Dynamic changes of CSF sTREM2 in preclinical Alzheimer's disease: the CABLE study.
Ontology highlight
ABSTRACT:
SUBMITTER: Ma LZ
PROVIDER: S-EPMC7149923 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
Publications
Dynamic changes of CSF sTREM2 in preclinical Alzheimer's disease: the CABLE study.
Ma Ling-Zhi LZ Tan Lan L Bi Yan-Lin YL Shen Xue-Ning XN Xu Wei W Ma Ya-Hui YH Li Hong-Qi HQ Dong Qiang Q Yu Jin-Tai JT
Molecular neurodegeneration 20200410 1
<h4>Background</h4>Loss of function of triggering receptor expressed on myeloid cell 2 (TREM2), a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). Whether TREM2 levels are pathologically altered during the preclinical phase, and whether cerebrospinal fluid (CSF) soluble TREM2 protein (sTREM2) has a relationship with major pathological processes including Aβ and tau deposition are still unclear.<h4>Methods</h4>According to t ...[more]
Similar Datasets
Project description:BackgroundThere is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer's disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD.MethodsWe included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores.ResultsMIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB).ConclusionInflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug-target engagement of inflammatory modulators.
| S-EPMC10163795 | biostudies-literature
Project description:Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer's disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aβ) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aβ-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN- , A- /TN+ , and A- /TN- . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aβ-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aβ-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aβ-PET rate of change only in the A+ /TN- group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aβ and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aβ plaque formation and tau aggregate accumulation only in the presence of Aβ pathology.
| S-EPMC11222555 | biostudies-literature
Project description:Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear. This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aβ42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter <2.5 μm (PM2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ) were estimated at each participant's residence. Multiple-adjusted models were approached to detect associations of air pollution with inflammatory markers and AD-related proteins. Ambient 2-year averaged exposure of PM2.5 was associated with changes of neuroinflammatory markers, that is, CSF sTREM2 (β = -0.116, p = 0.0002). Similar results were found for O3 exposure among the elderly (β = -0.111, p = 0.0280) or urban population (β = -0.090, p = 0.0144). No significant evidence supported NO2 related to CSF sTREM2. For potentially causal associations with accumulated AD pathologies, the total effects of PM2.5 on CSF amyloid-related protein (CSF Aβ42 and p-tau/Aβ42) were partly mediated by CSF sTREM2, with proportions of 14.22% and 47.15%, respectively. Additional analyses found inverse associations between peripheral inflammatory markers with PM2.5 and NO2 , but a positive correlation with O3 . These findings demonstrated a strong link between PM2.5 exposure and microglial dysfunction. Furthermore, CSF sTREM2 as a key mediator modulated the influences of PM2.5 exposure on AD amyloid pathologies.
| S-EPMC9639632 | biostudies-literature
Project description:BackgroundThe soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) is considered a biomarker of microglia activity. The objective of this study was to investigate the trajectory of CSF sTREM2 levels over time and examine its association with sex.MethodsA total of 1,017 participants from the Alzheimer's Disease Neuroimaging Initiative Study (ADNI) with at least one CSF sTREM2 record were included. The trajectory of CSF sTREM2 was analyzed using a growth curve model. The association between CSF sTREM2 levels and sex was assessed using linear mixed-effect models.ResultsCSF sTREM2 levels were increased with age over time (P < 0.0001). No significant sex difference was observed in sTREM2 levels across the entire sample; however, among the APOE ε4 allele carriers, women exhibited significantly higher sTREM2 levels than men (β = 0.146, P = 0.002).ConclusionOur findings highlight the association between CSF sTREM2 levels and age-related increments, underscoring the potential influence of aging on sTREM2 dynamics. Furthermore, our observations indicate a noteworthy association between sex and CSF sTREM2 levels, particularly in individuals carrying the APOE ε4 allele.
| S-EPMC11202383 | biostudies-literature
Project description:Emerging evidence supports a role for innate immunity and microglia in Alzheimer's disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs). We also determined the temporal sequence of changes in CSF sTREM2 and markers for amyloid deposition and neurodegeneration as well as cognitive performance. We included 218 participants consisting of 127 MC and 91 NC siblings from the Dominantly Inherited Alzheimer Network. We observed that CSF sTREM2 increased in MCs compared to NCs 5 years before the expected symptom onset and this difference remained significant until 5 years after the expected symptom onset. Changes in CSF sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. We propose that microglial activation occurs several years before the expected symptom onset, but after amyloidosis and neuronal injury have already occurred.
| S-EPMC5385711 | biostudies-literature
Project description:The effects of microglial activation on the associations between depression and Alzheimer's disease (AD) are still unclear. TREM2 gene plays a pivotal role in microglial activation, has been identified as a risk factor for AD. In this work, we aimed to assess the interrelationships of soluble TREM2 (sTREM2) level in cerebrospinal fluid (CSF), minimal depressive symptoms (MDSs), and CSF amyloid markers. The linear regression analyses were conducted on 796 cognitively unimpaired participants from the CABLE (Chinese Alzheimer's Biomarker and LifestylE) study. Causal mediation analyses with 10,000 bootstrapped iterations were used to test the mediation effects. In addition, similar statistical analyses were performed in subgroups stratified by sex, age, and APOE ε4 carrier status. In total subjects, MDSs were associated with lower CSF sTREM2 levels (p < 0.0001), lower CSF amyloid markers (p < 0.0001), and poorer cognitive performance (MMSE, p = 0.0014). The influence of MDSs on CSF amyloid markers was partially mediated by CSF sTREM2 (proportion from 2.91 to 32.58%, p < 0.0001). And we found that the sTREM2-amyloid pathway partially mediated the effects of MDSs on cognition. Of note, exploratory subgroup analyses showed that the above influences of CSF sTREM2 were pronounced in the APOE ε4 (-) group. These results suggest that early depression is associated with amyloid pathology, which might be partly mediated by microglial activation, especially in the absence of APOE ε4.
| S-EPMC8980028 | biostudies-literature
Project description:BackgroundDelirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer's disease.MethodsWe analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery (n = 120), and some of the patients developed delirium (n = 65). A medical delirium cohort (n = 26) was also examined. ELISA was used to determine the level of sTREM2 in CSF.ResultsDelirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia (p = 0.046, n = 15, n = 44), particularly among patients developing delirium after CSF sampling (p = 0.02, n = 7, n = 44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery (rS = 0.39, p = 0.002, n = 60) and correlated well with the CSF Alzheimer's disease biomarkers, Aβ42, and t-tau/p-tau (rS = 0.40, p = 0.002, rS = 0.46, p < 0.001/ rS = 0.49, p < 0.001, n = 60). Among patients with dementia, the level of Aβ38 and Aβ40 also correlated positively with sTREM2 in CSF (Aβ38MSDrS = 0.44, p = 0.001; Aβ40MSDrS = 0.48, p < 0.001; Aβ42MSDrS = 0.43, p < 0.001, n = 60).ConclusionThe findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk.
| S-EPMC6215363 | biostudies-literature
Project description:BackgroundClusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD.MethodsFollowing the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aβ42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aβ42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aβ42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aβ42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aβ42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups.ResultsCompared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P < 0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aβ42 (β = 0.040, P < 0. 001), CSF p-tau (β = 0.325, P < 0.001) and CSF t-tau (β = 0.346, P < 0.001).ConclusionsOur results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aβ pathology; and the increased levels are associated with tau pathology and neurodegeneration.
| S-EPMC9801612 | biostudies-literature
Project description:Alzheimer's disease (AD) is characterized by an accumulation of ?-amyloid (A?42) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that A?42 accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the so-called preclinical stage of the AD (pre-AD). It also has been proved that the GM atrophy profile is not linear, both in normal ageing but, especially, on AD. However, several other factors may influence this association and may have an impact on the generalization of results from different samples. In this work, we estimate differences in rates of GM volume change in cognitively healthy elders in association with baseline core cerebrospinal fluid (CSF) AD biomarkers, and assess to what these differences are sample dependent. We report the dependence of atrophy rates, measured in a two-year interval, on A?42, computed both over continuous and categorical values of A?42, at voxel-level (p?<?0.001; k?<?100) and corrected for sex, age and education. Analyses were performed jointly and separately, on two samples. The first sample was formed of 31 individuals (22 Ctrl and 9 pre-AD), aged 60-80 and recruited at the Hospital Clinic of Barcelona. The second sample was a replica of the first one with subjects selected from the ADNI dataset. We also investigated the dependence of the GM atrophy rate on the basal levels of continuous p-tau and on the p-tau/A?42 ratio. Correlation analyses on the whole sample showed a dependence of GM atrophy rates on A?42 in medial and orbital frontal, precuneus, cingulate, medial temporal regions and cerebellum. Correlations with p-tau were located in the left hippocampus, parahippocampus and striatal nuclei whereas correlation with p-tau/A?42 was mainly found in ventral and medial temporal areas. Regarding analyses performed separately, we found a substantial discrepancy of results between samples, illustrating the complexities of comparing two independent datasets even when using the same inclusion criteria. Such discrepancies may lead to significant differences in the sample size needed to detect a particular reduction on cerebral atrophy rates in prevention trials. Higher cognitive reserve and more advanced pathological progression in the ADNI sample could partially account for the observed discrepancies. Taken together, our findings in these two samples highlight the importance of comparing and merging independent datasets to draw more robust and generalizable conclusions on the structural changes in the preclinical stages of AD.
| S-EPMC6050455 | biostudies-literature
Project description:TMT Proteomic study of CSF from patients with Alzheimer's disease, non-cognitively impaired controls, and subjects with mild or subjective cognitive impairment
2020-12-04 | PXD019910 | Pride