Identification of Novel Fluid Biomarkers for Alzheimer\u27s Disease

Clinicopathological studies suggest that Alzheimer\u27s disease: AD) pathology begins to appear ~10-20 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression would, therefore, be invaluable for patient care and efficient clinical trial design. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid: CSF) using an unbiased proteomics approach: two-dimensional difference gel electrophoresis with liquid chromatography tandem mass spectrometry). From this, we identified 47 proteins that differed in abundance between cognitively normal: Clinical Dementia Rating [CDR] 0) and mildly demented: CDR 1) subjects. To validate these findings, we measured a subset of the identified candidate biomarkers by enzyme linked immunosorbent assay: ELISA); promising candidates in this discovery cohort: N=47) were further evaluated by ELISA in a larger validation CSF cohort: N=292) that contained an additional very mildly demented: CDR 0.5) group. Levels of four novel biomarkers were significantly altered in AD, and Receiver-operating characteristic: ROC) analyses using a stepwise logistic regression model identified optimal panels containing these markers that distinguished CDR 0 from CDR\u3e0: tau, YKL-40, NCAM) and CDR 1 from CDR\u3c1: tau, chromogranin-A, carnosinase-I). Plasma levels of the most promising marker, YKL-40, were also found to be increased in CDR 0.5 and 1 groups and to correlate with CSF levels. Importantly, the CSF YKL-40/Aâ42 ratio predicted risk of developing cognitive impairment: CDR 0 to CDR\u3e0 conversion) as well as the best CSF biomarkers identified to date, tau/Aâ42 and p-tau181/Aâ42. Additionally, YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aâ deposition. Utilizing an alternative, targeted proteomics approach to identify novel biomarkers, 333 CSF samples were evaluated for levels of 190 analytes using a multiplexed Luminex platform. The mean concentrations of 37 analytes were found to differ between CDR 0 and CDR\u3e0 participants. ROC and statistical machine learning algorithms identified novel biomarker panels that improved upon the ability of the current best biomarkers to discriminate very mildly demented from cognitively normal participants, and identified a novel biomarker, Calbindin, with significant prognostic potential

Multiplexed Immunoassay Panel Identifies Novel CSF Biomarkers for Alzheimer's Disease Diagnosis and Prognosis

Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ∼10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aβ42, tau, p-tau181).Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aβ42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aβ42, and age.Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential

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

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.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.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 might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

Biomarkers of Alzheimer's disease

U radu će se analizirati poslovni procesi u event menadžmentu, jednom od najzastupljenijih vrsta menadžmenta diljem svijeta. U prvom dijelu rada navesti će se i definirati opći pojam event menadžmenta te primjeri u kojim granama poslovanja je najčešće zastupljen event menadžment u Republici Hrvatskoj i ostalim zemljama Europske unije. Nadalje, u drugom dijelu rada biti će definiran pojam projekt menadžmenta te će se prikazati proces planiranja i koordinacije događaja primjenom poslovnih procesa. U trećem dijelu rada analizirati će se poslovni procesi potrebni za uspješno funkcioniranje event menadžmenta na stvarnim primjerima projekata koji su se odvijali u Republici Hrvatskoj i od strane autora ovog diplomskog rada