Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in Alzheimer Dementia.
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PROVIDER: S-EPMC3227514 | BioStudies |
REPOSITORIES: biostudies
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Project description:BACKGROUND:Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-?42 (A?42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD). OBJECTIVE:The goal was to determine the overall accuracy of CSF A?42, tTau, pTau, and the A?42/total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD. METHODS:From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF A?42, tTau, and pTau and the ATI in relation to the final clinical diagnosis. RESULTS:Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI?<?1.0 and pTau?>61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n?=?154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72. CONCLUSIONS:In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice.
| S-EPMC6218126 | BioStudies
Project description:<h4>Introduction</h4>This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau<sub>181</sub> /Aβ<sub>42</sub> status (+/-) and explored their value in predicting cognition.<h4>Methods</h4>CSF biomarkers amyloid beta (Aβ)<sub>42</sub> , pTau<sub>181</sub> , tTau, Aβ<sub>40</sub> , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired).<h4>Results</h4>Neurodegeneration and glial activation biomarkers were elevated in pTau<sub>181</sub> /Aβ<sub>42</sub> + MCI/dementia participants relative to all pTau<sub>181</sub> /Aβ<sub>42</sub> - participants. Neurodegeneration biomarkers increased with clinical severity among pTau<sub>181</sub> /Aβ<sub>42</sub> + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance.<h4>Discussion</h4>The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.
| S-EPMC8016695 | BioStudies
Project description:We evaluated the performance of CSF biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. CSF samples from patients in two multicentre longitudinal studies (ADNI, n?=?619; BioFINDER, n?=?431) were analysed. A?(1-42), tTau and pTau CSF concentrations were measured using Elecsys CSF immunoassays, and tTau/A?(1-42) and pTau/A?(1-42) ratios calculated. Patients were classified as biomarker (BM)-positive or BM-negative at baseline. Ability of biomarkers to predict risk of clinical decline and conversion to AD/dementia was assessed using pre-established cut-offs for A?(1-42) and ratios; tTau and pTau cut-offs were determined. BM-positive patients showed greater clinical decline than BM-negative patients, demonstrated by greater decreases in MMSE scores (all biomarkers: -2.10 to -0.70). Risk of conversion to AD/dementia was higher in BM-positive patients (HR: 1.67 to 11.48). Performance of Tau/A?(1-42) ratios was superior to single biomarkers, and consistent even when using cut-offs derived in a different cohort. Optimal pTau and tTau cut-offs were approximately 27?pg/mL and 300?pg/mL in both BioFINDER and ADNI. Elecsys pTau/A?(1-42) and tTau/A?(1-42) are robust biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients, and may support AD diagnosis in clinical practice.
| S-EPMC6911086 | BioStudies
Project description:<h4>Background</h4>?-amyloid (A?) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology.<h4>Methods</h4>Using automated Elecsys® assays (Roche Diagnostics) for A? (1-42) (A?42), A? (1-40) (A?40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging.<h4>Results</h4>Ratios A?42/A?40, tTau/A?42 and pTau/A?42 had higher receiver operator characteristic-area under the curve (all 0.94), and greater concordance with A?-PET (overall percentage agreement ~?90%), compared with individual biomarkers.<h4>Conclusion</h4>Strong concordance between CSF biomarkers and A?-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.
| S-EPMC7110644 | BioStudies
Project description:<h4>Background</h4>Hepatocyte growth factor (HGF) plays a role in neuronal survival and development, and has been implicated in neurodegenerative diseases. We sought to examine the associations of the CSF HGF with Alzheimer's disease (AD) pathology and cognitive function.<h4>Methods</h4>A total of 238 participants (including 90 cognitively normal (CN) and 148 mild cognitive impairment (MCI)) who had measurements of CSF HGF were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Multiple linear regression models were utilized to explore the cross-sectional associations of CSF HGF with AD biomarkers (including Aβ42, pTau, and tTau proteins) in non-demented participants. Moreover, linear mixed-effects regression models were utilized to explore the longitudinal associations of HGF subgroups with cognitive function. Mediation analyses were utilized to explore the mediation effects of AD markers.<h4>Results</h4>MCI individuals had significantly increased CSF HGF compared with the CN individuals. Results of multiple linear regressions showed significant correlations of CSF HGF with CSF Aβ42, pTau, and tTau in non-demented participants. Higher level of baseline CSF HGF was associated with faster cognitive decline. Influences of the baseline CSF HGF on cognition were partially mediated by Aβ42, pTau, and tTau pathologies.<h4>Conclusions</h4>High concentrations of HGF in CSF may be related to faster cognitive decline. The cognitive consequences of higher CSF HGF partly stem from AD pathology, which suggests that the CSF HGF may be an attractive biomarker candidate to track AD progression.
| S-EPMC8493684 | BioStudies
Project description:An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary.To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center.The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau).Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy 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 with 4-repeat tauopathy showed 92.0% sensitivity?and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n?=?51) and ALS Functional Rating Scale-Revised (n?=?42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n?=?10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex.The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS.
| S-EPMC3989393 | BioStudies
Project description:<h4>Objective</h4>To determine the cutoffs that optimized the agreement between <sup>18</sup> F-Florbetapir positron emission tomography (PET) and A?1-42, A?1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available <sup>18</sup> F-Florbetapir imaging.<h4>Methods</h4>Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of A?1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with <sup>18</sup> F-Florbetapir PET and evaluated concordance between markers of the amyloid category.<h4>Results</h4>A?1-42, tTau and pTau (but not A?1-40) and the ratios with A?1-42 had good diagnostic agreement with <sup>18</sup> F-Florbetapir PET. As a marker of amyloid pathology, the A?1-42/A?1-40 ratio had higher agreement and better correlation with amyloid PET than A?1-42 alone.<h4>Interpretation</h4>CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of A?1-42 with A?1-40 increases the agreement between markers of amyloid pathology.
| S-EPMC6764494 | BioStudies
Project description:INTRODUCTION:Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS:CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS:The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION:Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.
| S-EPMC6511459 | BioStudies
Project description:<h4>Background</h4>Alterations in the expression of human kallikrein-related peptidases (KLKs) have been described in patients with Alzheimer's disease (AD). We elucidated the suitability of KLK6, KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.<h4>Methods</h4>KLK levels in cerebrospinal fluid (CSF), as determined by ELISA, were compared between 32?AD patients stratified to A/T/(N) system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers. Associations between KLK levels and clinical severity, CSF and positron emission tomography (PET) based AD biomarkers were tested for.<h4>Results</h4>Levels of KLK6 and KLK10 were significantly increased in AD. KLK6 differed significantly between AD A+/T+/N+ and AD A+/T-/N+ or NC with an AUC of 0.922. CSF pTau and tTau levels were significantly associated with KLK6 in AD.<h4>Conclusions</h4>KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.
| S-EPMC6712703 | BioStudies
Project description:In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) A? ratios rather than A?42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET).Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of A?1-42, A?1-40, A?1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %.Seven out of 38 subjects (18 %) were positive on amyloid PET. A?42/ttau, A?42/A?40, A?42/A?38, and A?42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC)???0.908). A?40 and A?38 had significantly lower discriminative power (AUC?=?0.571). When specificity was fixed at 90 % and 95 %, A?42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of A?42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively).For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of A?42/ttau rather than using A?42 in isolation.
| S-EPMC4683859 | BioStudies