected at week 0 and week 78. Ethics and dissemination All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal. Trial registration number EUDRACT 2012-002764-27; Pre-results. PMID:27436668

  8. CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment.

    PubMed

    Stefani, Alessandro; Martorana, Alessandro; Bernardini, Sergio; Panella, Marta; Mercati, Flavio; Orlacchio, Antonio; Pierantozzi, Mariangela

    2006-12-21

    Standard markers in cerebrospinal fluid (CSF), as soluble amyloid beta 1-42 (Abeta1-42) and total tau protein (t-tau), may contribute to dementia subtypes diagnostic accuracy. Yet, their sensitivity to assess the different degree of cognitive deficit is not fully clarified. Our study analyses Abeta1-42 and t-tau CSF levels in different cohorts of Alzheimer's disease (AD) patients, distinguished as early AD (mild cognitively impaired subjects recently converted to AD), mild AD (MMSE<23; > or =18), and moderately advanced AD (MMSE<18). The control group was represented by age-matched patients affected by depressive pseudo-dementia. Reduced Abeta1-42 and increased t-tau CSF levels were confirmed as hallmarks of AD at any disease stage. In early AD patients, Abeta1-42 levels were already significantly low, if compared to the control group (336 vs 867 ng/L; p<0.0001). On the contrary, Abeta1-42 levels did not differ between AD subgroups, and in particular between mild to moderate AD. A significant progressive increase of t-tau concentration was found when comparing early AD (269 ng/L) to more advanced AD stages (468 ng/L and 495 ng/L for mild and moderate AD, respectively). Our findings confirm that the impairment of amyloidogenic cascade is an early, even pre-clinical process, but suggest that soluble Abeta1-42 concentration has a negligible correlation with the clinical progression. Conversely, t-tau concentration correlates with the transition towards marked cognitive impairment.

  9. rhCSF3 accelerates the proliferation of human melanocytes in culture through binding CSF3R and the expression of CSF3R transcripts.

    PubMed

    Lu, Yan; Guo, Ze; Zhou, Mei-Hua; Li, Xue; Sun, Jie; Gong, Qing-Li; Zhu, Wen-Yuan

    2015-05-01

    Melanogenic paracrine and autocrine cytokine networks have recently been discovered in vitro between melanocytes and other types of skin cells. Granulocyte colony-stimulating factor receptor (CSF3R) controls the survival, proliferation and differentiation of many kinds of cells, including neutrophils. To understand the function of CSF3R and recombinant human granulocyte colony-stimulating factor (rhCSF3) on melanocyte proliferation, this study compared the expression of CSF3R and the effects of rhCSF3 in primary human melanocytes, neutrophils and HEL 92.1.7 cells. The results show that CSF3R is localized in the cytoplasm and on cell membranes of melanocytes and neutrophils. The percentage of CSF3R(+) melanocytes was higher than CSF3R(+) HEL 92.1.7 cells, but was lower than CSF3R(+) neutrophils. Both CSF3R mRNA and CSF3R protein levels in melanocytes were higher than in HEL 92.1.7 cells, but were lower than in neutrophils. Treatment with rhCSF3 increased the proliferation of human melanocytes, but not their tyrosinase activity. Transcripts of CSF3R in human melanocytes, M14, A375 melanoma and A431 squamous cell carcinoma cells were also detected. Expression of the CSF3R V3 transcript was lower in melanocytes than in M14, A375 melanoma and A431 squamous cell carcinoma cells. In conclusion, rhCSF3 can promote melanocyte proliferation through CSF3R without affecting tyrosinase activity.

  10. Cognitive Performance and Cerebrospinal Fluid Biomarkers of Neurodegeneration: A Study of Patients with Bipolar Disorder and Healthy Controls

    PubMed Central

    Rolstad, Sindre; Jakobsson, Joel; Sellgren, Carl; Ekman, Carl-Johan; Blennow, Kaj; Zetterberg, Henrik; Pålsson, Erik; Landén, Mikael

    2015-01-01

    The purpose of the present study was to investigate if cerebrospinal fluid (CSF) biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (Aβ)1-42, ratios of Aβ42/40 and Aβ42/38, soluble amyloid precursor protein α and β, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 healthy controls. Linear regression models were applied to account for performance in five cognitive domains using the CSF biomarkers. In patients, the CSF biomarkers explained a significant proportion of the variance (15–36%, p=.002 - <.0005) in all cognitive domains independently of age, medication, disease status, and bipolar subtype I or II. However, the CSF biomarkers specifically mirroring Alzheimer-type brain changes, i.e., P-tau and Aβ1-42, did not contribute significantly. In healthy controls, CSF biomarkers did not explain the variance in cognitive performance. Selected CSF biomarkers of neurodegenerative processes accounted for cognitive performance in persons with bipolar disorder, but not for healthy controls. Specifically, the ratios of Aβ42/40 and Aβ42/38 were consistently associated with altered cognitive performance. PMID:25954806

  11. CSF and plasma vasopressin concentrations in dementia.

    PubMed Central

    Sørensen, P S; Hammer, M; Vorstrup, S; Gjerris, F

    1983-01-01

    In 16 patients with primary degenerative dementia mean CSF vasopressin concentration was lower (0.9 +/- 0.1 pg/ml (mean +/- SEM)) than in 28 control patients (1.3 +/- 0.1 (mean +/- SEM)) (p less than 0.01). In 18 patients with normal pressure hydrocephalus and potentially reversible dementia mean CSF vasopressin concentration (1.2 pg/ml +/- 0.1 (mean +/- SEM)) was not different from that found in controls. Several of the demented patients had inappropriate plasma vasopressin concentrations suggesting a defect in osmoregulation. These findings encourage further clinical trials of vasopressin in patients with primary degenerative dementia, but it is emphasised that the low CSF vasopressin concentration in these patients might be only a nonspecific phenomenon due to the diffuse loss of cells within the central nervous system. PMID:6644315

  12. Diagnostic cerebrospinal fluid biomarkers for Parkinson's disease: a pathogenetically based approach.

    PubMed

    van Dijk, Karin D; Teunissen, Charlotte E; Drukarch, Benjamin; Jimenez, Connie R; Groenewegen, Henk J; Berendse, Henk W; van de Berg, Wilma D J

    2010-09-01

    The inaccuracy of the early diagnosis of Parkinson's disease (PD) has been a major incentive for studies aimed at the identification of biomarkers. Brain-derived cerebrospinal fluid (CSF) proteins are potential biomarkers considering the major role that proteins play in PD pathogenesis. In this review, we discuss the current hypotheses about the pathogenesis of PD and identify the most promising candidate biomarkers among the CSF proteins studied so far. The list of potential markers includes proteins involved in various pathogenetic processes, such as oxidative stress and protein aggregation. This list will undoubtedly grow in the near future by application of CSF proteomics and subsequent validation of identified proteins. Probably a single biomarker will not suffice to reach high sensitivity and specificity, because PD is pathogenetically heterogeneous and shares etiological factors with other neurodegenerative diseases. Furthermore, identified candidate biomarkers will have to be thoroughly validated before they can be implemented as diagnostic aids.

  13. CSF hydrodynamics in superior sagittal sinus thrombosis.

    PubMed Central

    Kristensen, B; Malm, J; Markgren, P; Ekstedt, J

    1992-01-01

    Cerebrospinal fluid hydrodynamics were investigated with a constant pressure infusion method in patients with superior sagittal sinus thrombosis. Ten patients were studied with serial examinations up to 15 years after the onset of the disease. A total of 70 CSF hydrodynamic examinations were performed. A clear increase in intracranial pressure due to raised pressure in the major dural sinus was seen in all patients. A striking feature was the persistent intracranial pressure increase that declined only gradually. This had no obvious clinical impact. Change in CSF resorption facility played only a minor role in the intracranial pressure elevation. None of the patients developed hydrocephalus. PMID:1583513

  14. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism.

    PubMed

    Waight, Jeremy D; Hu, Qiang; Miller, Austin; Liu, Song; Abrams, Scott I

    2011-01-01

    Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy.

  15. Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative.

    PubMed

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy; Gerhard, Alexander; Jellinger, Kurt; Jeromin, Andreas; Krismer, Florian; Mollenhauer, Brit; Schlossmacher, Michael G; Shaw, Leslie M; Verbeek, Marcel M; Wenning, Gregor K; Winge, Kristian; Zhang, Jing; Meissner, Wassilios G

    2015-08-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.

  16. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling.

    PubMed

    Hume, David A; MacDonald, Kelli P A

    2012-02-23

    Macrophage-colony stimulating factor (CSF-1) signaling through its receptor (CSF-1R) promotes the differentiation of myeloid progenitors into heterogeneous populations of monocytes, macrophages, dendritic cells, and bone-resorbing osteoclasts. In the periphery, CSF-1 regulates the migration, proliferation, function, and survival of macrophages, which function at multiple levels within the innate and adaptive immune systems. Macrophage populations elicited by CSF-1 are associated with, and exacerbate, a broad spectrum of pathologies, including cancer, inflammation, and bone disease. Conversely, macrophages can also contribute to immunosuppression, disease resolution, and tissue repair. Recombinant CSF-1, antibodies against the ligand and the receptor, and specific inhibitors of CSF-1R kinase activity have been each been tested in a range of animal models and in some cases, in patients. This review examines the potential clinical uses of modulators of the CSF-1/CSF-1R system. We conclude that CSF-1 promotes a resident-type macrophage phenotype. As a treatment, CSF-1 has therapeutic potential in tissue repair. Conversely, inhibition of CSF-1R is unlikely to be effective in inflammatory disease but may have utility in cancer.

  17. The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor.

    PubMed

    Swierczak, Agnieszka; Cook, Andrew D; Lenzo, Jason C; Restall, Christina M; Doherty, Judy P; Anderson, Robin L; Hamilton, John A

    2014-08-01

    Treatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the inhibition of colony-stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here, we report that, surprisingly, treatment with neutralizing anti-CSF-1R and anti-CSF-1 antibodies, or with two different small-molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6C(hi) monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target.

  18. miRNAs as Circulating Biomarkers for Alzheimer's Disease and Parkinson's Disease.

    PubMed

    Mushtaq, Gohar; Greig, Nigel H; Anwar, Firoz; Zamzami, Mazin A; Choudhry, Hani; Shaik, Munvar M; Tamargo, Ian A; Kamal, Mohammad A

    2016-01-01

    Detection of biomarkers for neurodegenerative disorders (NDDs) within brain tissues of Alzheimer's disease (AD) and Parkinson's disease (PD) patients has always been hampered by our inability to access and biopsy tissue of key brain regions implicated in disease occurrence and progression. Currently, diagnosis of NDDs is principally based on clinical observations of symptoms that present at later stages of disease progression, followed by neuroimaging and, possibly, CSF evaluation. One way to potentially detect and diagnose NDDs at a far earlier stage is to screen for abnormal levels of specific disease markers within the peripheral circulation of patients with NDDs. Increasing evidence suggests that there is dysregulation of microRNAs (miRNAs) in NDDs. Peripheral blood mononuclear cells, as well as biofluids, such as plasma, serum, urine and cerebrospinal fluid, contain miRNAs that can be identified and quantified. Circulating miRNAs within blood and other biofluids may thus be characterized and used as non-invasive, diagnostic biomarkers that facilitate the early detection of disease and potentially the continual monitoring of disease progression for NDDs such as AD and PD. Plainly, such a screen is only possible with a clear understanding of which miRNAs change with disease, and when these changes occur during the progression of AD and PD. Such information is becoming increasingly available and, in the near future, may not only support disease diagnosis, but provide the opportunity to evaluate therapeutic interventions earlier in the disease process.

  19. New Developments in Biomarkers for Atopic Dermatitis.

    PubMed

    Thijs, Judith L; van Seggelen, Wouter; Bruijnzeel-Koomen, Carla; de Bruin-Weller, Marjolein; Hijnen, DirkJan

    2015-03-16

    The application of biomarkers in medicine is evolving. Biomarkers do not only give us a better understanding of pathogenesis, but also increase treatment efficacy and safety, further enabling more precise clinical care. This paper focuses on the current use of biomarkers in atopic dermatitis, new developments and future perspectives. Biomarkers can be used for many different purposes, including the objective determination of disease severity, confirmation of clinical diagnosis, and to predict response to treatment. In atopic dermatitis, many biomarkers have been investigated as a marker for disease severity. Currently serum thymus and activation-regulated chemokine (TARC) is the superior biomarker for assessing disease severity. However, we have recently shown that the use of a panel of serum biomarkers is more suitable for assessing disease severity than an individual biomarker. In this overview, we will discuss alternative sources for biomarkers, such as saliva and capillary blood, which can increase the user friendliness of biomarkers in atopic dermatitis (AD). Both methods offer simple, non-invasive and cost effective alternatives to venous blood. This provides great translational and clinical potential. Biomarkers will play an increasingly important role in AD research and personalized medicine. The use of biomarkers will enhance the efficacy of AD treatment by facilitating the individualization of therapy targeting the patients' specific biological signature and also by providing tools for predicting and monitoring of therapeutic response.

  20. [MRI evaluation of cervicothoracic CSF hypotension].

    PubMed

    Maraval, A; Brugieres, P; Combes, C; Thomas, P; Blanc, R; Gaston, A

    2006-06-01

    We propose studying signs of cervicothoracic CSF hypotension by MRI. Axial T1-weighted GRE sequence with and without saturation bands positioned above and below the selected image plane, MR venography and MR Angiography with contrast administration are helpful to confirm the venous nature of the epidural thickening and to make the differential diagnosis with infectious or neoplastic epiduritis.

  1. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer's disease using metabolomics.

    PubMed

    Trushina, Eugenia; Dutta, Tumpa; Persson, Xuan-Mai T; Mielke, Michelle M; Petersen, Ronald C

    2013-01-01

    Alzheimer's Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD.

  2. Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus

    PubMed Central

    Limbrick, David D.; Baksh, Brandon; Morgan, Clinton D.; Habiyaremye, Gakwaya; McAllister, James P.; Inder, Terrie E.; Mercer, Deanna; Holtzman, David M.; Strahle, Jennifer; Wallendorf, Michael J.; Morales, Diego M.

    2017-01-01

    Introduction Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value. Methods CSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPβ, Aβ42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC. Results CSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPβ (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC. Conclusions CSF proteins such as s

  3. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  4. Cerebrospinal fluid biomarkers in Alzheimer's and Parkinson's diseases-From pathophysiology to clinical practice.

    PubMed

    Blennow, Kaj; Biscetti, Leonardo; Eusebi, Paolo; Parnetti, Lucilla

    2016-06-01

    This review provides an update on the role, development, and validation of CSF biomarkers in the diagnosis and prognosis of Alzheimer's disease and PD. Some recent developments on novel biomarkers are also discussed. We also give an overview of methodological/technical factors still hampering the global validation and standardization of CSF Alzheimer's disease and PD biomarkers. CSF biomarkers have the potential to improve the diagnostic accuracy at the early stages not only for Alzheimer's disease but also for PD. This step is essential in view of the availability of disease-modifying treatments. Our vision for the future is that analyzing biomarker panels on a minute amount of CSF could provide important information on the whole spectrum of the molecular pathogenic events characterizing these neurodegenerative disorders. CSF core biomarkers have already been included in the diagnostic criteria for Alzheimer's disease, and they are also under consideration as tools to monitor the effects of disease-modifying drugs. With respect to PD, their potential for improving diagnostic accuracy in early diagnosis is under intense research, resembling the same path followed for Alzheimer's disease. © 2016 International Parkinson and Movement Disorder Society.

  5. [Sensitivity of neurochemical dementia diagnostics in CSF compared to 99mTc-SPECT in Alzheimer's dementia].

    PubMed

    Weih, M; Krinninger, M; Zimmermann, R; Lewczuk, P; Svitek, J; Schaller, G; Degirmenci, U; Richter-Schmidinger, T; Wiltfang, J; Kuwert, T; Kornhuber, J; Schmidt, D

    2009-07-01

    The diagnosis of Alzheimer's dementia is currently changing from a late and exclusion diagnosis towards a pathophysiology-based early and positive diagnosis. Especially advances in neuro-chemical dementia diagnostics in the cerebrospinal fluid (NDD-CSF) and imaging techniques like PET, SPECT or MRI are of particular interest. Unfortunately, many studies investigated only either one or other technique. In the present study 56 patients (average 67.1 years; average mini-mental status test (MMST) 22.2) were examined with the clinical diagnosis of Alzheimer's dementia. All patients both underwent NDD-CSF as well as 99mTc-SPECT. Only the SPECT, but not the NDD-CSF correlated with disease severity. Sensitivity of NDD-CSF was 89 % and SPECT 48 % for all patients and 93 % resp. 61 % for patients with MMST < 24. Below MMST 20 both methods had equal sensitivity. Both diagnostic techniques showed no statistic coherence (p = 0.27), neither after correction for subgroups like disease severity or the APOE genotype. Our results are compatible with the hypothesis that the NDD-CSF reflects beta-amyloid-aggregation and Tau-Protein pathology as a pathophysiologic biomarker. Our results suggest that SPECT is rather a state parameter for the rCBF changes following cortical neurodegeneration.

  6. Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer's disease mice.

    PubMed

    Shang, De S; Yang, Yi M; Zhang, Hu; Tian, Li; Jiang, Jiu S; Dong, Yan B; Zhang, Ke; Li, Bo; Zhao, Wei D; Fang, Wen G; Chen, Yu H

    2016-11-01

    Although tight junctions between human brain microvascular endothelial cells in the blood-brain barrier prevent molecules or cells in the bloodstream from entering the brain, in Alzheimer's disease, peripheral blood monocytes can "open" these tight junctions and trigger subsequent transendothelial migration. However, the mechanism underlying this migration is unclear. Here, we found that the CSF2RB, but not CSF2RA, subunit of the granulocyte-macrophage colony-stimulating factor receptor was overexpressed on monocytes from Alzheimer's disease patients. CSF2RB contributes to granulocyte-macrophage colony-stimulating factor-induced transendothelial monocyte migration. Granulocyte-macrophage colony-stimulating factor triggers human brain microvascular endothelial cells monolayer tight junction disassembly by downregulating ZO-1 expression via transcription modulation and claudin-5 expression via the ubiquitination pathway. Interestingly, intracerebral granulocyte-macrophage colony-stimulating factor blockade abolished the increased monocyte infiltration in the brains of APP/PS1 Alzheimer's disease model mice. Our results suggest that in Alzheimer's disease patients, high granulocyte-macrophage colony-stimulating factor levels in the brain parenchyma and cerebrospinal fluid induced blood-brain barrier opening, facilitating the infiltration of CSF2RB-expressing peripheral monocytes across blood-brain barrier and into the brain. CSF2RB might be useful as an Alzheimer's disease biomarker. Thus, our findings will help to understand the mechanism of monocyte infiltration in Alzheimer's disease pathogenesis.

  7. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS

    PubMed Central

    Bergman, Joakim; Dring, Ann; Zetterberg, Henrik; Blennow, Kaj; Norgren, Niklas; Gilthorpe, Jonathan; Bergenheim, Tommy

    2016-01-01

    Objective: In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum. Methods: Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point. Results: One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum. Conclusions: The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally. ClinicalTrials.gov identifier: NCT01719159. PMID:27536708

  8. Decreased CSF transferrin in sCJD: a potential pre-mortem diagnostic test for prion disorders.

    PubMed

    Singh, Ajay; Beveridge, Alim J; Singh, Neena

    2011-03-09

    Sporadic Creutzfeldt-Jakob-disease (sCJD) is a fatal neurodegenerative condition that escapes detection until autopsy. Recently, brain iron dyshomeostasis accompanied by increased transferrin (Tf) was reported in sCJD cases. The consequence of this abnormality on cerebrospinal-fluid (CSF) levels of Tf is uncertain. We evaluated the accuracy of CSF Tf, a 'new' biomarker, as a pre-mortem diagnostic test for sCJD when used alone or in combination with the 'current' biomarker total-tau (T-tau). Levels of total-Tf (T-Tf), isoforms of Tf (Tf-1 and Tf-β2), and iron saturation of Tf were quantified in CSF collected 0.3-36 months before death (duration) from 99 autopsy confirmed sCJD (CJD+) and 75 confirmed cases of dementia of non-CJD origin (CJD-). Diagnostic accuracy was estimated by non-parametric tests, logistic regression, and receiver operating characteristic (ROC) analysis. Area under the ROC curve (AUC), sensitivity, specificity, positive and negative predictive values (PV), and likelihood ratios (LR) of each biomarker and biomarker combination were calculated. We report that relative to CJD-, CJD+ cases had lower median CSF T-Tf (125,7093 vs. 217,7893) and higher T-tau (11530 vs. 1266) values. AUC was 0.90 (95% confidence interval (CI), 0.85-0.94) for T-Tf, and 0.93 (95% CI, 0.89-0.97) for T-Tf combined with T-tau. With cut-offs defined to achieve a sensitivity of ∼85%, T-Tf identified CJD+ cases with a specificity of 71.6% (95% CI, 59.1-81.7), positive LR of 3.0 (95% CI, 2.1-4.5), negative LR of 0.2 (95% CI, 0.1-0.3), and accuracy of 80.1%. The effect of patient age and duration was insignificant. T-Tf combined with T-tau identified CJD+ with improved specificity of 87.5% (95%CI, 76.3-94.1), positive LR of 6.8 (95% CI, 3.5-13.1), negative LR of 0.2 (95% CI, 0.1-0.3), positive-PV of 91.0%, negative-PV of 80.0%, and accuracy of 86.2%. Thus, CSF T-Tf, a new biomarker, when combined with the current biomarker T-tau, is a reliable pre-mortem diagnostic test for sCJD.

  9. Biomarkers in Parkinson's disease (recent update).

    PubMed

    Sharma, Sushil; Moon, Carolyn Seungyoun; Khogali, Azza; Haidous, Ali; Chabenne, Anthony; Ojo, Comfort; Jelebinkov, Miriana; Kurdi, Yousef; Ebadi, Manuchair

    2013-09-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of α-Syn, DJ-1, amyloid β and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T2 relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [(18)F]-DOPA for estimating dopaminergic neurotransmission, [(18)F]dG for mitochondrial bioenergetics, [(18)F]BMS for mitochondrial complex-1, [(11)C](R)-PK11195 for microglial activation, SPECT imaging with (123)Iflupane and βCIT for dopamine transporter, and urinary

  10. Biomarkers in chronic adult hydrocephalus

    PubMed Central

    Tarnaris, Andrew; Watkins, Laurence D; Kitchen, Neil D

    2006-01-01

    Awareness of the importance of chronic adult hydrocephalus has been raised again with the recent emergence of epidemiological studies. It is estimated that between 5 and 10% of patients suffering from dementia might, in fact, have chronic hydrocephalus. Although, surgical diversion of the cerebrospinal fluid (CSF) represents the only known procedure able to treat the symptoms of this condition, the selection of surgical patients has always been problematic. In the last 40 years, we have become wiser in using appropriate diagnostic tests for the selection of these patients; however, the area of biological markers has so far been overlooked in this condition, in contrast to that for other neurodegenerative disorders and dementias. Biomarkers are biological substances that may be used to indicate either the onset or the presence, and the progression of a clinical condition, being closely linked to its pathophysiology. In such a setting they might assist in the more appropriate selection of patients for shunt surgery. In this article, we have reviewed research carried out in the last 25 years regarding the identification of serum and CSF biomarkers for chronic hydrocephalus, discussed the potential for each one, and finally discussed the limitations for use, as well as future directions and possibilities in this field. It is concluded that tumour-necrosis factor, tau protein, lactate, sulfatide and neurofilament triple protein are the most promising CSF markers for chronic hydrocephalus. At present however, none of these meet the criteria required to justify a change clinical practice. In the future, collaborative multi-centre projects will be needed to obtain more substantial data that overcome the problems that arise from small individual and uncoordinated studies. PMID:17020616

  11. Associations between performance on an abbreviated CogState battery, other measures of cognitive function, and biomarkers in people at risk for Alzheimer’s disease

    PubMed Central

    Racine, Annie M.; Clark, Lindsay R.; Berman, Sara E.; Koscik, Rebecca L.; Mueller, Kimberly D.; Norton, Derek; Nicholas, Christopher R.; Blennow, Kaj; Zetterberg, Henrik; Jedynak, Bruno; Bilgel, Murat; Carlsson, Cynthia M.; Christian, Bradley T.; Asthana, Sanjay; Johnson, Sterling C.

    2016-01-01

    It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer’s disease (AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer’s Prevention (mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery (CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status (determined by consensus review); and biomarkers for amyloid and tau (CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury (CSF neurofilament light protein). CSF and PET-PiB were collected in n=71 and n=91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD. PMID:27589532

  12. CSF markers of Alzheimer’s pathology and microglial activation are associated with altered white matter microstructure in asymptomatic adults at risk for Alzheimer’s disease

    PubMed Central

    Melah, Kelsey E; Lu, Sharon Yuan-Fu; Hoscheidt, Siobhan M; Alexander, Andrew L; Adluru, Nagesh; Destiche, Daniel J; Carlsson, Cynthia M; Zetterberg, Henrik; Blennow, Kaj; Okonkwo, Ozioma C; Gleason, Carey E; Dowling, N Maritza; Bratzke, Lisa C; Rowley, Howard A; Sager, Mark A; Asthana, Sanjay; Johnson, Sterling C; Bendlin, Barbara B

    2015-01-01

    Background The immune response in Alzheimer’s disease (AD) involves activation of microglia which may remove β-amyloid. However, overproduction of inflammatory compounds may exacerbate neural damage in Alzheimer’s disease. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. Objective To determine whether neuroinflammation exacerbates neural damage in preclinical AD. Methods We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age=60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. Results Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. Conclusion Inflammation may play a role in neural damage in preclinical AD. PMID:26836182

  13. Hairy AdS solitons

    NASA Astrophysics Data System (ADS)

    Anabalón, Andrés; Astefanesei, Dumitru; Choque, David

    2016-11-01

    We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

  14. Combined dementia-risk biomarkers in Parkinson's disease: a prospective longitudinal study.

    PubMed

    Compta, Yaroslau; Pereira, Joana B; Ríos, Jose; Ibarretxe-Bilbao, Naroa; Junqué, Carme; Bargalló, Núria; Cámara, Ana; Buongiorno, Mariateresa; Fernández, Manel; Pont-Sunyer, Claustre; Martí, Maria J

    2013-08-01

    Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been separately related to worsening cognition in Parkinson's disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types (p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD.

  15. CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls.

    PubMed

    Herbert, Megan K; Eeftens, Jorine M; Aerts, Marjolein B; Esselink, Rianne A J; Bloem, Bastiaan R; Kuiperij, H Bea; Verbeek, Marcel M

    2014-01-01

    Differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA) is difficult, particularly at early disease stages, but is important for therapeutic management. The protein DJ-1 is implicated in the pathology of PD but little is known about its involvement in MSA. We aimed to determine the diagnostic value of CSF DJ-1 and tau proteins for discriminating PD and MSA. DJ-1 and total tau levels were quantified in the CSF of 43 PD patients, 23 MSA patients and 30 non-neurological controls matched for age and gender. Patients were part of a study with a 3-year prospective design with extended case-review follow-up of up to 9 years, ensuring maximum accuracy of the clinical diagnosis. Our results showed that CSF DJ-1 levels could distinguish MSA from PD with a 78% sensitivity and 78% specificity (AUC = 0.84). The combination of DJ-1 and tau proteins significantly improved this discrimination to 82% sensitivity and 81% specificity to identify MSA from PD (AUC = 0.92). Our results highlight the potential benefits of a combination of DJ-1 and total tau as biomarkers for differential diagnosis of MSA and PD.

  16. Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

    PubMed Central

    Kothur, Kavitha; Wienholt, Louise; Mohammad, Shekeeb S.; Tantsis, Esther M.; Pillai, Sekhar; Britton, Philip N.; Jones, Cheryl A.; Angiti, Rajeshwar R.; Barnes, Elizabeth H.; Schlub, Timothy; Bandodkar, Sushil; Brilot, Fabienne; Dale, Russell C.

    2016-01-01

    Background Despite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications. Aim To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis. Methods We measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups. Results In descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis

  17. Endoscopic endonasal repair of spontaneous CSF fistulae.

    PubMed

    Tormenti, Matthew J; Paluzzi, Alessandro; Pinheiro-Neto, Carlos D; Fernandez-Miranda, Juan C; Snyderman, Carl H; Gardner, Paul A

    2012-01-01

    The authors present a fully endoscopic endonasal repair of a spontaneous CSF leak caused by a defect in the anterior fossa floor. Patients were positioned supine in a Mayfield headholder in slight extension. A complete ethmoidectomy was performed to expose the defect. The middle turbinate was removed to increase visualization and allow for more working room. The defect was identified and exposed. A nasoseptal flap was raised and placed over the defect. A free-mucosal graft fashioned from the removed middle turbinate was placed on the nasoseptal donor site. The video can be found here: http://youtu.be/gAN2cvQVXCE .

  18. Reference measurement procedure for CSF amyloid beta (Aβ)1-42 and the CSF Aβ1-42 /Aβ1-40 ratio - a cross-validation study against amyloid PET.

    PubMed

    Pannee, Josef; Portelius, Erik; Minthon, Lennart; Gobom, Johan; Andreasson, Ulf; Zetterberg, Henrik; Hansson, Oskar; Blennow, Kaj

    2016-11-01

    A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aβ1-42 in CSF. The CSF Aβ1-42 /Aβ1-40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ production. Our aim was to cross-validate the reference measurement procedure as well as the Aβ1-42 /Aβ1-40 and Aβ1-42 /Aβ1-38 ratios in CSF, measured by high-resolution MS, with the cortical level of Aβ fibrils as measured by amyloid ((18) F-flutemetamol) positron emission tomography (PET). We included 100 non-demented patients with cognitive symptoms from the Swedish BioFINDER study, all of whom had undergone both lumbar puncture and (18) F-flutemetamol PET. Comparing CSF Aβ1-42 concentrations with (18) F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aβ1-42 /Aβ1-40 or Aβ1-42 /Aβ1-38 significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aβ1-42 /Aβ1-40 and Aβ1-42 /Aβ1-38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by (18) F-flutemetamol PET.

  19. Pivotal Roles of GM-CSF in Autoimmunity and Inflammation

    PubMed Central

    Shiomi, Aoi; Usui, Takashi

    2015-01-01

    Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells. In autoimmune and inflammatory diseases, Th17 cells have been considered as strong inducers of tissue inflammation. However, recent evidence indicates that GM-CSF has prominent proinflammatory functions and that this growth factor (not IL-17) is critical for the pathogenicity of CD4+ T cells. Therefore, the mechanism of GM-CSF-producing CD4+ T cell differentiation and the role of GM-CSF in the development of autoimmune and inflammatory diseases are gaining increasing attention. This review summarizes the latest knowledge of GM-CSF and its relationship with autoimmune and inflammatory diseases. The potential therapies targeting GM-CSF as well as their possible side effects have also been addressed in this review. PMID:25838639

  20. Homovanillic acid in CSF of mild stage Parkinson's disease patients correlates with motor impairment.

    PubMed

    Stefani, Alessandro; Pierantozzi, Mariangela; Olivola, Enrica; Galati, Salvatore; Cerroni, Rocco; D'Angelo, Vincenza; Hainsworth, Atticus H; Saviozzi, Valentina; Fedele, Ernesto; Liguori, Claudio

    2017-05-01

    In Parkinson's disease (PD), several efforts have been spent in order to find biochemical parameters able to identify the progression of the pathological processes at the basis of the disease. It is already known that advanced PD patients manifesting dyskinesia are featured by the high homovanillic acid (HVA)/dopamine (DA) ratio, suggesting the increased turnover of DA in these patients. Less clear is whether similar changes affect mild and moderate stages of the disease (between 1 and 2.5 of Hoehn & Yahr -H&Y- stage). Hence, here we tested whether cerebrospinal fluid (CSF) concentrations of DA and its major metabolites, either 3,4-dihydroxyphenylacetic acid (DOPAC) or HVA, correlate with motor performance in mild and moderate PD patients. CSF samples were collected after 2 days of anti-PD drugs washout, via lumbar puncture (LP) performed 130 min following administration of oral levodopa (LD) dose (200 mg). LP timing was determined in light of our previous tests clarifying that 2 h after oral LD administration CSF DA concentration reaches a plateau, which was un-respective of PD stage or duration. DA, DOPAC and HVA were assayed by high performance liquid chromatography in a group of 19 patients, distributed in two groups on the basis of the H&Y stage with a cut-off of 1.5. In these PD patients, HVA was correlated with DOPAC (R = 0,56, p < 0,01) and both HVA and DOPAC CSF levels increased in parallel with the motor impairment. More importantly, HVA correlated with motor impairment measured by the Unified Parkinson's Disease Score -III (UPDRS) (R = 0.61; p < 0.0001). The present findings showed the early alteration of the DA pre-synaptic machinery, as documented by the progressive increase of CSF HVA concentrations, which also correlated with PD motor impairment. Therefore, we suggest the potential use of measuring the CSF HVA level as a possible biomarker of PD stage changes in order to monitor the effectiveness of PD-modifying pharmacological therapies.

  1. Added Sugars

    MedlinePlus

    ... need sugar to function properly. Added sugars contribute zero nutrients but many added calories that can lead to extra pounds or even obesity, thereby reducing heart health. If you think of your daily calorie needs as a budget, you want to “spend” ...

  2. Value Added?

    ERIC Educational Resources Information Center

    UCLA IDEA, 2012

    2012-01-01

    Value added measures (VAM) uses changes in student test scores to determine how much "value" an individual teacher has "added" to student growth during the school year. Some policymakers, school districts, and educational advocates have applauded VAM as a straightforward measure of teacher effectiveness: the better a teacher,…

  3. GM-CSF and ipilimumab therapy in metastatic melanoma: Clinical outcomes and immunologic responses

    PubMed Central

    Kwek, Serena S.; Kahn, James; Greaney, Samantha K.; Lewis, Jera; Cha, Edward; Zhang, Li; Weber, Robert W.; Leonard, Lonnie; Markovic, Svetomir N.; Fong, Lawrence; Spitler, Lynn E.

    2016-01-01

    ABSTRACT We conducted a phase II clinical trial of anti-CTLA-4 antibody (ipilimumab) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 22 patients with metastatic melanoma and determined clinical outcomes and immunologic responses. The treatment consisted of a 3-mo induction with ipilimumab at 10 mg/kg administered every 3 weeks for four doses in combination with GM-CSF at 125 µg/m2 for 14 d beginning on the day of the ipilimumab infusion and then GM-CSF for 3 mo on the same schedule without ipilimumab. This was followed by maintenance therapy with the combination every 3 mo for up to 2 y or until disease progression or unacceptable toxicity. Blood samples for determination of immune subsets were obtained before treatment, at week 3 (end of cycle 1) and at week 6 (end of cycle 2). Blood samples were also obtained from seven subjects who were cancer-free. The immune response disease control (irDC) rate at 24 weeks was 41% and the overall response rate (ORR) was 32%. The median progression free-survival (PFS) was 3.5 mo and the median overall survival (OS) was 21.1 mo. 41% of the patients experienced Grade 3 to 4 adverse events. We conclude that this combination is safe and the results suggest the combination may be more effective than ipilimumab monotherapy. Further, the results suggest that lower levels of CD4+ effector T cells but higher levels of CD8+ T cells expressing PD-1 at pre-treatment could be a potential biomarker for disease control in patients who receive immunotherapy with ipilimumab and GM-CSF. Further trials of this combination are warranted. PMID:27141383

  4. CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters.

    PubMed

    Chatzittofis, Andreas; Nordström, Peter; Hellström, Christer; Arver, Stefan; Åsberg, Marie; Jokinen, Jussi

    2013-10-01

    The serotonin system and the hypothalamic-pituitary-adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters.

  5. Comparison of the cerebrospinal fluid (CSF) toluidine red unheated serum test and the CSF rapid plasma reagin test with the CSF venereal disease research laboratory test for diagnosis of neurosyphilis among HIV-negative syphilis patients in China.

    PubMed

    Zhu, Lin; Gu, Xin; Peng, Rui-Rui; Wang, Cuini; Gao, Zixiao; Zhou, Pingyu; Gao, Ying; Shi, Mei; Guan, Zhifang; Seña, Arlene C

    2014-03-01

    In this study, we aimed to investigate the performance of nontreponemal antibody tests in cerebrospinal fluid (CSF) specimens from syphilis patients. From September 2009 to September 2012, CSF specimens were collected at the Shanghai Skin Disease Hospital in Shanghai, China, from 1,132 syphilis patients without HIV infection, including 154 with symptomatic and 56 with asymptomatic neurosyphilis. All of the CSF specimens underwent testing with a rapid plasma reagin (RPR) test, an RPR-V (commercial RPR antigen diluted 1:2 in 10% saline) test, the toluidine red unheated serum test (TRUST), and the Venereal Disease Research Laboratory (VDRL) test. Specificities, sensitivities, positive predictive values (PPVs), negative predictive values (NPVs), and kappa values were calculated to determine the performances of the tests. We compared results of the CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST among patients with symptomatic and asymptomatic neurosyphilis who had reactive CSF-Treponema pallidum particle agglutination (TPPA) test results. Overall, the CSF-VDRL test was reactive in 261 patients (23.1%). There were no cases in which the CSF-VDRL was nonreactive and CSF-RPR, CSF-RPR-V, or CSF-TRUST was reactive. Agreement between the results of CSF-TRUST and CSF-RPR was almost perfect (κ=0.861), with substantial agreement between the results of CSF-RPR and CSF-RPR-V (κ=0.740). The sensitivities of CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST were 81.4%, 76.2%, 79.5%, and 76.2%, respectively. Compared to CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST had comparable PPVs and NPVs. However, the specificity of CSF-VDRL (90.3%) was significantly lower than those of the other tests (92.7 to 93.4%). Therefore, CSF-RPR, CSF-RPR-V, and CSF-TRUST can be considered alternative tests for neurosyphilis diagnosis in HIV-negative populations, particularly when the CSF-VDRL is not available.

  6. [Biology and clinical applications of GM-CSF].

    PubMed

    Robak, T

    1994-01-01

    Granulocyte, macrophage colony stimulating factor (GM-CSF) and granulocyte--colony--stimulating factor (G-CSF) are two of the growing number of recognized cytokines involved in the regulation of hematopoiesis. The purification of these factors and the subsequent cloning of the DNAs which encode these proteins have led to their widespread clinical use in the setting up of therapy of disease-induced myelosuppression. GM-CSF has a broader spectrum of potential targets than G-CSF and promotes growth of progenitors of several myeloid lines and, to a lesser extent, of the megakaryocyte line. The pleiotropic effects of GM-CSF could therefore, theoretically, be an advantage compared with the more restricted activity of G-CSF. Its greatest potential use appears to be in the amelioration of neutropenia following myelosuppressive therapy. GM-CSF has demonstrated efficacy in decreasing the duration of neutropenia, decreasing the attendant infection, and enhancing the ability to deliver full doses of myelosuppressive therapy. GM-CSF can also reverse the neutropenia of myelodysplastic syndrome and aplastic anemia. It enhances recovery from bone marrow transplantation and thus reduce the attendant morbidity of this procedure. This hematopoietic growth factor may also enhance recruitment and harvest to peripheral stem cells. At clinically usefull dosages GM-CSF is generally well tolerated.

  7. Cerebrospinal fluid biomarkers mirror rate of cognitive decline.

    PubMed

    Rolstad, Sindre; Berg, Anne Ingeborg; Bjerke, Maria; Johansson, Boo; Zetterberg, Henrik; Wallin, Anders

    2013-01-01

    The ability to predict future decline in cognitive systems using the cerebrospinal fluid (CSF) biomarkers 42 amino acid form of amyloid-β (Aβ42) and total tau (T-tau) is not fully understood. In a clinical sample ranging from cognitively healthy to dementia (n = 326), linear regression models were performed in order to investigate the ability of CSF biomarkers to predict cognitive decline in all cognitive domains from baseline to 2-year follow-up. Gender, age, and years of education were included as covariates. In patients with subjective cognitive impairment, T-tau had a small impact on executive functions (r2 = 0.07). T-tau had a small to moderate influence (r2 = 0.06-0.11) on all cognitive functions with the exception of visuospatial functions in patients with mild cognitive impairment (MCI). In patients with dementia, the impact of T-tau was large (r2 = 0.29) on semantic memory. Aβ42 had a small effect (r2 = 0.07) on speed and executive functions in MCI. In patients with dementia, Aβ42 had a moderate influence (r2 = 0.13-0.24) on semantic and verbal working memory/fluency. Our results speak in favor of the notion that CSF biomarkers reflect the rate of cognitive decline across the continuum of cognitive impairment from healthy to dementia. CSF predicted subsequent decline in more cognitive domains among MCI cases, but the impact was most pronounced in patients with dementia.

  8. Biomarkers of Guillain-Barré Syndrome: Some Recent Progress, More Still to Be Explored

    PubMed Central

    Wang, Ying; Sun, Shuang; Zhu, Jie; Cui, Li; Zhang, Hong-Liang

    2015-01-01

    Guillain-Barré syndrome (GBS), the axonal subtype of which is mainly triggered by C. jejuni with ganglioside-mimicking lipooligosaccharides (LOS), is an immune-mediated disorder in the peripheral nervous system (PNS) accompanied by the disruption of the blood-nerve barrier (BNB) and the blood-cerebrospinal fluid barrier (B-CSF-B). Biomarkers of GBS have been extensively explored and some of them are proved to assist in the clinical diagnosis and in monitoring disease progression as well as in assessing the efficacy of immunotherapy. Herein, we systemically review the literature on biomarkers of GBS, including infection-/immune-/BNB, B-CSF-B, and PNS damage-associated biomarkers, aiming at providing an overview of GBS biomarkers and guiding further investigations. Furthermore, we point out further directions for studies on GBS biomarkers. PMID:26451079

  9. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

    PubMed

    Teunissen, Charlotte; Menge, Til; Altintas, Ayse; Álvarez-Cermeño, José C; Bertolotto, Antonio; Berven, Frode S; Brundin, Lou; Comabella, Manuel; Degn, Matilde; Deisenhammer, Florian; Fazekas, Franz; Franciotta, Diego; Frederiksen, Jette L; Galimberti, Daniela; Gnanapavan, Sharmilee; Hegen, Harald; Hemmer, Bernhard; Hintzen, Rogier; Hughes, Steve; Iacobaeus, Ellen; Kroksveen, Ann C; Kuhle, Jens; Richert, John; Tumani, Hayrettin; Villar, Luisa M; Drulovic, Jelena; Dujmovic, Irena; Khalil, Michael; Bartos, Ales

    2013-11-01

    The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

  10. The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor.

    PubMed

    Meenhuis, Annemarie; Verwijmeren, Carola; Roovers, Onno; Touw, Ivo P

    2011-03-01

    Ubiquitination of the CSF3R [CSF3 (colony-stimulating factor 3) receptor] occurs after activated CSF3Rs are internalized and reside in early endosomes. CSF3R ubiquitination is crucial for lysosomal routing and degradation. The E3 ligase SOCS3 (suppressor of cytokine signalling 3) has been shown to play a major role in this process. Deubiquitinating enzymes remove ubiquitin moieties from target proteins by proteolytic cleavage. Two of these enzymes, AMSH [associated molecule with the SH3 domain of STAM (signal transducing adaptor molecule)] and UBPY (ubiquitin isopeptidase Y), interact with the general endosomal sorting machinery. Whether deubiquitinating enzymes control CSF3R trafficking from early towards late endosomes is unknown. In the present study, we asked whether AMSH, UBPY or a murine family of deubiquitinating enzymes could fulfil such a role. This DUB family (deubiquitin enzyme family) comprises four members (DUB1, DUB1A, DUB2 and DUB2A), which were originally described as being haematopoietic-specific and cytokine-inducible, but their function in cytokine receptor routing and signalling has remained largely unknown. We show that DUB2A expression is induced by CSF3 in myeloid 32D cells and that DUB2 decreases ubiquitination and lysosomal degradation of the CSF3R, leading to prolonged signalling. These results support a model in which CSF3R ubiquitination is dynamically controlled at the early endosome by feedback mechanisms involving CSF3-induced E3 ligase (SOCS3) and deubiquitinase (DUB2A) activities.

  11. Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis.

    PubMed

    Mori, Francesco; Rossi, Silvia; Sancesario, Giulia; Codecà, Claudia; Mataluni, Giorgia; Monteleone, Fabrizia; Buttari, Fabio; Kusayanagi, Hajime; Castelli, Maura; Motta, Caterina; Studer, Valeria; Bernardi, Giorgio; Koch, Giacomo; Bernardini, Sergio; Centonze, Diego

    2011-02-01

    Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β(1-42) and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.

  12. Cerebrospinal Fluid IL-12p40, CXCL13 and IL-8 as a Combinatorial Biomarker of Active Intrathecal Inflammation

    PubMed Central

    Bielekova, Bibiana; Komori, Mika; Xu, Quangang; Reich, Daniel S.; Wu, Tianxia

    2012-01-01

    Diagnosis and management of the neuroinflammatory diseases of the central nervous system (CNS) are hindered by the lack of reliable biomarkers of active intrathecal inflammation. We hypothesized that measuring several putative inflammatory biomarkers simultaneously will augment specificity and sensitivity of the biomarker to the clinically useful range. Based on our pilot experiment in which we measured 18 inflammatory biomarkers in 10-fold concentrated cerebrospinal fluid (CSF) derived from 16 untreated patients with highly active multiple sclerosis (MS) we selected a combination of three CSF biomarkers, IL-12p40, CXCL13 and IL-8, for further validation. Concentrations of IL-12p40, CXCL13 and IL-8 were determined in a blinded fashion in CSF samples from an initial cohort (n = 72) and a confirmatory cohort (n = 167) of prospectively collected, untreated subjects presenting for a diagnostic work-up of possible neuroimmunological disorder. Diagnostic conclusion was based on a thorough clinical workup, which included laboratory assessment of the blood and CSF, neuroimaging and longitudinal follow-up. Receiver operating characteristic (ROC) curve analysis in conjunction with principal component analysis (PCA), which was used to combine information from all three biomarkers, assessed the diagnostic value of measured biomarkers. Each of the three biomarkers was significantly increased in MS and other inflammatory neurological disease (OIND) in comparison to non-inflammatory neurological disorder patients (NIND) at least in one cohort. However, considering all three biomarkers together improved accuracy of predicting the presence of intrathecal inflammation to the consistently good to excellent range (area under the ROC curve = 0.868–0.924). Future clinical studies will determine if a combinatorial biomarker consisting of CSF IL-12p40, CXCL13 and IL-8 provides utility in determining the presence of active intrathecal inflammation in diagnostically uncertain

  13. Biomarkers in pediatrics: children as biomarker orphans.

    PubMed

    Savage, William J; Everett, Allen D

    2010-12-01

    Biomarkers have enormous potential to improve patient care by establishing tests of diagnosis, prognosis, and treatment effects. Successfully translating a biomarker from discovery to clinical application demands high-quality discovery research and high-quality clinical studies for biomarker validation; however, there are additional challenges that face biomarker research in pediatrics. There are also additional characteristics of pediatric medicine that make biomarker research especially needed. This review focuses on the fundamentals of biomarkers, the additional considerations needed for applying biomarker research to children, and recommendations for advancing pediatric biomarker research.

  14. CSF 5-HIAA Predicts Suicide Risk after Attempted Suicide.

    ERIC Educational Resources Information Center

    Nordstrom, Peter; And Others

    1994-01-01

    Studied suicide risk after attempted suicide, as predicted by cerebrospinal fluid (CSF) monoamine metabolite concentrations, in 92 psychiatric mood disorder inpatients admitted shortly after attempting suicide. Results revealed that low CSF 5-hydroxyindoleacetic acid (5-HIAA) predicted short-range suicide risk after attempted suicide in mood…

  15. CSF-endorphines in acute and chronic brain lesions.

    PubMed

    Hamel, E

    1988-01-01

    In order to answer the question of an opioid influence on consciousness, a radio-immuno-assay (n = 852) of beta-endorphin and beta-LPH (beta-lipotropic hormone) in both ventricular CSF and blood plasma was carried out in 101 neurosurgical patients. The following results were obtained: I) beta-END and beta-LPH levels were found to be lower in the CSF than in blood plasma. II) beta-END and beta-LPH in the CSF was the same in both sexes. III) beta-END levels in the CSF decreased with age. IV) beta-END and beta-LPH levels showed a diurnal rhythm with a maximum in the late a. m. hours. V) beta-END levels in the ventricular CSF tend to decrease parallel to a drop in conciousness as well as with longlasting comatous states. VI) beta-END in ventricular CSF becomes higher with increasing systolic arterial blood pressure. VII) beta-END and beta-LPH levels in ventricular CSF are not correlated with the type of the disease, CSF pressure, body temperature or respiratory changes.

  16. Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children

    PubMed Central

    Meraz, José Eugenio Vázquez; Arellano-Galindo, José; Avalos, Armando Martínez; Mendoza-García, Emma; Jiménez-Hernández, Elva

    2016-01-01

    Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4 g/m2 of cyclophosphamide (CFA) and 10 μg/kg/day of granulocyte colony stimulating factor (G-CSF), B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 × 109/L. The average number of MNC/kg body weight (BW)/aphaeresis was 0.4 × 108 (0.1–1.4), 2.25 × 108 (0.56–6.28), and 1.02 × 108 (0.34–2.5) whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 106/kg (0.09–0.34), 1.04 × 106 (0.19–9.3), and 0.59 × 106 (0.17–0.87) and the count of CFU/kg BW/aphaeresis was 1.11 × 105 (0.31–2.12), 1.16 × 105 (0.64–2.97), and 1.12 × 105 (0.3–6.63) in groups A, B, and C, respectively. The collection was better in group B versus group A (p = 0.007 and p = 0.05, resp.) and in group C versus group A (p = 0.08 and p = 0.05, resp.). The collection of PBPCs was more effective in the group mobilized with CFM + G-CSF when the WBC exceeded 10 × 103/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy. PMID:26880960

  17. Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children.

    PubMed

    Meraz, José Eugenio Vázquez; Arellano-Galindo, José; Avalos, Armando Martínez; Mendoza-García, Emma; Jiménez-Hernández, Elva

    2016-01-01

    Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4 g/m(2) of cyclophosphamide (CFA) and 10 μg/kg/day of granulocyte colony stimulating factor (G-CSF), B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 × 10(9)/L. The average number of MNC/kg body weight (BW)/aphaeresis was 0.4 × 10(8) (0.1-1.4), 2.25 × 10(8) (0.56-6.28), and 1.02 × 10(8) (0.34-2.5) whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 10(6)/kg (0.09-0.34), 1.04 × 10(6) (0.19-9.3), and 0.59 × 10(6) (0.17-0.87) and the count of CFU/kg BW/aphaeresis was 1.11 × 10(5) (0.31-2.12), 1.16 × 10(5) (0.64-2.97), and 1.12 × 10(5) (0.3-6.63) in groups A, B, and C, respectively. The collection was better in group B versus group A (p = 0.007 and p = 0.05, resp.) and in group C versus group A (p = 0.08 and p = 0.05, resp.). The collection of PBPCs was more effective in the group mobilized with CFM + G-CSF when the WBC exceeded 10 × 10(3)/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy.

  18. Differences in Abundances of Cell-Signalling Proteins in Blood Reveal Novel Biomarkers for Early Detection Of Clinical Alzheimer's Disease

    PubMed Central

    Rocha de Paula, Mateus; Gómez Ravetti, Martín; Berretta, Regina; Moscato, Pablo

    2011-01-01

    Background In November 2007 a study published in Nature Medicine proposed a simple test based on the abundance of 18 proteins in blood to predict the onset of clinical symptoms of Alzheimer's Disease (AD) two to six years before these symptoms manifest. Later, another study, published in PLoS ONE, showed that only five proteins (IL-1, IL-3, EGF, TNF- and G-CSF) have overall better prediction accuracy. These classifiers are based on the abundance of 120 proteins. Such values were standardised by a Z-score transformation, which means that their values are relative to the average of all others. Methodology The original datasets from the Nature Medicine paper are further studied using methods from combinatorial optimisation and Information Theory. We expand the original dataset by also including all pair-wise differences of z-score values of the original dataset (“metafeatures”). Using an exact algorithm to solve the resulting Feature Set problem, used to tackle the feature selection problem, we found signatures that contain either only features, metafeatures or both, and evaluated their predictive performance on the independent test set. Conclusions It was possible to show that a specific pattern of cell signalling imbalance in blood plasma has valuable information to distinguish between NDC and AD samples. The obtained signatures were able to predict AD in patients that already had a Mild Cognitive Impairment (MCI) with up to 84% of sensitivity, while maintaining also a strong prediction accuracy of 90% on a independent dataset with Non Demented Controls (NDC) and AD samples. The novel biomarkers uncovered with this method now confirms ANG-2, IL-11, PDGF-BB, CCL15/MIP-1; and supports the joint measurement of other signalling proteins not previously discussed: GM-CSF, NT-3, IGFBP-2 and VEGF-B. PMID:21479255

  19. Imaging Biomarkers or Biomarker Imaging?

    PubMed Central

    Mitterhauser, Markus; Wadsak, Wolfgang

    2014-01-01

    Since biomarker imaging is traditionally understood as imaging of molecular probes, we highly recommend to avoid any confusion with the previously defined term “imaging biomarkers” and, therefore, only use “molecular probe imaging (MPI)” in that context. Molecular probes (MPs) comprise all kinds of molecules administered to an organism which inherently carry a signalling moiety. This review highlights the basic concepts and differences of molecular probe imaging using specific biomarkers. In particular, PET radiopharmaceuticals are discussed in more detail. Specific radiochemical and radiopharmacological aspects as well as some legal issues are presented. PMID:24967536

  20. Low CSF oxytocin reflects high intent in suicide attempters.

    PubMed

    Jokinen, Jussi; Chatzittofis, Andreas; Hellström, Christer; Nordström, Peter; Uvnäs-Moberg, Kerstin; Asberg, Marie

    2012-04-01

    Data from animal studies suggest that oxytocin is an important modulating neuropeptide in regulation of social interaction. One human study has reported a negative correlation between CSF oxytocin levels, life history of aggression and suicidal behaviour. We hypothesized that CSF oxytocin levels would be related to suicidal behaviour, suicide intent, lifetime interpersonal violence and suicide risk. 28 medication free suicide attempters and 19 healthy volunteers participated in this cross sectional and longitudinal study. CSF and plasma morning basal levels of oxytocin were assessed with specific radio-immunoassays. The Beck Suicide Intent Scale (SIS), the Freeman scale and the Karolinska Interpersonal Violence Scale (KIVS) were used to assess suicide intent and lifetime violent behaviour. All patients were followed up for cause of death. The mean follow-up was 21 years. Suicide attempters had lower CSF oxytocin levels compared to healthy volunteers p=0.077. In suicide attempters CSF oxytocin showed a significant negative correlation with the planning subscale of SIS. CSF oxytocin showed a significant negative correlation with suicide intent, the planning subscale of SIS and Freeman interruption probability in male suicide attempters. Correlations between plasma oxytocin levels and the planning subscale of SIS and Freeman interruption probability were significant in male suicide attempters. Lifetime violent behaviour showed a trend to negative correlation with CSF oxytocin. In the regression analysis suicide intent remained a significant predictor of CSF oxytocin corrected for age and gender whereas lifetime violent behaviour showed a trend to be a predictor of CSF oxytocin. Oxytocin levels did not differ significantly in suicide victims compared to survivors. CSF oxytocin may be an important modulator of suicide intent and interpersonal violence in suicide attempters.

  1. Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.

    PubMed

    Kumar, R G; Diamond, M L; Boles, J A; Berger, R P; Tisherman, S A; Kochanek, P M; Wagner, A K

    2015-03-01

    Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p⩽0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1β and IL-6 levels compared with the low TRAJ group (p⩽0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (χ(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated

  2. Adding Value.

    ERIC Educational Resources Information Center

    Orsini, Larry L.; Hudack, Lawrence R.; Zekan, Donald L.

    1999-01-01

    The value-added statement (VAS), relatively unknown in the United States, is used in financial reports by many European companies. Saint Bonaventure University (New York) has adapted a VAS to make it appropriate for not-for-profit universities by identifying stakeholder groups (students, faculty, administrators/support personnel, creditors, the…

  3. Disease Type- and Status-Specific Alteration of CSF Metabolome Coordinated with Clinical Parameters in Inflammatory Demyelinating Diseases of CNS

    PubMed Central

    Kong, Byung Soo; Lee, Jung-Eun; Kim, Kyoung Heon; Lee, Do Yup; Kim, Ho Jin

    2016-01-01

    Central nervous system (CNS) inflammatory demyelinating diseases (IDDs) are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and idiopathic transverse myelitis (ITM). Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF) metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls). Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs. PMID:27855220

  4. Cloning and expression of porcine Colony Stimulating Factor-1 (CSF-1) and Colony Stimulating Factor-1 Receptor (CSF-1R) and analysis of the species specificity of stimulation by CSF-1 and Interleukin 34

    PubMed Central

    Gow, Deborah J.; Garceau, Valerie; Kapetanovic, Ronan; Sester, David P.; Fici, Greg J.; Shelly, John A.; Wilson, Thomas L.; Hume, David A.

    2012-01-01

    Macrophage Colony Stimulating Factor (CSF-1) controls the survival, differentiation and proliferation of cells of the mononuclear phagocyte system. A second ligand for the CSF-1R, Interleukin 34 (IL-34), has been described, but its physiological role is not yet known. The domestic pig provides an alternative to traditional rodent models for evaluating potential therapeutic applications of CSF-1R agonists and antagonists. To enable such studies, we cloned and expressed active pig CSF-1. To provide a bioassay, pig CSF-1R was expressed in the factor-dependent Ba/F3 cell line. On this transfected cell line, recombinant porcine CSF-1 and human CSF-1 had identical activity. Mouse CSF-1 does not interact with the human CSF-1 receptor but was active on pig. By contrast, porcine CSF-1 was active on mouse, human, cat and dog cells. IL-34 was previously shown to be species-specific, with mouse and human proteins demonstrating limited cross-species activity. The pig CSF-1R was equally responsive to both mouse and human IL-34. Based upon the published crystal structures of CSF-1/CSF-1R and IL34/CSF-1R complexes, we discuss the molecular basis for the species specificity. PMID:22974529

  5. The CSF-1 receptor fashions the intestinal stem cell niche.

    PubMed

    Akcora, Dilara; Huynh, Duy; Lightowler, Sally; Germann, Markus; Robine, Sylvie; de May, Jan R; Pollard, Jeffrey W; Stanley, E Richard; Malaterre, Jordane; Ramsay, Robert G

    2013-03-01

    Gastrointestinal (GI) homeostasis requires the action of multiple pathways. There is some controversy regarding whether small intestine (SI) Paneth cells (PCs) play a central role in orchestrating crypt architecture and their relationship with Lgr5+ve stem cells. Nevertheless, we previously showed that germline CSF-1 receptor (Csf1r) knock out (KO) or Csf1 mutation is associated with an absence of mature PC, reduced crypt proliferation and lowered stem cell gene, Lgr5 expression. Here we show the additional loss of CD24, Bmi1 and Olfm4 expression in the KO crypts and a high resolution 3D localization of CSF-1R mainly to PC. The induction of GI-specific Csf1r deletion in young adult mice also led to PC loss over a period of weeks, in accord with the anticipated long life span of PC, changed distribution of proliferating cells and this was with a commensurate loss of Lgr5 and other stem cell marker gene expression. By culturing SI organoids, we further show that the Csf1r(-/-) defect in PC production is intrinsic to epithelial cells as well as definitively affecting stem cell activity. These results show that CSF-1R directly supports PC maturation and that in turn PCs fashion the intestinal stem cell niche.

  6. CXCL13, CXCL10 and CXCL8 as Potential Biomarkers for the Diagnosis of Neurosyphilis Patients

    PubMed Central

    Wang, Cuini; Wu, Kaiqi; Yu, Qian; Zhang, Sufang; Gao, Zixiao; Liu, Yudan; Ni, Liyan; Cheng, Yuanyuan; Guan, Zhifang; Shi, Mei; Lu, Haikong; Lou, Yongliang; Zhou, Pingyu

    2016-01-01

    At present, diagnosis for neurosyphilis remains a major clinical challenge. Venereal Disease Research Laboratory (VDRL) titer of the cerebrospinal fluid (CSF) is suboptimally sensitive to diagnose neurosyphilis, which can be negative in neurosyphilis patients, especially in asymptomatic neurosyphilis patients. In the search for biomarkers of neurosyphilis, we investigated the chemokine profile in CSF of neurosyphilis patients and found that the concentrations of CXCL13, CXCL10 and CXCL8 were selectively elevated in neurosyphilis patients and correlated with CSF protein concentration and CSF-VDRL titer. After antibiotic treatment, the concentration of these chemokines was dramatically reduced. The area under the ROC curve (AUC) of CSF CXCL13, CXCL8,CXCL10 and the CSF/serum ratio of CXCL13, CXCL8,CXCL10 in the diagnosis of neurosyphilis were 0.940, 0.899, 0.915, 0.963, 0.846 and 0.926, respectively. The corresponding sensitivities/specificities of CSF CXCL13, CXCL8,CXCL10 and the CSF/serum ratio of CXCL13, CXCL8,CXCL10 in diagnosis of neurosyphilis were 85.4%/89.1%, 79%/90.1% and 79.6%/91.1%, 86.6%/99%, 79%/73.3% and 86%/92.1%, respectively. Our results suggest that the elevated concentrations of CXCL13, CXCL8, and CXCL10 or their increasing CSF/serum ratios may be potential biomarkers of neurosyphilis, particularly for asymptomatic neurosyphilis. Reduced concentration of these chemokines may indicate the prognosis of antibiotic therapy. PMID:27650493

  7. Management of CSF Leaks Following Vestibular Schwannoma Surgery

    PubMed Central

    Mangus, Brannon D.; Rivas, Alejandro; Yoo, Mi Jin; Alvarez, JoAnn; Wanna, George B.; Haynes, David S.; Bennett, Marc L.

    2011-01-01

    Objective To evaluate the incidence and treatment of CSF leaks after resection of vestibular schwannomas and to propose a treatment algorithm for their management. Study Design Retrospective chart review. Setting Tertiary referral center. Patients Review of 1,922 subjects who underwent resection of vestibular schwannomas from 1970 through 2010. Intervention Surgical resection of vestibular schwannoma. Main Outcome Measures Patient demographics, surgical approach used, CSF leak incidence, meningitis, treatment and success in the management of CSF leaks. Results Postoperative CSF leaks were observed in 12.9% of our patients. There was no significant difference between the type of approach and the presence of CSF leak with translabyrinthine, suboccipital and middle fossa CSF leak rates of 12%, 12%, and 13% respectively (p=0.07). Patients presented with a wound leak or rhinorrhea almost equally. Ultimately, 92% of patients with rhinorrhea underwent surgical intervention. The probability of a patient with rhinorrhea requiring a second intervention was higher when the initial intervention was conservative rather than surgical. However, the probability of a patient with a wound leak requiring a second intervention was essentially the same when initially treated conservatively or surgically. Conclusion Our data suggests that there is no difference in CSF leak rates between the different surgical approaches. The appropriate treatment strategy is dependent on the presentation of the CSF. While conservative treatment is effective for managing wound leaks, it is less effective in managing patients with rhinorrhea. Therefore, surgical treatments should play an early role in the treatment algorithm of patients with CSF rhinorrhea. PMID:21970847

  8. Cerebrospinal Fluid Biomarker Candidates Associated with Human WNV Neuroinvasive Disease

    PubMed Central

    Fraisier, Christophe; Papa, Anna; Granjeaud, Samuel; Hintzen, Rogier; Martina, Byron; Camoin, Luc; Almeras, Lionel

    2014-01-01

    During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presented the highest increasing fold-change (FC>12). The augmentation of DEFA1 abundance in patients with WNND was confirmed at the CSF, but also in serum, compared to the control individual groups. Furthermore, the DEFA1 serum level was significantly elevated in WNND patients compared to subjects diagnosed for WNF. The present study provided the first insight into the potential CSF biomarkers associated with WNV neuroinvasion. Further investigation in larger cohorts with kinetic sampling could determine the usefulness of measuring DEFA1 as diagnostic or prognostic biomarker of detrimental WNND evolution. PMID:24695528

  9. Developmental and functional significance of the CSF-1 proteoglycan chondroitin sulfate chain

    PubMed Central

    Nandi, Sayan; Akhter, Mohammed P.; Seifert, Mark F.; Dai, Xu-Ming; Stanley, E. Richard

    2006-01-01

    The primary macrophage growth factor, colony-stimulating factor-1 (CSF-1), is homodimeric and exists in 3 biologically active isoforms: a membrane-spanning, cell-surface glycoprotein (csCSF-1) and secreted glycoprotein (sgCSF-1) and proteoglycan (spCSF-1) isoforms. To investigate the in vivo role of the chondroitin sulfate glycosaminoglycan (GAG) chain of spCSF-1, we created mice that exclusively express, in a normal tissue-specific and developmental manner, either the secreted precursor of spCSF-1 or the corresponding precursor in which the GAG addition site was mutated. The reproductive, hematopoietic tooth eruption and tissue macrophage defects of CSF-1-deficient, osteopetrotic Csf1op/Csf1op mice were corrected by transgenic expression of the precursors of either sgCSF-1 or spCSF-1. Furthermore, in contrast to the transgene encoding csCSF-1, both failed to completely correct growth retardation, suggesting a role for csCSF-1 in the regulation of body weight. However, spCSF-1, in contrast to sgCSF-1, completely resolved the osteopetrotic phenotype. Furthermore, in transgenic lines expressing different concentrations of sgCSF-1 or spCSF-1, spCSF-1 more efficiently corrected Csf1op/Csf1op defects of tooth eruption, eyelid opening, macrophage morphology, and B-cell deficiency than sgCSF-1. These results indicate an important role of the CSF-1 chondroitin sulfate proteoglycan in in vivo signaling by secreted CSF-1. (Blood. 2006;107:786-795) PMID:16210339

  10. Improved multimodal biomarkers for Alzheimer's disease and mild cognitive impairment diagnosis: data from ADNI

    NASA Astrophysics Data System (ADS)

    Martinez-Torteya, Antonio; Treviño-Alvarado, Víctor; Tamez-Peña, José

    2013-02-01

    The accurate diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) confers many clinical research and patient care benefits. Studies have shown that multimodal biomarkers provide better diagnosis accuracy of AD and MCI than unimodal biomarkers, but their construction has been based on traditional statistical approaches. The objective of this work was the creation of accurate AD and MCI diagnostic multimodal biomarkers using advanced bioinformatics tools. The biomarkers were created by exploring multimodal combinations of features using machine learning techniques. Data was obtained from the ADNI database. The baseline information (e.g. MRI analyses, PET analyses and laboratory essays) from AD, MCI and healthy control (HC) subjects with available diagnosis up to June 2012 was mined for case/controls candidates. The data mining yielded 47 HC, 83 MCI and 43 AD subjects for biomarker creation. Each subject was characterized by at least 980 ADNI features. A genetic algorithm feature selection strategy was used to obtain compact and accurate cross-validated nearest centroid biomarkers. The biomarkers achieved training classification accuracies of 0.983, 0.871 and 0.917 for HC vs. AD, HC vs. MCI and MCI vs. AD respectively. The constructed biomarkers were relatively compact: from 5 to 11 features. Those multimodal biomarkers included several widely accepted univariate biomarkers and novel image and biochemical features. Multimodal biomarkers constructed from previously and non-previously AD associated features showed improved diagnostic performance when compared to those based solely on previously AD associated features.

  11. CSF interleukin-6 in neonatal Citrobacter ventriculitis after meningitis.

    PubMed

    Baumeister, F A; Hofer, M; Küster, H; Belohradsky, B H

    2000-01-01

    An infant with neonatal severe Citrobacter koseri (formerly Citrobacter diversus) meningoencephalitis developed necrosis with multicystic regression of both hemispheres. The ventriculitis persisted over months in spite of antibiotic therapy. The treatment succeeded with cefotaxime in a high dose (300 mg/kg/day) without surgical intervention. The infant had been previously treated with cefotaxime (200 mg/kg/day) over 5 weeks. High levels of CSF interleukin-6 (IL-6) permitted to attribute persisting CSF pleocytosis in spite of sterile CSF cultures to chronic infection and not to reminiscence of brain necrosis. This report reveals two main points. On the one hand, the importance of therapy monitoring with IL-6 in CSF for the consequent treatment of Citrobacter meningitis and on the other hand, high-dose cefotaxime (300 mg/kg/day) treatment of Citrobacter ventriculitis, which succeeded without surgical intervention.

  12. Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease

    PubMed Central

    Jiménez-Jiménez, Félix J.; Alonso-Navarro, Hortensia; García-Martín, Elena; Agúndez, José A. G.

    2014-01-01

    The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD. PMID:25426023

  13. Blood-based biomarkers of Alzheimer's disease: diagnostic algorithms and new technologies.

    PubMed

    Carmona, Pedro; Molina, Marina; Toledano, Adolfo

    2016-01-01

    New concepts about Alzheimer's disease (AD), considered as a clinical-biological entity, make essential the definition of biomarkers that could be used for the in vivo diagnosis of the disorder before dementia develops. Different types of genetic, biochemical and neuroimaging markers have been described, highlighting some of the changes that occur in the brain during the course of the disease, yet there is little proof of their pathognomonic and diagnostic value. Furthermore, many of the assays used are difficult to perform, the equipment/reagents are expensive or potentially hazardous (e.g.; use of radioactive compounds, CSF extraction). Thus, there is a need to define more suitable and convenient approaches, such as the determination of blood parameters that are easy to obtain and that can be repeated as necessary without contraindications. These data can be used by algorithms that combine specific and non-specific changes to classify patients at different stages of AD and/or distinguish AD from other related diseases with a greater specificity and reliability (> 80%). The blood parameters considered in this review are varied, including: β-amyloid, tau, apolipoproteins and proteins, as well as the metabolic behavior of blood cells, etc. Among the proteins, cytokines/chemokines and other cell factors related to both neuro-inflammatory and peripheral-inflammatory processes in AD are of prime importance. New technologies to detect and quantify these substances, reasonably priced such as the vibrational spectroscopy, panels of parameters and algorithms to assess the results, would be fundamental for the early AD diagnosis and to define new potential therapies.

  14. Use of biomarkers in clinical trials of Alzheimer disease: from concept to application.

    PubMed

    Wu, Liyong; Rosa-Neto, Pedro; Gauthier, Serge

    2011-12-01

    Research progress during the last decades has resulted in an unprecedented accumulation of knowledge regarding the molecular pathogenesis of Alzheimer disease (AD). These important achievements toward clarifying the mechanistic processes underlying AD are being translated into ongoing development of biomarkers and their use in clinical trials. AD biomarkers are biochemical and anatomical variables (e.g. cerebrospinal fluid, positron emission tomography, and structural MRI) that measure AD-related pathologic features (i.e. amyloid deposition and neurodegeneration) in vivo. Biomarkers are utilized as 'diagnostic biomarkers' and/or 'endpoint biomarkers' in symptomatic or disease-modifying clinical trials. Diagnostic biomarkers play an important role in population enrichment by refining selection criteria, stratifying populations, and increasing the statistical power of trials. Endpoint biomarkers may be used as outcome measures to monitor the rate of disease progression and detect treatment effects. AD biomarkers do not reach abnormal levels or peak simultaneously, but do so in a time-dependent order. The choice of biomarkers for a clinical trial must take into consideration the type of therapeutic intervention, the clinical stage of AD, and the time dependence of biomarker changes during disease progression. The combination of amyloid and neurodegeneration biomarkers is highly desirable since they capture different aspects of the disease. Clinical trials for every clinical stage of AD would benefit from quantification and standardization of biomarkers. However, this is still a work in progress.

  15. Elevated CSF outflow resistance associated with impaired lymphatic CSF absorption in a rat model of kaolin-induced communicating hydrocephalus

    PubMed Central

    2010-01-01

    Background We recently reported a lymphatic cerebrospinal fluid (CSF) absorption deficit in a kaolin model of communicating hydrocephalus in rats with ventricular expansion correlating negatively with the magnitude of the impediment to lymphatic function. However, it is possible that CSF drainage was not significantly altered if absorption at other sites compensated for the lymphatic defect. The purpose of this study was to investigate the impact of the lymphatic absorption deficit on global CSF absorption (CSF outflow resistance). Methods Kaolin was injected into the basal cisterns of Sprague Dawley rats. The development of hydrocephalus was assessed using magnetic resonance imaging (MRI). In one group of animals at about 3 weeks after injection, the movement of intraventricularly injected iodinated human serum albumin (125I-HSA) into the olfactory turbinates provided an estimate of CSF transport through the cribriform plate into nasal lymphatics (n = 18). Control animals received saline in place of kaolin (n = 10). In a second group at about 3.5 weeks after kaolin injection, intraventricular pressure was measured continuously during infusion of saline into the spinal subarachnoid space at various flow rates (n = 9). CSF outflow resistance was calculated as the slope of the steady-state pressure versus flow rate. Control animals for this group either received no injections (intact: n = 11) or received saline in place of kaolin (n = 8). Results Compared to saline injected controls, lateral ventricular volume in the kaolin group was significantly greater (0.087 ± 0.013 ml, n = 27 versus 0.015 ± 0.001 ml, n = 17) and lymphatic function was significantly less (2.14 ± 0.72% injected/g, n = 18 versus 6.38 ± 0.60% injected/g, n = 10). Additionally, the CSF outflow resistance was significantly greater in the kaolin group (0.46 ± 0.04 cm H2O.μL-1.min, n = 9) than in saline injected (0.28 ± 0.03 cm H2O.μL-1.min, n = 8) or intact animals (0.18 ± 0.03 cm H2O.μL-1

  16. Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study.

    PubMed

    Afifi, S; Adel, N G; Devlin, S; Duck, E; Vanak, J; Landau, H; Chung, D J; Lendvai, N; Lesokhin, A; Korde, N; Reich, L; Landgren, O; Giralt, S; Hassoun, H

    2016-04-01

    Cyclophosphamide plus G-CSF (C+G-CSF) is one of the most widely used stem cell (SC) mobilization regimens for patients with multiple myeloma (MM). Plerixafor plus G-CSF (P+G-CSF) has demonstrated superior SC mobilization efficacy when compared with G-CSF alone and has been shown to rescue patients who fail mobilization with G-CSF or C+G-CSF. Despite the proven efficacy of P+G-CSF in upfront SC mobilization, its use has been limited, mostly due to concerns of high price of the drug. However, a comprehensive comparison of the efficacy and cost effectiveness of SC mobilization using C+G-CSF versus P+G-CSF is not available. In this study, we compared 111 patients receiving C+G-CSF to 112 patients receiving P+G-CSF. The use of P+G-CSF was associated with a higher success rate of SC collection defined as ⩾5 × 10(6) CD34+ cells/kg (94 versus 83%, P=0.013) and less toxicities. Thirteen patients in the C+G-CSF arm were hospitalized owing to complications while none in the P+G-CSF group. C+G-CSF was associated with higher financial burden as assessed using institutional-specific costs and charges (P<0.001) as well as using Medicare reimbursement rates (P=0.27). Higher rate of hospitalization, increased need for salvage mobilization, and increased G-CSF use account for these differences.

  17. Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

    PubMed Central

    Raymond, Gerald V.; Pasquali, Marzia; Polgreen, Lynda E.; Dickson, Patricia I.; Miller, Weston P.; Orchard, Paul J.; Lund, Troy C.

    2016-01-01

    Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14–37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3–8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies. PMID:27910891

  18. Post craniotomy extra-ventricular drain (EVD) associated nosocomial meningitis: CSF diagnostic criteria.

    PubMed

    Muñoz-Gómez, Sigridh; Wirkowski, Elizabeth; Cunha, Burke A

    2015-01-01

    Because external ventricular drains (EVDs) provide access to cerebrospinal fluid (CSF), there is potential for EVD associated acute bacterial meningitis (EVD-AM). Post-craniotomy, in patients with EVDs, one or more CSF abnormalities are commonly present making the diagnosis of EVD-AM problematic. EVD-AM was defined as elevated CSF lactic acid (>6 nmol/L), plus CSF marked pleocytosis (>50 WBCs/mm(3)), plus a positive Gram stain (same morphology as CSF isolate), plus a positive CSF culture of neuropathogen (same morphology as Gram stained organism). We reviewed 22 adults with EVDs to determine if our four CSF parameters combined accurately identified EVD-AM. No single or combination of <4 CSF parameters correctly diagnosed or ruled out EVD-AM. Combined our four CSF parameters clearly differentiated EVD-AM from one case of pseudomeningitis due to E. cloacae. We conclude that our four CSF criteria combined are useful in diagnosing EVD-AM in adults.

  19. Development of the choroid plexus and blood-CSF barrier

    PubMed Central

    Liddelow, Shane A.

    2015-01-01

    Well-known as one of the main sources of cerebrospinal fluid (CSF), the choroid plexuses have been, and still remain, a relatively understudied tissue in neuroscience. The choroid plexus and CSF (along with the blood-brain barrier proper) are recognized to provide a robust protective effort for the brain: a physical barrier to impede entrance of toxic metabolites to the brain; a “biochemical” barrier that facilitates removal of moieties that circumvent this physical barrier; and buoyant physical protection by CSF itself. In addition, the choroid plexus-CSF system has been shown to be integral for normal brain development, central nervous system (CNS) homeostasis, and repair after disease and trauma. It has been suggested to provide a stem-cell like repository for neuronal and astrocyte glial cell progenitors. By far, the most widely recognized choroid plexus role is as the site of the blood-CSF barrier, controller of the internal CNS microenvironment. Mechanisms involved combine structural diffusion restraint from tight junctions between plexus epithelial cells (physical barrier) and specific exchange mechanisms across the interface (enzymatic barrier). The current hypothesis states that early in development this interface is functional and more specific than in the adult, with differences historically termed as “immaturity” actually correctly reflecting developmental specialization. The advanced knowledge of the choroid plexus-CSF system proves itself imperative to understand a range of neurological diseases, from those caused by plexus or CSF drainage dysfunction (e.g., hydrocephalus) to more complicated late-stage diseases (e.g., Alzheimer's) and failure of CNS regeneration. This review will focus on choroid plexus development, outlining how early specializations may be exploited clinically. PMID:25784848

  20. Biomarkers in Japanese Encephalitis: A Review

    PubMed Central

    Kant Upadhyay, Ravi

    2013-01-01

    JE is a flavivirus generated dreadful CNS disease which causes high mortality in various pediatric groups. JE disease is currently diagnosed by measuring the level of viral antigens and virus neutralization IgM antibodies in blood serum and CSF by ELISA. However, it is not possible to measure various disease-identifying molecules, structural and molecular changes occurred in tissues, and cells by using such routine methods. However, few important biomarkers such as cerebrospinal fluid, plasma, neuro-imaging, brain mapping, immunotyping, expression of nonstructural viral proteins, systematic mRNA profiling, DNA and protein microarrays, active caspase-3 activity, reactive oxygen species and reactive nitrogen species, levels of stress-associated signaling molecules, and proinflammatory cytokines could be used to confirm the disease at an earlier stage. These biomarkers may also help to diagnose mutant based environment specific alterations in JEV genotypes causing high pathogenesis and have immense future applications in diagnostics. There is an utmost need for the development of new more authentic, appropriate, and reliable physiological, immunological, biochemical, biophysical, molecular, and therapeutic biomarkers to confirm the disease well in time to start the clinical aid to the patients. Hence, the present review aims to discuss new emerging biomarkers that could facilitate more authentic and fast diagnosis of JE disease and its related disorders in the future. PMID:24455705

  1. CSF Concentrations of cAMP and cGMP Are Lower in Patients with Creutzfeldt-Jakob Disease but Not Parkinson's Disease and Amyotrophic Lateral Sclerosis

    PubMed Central

    Oeckl, Patrick; Steinacker, Petra; Lehnert, Stefan; Jesse, Sarah; Kretzschmar, Hans A.; Ludolph, Albert C.; Otto, Markus; Ferger, Boris

    2012-01-01

    Background The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) are important second messengers and are potential biomarkers for Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD). Methodology/Principal Findings Here, we investigated by liquid chromatography/tandem mass spectrometry (LC-MS/MS) the cerebrospinal fluid (CSF) concentrations of cAMP and cGMP of 82 patients and evaluated their diagnostic potency as biomarkers. For comparison with a well-accepted biomarker, we measured tau concentrations in CSF of CJD and control patients. CJD patients (n = 15) had lower cAMP (−70%) and cGMP (−55%) concentrations in CSF compared with controls (n = 11). There was no difference in PD, PD dementia (PDD) and ALS cases. Receiver operating characteristic (ROC) curve analyses confirmed cAMP and cGMP as valuable diagnostic markers for CJD indicated by the area under the curve (AUC) of 0.86 (cAMP) and 0.85 (cGMP). We calculated a sensitivity of 100% and specificity of 64% for cAMP and a sensitivity of 67% and specificity of 100% for cGMP. The combination of both nucleotides increased the sensitivity to 80% and specificity to 91% for the term cAMPxcGMP (AUC 0.92) and to 93% and 100% for the ratio tau/cAMP (AUC 0.99). Conclusions/Significance We conclude that the CSF determination of cAMP and cGMP may easily be included in the diagnosis of CJD and could be helpful in monitoring disease progression as well as in therapy control. PMID:22396786

  2. PHOSPHORYLATED TAU: CANDIDATE BIOMARKER FOR AMYOTROPHIC LATERAL SCLEROSIS

    PubMed Central

    Grossman, Murray; Elman, Lauren; McCluskey, Leo; McMillan, Corey T.; Boller, Ashley; Powers, John; Rascovsky, Katya; Hu, William; Shaw, Les; Irwin, David J.; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2014-01-01

    IMPORTANCE An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility is necessary. OBJECTIVE We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS. DESIGN Case-control study. SETTING Academic medical center. PARTICIPANTS 51 individuals with ALS and 23 individuals with a disorder associated with a four-repeat tauopathy (4R-tau). MAIN OUTCOME MEASURE CSF level of tau phosophorylated at threonine 181 (ptau), and ratio of ptau to total tau (ttau). RESULTS Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and ptau:ttau in ALS relative to 4R-tau and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS to 4R-tau showed sensitivity=92% and specificity=91.7%. Correct classification based on low CSF ptau:ttau was confirmed in 18 (85.7%) of 21 cases with autopsy-proven or genetically-determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity such as Mini Mental State Exam (n=51) and ALS Functional Rating Scale-Revised (n=42), and regression analyses related ptau:ttau to MRI (n=10) evidence of disease in the corticospinal tract and white matter projections involving prefrontal cortex. CONCLUSIONS AND RELEVANCE CSF ptau:ttau may be a candidate biomarker to provide objective support for the diagnosis of ALS. PMID:24492862

  3. Intracerebral microdialysis and CSF hydrodynamics in idiopathic adult hydrocephalus syndrome

    PubMed Central

    Agren-Wilsson, A; Roslin, M; Eklund, A; Koskinen, L; Bergenheim, A; Malm, J

    2003-01-01

    Background: In idiopathic adult hydrocephalus syndrome (IAHS), a pathophysiological model of "chronic ischaemia" caused by an arteriosclerotic process in association with a CSF hydrodynamic disturbance has been proposed. Objective: To investigate whether CSF hydrodynamic manipulation has an impact on biochemical markers related to ischaemia, brain tissue oxygen tension (PtiO2), and intracranial pressure. Methods: A microdialysis catheter, a PtiO2 probe, and an intracerebral pressure catheter were inserted into the periventricular white matter 0–7 mm from the right frontal horn in 10 patients with IAHS. A subcutaneous microdialysis probe was used as reference. Intracranial pressure and intracerebral PtiO2 were recorded continuously. Samples were collected for analysis between 2 and 4 pm on day 1 (baseline) and at the same time on day 2, two to four hours after a lumbar CSF hydrodynamic manipulation. The concentrations of glucose, lactate, pyruvate, and glutamate on day 1 and 2 were compared. Results: After CSF drainage, there was a significant rise in the intracerebral concentration of lactate and pyruvate. The lactate to pyruvate ratio was increased and remained unchanged after drainage. There was a trend towards a lowering of glucose and glutamate. Mean intracerebral PtiO2 was higher on day 2 than on day 1 in six of eight patients. Conclusions: There is increased glucose metabolism after CSF drainage, as expected in a situation of postischaemic recovery. These new invasive techniques are promising tools in the future study of the pathophysiological processes in IAHS. PMID:12531954

  4. GM-CSF alters dendritic cells in autoimmune diseases.

    PubMed

    Li, Bao-Zhu; Ye, Qian-Ling; Xu, Wang-Dong; Li, Jie-Hua; Ye, Dong-Qing; Xu, Yuekang

    2013-11-01

    Autoimmune diseases arise from an inappropriate immune response against self components, including macromolecules, cells, tissues, organs etc. They are often triggered or accompanied by inflammation, during which the levels of granulocyte macrophage colony-stimulating factor (GM-CSF) are elevated. GM-CSF is an inflammatory cytokine that has profound impact on the differentiation of immune system cells of myeloid lineage, especially dendritic cells (DCs) that play critical roles in immune initiation and tolerance, and is involved in the pathogenesis of autoimmune diseases. Although GM-CSF was discovered decades ago, recent studies with some new findings have shed an interesting light on the old hematopoietic growth factor. In the inflammatory autoimmune diseases, GM-CSF redirects the normal developmental pathway of DCs, conditions their antigen presentation capacities and endows them with unique cytokine signatures to affect autoimmune responses. Here we review the latest advances in the field, with the aim of demonstrating the effects of GM-CSF on DCs and their influences on autoimmune diseases. The summarized knowledge will help to design DC-based strategies for the treatment of autoimmune diseases.

  5. CSF hypocretin-1 assessment in sleep and neurological disorders.

    PubMed

    Bourgin, Patrice; Zeitzer, Jamie M; Mignot, Emmanuel

    2008-07-01

    Concentrations of CSF hypocretin-1 (formerly orexin A) have been measured in many patients with sleep or neurological conditions. Low CSF hypocretin-1 is most predictive of narcolepsy in patients positive for HLA allele DQB1*0602, most of whom have cataplexy. By contrast, the diagnostic significance of low CSF hypocretin-1 is unclear in the presence of acute CNS inflammation or trauma. The clinical usefulness of CSF testing in hypersomnia that is symptomatic of a neurological disorder remains to be evaluated. Determination of CSF hypocretin-1 concentration to diagnose narcolepsy might be most useful in ambulatory patients with cataplexy but with a normal multiple sleep latency test (MSLT) result, or if MSLT is not interpretable, conclusive, or feasible. Because 98% of patients with hypocretin-1 deficiency are positive for HLA DQB1*0602, we suggest that HLA typing is a useful screen before lumbar puncture. Although hypocretin-1 deficiency in narcolepsy might have therapeutic relevance, additional research is needed in this area.

  6. G-CSF attenuates noise-induced hearing loss.

    PubMed

    Shi, Ze-tao; Lin, Ying; Wang, Jie; Wu, Jin; Wang, Ren-feng; Chen, Fu-quan; Mi, Wen-juan; Qiu, Jian-hua

    2014-03-06

    In this study, we investigated the effects of granulocyte colony-stimulating factor (G-CSF) for the treatment of noise-induced hearing loss (NIHL) in a guinea pig model. Forty guinea pigs were randomly divided into four groups: control, noise (white noise, 3 h/d for 2 days at 115 dB), noise+G-CSF (350 μg/kg/d for 5 days), and noise+saline. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) were used to determine the hearing threshold and outer hair cell function, respectively, in each group. Cochlear morphology was examined to evaluate hair cell injury induced by intense noise exposure. Fourteen days after noise exposure, the noise+G-CSF group had a lower ABR value than the noise group (P<0.05) or the noise+saline group (P<0.01). At most frequencies, the DPOAE value of the noise+G-CSF group showed a significant rise (P<0.05) compared to the noise group or the noise+saline group. Neither the ABR value nor the DPOAE value differed between the noise group and the noise+saline group. The morphology of the phalloidin-stained organ of Corti was consistent with the functional measurements. In conclusion, G-CSF can preserve hearing in an experimental model of NIHL in guinea pigs, by preserving hair cells after intense noise exposure.

  7. Using biomarkers to improve detection of Alzheimer’s disease

    PubMed Central

    Biagioni, Milton C; Galvin, James E

    2011-01-01

    SUMMARY Disease-modifying approaches for Alzheimer’s disease (AD) might be most effective when initiated very early in the course, before the pathologic burden and neuronal and synaptic degeneration make it unlikely that halting disease progression would have a significant impact on patient outcomes. Biomarkers of disease may provide important avenues of research to enhance the diagnosis of individuals with early AD and could assist in the identification of those individuals at risk for developing AD. However, for such biomarkers to become clinically useful, long-term follow-up studies are necessary to evaluate the relevance of cross-sectional biomarker changes to the longitudinal course of the disease. The objective of this article is to review recent progress in AD biomarkers for the early diagnosis, classification, progression and prediction of AD and their usefulness in new treatment trials. PMID:22076127

  8. Using biomarkers to improve detection of Alzheimer's disease.

    PubMed

    Biagioni, Milton C; Galvin, James E

    2011-04-01

    Disease-modifying approaches for Alzheimer's disease (AD) might be most effective when initiated very early in the course, before the pathologic burden and neuronal and synaptic degeneration make it unlikely that halting disease progression would have a significant impact on patient outcomes. Biomarkers of disease may provide important avenues of research to enhance the diagnosis of individuals with early AD and could assist in the identification of those individuals at risk for developing AD. However, for such biomarkers to become clinically useful, long-term follow-up studies are necessary to evaluate the relevance of cross-sectional biomarker changes to the longitudinal course of the disease. The objective of this article is to review recent progress in AD biomarkers for the early diagnosis, classification, progression and prediction of AD and their usefulness in new treatment trials.

  9. Cerebrospinal Fluid Calbindin D Concentration as a Biomarker of Cerebellar Disease Progression in Niemann-Pick Type C1 Disease

    PubMed Central

    Bagel, Jessica; Sampson, Maureen; Farhat, Nicole; Ding, Wenge; Swain, Gary; Prociuk, Maria; O’Donnell, Patricia; Drobatz, Kenneth; Gurda, Brittney; Wassif, Christopher; Remaley, Alan; Porter, Forbes; Vite, Charles

    2016-01-01

    Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HPβCD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HPβCD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials. PMID:27307499

  10. Plasma and cerebrospinal fluid biomarkers predict cerebral injury in HIV-infected individuals on stable combination antiretroviral therapy

    PubMed Central

    Anderson, Albert M.; Harezlak, Jaroslaw; Bharti, Ajay; Mi, Deming; Taylor, Michael J.; Daar, Eric S.; Schifitto, Giovanni; Zhong, Jianhui; Alger, Jeffry R.; Brown, Mark S.; Singer, Elyse J.; Campbell, Thomas B.; McMahon, Deborah D.; Buchthal, Steven; Cohen, Ronald; Yiannoutsos, Constantin; Letendre, Scott L.; Navia, Bradford A.

    2015-01-01

    Objectives HIV-associated brain injury persists despite antiretroviral therapy (cART), but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy (MRS) in chronically HIV-infected subjects. Methods Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1β, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate+Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Predictive models were built via linear regression and the best models were chosen using the Akaike Information Criterion. Results Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG while metabolite changes in the FWM for NAA/Cr, GlxCr and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1β. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the three models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and MRS metabolites. Conclusions Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region dependent manner in chronically HIV-infected patients on stable cART. PMID:25622053

  11. White matter diffusivity predicts memory in patients with subjective and mild cognitive impairment and normal CSF total tau levels.

    PubMed

    Grambaite, Ramune; Stenset, Vidar; Reinvang, Ivar; Walhovd, Kristine B; Fjell, Anders M; Fladby, Tormod

    2010-01-01

    Subjective and mild cognitive impairment (SCI and MCI) are etiologically heterogeneous conditions. This poses problems for assessment of pathophysiological mechanisms and risk of conversion to dementia. Neuropsychological, imaging, and cerebrospinal fluid (CSF) findings serve to distinguish Alzheimer's disease (AD) and other etiological subgroups. Tau-molecules stabilize axonal microtubuli; high CSF total tau (T-tau) reflects ongoing axonal damage consistent with AD. Here, we stratify patients by CSF T-tau pathology to determine if memory network diffusion tensor imaging (DTI) predicts memory performance in the absence of elevated T-tau. We analyzed neuropsychological test results, hippocampus volume (HcV) and white matter diffusivity in 45 patients (35 with normal T-tau). The T-tau pathology group showed more hippocampus atrophy and memory impairment than the normal T-tau group. In the T-tau normal group: (1) memory was related with white matter diffusivity [fractional anisotropy (FA) and radial diffusivity (DR)], and (2) FA of the genu corpus callosum was a unique predictor of variance for verbal learning, and HcV did not contribute to this prediction. The smaller sample size in the T-tau pathology group precludes firm conclusions. In the normal T-tau group, white matter tract and memory changes may be associated with normal aging, or with non-tau related pathological mechanisms.

  12. Biomarkers in Frontotemporal Lobar Degenerations – Progress and Challenges

    PubMed Central

    Hu, William T.; Trojanowski, John Q.; Shaw, Leslie M.

    2011-01-01

    Neuronal and glial changes associated with tau, TAR DNA binding protein of ~43 kD (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice. PMID:21554923

  13. Segmentation and quantification for Alzheimer's disease (AD): a preliminary study

    NASA Astrophysics Data System (ADS)

    Lei, Tianhu; Udupa, Jayaram K.; Zhuge, Ying; Moonis, Gul; Clark, Christopher

    2003-05-01

    Alzheimer's is a progressive brain disease and is clinically characterized by cognitive symptoms that, in combination with behavioral disturbances, significantly interfere with activities of daily living. The purpose of this study is to investigate the possibility of developing volumetric measures of the structural damage and atrophy of brain derived from multiprotocol MR imaging. Our approach first applies intensity inhomogeneity correction and intensity standardization to PD and T2 weighted MR images to create base images for quantitative image analysis. Then, vectorial scale-based fuzzy connectedness segmentation (VSFCS) and morphological operations are applied to the base images to extract masks of cerebrospinal fluid (CSF), grey matter (GM), and white matter (WM), and further to create a clean and accurate intracranial (IC) mask. After separating CSF from brain parenchyma (BP), VSFCS is applied to BP (PD and T2) images to generate pure GM and WM masks, and then subtracting these pure from the BP mask to detect AD lesions. This method was applied to a set of conventional PD and T2 weighted MR images that were obtained from 5 patients with probable AD and 5 healthy normal control subjects. The segmented images of individual brain tissue regions (CSF, GM, WM, and AD lesion) are consistent with a Neuroradiologist's examination. The quantitative analysis shows that patients with AD have more atrophy. The mean value of the volume of brain parenchyma of patients with AD is about 10% less than that of healthy controls.

  14. Echocardiographic findings in patients with spontaneous CSF leak.

    PubMed

    Pimienta, Allen L; Rimoin, David L; Pariani, Mitchel; Schievink, Wouter I; Reinstein, Eyal

    2014-10-01

    The presence of cardiovascular abnormalities in patients with spontaneous cerebrospinal fluid (CSF) leaks are not well-documented in the literature, as cardiovascular evaluation is not generally pursued if a patient does not exhibit additional clinical features suggesting an inherited connective tissue disorder. We aimed to assess this association, enrolling a consecutive group of 50 patients referred for spinal CSF leak consultation. Through echocardiographic evaluation and detailed medical history, we estimate that up to 20% of patients presenting with a spontaneous CSF leak may have some type of cardiovascular abnormality. Further, the increase in prevalence of aortic dilatation in our cohort was statistically significant in comparison to the estimated population prevalence. This supports a clinical basis for echocardiographic screening of these individuals for cardiovascular manifestations that may have otherwise gone unnoticed or evolved into a more severe manifestation.

  15. Gene therapy for human nasopharyngeal carcinoma by adenovirus-mediated transfer of human p53, GM-CSF, and B7-1 genes in a mouse xenograft tumor model.

    PubMed

    Ren, Su-Ping; Wang, Lan; Wang, Hua; Wu, Bin; Han, Ying; Wang, Li-Sheng; Wu, Chu-Tse

    2008-10-01

    Incidence of nasopharyngeal carcinoma (NPC) remains high in endemic regions. Prevention of tumor recurrences and metastases is a crucial approach to improve therapeutic outcome in NPC patients. In this study, we investigated the effects of the cotransfer of the tumor suppressor gene, p53, in combination with the immunostimulatory genes, GM-CSF and B7-1, on tumor regression and subsequent tumor recurrence. We constructed a recombinant adenovirus carrying human wild-type p53, granulocyte-macrophage colony-stimulating factor (GM-CSF), and B7-1 genes (Ad-p53/GM-CSF/B7-1), which mediated high-level expression of these three genes in NPC CNE-1 cells. Ad-p53/GM-CSF/B7-1 infection inhibited the growth of CNE-1 cells and induced tumor-specific cytotoxic T-lymphocytes (CTLs) in vitro. In CNE-1 xenograft tumor models in huPBL-nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, an intratumoral injection of Ad-p53/GM-CSF/B7-1 resulted in a reduced tumor burden, compared to normal saline (NS) and Ad-p53 controls. Tumors in the Ad-p53/GM-CSF/B7-1 group displayed diffuse necrosis and infiltration of human T-cells. Further, the tumor occurrence of CNE-1 cell rechallenge largely decreased after the primary tumor was intratumorally injected with Ad-p53/GM-CSF/B7-1 in the HuPBL-NOD/SCID mice model. Only 2 of 8 (25%) animals in the Ad-p53/GM-CSF/B7-1 group had developed measurable tumors, which demonstrated extensive necrosis and much more human T-cell infiltration, compared to 5 of 7 (71%) in the NS and Ad-p53 groups. Therefore, the adenovirus-mediated introduction of p53, GM-CSF, and B7-1 genes could improve local control and prevent the recurrence or metastases of NPC tumors, which suggests a potential therapeutic value in NPC treatment.

  16. The role of G-CSF and IL-6 in the granulopoiesis-stimulating activity of murine blood serum induced by perorally administered ultrafiltered pig leukocyte extract, IMUNOR.

    PubMed

    Vacek, Antonín; Hofer, Michal; Holá, Jirina; Weiterová, Lenka; Streitová, Denisa; Svoboda, Jaroslav

    2007-05-01

    IMUNOR, a low-molecular weight (< 12 kD) ultrafiltered pig leukocyte extract, has been previously found to have significant stimulatory effects on murine hematopoiesis supressed by ionizing radiation or cytotoxic drugs. This communication shows data on the mechanisms of these effects. Using ELISA assay, significantly increased levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed. On the contrary, no detectable levels of granulocyte-macrophage colony-stimulating factor (GM-CFC) and interleukin-3 (IL-3) have been found in blood serum of IMUNOR-treated mice. Incubation of the serum from IMUNOR-treated mice with antibodies against G-CSF caused abrogation of the ability of the sera to stimulate in vitro growth of colonies originating from granulocyte-macrophage progenitor cells (GM-CFC). In contrast, incubation of the serum with antibodies against IL-6 did not change its colony-stimulating activity. It may be inferred from these findings that G-CSF is probably the main cytokine responsible for the granulopoiesis-stimulating effects of IMUNOR. When the serum from IMUNOR-treated mice with G-CSF inactivated by anti-G-CSF antibodies (but with elevated IL-6) was added to cultures of bone marrow cells together with a suboptimum concentration of IL-3, a significant increase in the numbers of GM-CFC colonies was found. Moreover, conjoint inactivation of G-CSF and IL-6 significantly decreased the numbers of GM-CFC colonies in comparison with those observed when only G-CSF was inactivated. This observation strongly suggests that though IMUNOR-induced IL-6 is not able to induce the growth of GM-CFC colonies alone, it is able to potentiate the hematopoiesis-stimulating effect of IL-3. These findings represent a new knowledge concerning the hematopoiesis-stimulating action of IMUNOR, a promising immunomodulatory agent.

  17. Migraine biomarkers in cerebrospinal fluid: A systematic review and meta-analysis.

    PubMed

    van Dongen, Robin M; Zielman, Ronald; Noga, Marek; Dekkers, Olaf M; Hankemeier, Thomas; van den Maagdenberg, Arn Mjm; Terwindt, Gisela M; Ferrari, Michel D

    2017-01-01

    Objective To perform a meta-analysis of migraine biomarkers in cerebrospinal fluid (CSF) and of corresponding blood concentrations. Methods We conducted a systematic search for studies that measured biochemical compounds in CSF of chronic or episodic migraineurs and non-headache controls. Subsequent searches retrieved studies with blood measurements of selected CSF biomarkers. If a compound was assessed in three or more studies, results were pooled in a meta-analysis with standardised mean differences (SMD) as effect measures. Results Sixty-two compounds were measured in 40 CSF studies. Most important results include: increased glutamate (five studies, SMD 2.22, 95% CI: 1.30, 3.13), calcitonin gene-related peptide (CGRP) (three studies, SMD: 3.80, 95% CI: 3.19, 4.41) and nerve growth factor (NGF) (three studies, SMD: 6.47, 95% CI: 5.55, 7.39) in chronic migraine patients and decreased β-endorphin (β-EP) in both chronic (four studies, SMD: -1.37, 95% CI: -1.80, -0.94) and interictal episodic migraine patients (three studies, SMD: -1.12, 95% CI: -1.65, -0.58). In blood, glutamate (interictal) and CGRP (chronic, interictal and ictal) were increased and β-EP (chronic, interictal and ictal) was decreased. Conclusions Glutamate, β-EP, CGRP and NGF concentrations are altered in CSF and, except for NGF, also in blood of migraineurs. Future research should focus on the pathophysiological roles of these compounds in migraine.

  18. [Aiming to develop biochemical biomarkers for Parkinson's disease and related disorders].

    PubMed

    Tokuda, Takahiko

    2012-01-01

    In Parkinson's disease (PD), its diagnosis, measurement of progression and response to therapeutic intervention currently rely upon clinical observation. However, there remains a critical need for validated biomarkers for PD. Among proteins in cerebrospinal fluid (CSF) there is ample biochemical, pathological, and genetic evidence that the metabolism of α-synuclein (α-syn) plays a crucial role in the pathogenesis of PD. We first reported that PD patients had significantly lower α-syn levels in their CSF than the control groups. We then investigated the levels of α-syn oligomers in CSF using a specific self-developed ELISA. The levels of α-syn oligomers were significantly higher in the PD compared to the controls, with a sensitivity of 75.0% and a specificity of 87.5% for the diagnosis of PD, demonstrating that CSF α-syn oligomers can be a useful biomarker for diagnosis of PD. We have recently developed a proteomic profiling strategy for PD. CSF proteins were purified with C8 magnetic beads, and mass spectra were obtained by mass spectrometry. By building a Support vector machine classifier, PD and multiple system atrophy (MSA) were classified effectively with good cross-validation accuracy. A proteomic pattern classification method can increase the accuracy of clinical diagnosis of PD and MSA.

  19. Orientifolded locally AdS3 geometries

    NASA Astrophysics Data System (ADS)

    Loran, F.; Sheikh-Jabbari, M. M.

    2011-01-01

    Continuing the analysis of [Loran F and Sheikh-Jabbari M M 2010 Phys. Lett. B 693 184-7], we classify all locally AdS3 stationary axi-symmetric unorientable solutions to AdS3 Einstein gravity and show that they are obtained by applying certain orientifold projection on AdS3, BTZ or AdS3 self-dual orbifold, respectively, O-AdS3, O-BTZ and O-SDO geometries. Depending on the orientifold fixed surface, the O-surface, which is either a space-like 2D plane or a cylinder, or a light-like 2D plane or a cylinder, one can distinguish four distinct cases. For the space-like orientifold plane or cylinder cases, these geometries solve AdS3 Einstein equations and are hence locally AdS3 everywhere except at the O-surface, where there is a delta-function source. For the light-like cases, the geometry is a solution to Einstein equations even at the O-surface. We discuss the causal structure for static, extremal and general rotating O-BTZ and O-SDO cases as well as the geodesic motion on these geometries. We also discuss orientifolding Poincaré patch AdS3 and AdS2 geometries as a way to geodesic completion of these spaces and comment on the 2D CFT dual to the O-geometries.

  20. Ongoing search for diagnostic biomarkers in idiopathic normal pressure hydrocephalus.

    PubMed

    Tarnaris, Andrew; Toma, Ahmed K; Kitchen, Neil D; Watkins, Laurence D

    2009-12-01

    Idiopathic normal pressure hydrocephalus is a syndrome, which typically has a clinical presentation of gait/balance disturbance, often accompanied by cognitive decline and/or urinary incontinence. Its diagnosis is based on relevant history and clinical examination, appropriate imaging findings and physiological testing. The clinical picture of idiopathic normal pressure hydrocephalus may occasionally be difficult to distinguish from that of Alzheimer's dementia, subcortical ischemic vascular dementia and Parkinson's disease. The aim of this article is to systematically review the literature from the last 29 years in order to identify cerebrospinal fluid (CSF) or imaging biomarkers that may aid in the diagnosis of the syndrome. The authors concluded that no CSF or imaging biomarker is currently fulfilling the criteria required to aid in the diagnosis of the condition. However, a few studies have revealed promising CSF and imaging markers that need to be verified by independent groups. The reasons that the progress in this field has been slow so far is also commented on, as well as steps required to apply the current evidence in the design of future studies within the field.

  1. Increased CSF Homocysteine in Pathological Gamblers Compared with Healthy Controls

    ERIC Educational Resources Information Center

    Nordin, Conny; Sjodin, Ingemar

    2009-01-01

    Neurocognitive disturbances suggesting a frontal lobe dysfunction have been observed in pathological gamblers and alcohol dependents. Given that a high homocysteine level has been suggested to be a mediating factor in alcohol-related cognitive decline, we have determined homocysteine and cobalamine in cerebrospinal fluid (CSF) obtained from 11…

  2. CSF B-Endorphin Levels in Patients with Infantile Autism.

    ERIC Educational Resources Information Center

    Nagamitsu, Shinichiro; And Others

    1997-01-01

    A Japanese study measured CSF (cerebrospinal fluid) levels of beta-endorphin in 19 children (ages 4-6) with infantile autism and in 3 children (ages 10-14) with Rett syndrome. In infantile autism, levels did not differ significantly from control participants (n=23). However, levels were significantly higher in those with Rett syndrome. (Author/CR)

  3. G-CSF Intrauterine for Thin Endometrium, and Pregnancy Outcome

    PubMed Central

    Tehraninejad, Ensieh; Davari Tanha, Fateme; Asadi, Ebrahim; Kamali, Koorosh; Aziminikoo, Elham; Rezayof, Elahe

    2015-01-01

    Objective: To evaluate effects of G-CSF on a cancelled ART cycle due to thin endometrium. Materials and methods: In a nonrandomized clinical trial from January 2011 to January 2013 in two tertiary university based hospitals fifteen patients undergoing embryo transfer and with the history of cycle cancellation due to thin endometrium were studied. Intrauterine infusion of G-CSF was done on the day of oocyte pick-up or 5 days before embryo transfer. The primary outcome to be measured was an endometrium thickened to at least 6 mm and the secondary outcome was clinical pregnancy rate and consequently take-home baby. All previous cycles were considered as control for each patient. Results: The G-CSF was infused at the day of oocyte retrieval or 5 days before embryo transfer. The endometrial thickness reached from 3.593±0.251 mm to 7.120 ± 0.84 mm. The mean age, gravidity, parity, and FSH were 35.13± 9.531 years, 3, 1 and 32.78 ± 31.10 mIU/ml, respectively. The clinical pregnancy rate was 20%, and there was one missed abortion, a mother death at 34 weeks, and a preterm labor at 30 weeks due to PROM. Conclusion: G-CSF may increase endometrial thickness in the small group of patients who had no choice except cycle cancellation or surrogacy. PMID:26622308

  4. Endoscopic Repair of CSF Fistulae: A Ten Year Experience

    PubMed Central

    Alexander, Arun; Mathew, John; Varghese, Ajoy Mathew

    2016-01-01

    Introduction Cerebrospinal Fluid (CFF) fistulae are repaired endoscopically with varying degrees of success around the world. Large series are still uncommon, and the results varied primarily because of the different techniques by different surgeons and also because of a variation in the patient profile in each series, for example, many series deal primarily with traumatic CSF leaks where the defects are larger and outcomes poorer. Aim To analyse the surgical outcomes of Endoscopic CSF rhinorrhea closure. Materials and Methods This is a series of 34 cases operated upon primarily by one surgeon in two different centres over a period of 10 years. Results Of the 34 cases, 76% of the patients were women. Among the patients only 20.6% patients had a history of trauma preceding the CSF leak. The most common site of leak was in the fovea ethmoidalis in 19 (55.8%) followed by 10 (29.4%) in the cribriform plate. An overlay technique of placing the multiple layers of fascia and mucosa was used in 26 (76.5%) patients and underlay technique in the remaining. Postoperative lumbar drain was used in all patients. Conclusion Based on the treatment outcome of the 34 patients, it can be concluded that the success rate of a single endoscopic procedure in our experience is 97% and 100% following the second. Endoscopic approach for closure of CSF leak is safe with minimal complications and little morbidity. PMID:27656471

  5. Macrophages and CSF-1: implications for development and beyond.

    PubMed

    Jones, Christina V; Ricardo, Sharon D

    2013-10-01

    Recent focus on the diversity of macrophage phenotype and function signifies that these trophic cells are no longer of exclusive interest to the field of immunology. As key orchestrators of organogenesis, the contribution of macrophages to fetal development is worthy of greater attention. This review summarizes the key functions of macrophages and their primary regulator, colony-stimulating factor (CSF)-1, during development; highlighting trophic mechanisms beyond phagocytosis and outlining their roles in a range of developing organ systems. Advances in the understanding of macrophage polarization and functional heterogeneity are discussed from a developmental perspective. In addition, this review highlights the relevance of CSF-1 as a pleiotropic developmental growth factor and summarizes recent experimental evidence and clinical advancements in the area of CSF-1 and macrophage manipulation in reproduction and organogenic settings. Interrogation of embryonic macrophages also has implications beyond development, with recent attention focused on yolk sac macrophage ontogeny and their role in homeostasis and mediating tissue regeneration. The regulatory networks that govern development involve a complex range of growth factors, signaling pathways and transcriptional regulators arising from epithelial, mesenchymal and stromal origins. A component of the organogenic milieu common to the majority of developing organs is the tissue macrophage. These hemopoietic cells are part of the mononuclear phagocyte system regulated primarily by colony-stimulating factor (CSF)-1 (1, 2). There is a resurgence in the field of CSF-1 and macrophage biology; where greater understanding of the heterogeneity of these cells is revealing contributions to tissue repair and regeneration beyond the phagocytic and inflammatory functions for which they were traditionally ascribed (3-6). The accumulation of macrophages during tissue injury is no longer viewed as simply a surrogate for disease

  6. Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer’s Disease

    PubMed Central

    Almdahl, Ina S.; Lauridsen, Camilla; Selnes, Per; Kalheim, Lisa F.; Coello, Christopher; Gajdzik, Beata; Møller, Ina; Wettergreen, Marianne; Grambaite, Ramune; Bjørnerud, Atle; Bråthen, Geir; Sando, Sigrid B.; White, Linda R.; Fladby, Tormod

    2017-01-01

    Introduction: Amyloid beta 1-43 (Aβ43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer’s disease pathology possibly different from that of amyloid beta 1-42 (Aβ42). Cerebrospinal fluid (CSF) Aβ43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer’s disease. However, the relationship between CSF Aβ43 and established imaging biomarkers of Alzheimer’s disease has never been assessed. Materials and Methods: In this observational study, CSF Aβ43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid Aβ43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aβ43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF Aβ43 and Aβ42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aβ43 average rho -0.73, Aβ42 -0.74. Both CSF Aβ peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aβ42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aβ43/42 and imaging biomarkers were significantly different for the two A

  7. Immunogenicity of granulocyte-macrophage colony-stimulating factor (GM-CSF) products in patients undergoing combination therapy with GM-CSF.

    PubMed

    Wadhwa, M; Skog, A L; Bird, C; Ragnhammar, P; Lilljefors, M; Gaines-Das, R; Mellstedt, H; Thorpe, R

    1999-06-01

    In this study, we have assessed the development of neutralizing and nonneutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in two groups of patients with metastatic colorectal carcinoma receiving two different GM-CSF products. Three clinical trials were carried out, and a combination of GM-CSF and a colon carcinoma-reactive antibody was used in the absence of any concomitant chemotherapy. Two different GM-CSF products, both rDNA-derived and produced in Escherichia coli, were used. Patients in Trial 1 received product X, and those in Trials 2 and 3 received product Y. Patients in Trial 2 also received interleukin 2 in an attempt to potentiate immune responses. After the first cycle of treatment, no GM-CSF antibodies were detected, but on subsequent therapy, 28 of the 38 patients tested receiving product Y (Trials 2 and 3) developed antibodies that bound to the GM-CSF product used for therapy. However, none of the patients developed antibodies that neutralized the biological activity of GM-CSF, as assessed using an in vitro bioassay. Furthermore, there was no in vivo impairment in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in the patients. In contrast, 19 of the 20 patients given product X (Trial 1) developed GM-CSF binding antibodies, and 9 of these patients were shown to develop antibodies that neutralized the biological activity of GM-CSF. The presence of the latter was associated with a significant reduction in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in patients. Therefore, product X appears to be more immunogenic than product Y. Immunochemical characterization confirmed that the specificity of the antibody responses varied depending on the product used for therapy. Whereas sera from Trial 1 patients treated with product X showed the presence of antibodies with strong recognition of GM-CSF proteins, sera from patients treated with product Y showed varied recognition of GM-CSF

  8. Biomarkers in major depressive disorder: the role of mass spectrometry.

    PubMed

    Woods, Alisa G; Iosifescu, Dan V; Darie, Costel C

    2014-01-01

    Major depressive disorder (MDD) is common. Despite numerous available treatments, many individuals fail to improve clinically. MDD continues to be diagnosed exclusively via behavioral rather than biological methods. Biomarkers-which include measurements of genes, proteins, and patterns of brain activity-may provide an important objective tool for the diagnosis of MDD or in the rational selection of treatments. Proteomic analysis and validation of its results as biomarkers is less explored than other areas of biomarker research in MDD. Mass spectrometry (MS) is a comprehensive, unbiased means of proteomic analysis, which can be complemented by directed protein measurements, such as Western Blotting. Prior studies have focused on MS analysis of several human biomaterials in MDD, including human post-mortem brain, cerebrospinal fluid (CSF), blood components, and urine. Further studies utilizing MS and proteomic analysis in MDD may help solidify and establish biomarkers for use in diagnosis, identification of new treatment targets, and understanding of the disorder. The ultimate goal is the validation of a biomarker or a biomarker signature that facilitates a convenient and inexpensive predictive test for depression treatment response and helps clinicians in the rational selection of next-step treatments.

  9. [Proteomics: biomarker research in psychiatry].

    PubMed

    Hünnerkopf, R; Grassl, J; Thome, J

    2007-10-01

    Over the last decade, genomics research in psychiatry and neuroscience has provided important insights into genes expressed under different physiological and pathophysiological conditions. Contrary to the great expectations regarding a clinical use of these datasets, genomics failed to improve markedly the diagnostic and therapeutic options in brain disorders. Due to alternative splicing and posttranslational modifications, one single gene determines a multitude of gene products. Therefore, in order to understand molecular processes in neuropsychiatric disorders, it is necessary to unravel signal transduction pathways and complex interaction networks on the level of proteins, not only DNA and mRNA. Proteomics utilises high-throughput mass spectrometric protein identification that can reveal protein expression levels, posttranslational modifications and protein-protein interactions. Proteomic tools have the power to identify quantitative and qualitative protein patterns in postmortem brain tissue, cerebrospinal fluid (CSF) or serum, thus increasing the knowledge about etiology and pathomechanisms of brain diseases. Comparing protein profiles in healthy and disease states provides an opportunity to establish specific diagnostic and prognostic biomarkers. In addition, proteomic studies of the effects of medication - in vitro and in vivo - might help to design specific pharmaceutical agents with fewer side effects. In this overview, we present the most widely used proteomic techniques and illustrate the potential and limitations of this field of research. Furthermore, we provide insight into the contributions of proteomics to the study of psychiatric diseases such as Alzheimer's disease, drug addiction, schizophrenia and depression.

  10. The effect of preanalytical factors on stability of the proteome and selected metabolites in cerebrospinal fluid (CSF).

    PubMed

    Rosenling, Therese; Slim, Christiaan L; Christin, Christin; Coulier, Leon; Shi, Shanna; Stoop, Marcel P; Bosman, Jan; Suits, Frank; Horvatovich, Peter L; Stockhofe-Zurwieden, Norbert; Vreeken, Rob; Hankemeier, Thomas; van Gool, Alain J; Luider, Theo M; Bischoff, Rainer

    2009-12-01

    To standardize the use of cerebrospinal fluid (CSF) for biomarker research, a set of stability studies have been performed on porcine samples to investigate the influence of common sample handling procedures on proteins, peptides, metabolites and free amino acids. This study focuses at the effect on proteins and peptides, analyzed by applying label-free quantitation using microfluidics nanoscale liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (chipLC-MS) as well as matrix-assisted laser desorption ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FT-ICR-MS) and Orbitrap LC-MS/MS to trypsin-digested CSF samples. The factors assessed were a 30 or 120 min time delay at room temperature before storage at -80 degrees C after the collection of CSF in order to mimic potential delays in the clinic (delayed storage), storage at 4 degrees C after trypsin digestion to mimic the time that samples remain in the cooled autosampler of the analyzer, and repeated freeze-thaw cycles to mimic storage and handling procedures in the laboratory. The delayed storage factor was also analyzed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS) for changes of metabolites and free amino acids, respectively. Our results show that repeated freeze/thawing introduced changes in transthyretin peptide levels. The trypsin digested samples left at 4 degrees C in the autosampler showed a time-dependent decrease of peak areas for peptides from prostaglandin D-synthase and serotransferrin. Delayed storage of CSF led to changes in prostaglandin D-synthase derived peptides as well as to increased levels of certain amino acids and metabolites. The changes of metabolites, amino acids and proteins in the delayed storage study appear to be related to remaining white blood cells. Our recommendations are to centrifuge CSF samples immediately after collection to remove white blood cells, aliquot, and then

  11. Proinflammatory cytokines and matrix metalloproteinases in CSF of patients with VZV vasculopathy

    PubMed Central

    Jones, Dallas; Alvarez, Enrique; Selva, Sean; Gilden, Don

    2016-01-01

    Objective: To determine the levels of proinflammatory cytokines and matrix metalloproteinases (MMPs) in the CSF of patients with virologically verified varicella zoster virus (VZV) vasculopathy. Methods: CSF from 30 patients with virologically verified VZV vasculopathy was analyzed for levels of proinflammatory cytokines and MMPs using the Meso Scale Discovery multiplex ELISA platform. Positive CNS inflammatory disease controls were provided by CSF from 30 patients with multiple sclerosis. Negative controls were provided by CSF from 20 healthy controls. Results: Compared to multiple sclerosis CSF and CSF from healthy controls, levels of interleukin (IL)-8, IL-6, and MMP-2 were significantly elevated in VZV vasculopathy CSF. Conclusions: CSF of patients with VZV vasculopathy revealed a unique profile of elevated proinflammatory cytokines, IL-8 and IL-6, along with elevated MMP-2. The relevance of these cytokines to the pathogenesis of VZV vasculopathy requires further study. PMID:27340684

  12. Group-based trajectory analysis applications for prognostic biomarker model development in severe TBI: a practical example.

    PubMed

    Niyonkuru, Christian; Wagner, Amy K; Ozawa, Haishin; Amin, Krutika; Goyal, Akash; Fabio, Anthony

    2013-06-01

    Over the last decade, biomarker research has identified potential biomarkers for the diagnosis, prognosis, and management of traumatic brain injury (TBI). Several cerebrospinal fluid (CSF) and serum biomarkers have shown promise in predicting long-term outcome after severe TBI. Despite this increased focus on identifying biomarkers for outcome prognostication after a severe TBI, several challenges still exist in effectively modeling the significant heterogeneity observed in TBI-related pathology, as well as the biomarker-outcome relationships. Biomarker data collected over time are usually summarized into single-point estimates (e.g., average or peak biomarker levels), which are, in turn, used to examine the relationships between biomarker levels and outcomes. Further, many biomarker studies to date have focused on the prediction power of biomarkers without controlling for potential clinical and demographic confounders that have been previously shown to affect long-term outcome. In this article, we demonstrate the application of a practical approach to delineate and describe distinct subpopulations having similar longitudinal biomarker profiles and to model the relationships between these biomarker profiles and outcomes while taking into account potential confounding factors. As an example, we demonstrate a group-based modeling technique to identify temporal S100 calcium-binding protein B (S100b) profiles, measured from CSF over the first week post-injury, in a sample of adult subjects with TBI, and we use multivariate logistic regression to show that the prediction power of S100b biomarker profiles can be superior to the prediction power of single-point estimates.

  13. Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation

    PubMed Central

    Kauwe, John S. K.; Bailey, Matthew H.; Ridge, Perry G.; Perry, Rachel; Wadsworth, Mark E.; Hoyt, Kaitlyn L.; Staley, Lyndsay A.; Karch, Celeste M.; Harari, Oscar; Cruchaga, Carlos; Ainscough, Benjamin J.; Bales, Kelly; Pickering, Eve H.; Bertelsen, Sarah; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Goate, Alison M.

    2014-01-01

    Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10−10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal

  14. Systematic review: new serological markers (anti-glycan, anti-GP2, anti-GM-CSF Ab) in the prediction of IBD patient outcomes.

    PubMed

    Bonneau, J; Dumestre-Perard, C; Rinaudo-Gaujous, M; Genin, C; Sparrow, M; Roblin, X; Paul, S

    2015-03-01

    Traditionally, IBD diagnosis is based on clinical, radiological, endoscopic, and histological criteria. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course and therapeutic response. No guideline recommends the detection of antibodies (including ASCA and ANCA) for diagnosis or prognosis of IBD to date. However, many recent data suggest the potential role of new serological markers (anti-glycan (ACCA, ALCA, AMCA, anti-L and anti-C), anti-GP2 and anti-GM-CSF Ab). This review focuses on clinical utility of these new serological markers in diagnosis, prognosis and therapeutic monitoring of IBD. Literature review of anti-glycan, anti-GP2 and anti-GM-CSF Ab and their impact on diagnosis, prognosis and prediction of therapeutic response was performed in PubMed/MEDLINE up to June 2014. Anti-glycan, anti-GP2 and anti-GM-CSF Ab are especially associated with CD and seem to be correlated with complicated disease phenotypes even if results differ between studies. Although anti-glycan Ab and anti-GP2 Ab have low sensitivity in diagnosis of IBD, they could identify a small number of CD patients not detected by other tests such as ASCA. Anti-glycan Abs are associated with a progression to a more severe disease course and a higher risk for IBD-related surgery. Anti-GP2 Ab could particularly contribute to better stratify cases of pouchitis. Anti-GM-CSF Ab seems to be correlated with disease activity and could help predict relapses. These new promising biomarkers could particularly be useful in stratification of patients according to disease phenotype and risk of complications. They could be a valuable aid in prediction of disease course and therapeutic response but more prospective studies are needed.

  15. G-CSF-mobilized Bone Marrow Mesenchymal Stem Cells Replenish Neural Lineages in Alzheimer's Disease Mice via CXCR4/SDF-1 Chemotaxis.

    PubMed

    Wu, Cheng-Chun; Wang, I-Fang; Chiang, Po-Min; Wang, Liang-Chao; Shen, Che-Kun James; Tsai, Kuen-Jer

    2016-10-05

    Recent studies reported granulocyte colony-stimulating factor (G-CSF) treatment can improve the cognitive function of Alzheimer's disease (AD) mice, and the mobilized hematopoietic stem cells (HSCs) or bone marrow mesenchymal stem cells (BM-MSCs) are proposed to be involved in this recovery effect. However, the exact role of mobilized HSC/BM-MSC in G-CSF-based therapeutic effects is still unknown. Here, we report that C-X-C chemokine receptor type 4 (CXCR4)/stromal cell-derived factor 1 (SDF-1) chemotaxis was a key mediator in G-CSF-based therapeutic effects, which was involved in the recruitment of repair-competent cells. Furthermore, we found both mobilized HSCs and BM-MSCs were able to infiltrate into the brain, but only BM-MSCs replenished the neural lineage cells and contributed to neurogenesis in the brains of AD mice. Together, our data show that mobilized BM-MSCs are involved in the replenishment of neural lineages following G-CSF treatment via CXCR4/SDF-1 chemotaxis and further support the potential use of BM-MSCs for further autogenically therapeutic applications.

  16. Defining Pesticide Biomarkers

    EPA Pesticide Factsheets

    Biomarkers are measurable substances or characteristics in the human body that can be used to monitor the presence of a chemical in the body, biological responses or harm to health. This Web page describes categories of biomarkers and provides examples.

  17. BIOMARKERS OF REPRODUCTIVE TOXICITY

    EPA Science Inventory

    Identification and verification of anatomical, endocrine, cellular and molecular biomarkers is crucial for successful clinical diagnosis and treatment of toxicity and disease, as well as basic toxicological, epidemiological and other research. Various in situ biomarkers of repro...

  18. Biomarkers in Computational Toxicology

    EPA Science Inventory

    Biomarkers are a means to evaluate chemical exposure and/or the subsequent impacts on toxicity pathways that lead to adverse health outcomes. Computational toxicology can integrate biomarker data with knowledge of exposure, chemistry, biology, pharmacokinetics, toxicology, and e...

  19. Warped AdS3 black holes

    NASA Astrophysics Data System (ADS)

    Anninos, Dionysios; Li, Wei; Padi, Megha; Song, Wei; Strominger, Andrew

    2009-03-01

    Three dimensional topologically massive gravity (TMG) with a negative cosmological constant -l-2 and positive Newton constant G admits an AdS3 vacuum solution for any value of the graviton mass μ. These are all known to be perturbatively unstable except at the recently explored chiral point μl = 1. However we show herein that for every value of μl ≠ 3 there are two other (potentially stable) vacuum solutions given by SL(2,Bbb R) × U(1)-invariant warped AdS3 geometries, with a timelike or spacelike U(1) isometry. Critical behavior occurs at μl = 3, where the warping transitions from a stretching to a squashing, and there are a pair of warped solutions with a null U(1) isometry. For μl > 3, there are known warped black hole solutions which are asymptotic to warped AdS3. We show that these black holes are discrete quotients of warped AdS3 just as BTZ black holes are discrete quotients of ordinary AdS3. Moreover new solutions of this type, relevant to any theory with warped AdS3 solutions, are exhibited. Finally we note that the black hole thermodynamics is consistent with the hypothesis that, for μl > 3, the warped AdS3 ground state of TMG is holographically dual to a 2D boundary CFT with central charges c_R-formula and c_L-formula.

  20. Warped AdS3 black holes

    NASA Astrophysics Data System (ADS)

    Song, Wei; Anninos, Dionysios; Li, Wei; Padi, Megha; Strominger, Andrew

    2009-03-01

    Three dimensional topologically massive gravity (TMG) with a negative cosmological constant -ell-2 and positive Newton constant G admits an AdS3 vacuum solution for any value of the graviton mass μ. These are all known to be perturbatively unstable except at the recently explored chiral point μell = 1. However we show herein that for every value of μell ≠ 3 there are two other (potentially stable) vacuum solutions given by SL(2,Bbb R) × U(1)-invariant warped AdS3 geometries, with a timelike or spacelike U(1) isometry. Critical behavior occurs at μell = 3, where the warping transitions from a stretching to a squashing, and there are a pair of warped solutions with a null U(1) isometry. For μell > 3, there are known warped black hole solutions which are asymptotic to warped AdS3. We show that these black holes are discrete quotients of warped AdS3 just as BTZ black holes are discrete quotients of ordinary AdS3. Moreover new solutions of this type, relevant to any theory with warped AdS3 solutions, are exhibited. Finally we note that the black hole thermodynamics is consistent with the hypothesis that, for μell > 3, the warped AdS3 ground state of TMG is holographically dual to a 2D boundary CFT with central charges c_R-formula and c_L-formula.

  1. Biomarkers in Veterinary Medicine.

    PubMed

    Myers, Michael J; Smith, Emily R; Turfle, Phillip G

    2017-02-08

    This article summarizes the relevant definitions related to biomarkers; reviews the general processes related to biomarker discovery and ultimate acceptance and use; and finally summarizes and reviews, to the extent possible, examples of the types of biomarkers used in animal species within veterinary clinical practice and human and veterinary drug development. We highlight opportunities for collaboration and coordination of research within the veterinary community and leveraging of resources from human medicine to support biomarker discovery and validation efforts for veterinary medicine.

  2. α-Synuclein and DJ-1 as potential biological fluid biomarkers for Parkinson's Disease.

    PubMed

    Waragai, Masaaki; Sekiyama, Kazunari; Sekigawa, Akio; Takamatsu, Yoshiki; Fujita, Masayo; Hashimoto, Makoto

    2010-10-29

    Parkinson's disease (PD) is the most common form of movement disorder and affects approximately 4% of the population aged over 80 years old. Currently, PD cannot be prevented or cured, and no single diagnostic biomarkers are available. Notably, recent studies suggest that two familial PD-linked molecules, α-synuclein and DJ-1, are present in cerebrospinal fluid (CSF) and that their levels may be altered during the progression of PD. In this regard, sensitive and accurate methods for evaluation of α-synuclein and DJ-1 levels in the CSF and blood have been developed, and the results suggest that the levels of both molecules are significantly decreased in the CSF in patients with PD compared with age-matched controls. Furthermore, specific detection and quantification of neurotoxic oligometric forms of α-synuclein in the blood using enzyme-linked immunosorbent assays might be expected as potential peripheral biomarkers for PD, although further validation is required. Currently, neither α-synuclein nor DJ-1 is satisfactory as a single biomarker for PD, but combinatory evaluation of these biological fluid molecules with other biomarkers and imaging techniques may provide reliable information for diagnosis of PD.

  3. [Potential for the cytochemical study of CSF smears in the determination of neuroleukemia variants].

    PubMed

    Berliner, G B; Mendeleev, I M; Kheĭfets, L M; Polezhaev, Iu N; Gavrilova, S A

    1986-01-01

    The cytochemical test for PAS-positive material in CSF smears can be used for identification of leukemic cells of the lymphoid line. Qualitative smears were obtained from the CSF by the sedimentation method. Five patients were examined. A very suggestive case is described. The cytochemical studies of CSF smears help diagnose neuroleukemia and evaluate the treatment efficacy.

  4. Incorporation of GM-CSF or CD40L Enhances the Immunogenicity of Hantaan Virus-Like Particles

    PubMed Central

    Cheng, Lin-Feng; Wang, Fang; Zhang, Liang; Yu, Lan; Ye, Wei; Liu, Zi-Yu; Ying, Qi-Kang; Wu, Xing-An; Xu, Zhi-Kai; Zhang, Fang-Lin

    2016-01-01

    A safe and effective Hantaan virus (HTNV) vaccine is highly desirable because HTNV causes an acute and often fatal disease (hemorrhagic fever with renal syndrome, HFRS). Since the immunity of the inactivated vaccine is weak and the safety is poor, HTNV virus-like particles (VLPs) offer an attractive and safe alternative. These particles lack the viral genome but are perceived by the immune system as virus particles. We hypothesized that adding immunostimulatory signals to VLPs would enhance their efficacy. To accomplish this enhancement, we generated chimeric HTNV VLPs containing glycosylphosphatidylinositol (GPI)-anchored granulocyte macrophage colony-stimulating factor (GM-CSF) or CD40 ligand (CD40L) and investigated their biological activity in vitro. The immunization of mice with chimeric HTNV VLPs containing GM-CSF or CD40L induced stronger humoral immune responses and cellular immune responses compared to the HTNV VLPs and Chinese commercial inactivated hantavirus vaccine. Chimeric HTNV VLPs containing GM-CSF or CD40L also protected mice from an HTNV challenge. Altogether, our results suggest that anchoring immunostimulatory molecules into HTNV VLPs can be a potential approach for the control and prevention of HFRS. PMID:28066721

  5. The critical need for defining preclinical biomarkers in Alzheimer's disease.

    PubMed

    Fiandaca, Massimo S; Mapstone, Mark E; Cheema, Amrita K; Federoff, Howard J

    2014-06-01

    The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.

  6. The biomarker-based diagnosis of Alzheimer's disease. 2-lessons from oncology.

    PubMed

    Boccardi, Marina; Gallo, Valentina; Yasui, Yutaka; Vineis, Paolo; Padovani, Alessandro; Mosimann, Urs; Giannakopoulos, Panteleimon; Gold, Gabriel; Dubois, Bruno; Jack, Clifford R; Winblad, Bengt; Frisoni, Giovanni B; Albanese, Emiliano

    2017-04-01

    Biomarkers for the diagnosis of Alzheimer's disease (AD) are not yet validated for use in clinical settings. We aim to provide a methodological framework for their systematic validation, by reference to that developed for oncology biomarkers. As for this discipline, the steps for the systematic validation of AD biomarkers need to target analytical validity, clinical validity, and clinical utility. However, the premises are different from oncology: the nature of disease (neurodegeneration vs. cancer), the purpose (improve diagnosis in clinically affected vs. screening preclinical individuals), and the target population (mild cognitive impairment patients referring to memory clinics vs. general population) lead to important differences, influencing both the design of validation studies and the use of selected biomarkers. This framework is applied within a wider initiative to assess the current available evidence on the clinical validity of biomarkers for AD, for the final aim to identify gaps and research priorities, and to inform coordinated research efforts boosting AD biomarkers research.

  7. Segmented strings in AdS 3

    NASA Astrophysics Data System (ADS)

    Callebaut, Nele; Gubser, Steven S.; Samberg, Andreas; Toldo, Chiara

    2015-11-01

    We study segmented strings in flat space and in AdS 3. In flat space, these well known classical motions describe strings which at any instant of time are piecewise linear. In AdS 3, the worldsheet is composed of faces each of which is a region bounded by null geodesics in an AdS 2 subspace of AdS 3. The time evolution can be described by specifying the null geodesic motion of kinks in the string at which two segments are joined. The outcome of collisions of kinks on the worldsheet can be worked out essentially using considerations of causality. We study several examples of closed segmented strings in AdS 3 and find an unexpected quasi-periodic behavior. We also work out a WKB analysis of quantum states of yo-yo strings in AdS 5 and find a logarithmic term reminiscent of the logarithmic twist of string states on the leading Regge trajectory.

  8. Catecholamine-Based Treatment in AD Patients: Expectations and Delusions

    PubMed Central

    Stefani, Alessandro; Olivola, Enrica; Liguori, Claudio; Hainsworth, Atticus H.; Saviozzi, Valentina; Angileri, Giacoma; D’Angelo, Vincenza; Galati, Salvatore; Pierantozzi, Mariangela

    2015-01-01

    In Alzheimer disease, the gap between excellence of diagnostics and efficacy of therapy is wide. Despite sophisticated imaging and biochemical markers, the efficacy of available therapeutic options is limited. Here we examine the possibility that assessment of endogenous catecholamine levels in cerebrospinal fluid (CSF) may fuel new therapeutic strategies. In reviewing the available literature, we consider the effects of levodopa, monoamine oxidase inhibitors, and noradrenaline (NE) modulators, showing disparate results. We present a preliminary assessment of CSF concentrations of dopamine (DA) and NE, determined by HPLC, in a small dementia cohort of either Alzheimer’s disease (AD) or frontotemporal dementia patients, compared to control subjects. Our data reveal detectable levels of DA, NE in CSF, though we found no significant alterations in the dementia population as a whole. AD patients exhibit a small impairment of the DA axis and a larger increase of NE concentration, likely to represent a compensatory mechanism. While waiting for preventive strategies, a pragmatic approach to AD may re-evaluate catecholamine modulation, possibly stratified to dementia subtypes, as part of the therapeutic armamentarium. PMID:25999852

  9. Photocopy of photograph (from NBPPNSY, CSF 4036766) Joseph P. Garfinkel, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Photocopy of photograph (from NBP-PNSY, CSF 4036-7-66) Joseph P. Garfinkel, photographer, July 20, 1966 oblique aerial photo taken from an altitude of approximately 6,000 feet; view north of Philadelphia Naval Base and Shipyard. Reserve basin (Haer no. Pa-387-W) is at left center of photograph. - Naval Base Philadelphia-Philadelphia Naval Shipyard, League Island, Philadelphia, Philadelphia County, PA

  10. PET measurements of cerebral metabolism corrected for CSF contributions

    SciTech Connect

    Chawluk, J.; Alavi, A.; Dann, R.; Kushner, M.J.; Hurtig, H.; Zimmerman, R.A.; Reivich, M.

    1984-01-01

    Thirty-three subjects have been studied with PET and anatomic imaging (proton-NMR and/or CT) in order to determine the effect of cerebral atrophy on calculations of metabolic rates. Subgroups of neurologic disease investigated include stroke, brain tumor, epilepsy, psychosis, and dementia. Anatomic images were digitized through a Vidicon camera and analyzed volumetrically. Relative areas for ventricles, sulci, and brain tissue were calculated. Preliminary analysis suggests that ventricular volumes as determined by NMR and CT are similar, while sulcal volumes are larger on NMR scans. Metabolic rates (18F-FDG) were calculated before and after correction for CSF spaces, with initial focus upon dementia and normal aging. Correction for atrophy led to a greater increase (%) in global metabolic rates in demented individuals (18.2 +- 5.3) compared to elderly controls (8.3 +- 3.0,p < .05). A trend towards significantly lower glucose metabolism in demented subjects before CSF correction was not seen following correction for atrophy. These data suggest that volumetric analysis of NMR images may more accurately reflect the degree of cerebral atrophy, since NMR does not suffer from beam hardening artifact due to bone-parenchyma juxtapositions. Furthermore, appropriate correction for CSF spaces should be employed if current resolution PET scanners are to accurately measure residual brain tissue metabolism in various pathological states.

  11. Integrative EEG biomarkers predict progression to Alzheimer's disease at the MCI stage

    PubMed Central

    Poil, Simon-Shlomo; de Haan, Willem; van der Flier, Wiesje M.; Mansvelder, Huibert D.; Scheltens, Philip; Linkenkaer-Hansen, Klaus

    2013-01-01

    Alzheimer's disease (AD) is a devastating disorder of increasing prevalence in modern society. Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and AD; however, not all subjects with MCI progress to AD. Prediction of conversion to AD at an early stage would enable an earlier, and potentially more effective, treatment of AD. Electroencephalography (EEG) biomarkers would provide a non-invasive and relatively cheap screening tool to predict conversion to AD; however, traditional EEG biomarkers have not been considered accurate enough to be useful in clinical practice. Here, we aim to combine the information from multiple EEG biomarkers into a diagnostic classification index in order to improve the accuracy of predicting conversion from MCI to AD within a 2-year period. We followed 86 patients initially diagnosed with MCI for 2 years during which 25 patients converted to AD. We show that multiple EEG biomarkers mainly related to activity in the beta-frequency range (13–30 Hz) can predict conversion from MCI to AD. Importantly, by integrating six EEG biomarkers into a diagnostic index using logistic regression the prediction improved compared with the classification using the individual biomarkers, with a sensitivity of 88% and specificity of 82%, compared with a sensitivity of 64% and specificity of 62% of the best individual biomarker in this index. In order to identify this diagnostic index we developed a data mining approach implemented in the Neurophysiological Biomarker Toolbox (http://www.nbtwiki.net/). We suggest that this approach can be used to identify optimal combinations of biomarkers (integrative biomarkers) also in other modalities. Potentially, these integrative biomarkers could be more sensitive to disease progression and response to therapeutic intervention. PMID:24106478

  12. European Mitochondrial DNA Haplogroups are Associated with Cerebrospinal Fluid Biomarkers of Inflammation in HIV Infection

    PubMed Central

    Samuels, David C.; Kallianpur, Asha R.; Ellis, Ronald J.; Bush, William S.; Letendre, Scott; Franklin, Donald; Grant, Igor; Hulgan, Todd

    2017-01-01

    Background Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults. Methods CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is a US-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments. Participants who consented to DNA collection underwent whole blood mtDNA sequencing, and a subset also underwent lumbar puncture. IL-6, IL-8, TNF-α (high-sensitivity), and IP-10 were measured in cerebrospinal fluid (CSF) by immunoassay. Multivariable regression of mtDNA haplogroups and log-transformed CSF biomarkers were stratified by genetic ancestry using whole-genome nuclear DNA genotyping (European [EA], African [AA], or Hispanic ancestry [HA]), and adjusted for age, sex, antiretroviral therapy (ART), detectable CSF HIV RNA, and CD4 nadir. A total of 384 participants had both CSF cytokine measures and genetic data (45% EA, 44% AA, 11% HA, 22% female, median age 43 years, 74% on ART). Results In analyses stratified by the 3 continental ancestry groups, no haplogroups were significantly associated with the 4 biomarkers. In the subgroup of participants with undetectable plasma HIV RNA on ART, European haplogroup H participants had significantly lower CSF TNF-α (P = 0.001). Conclusions Lower CSF TNF-α may indicate lower neuroinflammation in the haplogroup H participants with well-controlled HIV on ART.

  13. Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Henderson, Robert David; David, Michael; McCombe, Pamela Ann

    2016-01-01

    Background To allow early diagnosis and monitoring of disease progression, there is a need for biomarkers in amyotrophic lateral sclerosis (ALS). Neurofilaments (NF) are emerging protein biomarkers in other neurological diseases, and are of possible use in ALS. Objective The aim of this study is to evaluate the utility of NF levels as blood or cerebrospinal fluid (CSF) biomarker in patients with ALS. Methods A systematic search of Pubmed, Embase and Scopus was performed. Methodological quality assessment was applied to refine the final search results. Meta-analysis of the data was performed. Results Level of NF heavy chain and light chains were significantly elevated in the CSF of ALS patients compared to healthy controls/controls without parenchymal central nervous system (CNS) involvement and ALS mimic disease patients. NF light chain level in CSF was higher in ALS patients than in neurological patients with CNS involvement (SMD = 1.352, P = 0.01). NF light chain concentration in blood was higher in ALS patients than healthy controls/controls without CNS involvement (SMD = 1.448, P<0.0001). NF heavy chain levels in CSF were negatively correlated disease duration and ALSFRS-R ((r = -0.447, P<0.0001; r = -0.486, P<0.0001). NF light chain levels in CSF were negatively correlated with disease duration (r = -0.273, P = 0.011). Conclusion NF heavy and light chain levels have potential use as a marker of neural degeneration in ALS, but are not specific for the disease, and are more likely to be used as measures of disease progression. PMID:27732645

  14. Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis

    PubMed Central

    Vincent, Isabel M.; Daly, Rónán; Courtioux, Bertrand; Cattanach, Amy M.; Biéler, Sylvain; Ndung’u, Joseph M.; Bisser, Sylvie; Barrett, Michael P.

    2016-01-01

    Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of “sleeping sickness”. Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control. PMID:27941966

  15. Biomarkers of Parkinson's disease and Dementia with Lewy bodies.

    PubMed

    Henchcliffe, Claire; Dodel, Richard; Beal, M Flint

    2011-12-01

    Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are progressive and disabling neurodegenerative disorders, in which signs and symptoms overlap with each other and with other neurodegenerative conditions. Currently, diagnosis, measurement of progression, and response to therapeutic intervention rely upon clinical observation. However, there remains a critical need for validated biomarkers in each of these areas. A definitive diagnostic test would improve clinical management and enrollment into clinical trials. An objective measure of progression is vitally important in identifying neuroprotective interventions. Biomarkers may also provide insight into pathogenesis, and might therefore suggest possible novel targets for therapeutic intervention. In addition, certain biomarkers might be of use in monitoring the biochemical and physiological effects of therapeutic interventions. Development of diagnostic biomarkers has focused until recently upon imaging techniques based upon measuring loss of dopamine neurons. Additionally, advances in understanding the genetic contribution to neurodegenerative disorders, in particular in PD, have identified multiple causative genes and risk factors that in some cases may help estimate PD risk. However, recent availability of increasingly sophisticated bioinformatics technology has rendered development of fluid biomarkers feasible, opening the possibility of generally accessible blood or cerebrospinal fluid (CSF) tests that could impact upon diagnosis, management, and research in PD, PDD, and DLB.

  16. Biomarkers in clinical medicine.

    PubMed

    Chen, Xiao-He; Huang, Shuwen; Kerr, David

    2011-01-01

    Biomarkers have been used in clinical medicine for decades. With the rise of genomics and other advances in molecular biology, biomarker studies have entered a whole new era and hold promise for early diagnosis and effective treatment of many diseases. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention (1). They can be classified into five categories based on their application in different disease stages: 1) antecedent biomarkers to identify the risk of developing an illness, 2) screening biomarkers to screen for subclinical disease, 3) diagnostic biomarkers to recognize overt disease, 4) staging biomarkers to categorise disease severity, and 5) prognostic biomarkers to predict future disease course, including recurrence, response to therapy, and monitoring efficacy of therapy (1). Biomarkers can indicate a variety of health or disease characteristics, including the level or type of exposure to an environmental factor, genetic susceptibility, genetic responses to environmental exposures, markers of subclinical or clinical disease, or indicators of response to therapy. This chapter will focus on how these biomarkers have been used in preventive medicine, diagnostics, therapeutics and prognostics, as well as public health and their current status in clinical practice.

  17. Overview of use of G-CSF and GM-CSF in the treatment of acute radiation injury.

    PubMed

    Reeves, Glen

    2014-06-01

    Depression of hematopoietic elements due to significant levels of whole-body or partial-body irradiation due to radiation-induced suppression of mitosis in the stem and progenitor cells can result in life-threatening injury. Successful administration of intensive care of patients experiencing acute radiation sickness (ARS; also called acute radiation syndrome) is dependent upon the ability to stimulate the recovery of surviving hematopoietic stem cells (HSC), assuming the non-hematopoietic injuries are also survivable with treatment. To date, there have been a number of studies involving radiation accidents where patients were treated with cytokines. Although the data overall seem to indicate that the period of neutropenia is shortened and survival prolonged, so far there is no statistically significant proof that cytokine administration actually decreases mortality in radiation-injured humans. Some studies have shown no improved survival when used in a mouse model; however, studies in canines and primates have shown improved survival. CSF therapy is considered a valuable adjunct to treatment with antibiotics and strict hygiene controls in certain irradiated patients. It appears that these drugs do shorten the periods of neutropenia in irradiated patients and must be considered part of the therapeutic armamentarium in the treatment of ARS in a mass casualty situation. Based on review of the human experience with G-CSF and GM-CSF, as well as some animal studies, current consensus opinions support the prompt administration of these materials to patients suffering significant bone marrow depression from exposure to ionizing radiation.

  18. [Alzheimer's disease cerebro-spinal fluid biomarkers: A clinical research tool sometimes useful in daily clinical practice of memory clinics for the diagnosis of complex cases].

    PubMed

    Magnin, E; Dumurgier, J; Bouaziz-Amar, E; Bombois, S; Wallon, D; Gabelle, A; Lehmann, S; Blanc, F; Bousiges, O; Hannequin, D; Jung, B; Miguet-Alfonsi, C; Quillard, M; Pasquier, F; Peoc'h, K; Laplanche, J-L; Hugon, J; Paquet, C

    2017-04-01

    The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aβ1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aβ1-40 amyloid peptide dosage helps to interpret Aβ1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorité de santé) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.

  19. Chimeric classical swine fever (CSF)-Japanese encephalitis (JE) viral particles as a non-transmissible bivalent marker vaccine candidate against CSF and JE infections

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A trans-complemented CSF- JE chimeric viral replicon was constructed using an infectious cDNA clone of the CSF virus (CSFV) Alfort/187 strain. The E2 gene of CSFV Alfort/187 strain was deleted and the resultant plasmid pA187delE2 was inserted by a fragment containing the region coding for a truncate...

  20. Combined administration of G-CSF and GM-CSF stimulates monocyte-derived pro-angiogenic cells in patients with acute myocardial infarction.

    PubMed

    Bruno, Stefania; Bussolati, Benedetta; Scacciatella, Paolo; Marra, Sebastiano; Sanavio, Fiorella; Tarella, Corrado; Camussi, Giovanni

    2006-04-01

    Mobilization of endothelial progenitor cells has been suggested to contribute to neo-vascularization of ischemic organs. Aim of this study was to investigate whether the combination of granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage (GM)-CSF may influence the expansion of circulating KDR+ cells in patients with acute myocardial infarction (AMI). KDR+ cells significantly increased in peripheral blood of AMI patients treated with G-CSF and GM-CSF compared to untreated patients. This KDR+ cells population was CD14+ but not CD34+ or CD133+. CD14+/KDR+ cells were also obtained in vitro by culturing mononuclear cells from healthy donors in a Rotary Cell Culture System in the presence of G-CSF + GM-CSF, but not of the individual growth factors. CD14+/KDR+ cells, obtained from patients or from in vitro culture, co-expressed hematopoietic (CD45, CD14) and endothelial markers (CD31, CD105, and VE-cadherin). CD14+/KDR+, but not CD14+/KDR- cells, stimulated the organization of human microvascular endothelial cells into capillary-like structures on Matrigel both in vitro and in vivo. The combination of G-CSF and GM-CSF induced a CD14+/KDR+ cell population with potential pro-angiogenic properties.

  1. Circulating glioma biomarkers

    PubMed Central

    Kros, Johan M.; Mustafa, Dana M.; Dekker, Lennard J.M.; Sillevis Smitt, Peter A.E.; Luider, Theo M.; Zheng, Ping-Pin

    2015-01-01

    Validated biomarkers for patients suffering from gliomas are urgently needed for standardizing measurements of the effects of treatment in daily clinical practice and trials. Circulating body fluids offer easily accessible sources for such markers. This review highlights various categories of tumor-associated circulating biomarkers identified in blood and cerebrospinal fluid of glioma patients, including circulating tumor cells, exosomes, nucleic acids, proteins, and oncometabolites. The validation and potential clinical utility of these biomarkers is briefly discussed. Although many candidate circulating protein biomarkers were reported, none of these have reached the required validation to be introduced for clinical practice. Recent developments in tracing circulating tumor cells and their derivatives as exosomes and circulating nuclear acids may become more successful in providing useful biomarkers. It is to be expected that current technical developments will contribute to the finding and validation of circulating biomarkers. PMID:25253418

  2. Biomarkers for Parkinson's disease.

    PubMed

    Sherer, Todd B

    2011-04-20

    Biomarkers for detecting the early stages of Parkinson's disease (PD) could accelerate development of new treatments. Such biomarkers could be used to identify individuals at risk for developing PD, to improve early diagnosis, to track disease progression with precision, and to test the efficacy of new treatments. Although some progress has been made, there are many challenges associated with developing biomarkers for detecting PD in its earliest stages.

  3. Biomarker in archaeological soils

    NASA Astrophysics Data System (ADS)

    Wiedner, Katja; Glaser, Bruno; Schneeweiß, Jens

    2015-04-01

    The use of biomarkers in an archaeological context allow deeper insights into the understanding of anthropogenic (dark) earth formation and from an archaeological point of view, a completely new perspective on cultivation practices in the historic past. During an archaeological excavation of a Slavic settlement (10th/11th C. A.D.) in Brünkendorf (Wendland region in Northern Germany), a thick black soil (Nordic Dark Earth) was discovered that resembled the famous terra preta phenomenon. For the humid tropics, terra preta could act as model for sustainable agricultural practices and as example for long-term CO2-sequestration into terrestrial ecosystems. The question was whether this Nordic Dark Earth had similar properties and genesis as the famous Amazonian Dark Earth in order to find a model for sustainable agricultural practices and long term CO2-sequestration in temperate zones. For this purpose, a multi-analytical approach was used to characterize the sandy-textured Nordic Dark Earth in comparison to less anthropogenically influenced soils in the adjacent area in respect of ecological conditions (e.g. amino sugar), input materials (faeces) and the presence of stable soil organic matter (black carbon). Amino sugar analyses showed that Nordic Dark Earth contained higher amounts of microbial residues being dominated by soil fungi. Faecal biomarkers such as stanols and bile acids indicated animal manure from omnivores and herbivores but also human excrements. Black carbon content of about 30 Mg ha-1 in the Nordic Dark Earth was about four times higher compared to the adjacent soil and in the same order of magnitude compared to terra preta. Our data strongly suggest parallels to anthropogenic soil formation in Amazonia and in Europe by input of organic wastes, faecal material and charred organic matter. An obvious difference was that in terra preta input of human-derived faecal material dominated while in NDE human-derived faecal material played only a minor role

  4. Serotonin Metabolites in the Cerebrospinal Fluid in the Sudden Infant Death Syndrome: In Search of a Biomarker of Risk

    PubMed Central

    Rognum, Ingvar J.; Tran, Hoa; Haas, Elisabeth A.; Hyland, Keith; Paterson, David S.; Haynes, Robin L.; Broadbelt, Kevin G.; Harty, Brian J.; Mena, Othon; Krous, Henry F.; Kinney, Hannah C.

    2015-01-01

    Clinical biomarkers are urgently needed in the sudden infant death syndrome (SIDS) to identify living infants at risk because it because it occurs without occurs without clinical warning. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. Here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared to autopsy controls, as a first step towards their assessment as diagnostic biomarkers of medullary pathology. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high performance liquid chromatography in 57 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude use of 5-HIAA, HVA, Trp or Tyr measurements as CSF biomarkers of 5-HT medullary pathology in infants at risk. They provide, however, important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS. PMID:24423636

  5. Injured sensory neuron-derived CSF1 induces microglia proliferation and DAP12-dependent pain

    PubMed Central

    Guan, Zhonghui; Kuhn, Julia A.; Wang, Xidao; Colquitt, Bradley; Solorzano, Carlos; Vaman, Smitha; Guan, Andrew K.; Evans-Reinsch, Zoe; Braz, Joao; Devor, Marshall; Abboud-Werner, Sherry L.; Lanier, Lewis L.; Lomvardas, Stavros; Basbaum, Allan I.

    2015-01-01

    SUMMARY Although microglia are implicated in nerve injury-induced neuropathic pain, how injured sensory neurons engage microglia is unclear. Here we demonstrate that peripheral nerve injury induces de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. The CSF1 is transported to the spinal cord where it targets the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglia activation and proliferation. In contrast, intrathecal injection of CSF1 induces mechanical hypersensitivity and microglial proliferation. Nerve injury also upregulated CSF1 in motoneurons, where it is required for ventral horn microglial activation and proliferation. Downstream of CSF1R, we found that the microglial membrane adapter protein DAP12 is required for both nerve injury- and intrathecal CSF1-induced upregulation of pain-related microglial genes and the ensuing pain, but not for microglia proliferation. Thus, both CSF1 and DAP12 are potential targets for the pharmacotherapy of neuropathic pain. PMID:26642091

  6. The Biomarker Guide

    NASA Astrophysics Data System (ADS)

    Peters, K. E.; Walters, C. C.; Moldowan, J. M.

    2005-01-01

    Biomarkers are compounds found in crude oil with structures inherited from once-living organisms. They persist in oil spills, refinery products and archaeological artifacts, and can be used to identify the origin, geological age and environmental conditions prevalent during their formation and alteration. These two volumes will be an invaluable resource for geologists, petroleum geochemists, biogeochemists, environmental and forensic scientists, natural product chemists and archaeologists. The first of two volumes of The Biomarker Guide discusses the origins of biomarkers and introduces basic chemical principles relevant to their study. It goes on to discuss analytical techniques, and the applications of biomarkers in environmental and archaeological problems.

  7. Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy.

    PubMed

    Wadhwa, M; Bird, C; Fagerberg, J; Gaines-Das, R; Ragnhammar, P; Mellstedt, H; Thorpe, R

    1996-05-01

    In this study, the development of neutralizing and non-neutralizing GM-CSF antibodies and the clinical consequences related to the induction of these antibodies were analysed in 20 patients with metastatic colorectal carcinoma receiving a combination therapy of Escherichia coli-derived GM-CSF and a colon carcinoma-reactive MoAb in the absence of any concomitant chemotherapy. The recombinant human GM-CSF was administered subcutaneously for 10 days every month for 4 months. Following the first cycle of treatment, no GM-CSF antibodies were detected, but during subsequent therapy, 19 of the 20 patients studied developed GM-CSF binding antibodies. However, only a proportion (40%) of the 19 antibody-positive patients developed antibodies that neutralized the biological activity of GM-CSF in an in vitro bioassay. The presence of GM-CSF neutralizing antibodies was associated with a significant reduction in GM-CSF-induced expansion of leucocytes, neutrophils and eosinophils. Such clinical effects were not apparent in patients with non-neutralizing antibodies. Further characterization of sera from patients with neutralizing antibodies showed that, in most cases, the antibodies neutralized the biological activity of GM-CSF preparations derived using different expression systems (Chinese hamster ovary cells and yeast), suggesting that these antibodies may have the potential to cross-react with endogenously produced GM-CSF. These effects should be considered before therapeutic use of cytokines, particularly in patients who are not immunosuppressed, and therefore capable of mounting an effective immune response. Our results indicate that assessment of production of neutralizing antibodies induced during cytokine therapy can be used to predict diminished clinical response to further therapy.

  8. Phorbol ester-treated human acute myeloid leukemia cells secrete G-CSF, GM-CSF and erythroid differentiation factor into serum-free media in primary culture.

    PubMed

    Scher, W; Eto, Y; Ejima, D; Den, T; Svet-Moldavsky, I A

    1990-12-10

    Upon treatment with the phorbol ester, tetradecanoylphorbol 13-acetate (PMA), peripheral mononuclear blood cells from patients with acute myeloid leukemia secrete into serum-free cell-conditioned media (PMA-CCM) at least three distinct nondialysable 'hematopoietic' factors: granulocyte-colony-stimulating factor (G-CSF), granulocyte/macrophage-colony-stimulating factor (GM-CSF) and erythroid differentiation factor (EDF, activin A). G-CSF was identified by its stimulation of [3H]thymidine incorporation into a G-CSF-responsive cell line, NSF-60, and the inhibition of its stimulation by a G-CSF-specific monoclonal antibody (MAB). GM-CSF was identified by its stimulation of [3H]thymidine incorporation into a GM-CSF-responsive line, TALL-101, and the inhibition of its stimulation by a GM-CSF-specific MAB. EDF was identified by its ability to stimulate erythroid differentiation in mouse erythroleukemia cell lines, its identical retention times to those of authentic EDF on three successive reverse-phase HPLC columns and characterization of its penultimate N-terminal residue as leucine which is the same as that of authentic EDF. Both authentic EDF and the erythroid-stimulating activity in PMA-CCM were found to act synergistically with a suboptimal inducing concentration of a well-studied inducing agent, dimethyl sulfoxide, in inducing erythroid differentiation. In addition, a fourth activity was observed in PMA-CCM: normal human fetal bone marrow cell-proliferation stimulating activity (FBMC-PSA). FBMC-PSA was identified by its ability to stimulate the growth of granulocytes and macrophages in FBMC suspension cultures, which neither recombinant G-CSF or GM-CSF were found to do.

  9. The Potential for Bio-Mediators and Biomarkers in Pediatric Traumatic Brain Injury and Neurocritical Care

    PubMed Central

    Kochanek, Patrick M.; Berger, Rachel P.; Fink, Ericka L.; Au, Alicia K.; Bayır, Hülya; Bell, Michael J.; Dixon, C. Edward; Clark, Robert S. B.

    2013-01-01

    The use of biomarkers of brain injury in pediatric neurocritical care has been explored for at least 15 years. Two general lines of research on biomarkers in pediatric brain injury have been pursued: (1) studies of “bio-mediators” in cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) to explore the components of the secondary injury cascades in an attempt to identify potential therapeutic targets and (2) studies of the release of structural proteins into the CSF, serum, or urine in order to diagnose, monitor, and/or prognosticate in patients with TBI or other pediatric neurocritical care conditions. Unique age-related differences in brain biology, disease processes, and clinical applications mandate the development and testing of brain injury bio-mediators and biomarkers specifically in pediatric neurocritical care applications. Finally, although much of the early work on biomarkers of brain injury in pediatrics has focused on TBI, new applications are emerging across a wide range of conditions specifically for pediatric neurocritical care including abusive head trauma, cardiopulmonary arrest, septic shock, extracorporeal membrane oxygenation, hydrocephalus, and cardiac surgery. The potential scope of the utility of biomarkers in pediatric neurocritical care is thus also discussed. PMID:23637695

  10. AdS duals of matrix strings

    NASA Astrophysics Data System (ADS)

    Morales, Jose F.; Samtleben, Henning

    2003-06-01

    We review recent work on the holographic duals of type II and heterotic matrix string theories described by warped AdS3 supergravities. In particular, we compute the spectra of Kaluza-Klein primaries for type I, II supergravities on warped AdS3 × S7 and match them with the primary operators in the dual two-dimensional gauge theories. The presence of non-trivial warp factors and dilaton profiles requires a modification of the familiar dictionary between masses and 'scaling' dimensions of fields and operators. We present these modifications for the general case of domain wall/QFT correspondences between supergravities on warped AdSd+1 × Sq geometries and super Yang-Mills theories with 16 supercharges.

  11. A Review of GM-CSF Therapy in Sepsis

    PubMed Central

    Mathias, Brittany; Szpila, Benjamin E.; Moore, Frederick A.; Efron, Philip A.; Moldawer, Lyle L.

    2015-01-01

    Abstract Determine what clinical role, if any, GM-CSF may have in the clinical treatment of sepsis in the adult patient. Advancements in the management of sepsis have led to significant decreases in early mortality; however, sepsis remains a significant source of long-term mortality and disability which places strain on healthcare resources with a substantial growing economic impact. Historically, early multiple organ failure (MOF) and death in patients with severe sepsis was thought to result from an exaggerated proinflammatory response called the systemic inflammatory response syndrome (SIRS). Numerous prospective randomized controlled trials (PRCTs) tested therapies aimed at decreasing the organ injury associated with an exaggerated inflammatory response. With few exceptions, the results from these PRCTs have been disappointing, and currently no specific therapeutic agent is approved to counteract the early SIRS response in patients with severe sepsis. It has long been recognized that there is a delayed immunosuppressive state that contributes to long-term morbidity. However, recent findings now support a concurrent proinflammatory and anti-inflammatory response present throughout sepsis. Multiple immunomodulating agents have been studied to combat the immunosuppressive phase of sepsis with the goal of decreasing secondary infection, reducing organ dysfunction, decreasing ICU stays, and improving survival. Granulocyte-macrophage colony stimulating factor (GM-CSF), a myelopoietic growth factor currently used in patients with neutropenia secondary to chemotherapy-induced myelosuppression, has been studied as a potential immune-activating agent. The applicability of GM-CSF as a standard therapy for generalized sepsis is still largely understudied; however, small-scale studies available have demonstrated some improved recovery from infection, decreased hospital length of stay, decreased days requiring mechanical ventilation, and decreased medical costs. PMID

  12. Alzheimer’s Disease: Biomarkers in the Genome, Blood, and Cerebrospinal Fluid

    PubMed Central

    Huynh, Rose Ann; Mohan, Chandra

    2017-01-01

    Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that slowly destroys memory and thinking skills, resulting in behavioral changes. It is estimated that nearly 36 million are affected globally with numbers reaching 115 million by 2050. AD can only be definitively diagnosed at autopsy since its manifestations of senile plaques and neurofibrillary tangles throughout the brain cannot yet be fully captured with current imaging technologies. Current AD therapeutics have also been suboptimal. Besides identifying markers that distinguish AD from controls, there has been a recent drive to identify better biomarkers that can predict the rates of cognitive decline and neocortical amyloid burden in those who exhibit preclinical, prodromal, or clinical AD. This review covers biomarkers of three main types: genes, cerebrospinal fluid-derived, and blood-derived biomarkers. Looking ahead, cutting-edge OMICs technologies, including proteomics and metabolomics, ought to be fully tapped in order to mine even better biomarkers for AD that are more predictive. PMID:28373857

  13. Biomarkers of chemotaxis and inflammation in cerebrospinal fluid and serum in individuals with HIV-1 subtype C versus B.

    PubMed

    de Almeida, Sergio M; Rotta, Indianara; Jiang, Yanxin; Li, Xiao; Raboni, Sonia M; Ribeiro, Clea E; Smith, Davey; Potter, Michael; Vaida, Florin; Letendre, Scott; Ellis, Ronald J

    2016-12-01

    A defective chemokine motif in the HIV-1 Tat protein has been hypothesized to alter central nervous system cellular trafficking and inflammation, rendering HIV-1 subtype C less neuropathogenic than B. To evaluate this hypothesis, we compared biomarkers of cellular chemotaxis and inflammation in cerebrospinal fluid (CSF) and serum in individuals infected with HIV-1 subtypes B (n = 27) and C (n = 25) from Curitiba, Brazil. None had opportunistic infections. Chemokines (MCP-1, MIP-1α, MIP-1β, RANTES, IP-10) and cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10) were measured using the multiplex bead suspension array immunoassays or ELISA HD. CSF and serum biomarker concentrations were compared between subtype B and C groups and HIV-positive and HIV-negative subjects (N = 19) using an independent group t test (unadjusted analysis) and linear regression (adjusted analysis), controlling for nadir CD4 and CSF and plasma HIV RNA suppression. CSF levels of cytokines and chemokines were significantly (p < 0.05) elevated in HIV-positive versus HIV-negative participants for 7/13 biomarkers measured, but levels did not differ for subtypes B and C. Serum levels were significantly elevated for 4/13 markers, with no significant differences between subtypes B and C. Although pleocytosis was much more frequent in HIV-positive than in HIV-negative individuals (27 vs. 0 %), subtypes B and C did not differ (32 and 22 %; p = 0.23). We did not find molecular evidence to support the hypothesis that intrathecal chemotaxis and inflammation is less in HIV-1 subtype C than in subtype B. Biomarker changes in CSF were more robust than in serum, suggesting compartmentalization of the immunological response to HIV.

  14. Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward

    PubMed Central

    Roberts, Ruth A.; Aschner, Michael; Calligaro, David; Guilarte, Tomas R.; Hanig, Joseph P.; Herr, David W.; Hudzik, Thomas J.; Jeromin, Andreas; Kallman, Mary J.; Liachenko, Serguei; Lynch, James J.; Miller, Diane B.; Moser, Virginia C.; O’Callaghan, James P.; Slikker, William; Paule, Merle G.

    2015-01-01

    Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues. Increasing evidence supports the potential utility of fluid-based biomarkers of neurotoxicity such as microRNAs, F2-isoprostanes, translocator protein, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, microtubule-associated protein-2, and total tau. However, some of these biomarkers such as those in CSF require invasive sampling or are specific to one disease such as Alzheimer’s, while others require further validation. Additionally, neuroimaging methodologies, including magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, may also serve as potential biomarkers and have several advantages including being minimally invasive. The development of biomarkers of neurotoxicity is a goal shared by scientists across academia, government, and industry and is an ideal topic to be addressed via the Health and Environmental Sciences Institute (HESI) framework which provides a forum to collaborate on key challenging scientific topics. Here we utilize the HESI framework to propose a consensus on the relative potential of currently described biomarkers of neurotoxicity to assess utility of the selected biomarkers using a nonclinical model. PMID:26609132

  15. CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

    NASA Astrophysics Data System (ADS)

    Pridans, Clare; Sauter, Kristin A.; Baer, Kristin; Kissel, Holger; Hume, David A.

    2013-10-01

    Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS.

  16. A Csf1r-EGFP Transgene Provides a Novel Marker for Monocyte Subsets in Sheep

    PubMed Central

    Pridans, Clare; Davis, Gemma M.; Sauter, Kristin A.; Lisowski, Zofia M.; Corripio-Miyar, Yolanda; Raper, Anna; Lefevre, Lucas; Young, Rachel; McCulloch, Mary E.; Lillico, Simon; Milne, Elspeth; Whitelaw, Bruce

    2016-01-01

    Expression of Csf1r in adults is restricted to cells of the macrophage lineage. Transgenic reporters based upon the Csf1r locus require inclusion of the highly conserved Fms-intronic regulatory element for expression. We have created Csf1r-EGFP transgenic sheep via lentiviral transgenesis of a construct containing elements of the mouse Fms-intronic regulatory element and Csf1r promoter. Committed bone marrow macrophage precursors and blood monocytes express EGFP in these animals. Sheep monocytes were divided into three populations, similar to classical, intermediate, and nonclassical monocytes in humans, based upon CD14 and CD16 expression. All expressed EGFP, with increased levels in the nonclassical subset. Because Csf1r expression coincides with the earliest commitment to the macrophage lineage, Csf1r-EGFP bone marrow provides a tool for studying the earliest events in myelopoiesis using the sheep as a model. PMID:27521343

  17. CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

    PubMed Central

    Pridans, Clare; Sauter, Kristin A.; Baer, Kristin; Kissel, Holger; Hume, David A.

    2013-01-01

    Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS. PMID:24145216

  18. A Csf1r-EGFP Transgene Provides a Novel Marker for Monocyte Subsets in Sheep.

    PubMed

    Pridans, Clare; Davis, Gemma M; Sauter, Kristin A; Lisowski, Zofia M; Corripio-Miyar, Yolanda; Raper, Anna; Lefevre, Lucas; Young, Rachel; McCulloch, Mary E; Lillico, Simon; Milne, Elspeth; Whitelaw, Bruce; Hume, David A

    2016-09-15

    Expression of Csf1r in adults is restricted to cells of the macrophage lineage. Transgenic reporters based upon the Csf1r locus require inclusion of the highly conserved Fms-intronic regulatory element for expression. We have created Csf1r-EGFP transgenic sheep via lentiviral transgenesis of a construct containing elements of the mouse Fms-intronic regulatory element and Csf1r promoter. Committed bone marrow macrophage precursors and blood monocytes express EGFP in these animals. Sheep monocytes were divided into three populations, similar to classical, intermediate, and nonclassical monocytes in humans, based upon CD14 and CD16 expression. All expressed EGFP, with increased levels in the nonclassical subset. Because Csf1r expression coincides with the earliest commitment to the macrophage lineage, Csf1r-EGFP bone marrow provides a tool for studying the earliest events in myelopoiesis using the sheep as a model.

  19. The Effects of Rm-CSF and Ril-6 Therapy on Immunosuppressed Antiorthostatically Suspended Mice

    NASA Technical Reports Server (NTRS)

    Armstong, Jason W.; Kirby-Dobbels, Kathy; Chapes, Steven K.

    1995-01-01

    Antiorthostatically suspended mice had suppressed macrophage development in both unloaded and loaded bones, indicating a systemic effect. Bone marrow cells from those mice secreted less macrophage colony-stimulating factor (M-CSF) and interleukin-6 (IL-6) than did control mice. Because M-CSF and IL-6 are important to bone marrow macrophage maturation, we formulated the hypothesis that suppressed macrophage development occurred as a result of the depressed levels of either M-CSF or IL-6. To test the hypothesis, mice were administered recombinant M-CSF or IL-6 intraperitoneally. We showed that recombinant M-CSF therapy, but not recombinant IL-6 therapy, reversed the suppressive effects of orthostatic suspension on macrophage development. These data suggest that bone marrow cells that produce M-CSF are affected by antiorthostatic suspension and may contribute to the inhibited maturation of bone marrow macrophage progenitors.

  20. Biomarkers present in asphaltenes

    SciTech Connect

    Philp, R.P.

    1985-01-01

    The significance and distribution of biomarkers in sediments, source rocks and crude oils are well documented in the literature. Little attention has been directed towards the biomarkers that are present in the asphaltene fractions of crude oils and source rock extracts. Asphaltene fractions by definition are insoluble in certain solvents and consist of high molecular components which makes them difficult to analyze by techniques commonly used to characterize the soluble extracts. Asphaltenes are ideally suited for analysis by microscale pyrolysis techniques (py) combined with gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Utilization of the multiple ion detection technique in conjunction with the py-GC-MS analyses permits the distribution of the steranes, triterpanes and other biomarker produced by pyrolysis of the asphaltenes to be easily determined. It is proposed in this paper to discuss the pyrolysis of asphaltene from a variety of source rocks and analysis of the biomarkers, released by the pyrolysis. These biomarkers distributions can be used to obtain information on source and maturity of the organic matter in a similar manner to using the soluble biomarkers. It is proposed to discuss the asphaltene biomarker distributions and also to speculate as to why certain biomarkers are present only in the extracts and asphaltenes and not produced by pyrolysis of the kerogens.

  1. Respiratory Toxicity Biomarkers

    EPA Science Inventory

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  2. IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization.

    PubMed

    Ségaliny, Aude I; Brion, Régis; Brulin, Bénédicte; Maillasson, Mike; Charrier, Céline; Téletchéa, Stéphane; Heymann, Dominique

    2015-12-01

    Interleukin-34 (IL-34) is a newly-discovered homodimeric cytokine that regulates, like Macrophage Colony-Stimulating Factor (M-CSF), the differentiation of the myeloid lineage through M-CSF receptor (M-CSFR) signaling pathways. To date, both cytokines have been considered as competitive cytokines with regard to the M-CSFR. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the M-CSFR. We demonstrate that simultaneous addition of M-CSF and IL-34 led to a specific activation pattern on the M-CSFR, with higher phosphorylation of the tyrosine residues at low concentrations. Similarly, both cytokines showed an additive effect on cellular proliferation or viability. In addition, BIAcore experiments demonstrated that M-CSF binds to IL-34, and molecular docking studies predicted the formation of a heteromeric M-CSF/IL-34 cytokine. A proximity ligation assay confirmed this interaction between the cytokines. Finally, co-expression of the M-CSFR and its ligands differentially regulated M-CSFR trafficking into the cell. This study establishes a new foundation for the understanding of the functional relationship between IL-34 and M-CSF, and gives a new vision for the development of therapeutic approaches targeting the IL-34/M-CSF/M-CSFR axis.

  3. Reduced CSF turnover and decreased ventricular Aβ42 levels are related

    PubMed Central

    2011-01-01

    Background The appearance of Aβ42 peptide deposits is admitted to be a key event in the pathogenesis of Alzheimer's disease, although amyloid deposits also occur in aged non-demented subjects. Aβ42 is a degradation product of the amyloid protein precursor (APP). It can be catabolized by several enzymes, reabsorbed by capillaries or cleared into cerebrospinal fluid (CSF). The possible involvement of a decrease in CSF turnover in A4β2 deposit formation is up to now poorly known. We therefore investigated a possible relationship between a reduced CSF turnover and the CSF levels of the A4β2 peptide. To this aim, CSF of 31 patients with decreased CSF turnover were studied. These patients presented chronic hydrocephalus communicating or obstructive, which required surgery (ventriculostomy or ventriculo-peritoneal shunt). Nine subjects had idiopathic normal pressure hydrocephalus (iNPH), and the other 22 chronic hydrocephalus from other origins (oCH). The Aβ42 peptide concentration was measured by an ELISA test in 31 ventricular CSF samples and in 5 lumbar CSF samples from patients with communicating hydrocephalus. Results The 5 patients with lumbar CSF analysis had similar levels of lumbar and ventricular Aβ42. A significant reduction in Aβ42 ventricular levels was observed in 24 / 31 patients with hydrocephalus. The values were lower than 300 pg/ml in 5 out of 9 subjects with iNPH, and in 15 out of 22 subjects with oCH. Conclusion The decrease of CSF Aβ42 seems to occur independently of the surgical hydrocephalus aetiology. This suggests that a CSF reduced turnover may play an important role in the decrease of CSF Aβ42 concentration. PMID:21569454

  4. Conductance to outflow of CSF in normal pressure hydrocephalus.

    PubMed

    Børgesen, S E

    1984-01-01

    Normal pressure hydrocephalus (NPH) is defined as a combination of dementia, gait disturbances and/or urinary incontinence, hydrocephalus, and a normal intracranial mean pressure. The clinical effect of CSF shunting in patients with this syndrome is sometimes striking, but generally only 50-60% of the shunted patients benefit from the treatment. It is assumed that the condition is caused by reduced conductance to outflow of CSF ( Cout ). A clinically usable method for the measurement of Cout has been developed. Cout has been measured in 80 patients with NPH. The results of clinical examination, computed tomography (CT), long-term intracranial pressure recording, isotope cisternography (ICG), and Cout have been compared to the clinical results of shunting 3 and 12 months after operation. Among the preoperative investigations Cout proved to have the best diagnostic specificity and sensitivity. Thus, selection of patients for shunting on the basis of Cout should lead to a satisfyingly high success rate. The different methods for measurement of Cout are discussed, and a theory on the pathophysiology of NPH is proposed. A clinical investigational programme, based on the results from clinical examination, CT, pressure recording, and measurements of Cout is suggested.

  5. Biomarkers in Parkinson's disease.

    PubMed

    Morgan, John C; Mehta, Shyamal H; Sethi, Kapil D

    2010-11-01

    Biomarkers are objectively measured characteristics that are indicators of normal biological processes, pathogenic processes, or responses to therapeutic interventions. To date, clinical assessment remains the gold standard in the diagnosis of Parkinson's disease (PD) and clinical rating scales are well established as the gold standard for tracking progression of PD. Researchers have identified numerous potential biomarkers that may aid in the differential diagnosis of PD and/or tracking disease progression. Clinical, genetic, blood and cerebrospinal fluid (proteomics, transcriptomics, metabolomics), and neuroimaging biomarkers may provide useful tools in the diagnosis of PD and in measuring disease progression and response to therapies. Some potential biomarkers are inexpensive and do not require much technical expertise, whereas others are expensive or require specialized equipment and technical skills. Many potential biomarkers in PD show great promise; however, they need to be assessed for their sensitivity and specificity over time in large and varied samples of patients with and without PD.

  6. Biomarkers of Reflux Disease.

    PubMed

    Kia, Leila; Pandolfino, John E; Kahrilas, Peter J

    2016-06-01

    Gastroesophageal reflux disease (GERD) encompasses an array of disorders unified by the reflux of gastric contents. Because there are many potential disease manifestations, esophageal and extraesophageal, there is no single biomarker of the entire disease spectrum; a set of GERD biomarkers that each quantifies specific aspects of GERD-related pathology might be needed. We review recent reports of biomarkers of GERD, specifically in relation to endoscopically negative esophageal disease and excluding conventional pH-impedance monitoring. We consider histopathologic biomarkers, baseline impedance, and serologic assays to determine that most markers are based on manifestations of impaired esophageal mucosal integrity, which is based on increased ionic and molecular permeability, and/or destruction of tight junctions. Impaired mucosal integrity quantified by baseline mucosal impedance, proteolytic fragments of junctional proteins, or histopathologic features has emerged as a promising GERD biomarker.

  7. Biomarkers and infection in the emergency unit.

    PubMed

    Hausfater, P

    2014-04-01

    The emergency unit is one of the main places for acute medical care and therefore, has a pivotal role in determining a diagnosis of bacterial infection and initiating antibiotic therapy. There is an unquestionable and growing interest for infection biomarkers because of the polymorphism of septic state presentations in the emergency unit and the lack of accuracy of available biological tools. The C Reactive protein (CRP) is a biomarker of inflammation, not of infection. CRP is highly sensitive but lacks specificity. Moreover, there are few interventional studies evaluating its true added diagnostic value in the emergency unit, therefore preventing using CRP as a biomarker of infection. Serum procalcitonin (PCT) dosage is more specific for the diagnosis of bacterial infection. PCT levels do not increase or only slightly in non-bacterial inflammatory syndromes. PCT also provides prognostic information and risk stratification assessment in the emergency unit. Moreover, many authors of interventional studies have validated the contribution of PCT in decision taking for antibiotic therapy when suspecting low respiratory tract infection. It is currently the first-line biomarker of infection in the emergency unit. Other biomarkers such as presepsin (sCD14) may be contributive for the diagnosis and prognosis.

  8. CSF proteomic fingerprints for HIV- associated cognitive impairment

    PubMed Central

    Laspiur, Juliana Pérez; Anderson, Eric R.; Ciborowski, Pawel; Wojna, Valerie; Rozek, Wojciech; Duan, Fenghai; Mayo, Raul; Rodríguez, Elaine; Plaud-Valentín, Marinés; Rodríguez-Orengo, José; Gendelman, Howard E.; Meléndez, Loyda M.

    2008-01-01

    Cognitive impairment remains a major complication of advanced human immunodeficiency virus (HIV) infection despite the wide spread use of anti-retroviral therapy. Diagnosis is made by exclusion making biomarkers of great potential use. Thus, we used an integrated proteomics platform to assess cerebrospinal fluid protein profiles from 50 HIV-1 seropositive Hispanic women. Nine of 38 proteins identified were unique in those patients with cognitive impairment. These proteins were linked to cell signaling, structural function, and antioxidant activities. This work highlights, in a preliminary manner, the utility of proteomic profiling for biomarker discovery for HIV-1 associated cognitive dysfunction. PMID:17950469

  9. The effect of vaccination with the PAV-250 strain classical swine fever (CSF) virus on the airborne transmission of CSF virus.

    PubMed

    Gonzalez, C; Pijoan, C; Ciprian, A; Correa, P; Mendoza, S

    2001-09-01

    The airborne transmission of Classical Swine Fever (CSF) virus to susceptible pigs, as well as the effect of vaccination with the CSF virus PAV-250 strain was investigated on this mode of transmission. Experiment I: four pigs were inoculated with the ALD CSFV strain (10(4.3) 50% TCID) by the intramuscular route, and at the onset of fever, they were introduced into an enclosed chamber. At the end of the experiment surviving pigs were sedated, anesthetized and euthanatized. Experiment II: four pigs were previously vaccinated with the CSF virus PAV-250 strain, and at 14 days post-vaccination they were challenged with the CSF virus ALD strain. In both experiments, four susceptible pigs were exposed to infectious aerosols by placing them in a chamber connected by a duct to the adjacent pen containing the infected animals and were kept there for 86 hs. In Experiment I, pigs exposed to contaminated air died as a result of infection with CSF virus on days 14, 21 and 28 post-inhalation. These four pigs seroconverted from day 12 post-inhalation. CSF virus was isolated from these animals, and the fluorescent antibody test on tonsils was positive. In Experiment II, a vaccinated pig exposed to contaminated air did not seroconvert, nor was CSF virus isolated from lymphoid tissues. However, mild fluorescence in tonsil sections from these pigs was observed. In conclusion, CSF virus was shown to be transmitted by air at a distance of 1 m to susceptible pigs. Vaccination with the PAV-250 CSF virus strain protected the pigs from clinical disease under the same conditions.

  10. Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization.

    PubMed

    Chen, Chong; Song, Xuguang; Ma, Sha; Wang, Xue; Xu, Jie; Zhang, Huanxin; Wu, Qingyun; Zhao, Kai; Cao, Jiang; Qiao, Jianlin; Sun, Xiaoshen; Li, Depeng; Zeng, Lingyu; Li, Zhengyu; Xu, Kailin

    2015-01-01

    G-CSF is the most often used agent in clinical hematopoietic stem and progenitor cell (HSPC) mobilization. However, in about 10 % of patients, G-CSF does not efficiently mobilize HSPC in clinically sufficient amounts. Cdc42 activity is involved in HSPC mobilization. In the present study, we explore the impact of Cdc42 inhibitor ML141 on G-CSF-mediated HSPC mobilization in mice. We found that the use of ML141 alone only triggered modest HSPC mobilization effect in mice. However, combination of G-CSF and ML141 significantly promoted HPSC counts and colony forming units in peripheral blood, as compared to mice treated with G-CSF alone. ML141 did not significantly alter the levels of SDF-1 and MMP-9 in the bone marrow, when used alone or in combination with G-CSF. We also found that G-CSF administration significantly increases the level of GTP-bound Cdc42, but does not alter the expression of Cdc42 in the bone marrow. Our data indicate that the Cdc42 signal is a negative regulator in G-CSF-mediated HSPC mobilization, and that inhibition of the Cdc42 signal efficiently improves mobilization efficiency. These findings may provide a new strategy for efficient HSPC mobilization, especially in patients with poor G-CSF response.

  11. Diabetes Limits Stem Cell Mobilization Following G-CSF but Not Plerixafor.

    PubMed

    Fadini, Gian Paolo; Fiala, Mark; Cappellari, Roberta; Danna, Marianna; Park, Soo; Poncina, Nicol; Menegazzo, Lisa; Albiero, Mattia; DiPersio, John; Stockerl-Goldstein, Keith; Avogaro, Angelo

    2015-08-01

    Previous studies suggest that diabetes impairs hematopoietic stem cell (HSC) mobilization in response to granulocyte colony-stimulating factor (G-CSF). In this study, we tested whether the CXCR4 antagonist plerixafor, differently from G-CSF, is effective in mobilizing HSCs in patients with diabetes. In a prospective study, individuals with and without diabetes (n = 10/group) were administered plerixafor to compare CD34(+) HSC mobilization; plerixafor was equally able to mobilize CD34(+) HSCs in the two groups, whereas in historical data, G-CSF was less effective in patients with diabetes. In a retrospective autologous transplantation study conducted on 706 patients, diabetes was associated with poorer mobilization in patients who received G-CSF with/without chemotherapy, whereas it was not in patients who received G-CSF plus plerixafor. Similarly in an allogeneic transplantation study (n = 335), diabetes was associated with poorer mobilization in patients who received G-CSF. Patients with diabetes who received G-CSF without plerixafor had a lower probability of reaching >50/μL CD34(+) HSCs, independent from confounding variables. In conclusion, diabetes negatively impacted HSC mobilization after G-CSF with or without chemotherapy but had no effect on mobilization induced by G-CSF with plerixafor. This finding has major implications for the care of patients with diabetes undergoing stem cell mobilization and transplantation and for the vascular regenerative potential of bone marrow stem cells.

  12. Identification of CSF-1 as a brain macrophage migratory activity produced by astrocytes.

    PubMed

    Calvo, C F; Dobbertin, A; Gelman, M; Glowinski, J; Mallat, M

    1998-10-01

    Intraparenchymal migration of macrophages occurs in the CNS during development or as a consequence of tissue injuries. In the present study, we have shown, by using an in vitro chemotaxis assay, that cultured rat astrocytes obtained from the developing cerebral cortex and striatum produce soluble factors, which attract purified brain macrophages. The effect of astrocyte-derived factors on macrophages was strongly reduced in the presence of antibodies neutralizing colony-stimulating factor 1 (CSF-1, also called M-CSF), and recombinant CSF-1 was found to act as a chemotactic agent on brain macrophages. Synthesis of CSF-1 by cultured astrocytes was confirmed by northern detection of CSF-1 transcripts. In contrast, the CSF-1 gene was not expressed by cultured neurons from the cerebral cortex and striatum or by the brain macrophage population responsive to CSF-1 gradient. ELISA detection of CSF-1 in tissue extracts revealed the occurrence of this cytokine in the rat cerebral cortex during postnatal development and in adults. Altogether, our results demonstrate that astrocytes, through CSF-1 secretion, can trigger the polarized migration of brain macrophages and suggest a new mechanism which could regulate the locomotion of these cells in the cerebral cortex during ontogenesis or following lesions.

  13. Plasma levels of M-CSF are increased in ANCA-associated vasculitides with active nephritis.

    PubMed

    Ramirez, Giuseppe A; Blasi, Miriam; Sciorati, Clara; Rovere-Querini, Patrizia; Manfredi, Angelo A

    2015-01-01

    Anti-Neutrophil Cytoplasmic Antibodies (ANCA)-associated vasculitides (AAV) are characterized by small vessel injury and in some cases granulomatous lesions and glomerular inflammation. The pathogenic bases of these clinical phenotypes are incompletely understood, but evidence from patients with AAV and other inflammatory diseases suggest a role for monocyte/macrophages in the perpetuation of tissue injury. Macrophage colony stimulating factor (M-CSF) is a promoter of monocyte recruitment and macrophage proliferation, involved in mesangial cell proliferation and experimental nephritis development. Serum concentrations of M-CSF mark and herald the onset of lupus nephritis. Plasma samples from 29 patients with AAV (18 granulomatosis with polyangiitis, GPA, 6 eosinophilic granulomatosis with polyangiitis, EGPA, and 5 microscopic polyangiitis, MPA) and from 10 healthy controls were collected together with clinical data. Patients with AAV had higher levels of M-CSF when compared to controls. M-CSF levels correlated positively with the BVAS, serum C-reactive protein and erythrocyte sedimentation rate, while haemoglobin correlated inversely with M-CSF. Patients with active renal disease had significantly higher levels of M-CSF when compared to the other subgroups. M-CSF levels did not differ between ANCA subserotypes and were not associated with the involvement of other organs. In conclusion, M-CSF is higher in patients with AAV and active nephritis and could contribute to the pathogenesis of these diseases. In addition, M-CSF could behave as a useful marker of renal involvement in AAV.

  14. Pleiotropic effects of extended blockade of CSF1R signaling in adult mice.

    PubMed

    Sauter, Kristin A; Pridans, Clare; Sehgal, Anuj; Tsai, Yi Ting; Bradford, Barry M; Raza, Sobia; Moffat, Lindsey; Gow, Deborah J; Beard, Philippa M; Mabbott, Neil A; Smith, Lee B; Hume, David A

    2014-08-01

    We investigated the role of CSF1R signaling in adult mice using prolonged treatment with anti-CSF1R antibody. Mutation of the CSF1 gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the CSF1R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of CSF1R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-CSF1R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for CSF1R signaling in macrophage and OCL homeostasis but indicate that most effects of CSF1 and CSF1R mutations are due to effects on development.

  15. Development and characterisation of monoclonal antibodies reactive with porcine CSF1R (CD115).

    PubMed

    Moffat, L; Rothwell, L; Garcia-Morales, C; Sauter, K A; Kapetanovic, R; Gow, D J; Hume, D A

    2014-11-01

    Macrophage colony-stimulating factor (CSF1) controls the proliferation and differentiation of cells of the mononuclear phagocyte system. CSF1, alongside a second ligand, interleukin-34 (IL-34), acts by binding to a cell surface receptor (CSF1R). We previously cloned and expressed pig CSF1 and IL-34. Here we produced a pig CSF1R-Ig+pFUSE Fc fusion protein and used it as an immunogen to produce three monoclonal antibodies (ROS8G11, ROS3A5 and ROS3B10) targeted against porcine CSF1R. Specific binding of each monoclonal antibody was confirmed by ELISA, Western blot, flow cytometry and immunocytochemistry. The antibodies did not block CSF1 signalling. The surface expression of CSF1R in pig peripheral blood was restricted to CD14-positive monocytes and was also detected on lung macrophages. These antibodies provided an opportunity to investigate the increase of available CSF1R during pig BMDM differentiation. The new monoclonal antibodies provide useful reagents to support the study of monocyte and macrophage biology in the pig.

  16. CSF Flow in the Brain in the Context of Normal Pressure Hydrocephalus.

    PubMed

    Bradley, W G

    2015-05-01

    CSF normally flows back and forth through the aqueduct during the cardiac cycle. During systole, the brain and intracranial vasculature expand and compress the lateral and third ventricles, forcing CSF craniocaudad. During diastole, they contract and flow through the aqueduct reverses. Hyperdynamic CSF flow through the aqueduct is seen when there is ventricular enlargement without cerebral atrophy. Therefore, patients presenting with clinical normal pressure hydrocephalus who have hyperdynamic CSF flow have been found to respond better to ventriculoperitoneal shunting than those with normal or decreased CSF flow. Patients with normal pressure hydrocephalus have also been found to have larger intracranial volumes than sex-matched controls, suggesting that they may have had benign external hydrocephalus as infants. While their arachnoidal granulations clearly have decreased CSF resorptive capacity, it now appears that this is fixed and that the arachnoidal granulations are not merely immature. Such patients appear to develop a parallel pathway for CSF to exit the ventricles through the extracellular space of the brain and the venous side of the glymphatic system. This pathway remains functional until late adulthood when the patient develops deep white matter ischemia, which is characterized histologically by myelin pallor (ie, loss of lipid). The attraction between the bare myelin protein and the CSF increases resistance to the extracellular outflow of CSF, causing it to back up, resulting in hydrocephalus. Thus idiopathic normal pressure hydrocephalus appears to be a "2 hit" disease: benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood.

  17. Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma

    PubMed Central

    Song, Yang; Zhang, Wei; Zhang, Li; Wu, Wei; Zhang, Yan; Han, Xiao; Yang, Chen; Zhang, Lu; Zhou, Daobin

    2016-01-01

    Early diagnosis of primary central nervous system lymphoma (PCNSL) represents a challenge, and cerebrospinal fluid (CSF) cytokines may be diagnostic biomarkers for PCNSL. We used an electrochemiluminescence immunoassay to measure interleukin (IL)-10, IL-6, IL-8 and tumor necrosis factor α (TNF-α) in the CSF of 22 B cell PCNSL patients and 80 patients with other CNS diseases. CSF IL-10 was significantly higher in PCNSL patients than in the control group (median 74.7 pg/ml vs < 5.0 pg/ml, P < 0.000). Using a CSF IL-10 cutoff value of 8.2 pg/ml, the diagnostic sensitivity and specificity were 95.5% and 96.1%, respectively (AUC, 0.957; 95% CI, 0.901–1.000). For a CSF IL-10/IL-6 cutoff value of 0.72, the sensitivity was 95.5%, and the specificity was 100.0% (AUC, 0.976; 95% CI, 0.929–1.000). An increased CSF IL-10 level at diagnosis and post-treatment was associated with poor Progression free survival (PFS) for patients with PCNSL (P = 0.0181 and P = 0.0002, respectively). A low diagnostic value for PCNSL was found with CSF IL-8 or TNF-α. In conclusion, increased CSF IL-10 was a reliable diagnostic biomarker for large B cell PCNSL, and an IL-10/IL-6 ratio facilitates differentiation from other conditions, especially a CNS infection. PMID:27924864

  18. Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans.

    PubMed

    Banks, William A; Dohi, Kenji; Hansen, Kim; Thompson, Hilaire J

    2016-02-01

    Previous work has found that serum G-CSF was acutely elevated in mice 24h but not one week after controlled cortical impact (CCI). The purpose of this study was to investigate whether blood G-CSF correlates with the elevated brain cytokines in mice after CCI and also if it correlates with traumatic brain injury (TBI) in humans. Here, we found in mice undergoing CCI, a procedure that induces direct injury to the brain, that serum G-CSF correlated directly or indirectly with several brain cytokines, indicating it is a useful marker for the neuroinflammation of TBI. A pilot study in humans (phase I, n=19) confirmed that plasma G-CSF is acutely elevated on day 1 (p<0.001) of TBI and has returned to baseline by one week. In a second human sample (phase II) (n=80), we found plasma G-CSF peaks about 12h after arriving in the emergency department (41.6+/-5.4 pg/ml). Aging was weakly associated (p<0.05) with a less robust elevation in serum G-CSF, but there was no difference with gender. ISS, a measure of total severity of injury, correlated with the degree of elevation in serum G-CSF (r=.419; p<0.05), but severity of head injury (via AIS) did not. The latter may have been because of the statistically narrow range of head injuries among our cases and the high number of cases diagnosed with closed head injury (a non-codable diagnosis). In conclusion, plasma G-CSF may be a useful biomarker of TBI, correlating with neuroinflammation in the animal model and in the human studies with time since injury and total severity of injury. As such, it may be useful in determining whether TBI has occurred within the last 24h.

  19. Biomarkers for dementia and mild cognitive impairment in Parkinson's disease.

    PubMed

    Delgado-Alvarado, Manuel; Gago, Belén; Navalpotro-Gomez, Irene; Jiménez-Urbieta, Haritz; Rodriguez-Oroz, María C

    2016-06-01

    Cognitive decline is one of the most frequent and disabling nonmotor features of Parkinson's disease. Around 30% of patients with Parkinson's disease experience mild cognitive impairment, a well-established risk factor for the development of dementia. However, mild cognitive impairment in patients with Parkinson's disease is a heterogeneous entity that involves different types and extents of cognitive deficits. Because it is not currently known which type of mild cognitive impairment confers a higher risk of progression to dementia, it would be useful to define biomarkers that could identify these patients to better study disease progression and possible interventions. In this sense, the identification among patients with Parkinson's disease and mild cognitive impairment of biomarkers associated with dementia would allow the early detection of this process. This review summarizes studies from the past 25 years that have assessed the potential biomarkers of dementia and mild cognitive impairment in Parkinson's disease patients. Despite the potential importance, no biomarker has as yet been validated. However, features such as low levels of epidermal and insulin-like growth factors or uric acid in plasma/serum and of Aß in CSF, reduction of cerebral cholinergic innervation and metabolism measured by PET mainly in posterior areas, and hippocampal atrophy in MRI might be indicative of distinct deficits with a distinct risk of dementia in subgroups of patients. Longitudinal studies combining the existing techniques and new approaches are needed to identify patients at higher risk of dementia. © 2016 International Parkinson and Movement Disorder Society.

  20. Rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3L exhibit distinct phenotypical and functional characteristics.

    PubMed

    N'diaye, Marie; Warnecke, Andreas; Flytzani, Sevasti; Abdelmagid, Nada; Ruhrmann, Sabrina; Olsson, Tomas; Jagodic, Maja; Harris, Robert A; Guerreiro-Cacais, Andre Ortlieb

    2016-03-01

    Dendritic cells are professional APCs that play a central role in the initiation of immune responses. The limited ex vivo availability of dendritic cells inspires the widespread use of bone marrow-derived dendritic cells as an alternative in research. However, the functional characteristics of bone marrow-derived dendritic cells are incompletely understood. Therefore, we compared functional and phenotypic characteristics of rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3 ligand bone marrow-derived dendritic cells. A comparison of surface markers revealed that FLT3 ligand-bone marrow-derived dendritic cells expressed signal regulatory protein α, CD103, and CD4 and baseline levels of MHC class II, CD40, and CD86, which were highly up-regulated upon stimulation. Conversely, GM-CSF/IL-4-bone marrow-derived dendritic cells constitutively expressed signal regulatory protein α, CD11c, and CD11b but only mildly up-regulated MHC class II, CD40, or CD86 following stimulation. Expression of dendritic cell-associated core transcripts was restricted to FLT3 ligand-bone marrow-derived dendritic cells . GM-CSF/IL-4-bone marrow-derived dendritic cells were superior at phagocytosis but were outperformed by FLT3 ligand-bone marrow-derived dendritic cells at antigen presentation and T cell stimulation in vitro. Stimulated GM-CSF/IL-4-bone marrow-derived dendritic cells secreted more TNF, CCL5, CCL20, and NO, whereas FLT3 ligand-bone marrow-derived dendritic cells secreted more IL-6 and IL-12. Finally, whereas GM-CSF/IL-4-bone marrow-derived dendritic cell culture supernatants added to resting T cell cultures promoted forkhead box p3(+) regulatory T cell populations, FLT3 ligand-bone marrow-derived dendritic cell culture supernatants drove Th17 differentiation. We conclude that rat GM-CSF/IL-4-bone marrow-derived dendritic cells and FLT3 ligand-bone marrow-derived dendritic cells are functionally distinct. Our data support the current rationale that FLT3

  1. (Very) Early technology assessment and translation of predictive biomarkers in breast cancer.

    PubMed

    Miquel-Cases, Anna; Schouten, Philip C; Steuten, Lotte M G; Retèl, Valesca P; Linn, Sabine C; van Harten, Wim H

    2017-01-01

    Predictive biomarkers can guide treatment decisions in breast cancer. Many studies are undertaken to discover and translate these biomarkers, yet few biomarkers make it to practice. Before use in clinical decision making, predictive biomarkers need to demonstrate analytical validity, clinical validity and clinical utility. While attaining analytical and clinical validity is relatively straightforward, by following methodological recommendations, the achievement of clinical utility is extremely challenging. It requires demonstrating three associations: the biomarker with the outcome (prognostic association), the effect of treatment independent of the biomarker, and the differential treatment effect between the prognostic and the predictive biomarker (predictive association). In addition, economical, ethical, regulatory, organizational and patient/doctor-related aspects are hampering the translational process. Traditionally, these aspects do not receive much attention until formal approval or reimbursement of a biomarker test (informed by Health Technology Assessment (HTA)) is at stake, at which point the clinical utility and sometimes price of the test can hardly be influenced anymore. When HTA analyses are performed earlier, during biomarker research and development, they may prevent further development of those biomarkers unlikely to ever provide sufficient added value to society, and rather facilitate translation of the promising ones. Early HTA is particularly relevant for the predictive biomarker field, as expensive medicines are under pressure and the need for biomarkers to guide their appropriate use is huge. Closer interaction between clinical researchers and HTA experts throughout the translational research process will ensure that available data and methodologies will be used most efficiently to facilitate biomarker translation.

  2. Reducing CSF shunt placement in patients with spinal myelomeningocele

    PubMed Central

    Sankhla, Suresh; Khan, G. M.

    2009-01-01

    Object: The incidence of hydrocephalus requiring shunts in children with myelomeningocele (MMC) is reported to be very high. Shunt-related complications are a significant cause of morbidity and mortality in this population. In order to minimize shunt placements, we used very rigid clinical selection criteria and followed them in all patients who had myelomeningocele and enlarged ventricles. The follow-up outcome of this retrospective study is reported. Methods: From 2000 to 2007, 23 patients with myelomeningocele and variable degree of hydrocephalus were treated at our institute with primary surgical closure of their myelomeningoceles without a CSF diversion procedure. Patients with severe hydrocephalus who required immediate shunt insertion, and those with no significant associated hydrocephalus were not included in this study. Data regarding the surgical results and complications, postoperative management, and the outcome at follow-up were obtained from their hospital records. Results: Initially increased size of the ventricular system was found to have decreased or stabilized in 17 (81%) patients postoperatively. However, ventriculomegaly continued to progress further in 4 (19%) out of 21 patients. Of 11 patients who presented with enlarged head, eight (73%) patients showed reduction or stabilization in their head circumference. Three (27%) children continued to have progressive head enlargement in the postoperative period and required shunt placement. Signs of raised intracranial pressure observed in six patients on admission, improved in two (33%) and persisted or worsened in four (67%) patients who eventually improved after the insertion of a shunt. Eight (35%) patients experienced wound-related complications following closure of the MMC, including CSF leak in four, wound infection in three, wound breakdown in three, and pseudomeningocele in two patients. Shunt placement was required in the postoperative period in 13 (56.5%) patients to treat raised

  3. An AdS Crunch in Supergravity

    NASA Astrophysics Data System (ADS)

    Hertog, Thomas

    2004-12-01

    We review some properties of N=8 gauged supergravity in four dimensions with modified, but AdS invariant boundary conditions on the m2 = -2 scalars. There is a one-parameter class of asymptotic conditions on these fields and the metric components, for which the full AdS symmetry group is preserved. The generators of the asymptotic symmetries are finite, but acquire a contribution from the scalar fields. For a large class of such boundary conditions, we find there exist black holes with scalar hair that are specified by a single conserved charge. Since Schwarschild-AdS is a solution too for all boundary conditions, this provides an example of black hole non-uniqueness. We also show there exist solutions where smooth initial data evolve to a big crunch singularity. This opens up the possibility of using the dual conformal field theory to obtain a fully quantum description of the cosmological singularity, and we report on a preliminary study of this.

  4. MafB antagonizes phenotypic alteration induced by GM-CSF in microglia

    SciTech Connect

    Koshida, Ryusuke Oishi, Hisashi Hamada, Michito; Takahashi, Satoru

    2015-07-17

    Microglia are tissue-resident macrophages which are distributed throughout the central nervous system (CNS). Recent studies suggest that microglia are a unique myeloid population distinct from peripheral macrophages in terms of origin and gene expression signature. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine regulating myeloid development, has been shown to stimulate proliferation and alter phenotype of microglia in vitro. However, how its signaling is modulated in microglia is poorly characterized. MafB, a bZip transcriptional factor, is highly expressed in monocyte-macrophage lineage cells including microglia, although its role in microglia is largely unknown. We investigated the crosstalk between GM-CSF signaling and MafB by analyzing primary microglia. We found that Mafb-deficient microglia grew more rapidly than wild-type microglia in response to GM-CSF. Moreover, the expression of genes associated with microglial differentiation was more downregulated in Mafb-deficient microglia cultured with GM-CSF. Notably, such differences between the genotypes were not observed in the presence of M-CSF. In addition, we found that Mafb-deficient microglia cultured with GM-CSF barely extended their membrane protrusions, probably due to abnormal activation of RhoA, a key regulator of cytoskeletal remodeling. Altogether, our study reveals that MafB is a negative regulator of GM-CSF signaling in microglia. These findings could provide new insight into the modulation of cytokine signaling by transcription factors in microglia. - Highlights: • GM-CSF alters the phenotype of microglia in vitro more potently than M-CSF. • Transcription factor MafB antagonizes the effect of GM-CSF on microglia in vitro. • MafB deficiency leads to RhoA activation in microglia in response to GM-CSF. • We show for the first time the function of MafB in microglia.

  5. Commentary: statistics for biomarkers.

    PubMed

    Lovell, David P

    2012-05-01

    This short commentary discusses Biomarkers' requirements for the reporting of statistical analyses in submitted papers. It is expected that submitters will follow the general instructions of the journal, the more detailed guidance given by the International Committee of Medical Journal Editors, the specific guidelines developed by the EQUATOR network, and those of various specialist groups. Biomarkers expects that the study design and subsequent statistical analyses are clearly reported and that the data reported can be made available for independent assessment. The journal recognizes that there is continuing debate about different approaches to statistical science. Biomarkers appreciates that the field continues to develop rapidly and encourages the use of new methodologies.

  6. Metabolic products as biomarkers

    USGS Publications Warehouse

    Melancon, M.J.; Alscher, R.; Benson, W.; Kruzynski, G.; Lee, R.F.; Sikka, H.C.; Spies, R.B.; Huggett, Robert J.; Kimerle, Richard A.; Mehrle, Paul M.=; Bergman, Harold L.

    1992-01-01

    Ideally, endogenous biomarkers would indicate both exposure and environmental effects of toxic chemicals; however, such comprehensive biochemical and physiological indices are currently being developed and, at the present time, are unavailable for use in environmental monitoring programs. Continued work is required to validate the use of biochemical and physiological stress indices as useful components of monitoring programs. Of the compounds discussed only phytochelatins and porphyrins are currently in biomarkers in a useful state; however, glutathione,metallothioneins, stress ethylene, and polyamines are promising as biomarkers in environmental monitoring.

  7. Increased CSF levels of endorphines in chronic psychosis.

    PubMed

    Terenius, L; Wahlström, A; Lindström, L; Widerlöv, E

    1976-10-01

    The levels of two endorphines, endogenously occurring morphinomimetic peptides, were measured in serial samples of CSF from seven psychiatric patients. Four cases with chronic schizophrenia were studied before and after treatment with the antipsychotic agent clozapine (Leponex). Supernormal fraction II levels were found on at least one sampling occasion in each patient. Two patients, who responded well to clozapine treatment, showed a clear-cut drop in fraction II levels, whereas two patients showed increased levels which paralleled a deterioration of the schizophrenic symptoms. Three manic-depressive cases showed abnormally high levels of endorphine fraction I in the manic phase which declined during normal or depressed phases. Levels of fraction II varied in a less consistent manner and appeared to be at maximum during the apparently normal phases. Although preliminary, the data indicate that endorphines may reach supernormal levels in patients with chronic psychoses.

  8. Macrophage production during murine listeriosis: colony-stimulating factor 1 (CSF-1) and CSF-1-binding cells in genetically resistant and susceptible mice.

    PubMed Central

    Cheers, C; Stanley, E R

    1988-01-01

    The concentration of the macrophage-specific colony-stimulating factor (CSF-1) and the numbers of bone marrow and spleen cells with specific receptors for that factor have been investigated in a number of mouse strains under normal conditions and after infection with the facultative intracellular bacterium Listeria monocytogenes. The CSF-1 concentration in serum and tissue was markedly elevated in infected mice, the degree of stimulation reflecting the dose of L. monocytogenes. The CSF-1 titer did not correlate with genetic resistance or susceptibility of the mice to L. monocytogenes. In contrast to the effect of lipopolysaccharide, Listeria infection was able to increase the level of CSF-1 in the lipopolysaccharide nonresponder strain C3H/HeJ. In line with earlier findings on colony-forming cells, cells bearing receptors for CSF-1 in uninfected susceptible BALB/cJ mice were only half those in resistant C57BL/6J mice. After infection the majority of these cells disappeared from the bone marrow and spleen cells of both resistant and susceptible mice. The number of CSF-1 receptor-bearing cells in the normal bone marrow may determine the degree of resistance to L. monocytogenes. PMID:3262588

  9. G-CSF preferentially supports the generation of gut-homing Gr-1high macrophages in M-CSF-treated bone marrow cells.

    PubMed

    Meshkibaf, Shahab; Gower, Mark William; Dekaban, Gregory A; Kim, Sung Ouk

    2014-10-01

    The G-CSF is best known for its activity in the generation and activation of neutrophils. In addition, studies on G-CSF(-/-) or G-CSFR(-/-) mice and BMC cultures suggested a role of G-CSF in macrophage generation. However, our understanding on the role of G-CSF in macrophage development is limited. Here, using in vitro BMC models, we demonstrated that G-CSF promoted the generation of Gr-1(high)/F4/80(+) macrophage-like cells in M-BMCs, likely through suppressing cell death and enhancing generation of Gr-1(high)/F4/80(+) macrophage-like cells. These Gr-1(high) macrophage-like cells produced "M2-like" cytokines and surface markers in response to LPS and IL-4/IL-13, respectively. Adoptive transfer of EGFP-expressing (EGFP(+)) M-BMCs showed a dominant, gut-homing phenotype. The small intestinal lamina propria of G-CSFR(-/-) mice also harbored significantly reduced numbers of Gr-1(high)/F4/80(+) macrophages compared with those of WT mice, but levels of Gr-1(+)/F4/80(-) neutrophil-like cells were similar between these mice. Collectively, these results suggest a novel function of G-CSF in the generation of gut-homing, M2-like macrophages.

  10. Chronicity following ischaemia-reperfusion injury depends on tubular-macrophage crosstalk involving two tubular cell-derived CSF-1R activators: CSF-1 and IL-34.

    PubMed

    Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Ortiz, Alberto

    2016-09-01

    Two structurally unrelated ligands activate the macrophage colony stimulating factor receptor (CSF-1R, c-fms, CD115): M-CSF/CSF-1 and interleukin-34 (IL-34). Both ligands promote macrophage proliferation, survival and differentiation. IL-34 also activates the protein-tyrosine phosphatase ζ receptor (PTP-ζ, PTPRZ1). Both receptors and cytokines are increased during acute kidney injury. While tubular cell-derived CSF-1 is required for kidney repair, Baek et al (J Clin Invest 2015; 125: 3198-3214) have now identified tubular epithelial cell-derived IL-34 as a promoter of kidney neutrophil and macrophage infiltration and tubular cell destruction during experimental kidney ischaemia-reperfusion, leading to chronic injury. IL-34 promoted proliferation of both intrarenal macrophages and bone marrow cells, increasing circulating neutrophils and monocytes and their kidney recruitment. Thus, injured tubular cells release two CSF-1R activators, one (CSF-1) that promotes tubular cell survival and kidney repair and another (IL-34) that promotes chronic kidney damage. These results hold promise for the development of IL-34-targeting strategies to prevent ischaemia-reperfusion kidney injury in contexts such as kidney transplantation. However, careful consideration should be given to the recent characterization by Bezie et al. (J Clin Invest 2015; 125: 3952-3964) of IL-34 as a T regulatory cell (Treg) cytokine that modulates macrophage responses so that IL-34-primed macrophages potentiate the immune suppressive capacity of Tregs and promote graft tolerance.

  11. Expression of granulocyte-macrophage colony stimulating factor (GM-CSF) in male germ cells: GM-CSF enhances sperm motility.

    PubMed

    Vilanova, Lourdes T; Rauch, M Cecilia; Mansilla, Alejandra; Zambrano, Angara; Brito, Mónica; Werner, Enrique; Alfaro, Víctor; Cox, José F; Concha, Ilona I

    2003-10-01

    The granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine capable of stimulating proliferation, maturation and function of hematopoietic cells. Receptors for this cytokine are composed of two subunits, alpha and beta, and are expressed on myeloid progenitors and mature mononuclear phagocytes, monocytes, eosinophils and neutrophils, as well as in other nonhematopietic cells. We have recently demonstrated that bull spermatozoa express functional GM-CSF receptors that signal for increased glucose and Vitamin C uptake. In this study, we analyzed the expression of GM-CSF in bovine and human germ cells and its influence in bovine sperm motility. Reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization and immunoblotting analysis demonstrated that adult bovine and human testes expressed GM-CSF. In addition, immunolocalization studies confirmed the presence of GM-CSF in the germ cell line in bovine and human testes. Computer-assisted evaluation of patterns of sperm motility demonstrated that the addition of GM-CSF enhances several parameters of sperm motility in the presence of glucose or fructose substrates.

  12. Biomarkers of Parkinson's disease: present and future.

    PubMed

    Miller, Diane B; O'Callaghan, James P

    2015-03-01

    Sporadic or idiopathic Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown origin that ranks only second behind Alzheimer's disease (AD) in prevalence and its consequent social and economic burden. PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta; however, more widespread involvement of other CNS structures and peripheral tissues now is widely documented. The onset of molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD. The hallmark symptoms of PD, resting tremors, rigidity and postural disabilities, are related to dopamine (DA) deficiency. Current therapies treat these symptoms by replacing or boosting existing DA. All current interventions have limited therapeutic benefit for disease progression because damage likely has progressed over an estimated period of ~5 to 15years to a loss of 60%-80% of the nigral DA neurons, before symptoms emerge. There is no accepted definitive biomarker of PD. An urgent need exists to develop early diagnostic biomarkers for two reasons: (1) to intervene at the onset of disease and (2) to monitor the progress of therapeutic interventions that may slow or stop the course of the disease. In the context of disease development, one of the promises of personalized medicine is the ability to predict, on an individual basis, factors contributing to the susceptibility for the development of a given disease. Recent advances in our understanding of genetic factors underlying or contributing to PD offer the potential for monitoring susceptibility biomarkers that can be used to identify at-risk individuals and possibly prevent the onset of disease through treatment. Finally, the exposome concept is new in the biomarker discovery arena and it is suggested as a way to move forward in identifying biomarkers of neurological diseases. It is a two-stage scheme involving a first stage

  13. Biomarker time out.

    PubMed

    Petzold, Axel; Bowser, Robert; Calabresi, Paolo; Zetterberg, Henrik; Uitdehaag, Bernard M J

    2014-10-01

    The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies. This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept. The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias.

  14. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients

    PubMed Central

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

    Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34+ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. PMID:27043535

  15. Using 10AFC to further improve the efficiency of the quick CSF method

    PubMed Central

    Hou, Fang; Lesmes, Luis; Bex, Peter; Dorr, Michael; Lu, Zhong-Lin

    2015-01-01

    The contrast sensitivity function (CSF) provides a fundamental characterization of spatial vision, important for basic and clinical applications, but its long testing times have prevented easy, widespread assessment. The original quick CSF method was developed using a two-alternative forced choice (2AFC) grating orientation identification task (Lesmes, Lu, Baek, & Albright, 2010), and obtained precise CSF assessments while reducing the testing burden to only 50 trials. In this study, we attempt to further improve the efficiency of the quick CSF method by exploiting the properties of psychometric functions in multiple-alternative forced choice (m-AFC) tasks. A simulation study evaluated the effect of the number of alternatives m on the efficiency of the sensitivity measurement by the quick CSF method, and a psychophysical study validated the quick CS method in a 10AFC task. We found that increasing the number of alternatives of the forced-choice task greatly improved the efficiency of CSF assessment in both simulation and psychophysical studies. The quick CSF method based on a 10-letter identification task can assess the CSF with an averaged standard deviation of 0.10 decimal log unit in less than 2 minutes. PMID:26161631

  16. Biomarkers in ALH84001???

    NASA Technical Reports Server (NTRS)

    Treiman, Allen H.

    1999-01-01

    D. McKay and colleagues suggested that four sets of features in ALH84001 were biomarkers, signs of an ancient martian biota that once inhabited the meteorite. Subsequent work has not validated their hypothesis; each suggested biomarker has been found to be ambiguous or immaterial. Nor has their hypothesis been disproved. Rather, it is now one of many hypotheses about the alteration of ALH84001. Additional information is contained in the original extended abstract.

  17. Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach

    PubMed Central

    Thelin, Eric P.; Nelson, David W.; Ghatan, Per Hamid; Bellander, Bo-Michael

    2014-01-01

    Background: Neuro-intensive care following traumatic brain injury (TBI) is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD) is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebrospinal fluid (CSF) monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome. Materials and Methods: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using (1) a MD catheter (CMA64-iView, n = 7448 MD samples) located in a CSF-pump connected to the ventricular drain and (2) an intraparenchymal MD catheter (CMA70, n = 8358 MD samples). CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6–8) and unfavorable (GOSe 1–5) outcome. Results: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median MD recovery using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64) lactate (p = 0.0057) and pyruvate (p = 0.0011) levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR), or any of the regional MD-Brain monitoring in our analyzed cohort. Conclusion: This new technique of global MD-CSF monitoring correlates with conventional CSF levels of glucose and lactate, and the MD recovery is higher than previously described. Increase in lactate and pyruvate, without any effect on the LPR, correlates to unfavorable outcome, perhaps related to the

  18. Expression and purification of canine granulocyte colony-stimulating factor (cG-CSF).

    PubMed

    Yamamoto, Akira; Iwata, Akira; Saito, Toshiki; Watanabe, Fumiko; Ueda, Susumu

    2009-08-15

    Canine granulocyte colony-stimulating factor (cG-CSF) with modification of cysteine at position 17 to serine was expressed in Brevibacillus choshinensis HPD31. cG-CSF secreted into the culture medium was purified by ammonium sulfate precipitation and consecutive column chromatography, using butyl sepharose and DEAE sepharose. Biological activity of the recombinant cG-CSF was 8.0 x 10(6) U/mg protein, as determined by its stimulatory effect on NFS-60 cell proliferation. Purified cG-CSF was subcutaneously administered once a day for two successive days to dogs (1, 5, 25, or 125 microg). Neutrophil count increased the following day in all dogs except those administered the lowest dose (1 microg). No severe side effects were observed in dogs after administration of cG-CSF.

  19. Highlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA.

    PubMed

    Joseph, Jeymohan; Cinque, Paola; Colosi, Deborah; Dravid, Ameet; Ene, Luminita; Fox, Howard; Gabuzda, Dana; Gisslen, Magnus; Beth Joseph, Sarah; Letendre, Scott; Mukerji, Shibani S; Nath, Avindra; Perez-Valero, Ignacio; Persaud, Deborah; Price, Richard W; Rao, Vasudev R; Sacktor, Ned; Swanstrom, Ronald; Winston, Alan; Wojna, Valerie; Wright, Edwina; Spudich, Serena

    2016-10-05

    CSF HIV escape is a recently recognised phenomenon that suggests that despite suppressive treatment, HIV RNA may be detected in the CNS compartment in some individuals. In rare cases this is associated with clinical neurological disease, while in most cases, neurological consequences are not apparent. Attempts at characterising the biological substrates of CSF escape and further investigating the neurological consequences need to be made to better understand the implications of this condition for the HIV cure agenda as well as for clinical outcomes. The Global CSF HIV-1 Escape Consortium meeting, convened by the US National Institute of Mental Health, was a first step to gather investigators from diverse sites to discuss opportunities for future collaborative work on this emerging issue. To better understand CSF HIV escape and allow cross-site data reconciliation, it will be useful to reach a consensus set of definitions of the distinct forms of CSF escape, without which concerted cross-site efforts are difficult.

  20. A Simplified Method for the Efficient Refolding and Purification of Recombinant Human GM-CSF

    PubMed Central

    Thomson, Christy A.; Olson, Melanie; Jackson, Linda M.; Schrader, John W.

    2012-01-01

    Human granulocyte macrophage colony-stimulating factor (hGM-CSF) is a haematopoietic growth factor and proinflammatory cytokine. Recombinant hGM-CSF is important not only as a research tool but also as a biotherapeutic. However, rhGM-CSF expressed in E. coli is known to form inclusion bodies of misfolded, aggregated protein. Refolding and subsequent purification of rhGM-CSF from inclusion bodies is difficult with low yields of bioactive protein being produced. Here we describe a method for the isolation, refolding and purification of bioactive rhGM-CSF from inclusion bodies. The method is straightforward, not requiring extensive experience in protein refolding nor purification and using standard laboratory equipment. PMID:23166789

  1. Detection of Listeria monocytogenes in CSF from Three Patients with Meningoencephalitis by Next-Generation Sequencing

    PubMed Central

    Yao, Ming; Zhou, Jiali; Zhu, Yicheng; Zhang, Yinxin; Lv, Xia; Sun, Ruixue; Shen, Ao; Ren, Haitao; Cui, Liying

    2016-01-01

    Background and Purpose Encephalitis caused by Listeria monocytogenes (L. monocytogenes) is rare but sometimes fatal. Early diagnosis is difficult using routine cerebrospinal fluid (CSF) tests, while next-generation sequencing (NGS) is increasingly being used for the detection and characterization of pathogens. Methods This study set up and applied unbiased NGS to detect L. monocytogenes in CSF collected from three cases of clinically suspected listeria meningoencephalitis. Results Three cases of patients with acute/subacute meningoencephalitis are reported. Magnetic resonance imaging and blood cultures led to a suspected diagnosis of L. monocytogenes, while the CSF cultures were negative. Unbiased NGS of CSF identified and sequenced reads corresponding to L. monocytogenes in all three cases. Conclusions This is the first report highlighting the feasibility of applying NGS of CSF as a diagnostic method for central nervous system (CNS) L. monocytogenes infection. Routine application of this technology in clinical microbiology will significantly improve diagnostic methods for CNS infectious diseases. PMID:27486935

  2. CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease

    PubMed Central

    Alexander, Kylie A.; Flynn, Ryan; Lineburg, Katie E.; Kuns, Rachel D.; Teal, Bianca E.; Olver, Stuart D.; Lor, Mary; Raffelt, Neil C.; Koyama, Motoko; Leveque, Lucie; Le Texier, Laetitia; Melino, Michelle; Markey, Kate A.; Varelias, Antiopi; Engwerda, Christian; Serody, Jonathan S.; Janela, Baptiste; Ginhoux, Florent; Clouston, Andrew D.; Blazar, Bruce R.; Hill, Geoffrey R.; MacDonald, Kelli P.A.

    2014-01-01

    Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17–dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS–). Cutaneous cGVHD developed in a CSF-1/CSF-1R–dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r–/– mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti–CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD. PMID:25157821

  3. CSF/serum quotient graphs for the evaluation of intrathecal C4 synthesis

    PubMed Central

    Padilla-Docal, Barbara; Dorta-Contreras, Alberto J; Bu-Coifiu-Fanego, Raisa; Rey, Alexis Rodriguez

    2009-01-01

    Background Cerebrospinal fluid (CSF)/serum quotient graphs have been used previously to determine local synthesis in brain of immunoglobulins and C3 complement component. The aim of this study was to use the same technique to construct quotient graphs, or Reibergrams, for the beta globulin C4 and to evaluate the method for assessing intrathecal synthesis in neurological disease. Methods The constants in the previously-defined Reibergram for immunoglobulin IgA were used to calculate the CSF/serum quotient for C4. CSF and serum were analyzed for C4, IgA and albumin from a total of 12 patients with meningoencephalitis caused by encapsulated microorganisms and 10 subjects without infections or inflammatory neurological disease, some of which had dysfunction of the blood-CSF barrier, Results The formula and C4 Reibergram with the constants previously found for IgA, determined the intrathecal C4 synthesis in CSF. The intrathecal C4 fraction in CSF (C4 loc in mg/l) was compared to the C4-Index (fraction of CSF: serum for C 4/fraction of CSF: serum for albumin). There was a significant correlation between the two formulae. The CSF/Serum quotient graph was superior for detecting intrathecal synthesis of C4 under variable conditions of blood-CSF barrier permeability. Conclusion The C4 Reibergram can be used to quantify the intrathecal synthesis of this component of the complement system in different infectious diseases of the central nervous system and is especially useful for patients with blood-brain barrier dysfunction. PMID:19573230

  4. Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after cyclophosphamide (4 g/m2) enhance the peripheral blood progenitor cell harvest: results of two randomized studies including 120 patients

    PubMed Central

    Quittet, Philippe; Ceballos, Patrice; Lopez, Ernesto; Lu, Zhao-Yang; Latry, Pascal; Becht, Catherine; Legouffe, Eric; Fegueux, Nathalie; Exbrayat, Carole; Pouessel, Damien; Rouillé, Valérie; Daures, Jean-Pierre; Klein, Bernard; Rossi, Jean-François

    2006-01-01

    The use of a combination of G-CSF and GM-CSF to G-CSF alone, after cyclophosphamide (4g/m2) was compared in 2 randomized phase III studies, including 120 patients. In study A, 60 patients received 5 × 2 μg/kg/day of G-CSF and GM-CSF compared to 5 μg/kg/day of G-CSF. In study B, 60 patients received 2.5 × 2 μg/kg/day G-CSF and GM-CSF compared to G-CSF alone (5 μg/kg/day). With the aim to collect at least 5 × 106/kg CD34 cells in a maximum of 3 large volume leukapherisis (LK), 123 LK were performed in study A, showing significant higher number of patients reaching 10 × 106/kg CD34 cells (21/29 in G+GM-CSF arm vs 11/27 in G-CSF arm, P= .00006). In study B, 109 LK were performed, with similar results (10/27 vs 15/26, P= .003). In both the study, the total harvest of CD34 cells/kg was 2-fold higher in G-CSF plus GM-CSF group (18.3 × 106 in study A and 15.85 × 106 in study B) than in G-CSF group (9 × 106 in study A and 8.1 × 106 in study B), a difference particularly seen in multiple myeloma, with no significant difference in terms of mobilized myeloma cells between G-CSF and GM-CSF groups. PMID:16883311

  5. Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer's Disease.

    PubMed

    Edmonds, Emily C; Delano-Wood, Lisa; Galasko, Douglas R; Salmon, David P; Bondi, Mark W

    2015-01-01

    The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.

  6. Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

    PubMed

    Collins, Mahlon A; An, Jiyan; Hood, Brian L; Conrads, Thomas P; Bowser, Robert P

    2015-11-06

    Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

  7. A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients

    PubMed Central

    Freyhult, Eva; Bodolea, Constantin; Ekegren, Titti; Larsson, Anders; Gustafsson, Mats G.; Katila, Lenka; Bergquist, Jonas; Gordh, Torsten; Landegren, Ulf; Kamali-Moghaddam, Masood

    2016-01-01

    The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest. PMID:26914813

  8. Emerging biomarkers and screening for cognitive frailty.

    PubMed

    Ruan, Qingwei; D'Onofrio, Grazia; Sancarlo, Daniele; Greco, Antonio; Lozupone, Madia; Seripa, Davide; Panza, Francesco; Yu, Zhuowei

    2017-03-04

    Physical frailty and cognitive frailty are two important targets of secondary intervention in aging research to narrow the gap between life and health span. The objective of the present narrative review was to examine clinical and epidemiological studies investigating the recently proposed construct of cognitive frailty and its subtypes, with a focus on operational definitions, clinical criteria, and emerging biomarkers potentially useful for the screening of this novel entity. Both physical frailty and frailty indexes with a multidimensional nature were associated with late-life cognitive impairment/decline, incident dementia, Alzheimer's disease (AD), mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology proposing cognitive frailty as a clinical entity with cognitive impairment related to physical causes with a potential reversibility. The new clinical and research AD criteria established by the National Institute on Aging-Alzheimer's Association and the American Psychiatric Association could improve the differential diagnosis of cognitive impairment within the cognitive frailty construct. The emerging biomarkers of sarcopenia, physical frailty, and cognitive impairment will provide the basis to establish more reliable clinical and research criteria for cognitive frailty, using different operational definitions for frailty and cognitive impairment and useful clinical, biological, and imaging markers for this novel clinical construct.

  9. AdS3: the NHEK generation

    NASA Astrophysics Data System (ADS)

    Bena, Iosif; Heurtier, Lucien; Puhm, Andrea

    2016-05-01

    It was argued in [1] that the five-dimensional near-horizon extremal Kerr (NHEK) geometry can be embedded in String Theory as the infrared region of an infinite family of non-supersymmetric geometries that have D1, D5, momentum and KK monopole charges. We show that there exists a method to embed these geometries into asymptotically- {AdS}_3× {S}^3/{{Z}}_N solutions, and hence to obtain infinite families of flows whose infrared is NHEK. This indicates that the CFT dual to the NHEK geometry is the IR fixed point of a Renormalization Group flow from a known local UV CFT and opens the door to its explicit construction.

  10. AdS2 holographic dictionary

    NASA Astrophysics Data System (ADS)

    Cvetič, Mirjam; Papadimitriou, Ioannis

    2016-12-01

    We construct the holographic dictionary for both running and constant dilaton solutions of the two dimensional Einstein-Maxwell-Dilaton theory that is obtained by a circle reduction from Einstein-Hilbert gravity with negative cosmological constant in three dimensions. This specific model ensures that the dual theory has a well defined ultraviolet completion in terms of a two dimensional conformal field theory, but our results apply qualitatively to a wider class of two dimensional dilaton gravity theories. For each type of solutions we perform holographic renormalization, compute the exact renormalized one-point functions in the presence of arbitrary sources, and derive the asymptotic symmetries and the corresponding conserved charges. In both cases we find that the scalar operator dual to the dilaton plays a crucial role in the description of the dynamics. Its source gives rise to a matter conformal anomaly for the running dilaton solutions, while its expectation value is the only non trivial observable for constant dilaton solutions. The role of this operator has been largely overlooked in the literature. We further show that the only non trivial conserved charges for running dilaton solutions are the mass and the electric charge, while for constant dilaton solutions only the electric charge is non zero. However, by uplifting the solutions to three dimensions we show that constant dilaton solutions can support non trivial extended symmetry algebras, including the one found by Compère, Song and Strominger [1], in agreement with the results of Castro and Song [2]. Finally, we demonstrate that any solution of this specific dilaton gravity model can be uplifted to a family of asymptotically AdS2 × S 2 or conformally AdS2 × S 2 solutions of the STU model in four dimensions, including non extremal black holes. The four dimensional solutions obtained by uplifting the running dilaton solutions coincide with the so called `subtracted geometries', while those obtained

  11. Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease

    PubMed Central

    Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V

    2015-01-01

    Alzheimer's disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer's disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD. PMID:25899298

  12. Biomarkers for antipsychotic therapies.

    PubMed

    Pich, Emilio Merlo; Vargas, Gabriel; Domenici, Enrico

    2012-01-01

    Molecular biomarkers for antipsychotic treatments have been conceptually linked to the measurements of dopamine functions, mostly D(2) receptor occupancy, either by imaging using selective PET/SPECT radioactive tracers or by assessing plasma prolactin levels. A quest for novel biomarkers was recently proposed by various academic, health service, and industrial institutions driven by the need for better treatments of psychoses. In this review we conceptualize biomarkers within the Translational Medicine paradigm whose goal was to provide support to critical decision-making in drug discovery. At first we focused on biomarkers as outcome measure of clinical studies by searching into the database clinicaltrial.gov. The results were somewhat disappointing, showing that out of 1,659 antipsychotic trials only 18 used a biomarker as an outcome measure. Several of these trials targeted plasma lipids as sentinel marker for metabolic adverse effects associated with the use of atypical antipsychotics, while only few studies were aimed to new disease specific biological markers. As an example of a mechanistic biomarker, we described the work done to progress the novel class of glycine transporter inhibitors as putative treatment for negative symptoms of schizophrenia. We also review how large-scale multiplex biological assays were applied to samples from tissues of psychiatric patients, so to learn from changes of numerous analytes (metabolic products, lipids, proteins, RNA transcripts) about the substrates involved in the disease. We concluded that a stringent implementation of these techniques could contribute to the endophenotypic characterization of patients, helping in the identification of key biomarkers to drive personalized medicine and new treatment development.

  13. Kidney biomarkers in cirrhosis.

    PubMed

    Francoz, Claire; Nadim, Mitra K; Durand, François

    2016-10-01

    Impaired renal function due to acute kidney injury (AKI) and/or chronic kidney diseases (CKD) is frequent in cirrhosis. Recurrent episodes of AKI may occur in end-stage cirrhosis. Differential diagnosis between functional (prerenal and hepatorenal syndrome) and acute tubular necrosis (ATN) is crucial. The concept that AKI and CKD represent a continuum rather than distinct entities, is now emerging. Not all patients with AKI have a potential for full recovery. Precise evaluation of kidney function and identification of kidney changes in patients with cirrhosis is central in predicting reversibility. This review examines current biomarkers for assessing renal function and identifying the cause and mechanisms of impaired renal function. When CKD is suspected, clearance of exogenous markers is the reference to assess glomerular filtration rate, as creatinine is inaccurate and cystatin C needs further evaluation. Recent biomarkers may help differentiate ATN from hepatorenal syndrome. Neutrophil gelatinase-associated lipocalin has been the most extensively studied biomarker yet, however, there are no clear-cut values that differentiate each of these conditions. Studies comparing ATN and hepatorenal syndrome in cirrhosis, do not include a gold standard. Combinations of innovative biomarkers are attractive to identify patients justifying simultaneous liver and kidney transplantation. Accurate biomarkers of underlying CKD are lacking and kidney biopsy is often contraindicated in this population. Urinary microRNAs are attractive although not definitely validated. Efforts should be made to develop biomarkers of kidney fibrosis, a common and irreversible feature of CKD, whatever the cause. Biomarkers of maladaptative repair leading to irreversible changes and CKD after AKI are also promising.

  14. Lung Cancer Biomarkers.

    PubMed

    I, Hoseok; Cho, Je-Yoel

    2015-01-01

    Lung cancer is the most frequently occurring cancer in the world and continually leads in mortality among cancers. The overall 5-year survival rate for lung cancer has risen only 4% (from 12% to 16%) over the past 4 decades, and late diagnosis is a major obstacle in improving lung cancer prognosis. Survival of patients undergoing lung resection is greater than 80%, suggesting that early detection and diagnosis of cancers before they become inoperable and lethal will greatly improve mortality. Lung cancer biomarkers can be used for screening, detection, diagnosis, prognosis, prediction, stratification, therapy response monitoring, and so on. This review focuses on noninvasive diagnostic and prognostic biomarkers. For that purpose, our discussion in this review will focus on biological fluid-based biomarkers. The body fluids include blood (serum or plasma), sputum, saliva, BAL, pleural effusion, and VOC. Since it is rich in different cellular and molecular elements and is one of the most convenient and routine clinical procedures, serum or plasma is the main source for the development and validation of many noninvasive biomarkers. In terms of molecular aspects, the most widely validated ones are proteins, some of which are used in the clinical sector, though in limited accessory purposes. We will also discuss the lung cancer (protein) biomarkers in clinical trials and currently in the validation phase with hundreds of samples. After proteins, we will discuss microRNAs, methylated DNA, and circulating tumor cells, which are being vigorously developed and validated as potential lung cancer biomarkers. The main aim of this review is to provide researchers and clinicians with an understanding of the potential noninvasive lung cancer biomarkers in biological fluids that have recently been discovered.

  15. MicroRNAs in Cerebrospinal Fluid as Potential Biomarkers for Parkinson's Disease and Multiple System Atrophy.

    PubMed

    Marques, Tainá M; Kuiperij, H Bea; Bruinsma, Ilona B; van Rumund, Anouke; Aerts, Marjolein B; Esselink, Rianne A J; Bloem, Bas R; Verbeek, Marcel M

    2016-11-14

    Parkinson's disease (PD) and multiple system atrophy (MSA) are both part of the spectrum of neurodegenerative movement disorders and α-synucleinopathies with overlap of symptoms especially at early stages of the disease but with distinct disease progression and responses to dopaminergic treatment. Therefore, having biomarkers that specifically classify patients, which could discriminate PD from MSA, would be very useful. MicroRNAs (miRNAs) regulate protein translation and are observed in biological fluids, including cerebrospinal fluid (CSF), and may therefore have potential as biomarkers of disease. The aim of our study was to determine if miRNAs in CSF could be used as biomarkers for either PD or MSA. Using quantitative PCR (qPCR), we evaluated expression levels of 10 miRNAs in CSF patient samples from PD (n = 28), MSA (n = 17), and non-neurological controls (n = 28). We identified two miRNAs (miR-24 and miR-205) that distinguished PD from controls and four miRNAs that differentiated MSA from controls (miR-19a, miR-19b, miR-24, and miR-34c). Combinations of miRNAs accurately discriminated either PD (area under the curve (AUC) = 0.96) or MSA (AUC = 0.86) from controls. In MSA, we also observed that miR-24 and miR-148b correlated with cerebellar ataxia symptoms, suggesting that these miRNAs are involved in cerebellar degeneration in MSA. Our findings support the potential of miRNA panels as biomarkers for movement disorders and may provide more insights into the pathological mechanisms related to these disorders.

  16. Expanding the Repertoire of Biomarkers for Alzheimer’s Disease: Targeted and Non-targeted Approaches

    PubMed Central

    Galasko, Douglas

    2015-01-01

    The first biofluid markers developed for Alzheimer’s disease (AD) used targeted approaches for discovery. These initial biomarkers were directed at key protein constituents of the hallmark brain lesions in AD. Biomarkers for plaques targeted the amyloid beta protein (Aβ) and for tangles, the microtubule-associated protein tau. Cerebrospinal fluid levels of Aβ and tau have excellent diagnostic utility and can be used to monitor aspects of therapeutic development. Recent research has extended our current concepts of AD, which now include a slow buildup of pathology during a long pre-symptomatic period, a complex cascade of pathological pathways in the brain that may accelerate once symptoms develop, the potential of aggregated proteins to spread across brain pathways, and interactions with vascular and other age-associated brain pathologies. There are many potential roles for biomarkers within this landscape. A more diverse set of biomarkers would provide a better picture of the staging and state of pathological events in the brain across the stages of AD. The aim of this review is to focus on methods of biomarker discovery that may help to expand the currently accepted biomarkers. Opportunities and approaches for targeted and non-targeted (or −omic) biomarker discovery are highlighted, with examples from recent studies. How biomarker discoveries can be developed and integrated to become useful tools in diagnostic and therapeutic efforts is discussed. PMID:26733934

  17. Reply to comment on “An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice”

    PubMed Central

    Sheline, Yvette I.; West, Tim; Yarasheski, Kevin; Jasielec, Mateusz S.; Hettinger, Jane C.; Tripoli, Danielle L.; Xiong, Chengjie; Frederiksen, Christine; Grzelak, Monica V.; Bateman, Randall J.; Morris, John C.; Lee, Jin-Moo; Cirrito, John R.

    2016-01-01

    Possible reasons for why a new study could not replicate our finding that the serotonin reuptake inhibitor citalopram decreased amyloid β concentrations in the cerebrospinal fluid of healthy volunteers. PMID:25540323

  18. Metallomic Biomarkers in Cerebrospinal fluid and Serum in patients with Parkinson’s disease in Indian population

    PubMed Central

    Sanyal, Jaya; Ahmed, Shiek S. S. J.; Ng, Hon Keung Tony; Naiya, Tufan; Ghosh, Epsita; Banerjee, Tapas Kumar; Lakshmi, Jaya; Guha, Gautam; Rao, Vadlamudi Raghavendra

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease with the absence of markers for diagnosis. Several studies on PD reported the elements imbalance in biofluids as biomarkers. However, their results remained inconclusive. This study integrates metallomics, multivariate and artificial neural network (ANN) to understand element variations in CSF and serum of PD patients from the largest cohort of Indian population to solve the inconsistent results of previous studies. Also, this study is aimed to (1) ascertain a common element signature between CSF and serum. (2) Assess cross sectional element variation with clinical symptoms. (3) Develop ANN models for rapid diagnosis. A metallomic profile of 110 CSF and 530 serum samples showed significant variations in 10 elements of CSF and six in serum of patients compared to controls. Consistent variations in elements pattern were noticed for Calcium, Magnesium and Iron in both the fluids of PD, which provides feasible diagnosis from serum. Furthermore, implementing multivariate analyses showed clear classification between normal and PD in both the fluids. Also, ANN provides 99% accuracy in detection of disease from CSF and serum. Overall, our analyses demonstrate that elements profile in biofluids of PD will be useful in development of diagnostic markers for PD. PMID:27752066

  19. Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for primary central nervous system lymphoma

    PubMed Central

    Baraniskin, Alexander; Zaslavska, Elena; Nöpel-Dünnebacke, Stefanie; Ahle, Guido; Seidel, Sabine; Schlegel, Uwe; Schmiegel, Wolff; Hahn, Stephan; Schroers, Roland

    2016-01-01

    Background Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies. We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients. Methods CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction. Results Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease. Conclusions Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results ne