CSF Biomarkers in Longitudinal Alzheimer Disease Cohorts: Pre-Analytic Challenges
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PROVIDER: S-EPMC10908554 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Project description:ObjectivesTo test whether CSF Alzheimer disease biomarkers (β-amyloid 42 [Aβ42], tau, phosphorylated tau at threonine 181 [ptau181], tau/Aβ42, and ptau181/Aβ42) predict future decline in noncognitive outcomes among individuals cognitively normal at baseline.MethodsLongitudinal data from participants (N = 430) who donated CSF within 1 year of a clinical assessment indicating normal cognition and were aged 50 years or older were analyzed. Mixed linear models were used to test whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination scores were also examined.ResultsAbnormal levels of each biomarker were related to greater impairment with time in behavior (p < 0.035) and mood (p < 0.012) symptoms, and more difficulties with independent activities of daily living (p < 0.012). However, biomarker levels were unrelated to weight change with time (p > 0.115). As expected, abnormal biomarker values also predicted more rapidly changing Mini-Mental State Examination (p < 0.041) and Clinical Dementia Rating Sum of Boxes (p < 0.001) scores compared with normal values.ConclusionsCSF biomarkers among cognitively normal individuals are associated with future decline in some, but not all, noncognitive Alzheimer disease symptoms studied. Additional work is needed to determine the extent to which these findings generalize to other samples.
| S-EPMC3854826 | biostudies-literature
Project description:ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.
| S-EPMC7238945 | biostudies-literature
Project description:ObjectivesCore CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), 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.MethodsWe 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.ResultsThe 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.ConclusionAlthough 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.
| S-EPMC3280049 | biostudies-literature
Project description:ObjectiveTo measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time.MethodsThe study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years).ResultsCSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia.ConclusionsNeuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.
| S-EPMC6133624 | biostudies-literature
Project description:The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer's disease (AD). We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF) samples of AD patients (n = 22) and controls (n = 28). Using a Cq of 34 as cut-off, we identified positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37% of miRNAs are present in the brain. We found 74 miRNAs being down- and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative "Measure of relevance" method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliable miR-100, miR-146a and miR-1274a as differentially expressed in AD reaching Bonferroni corrected significance. MANCOVA also confirmed differential expression of informative miR-103, miR-375, miR-505#, miR-708, miR-4467, miR-219, miR-296, miR-766 and miR-3622b-3p. Discrimination analysis using a combination of miR-100, miR-103 and miR-375 was able to detect AD in CSF by positively classifying controls and AD cases with 96.4% and 95.5% accuracy, respectively. Referring to the Ingenuity database we could identify a set of AD associated genes that are targeted by these miRNAs. Highly predicted targets included genes involved in the regulation of tau and amyloid pathways in AD like MAPT, BACE1 and mTOR.
| S-EPMC4439119 | biostudies-literature
Project description:ObjectiveTo examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure.MethodsParticipants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ42, total tau, and p-tau181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status.ResultsChanges from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aβ42, total tau, and p-tau181, respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau181 (p = 0.003), where greater decreases from baseline in CSF p-tau181 concentrations were associated with higher baseline LDL level for the simvastatin group.ConclusionsSimvastatin-related reductions in CSF p-tau181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.
| S-EPMC5606918 | biostudies-literature
Project description: Not available
| S-BSST1456 | biostudies-other
Project description:ObjectiveTo compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD).MethodsFrom the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). β-Amyloid (Aβ) deposition in 9 brain regions was examined with [18F]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study.ResultsThe best CSF measures for identifying MCI-AD were Aβ42/total tau (t-tau) and Aβ42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93-0.94). The best PET measures performed similarly (AUC 0.92-0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF Aβ42/t-tau and Aβ42/p-tau performed better than CSF Aβ42 and Aβ42/40 (AUC difference 0.03-0.12, p<0.05). Using nonoptimized cutoffs, CSF Aβ42/t-tau had the highest accuracy of all CSF/PET biomarkers (sensitivity 97%, specificity 83%). The combination of CSF and PET was not better than using either biomarker separately.ConclusionsAmyloid PET and CSF biomarkers can identify early AD with high accuracy. There were no differences between the best CSF and PET measures and no improvement when combining them. Regional PET measures were not better than assessing the global Aβ deposition. The results were replicated in an independent cohort using another CSF assay and PET tracer. The choice between CSF and amyloid PET biomarkers for identifying early AD can be based on availability, costs, and doctor/patient preferences since both have equally high diagnostic accuracy.Classification of evidenceThis study provides Class III evidence that amyloid PET and CSF biomarkers identify early-stage AD equally accurately.
| S-EPMC4607601 | biostudies-literature
Project description:Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-?1-42 (A?1-42) associated with the presence of A? plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
| S-EPMC4038930 | biostudies-literature
Project description:BackgroundAbnormal metabolism of amyloid-β (Aβ) and soluble P-tau, as well as neurodegeneration, are key components of Alzheimer's disease (AD), but it is unclear how these different processes are related to genetic risk factors for AD.MethodIn the Swedish BioFINDER study, we tested associations between a priori defined polygenic risk scores (PRSs) for AD (excluding Single Nucleotide Polymorphism [SNPs] within the apolipoprotein E [APOE] region in the main analysis) and biomarkers in cerebrospinal fluid (CSF) (Total tau [T-tau] and Phosphorylated tau181 [P-tau181], Aβ1-38, Aβ1-40, Aβ1-42 and Aβ1-42/1-40, neurofilament light [NfL]) in Cognitively Unimpaired (CU) individuals (n=751), and in Mild Cognitive Impairment (MCI) (n=212), and AD dementia (n=150) patients. Results were validated in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with 777 individuals (AD=119, MCI=442, and CU=216).ResultA PRS with SNPs significant at P<5e-03 (∼1742 variants) were associated with higher CSF P-tau181 (beta=0.13, P=5.6e-05) and T-tau (beta=0.12, P=4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for Aβ status. Aβ pathology mediated 37% of the effect of this PRS on tau levels. Aβ-dependent and independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF Aβ biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL.ConclusionGenetic pathways implicated in causing AD are related to altered levels of soluble tau through both Aβ-dependent and Aβ-independent mechanisms, which may have relevance for anti-tau drug development.
| S-EPMC9421595 | biostudies-literature