Dataset Information

Dynamic changes of CSF sTREM2 in preclinical Alzheimer's disease: the CABLE study.

ABSTRACT: BACKGROUND: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 A? and tau deposition are still unclear. METHODS:According to the NIA-AA criteria, 659 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups, stage 0 (normal A?1-42, T-tau and P-tau), stage 1 (low A?1-42, normal T-tau and P-tau), stage 2 (low A?1-42 and high T-tau or P-tau), and suspected non-AD pathology (SNAP) (normal A?1-42 and high T-tau or P-tau), to examine changes of CSF sTREM2 in the preclinical AD. Biomarker cut-off was based on the assumption that one-third of adults with normal cognition have AD pathology. RESULTS:The level of CSF sTREM2 in the stage 1 decreased compared with the stage 0 (P?

SUBMITTER: Ma LZ

PROVIDER: S-EPMC7149923 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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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]

PMID: 32276587

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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, A?42, 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 A?38 and A?40 also correlated positively with sTREM2 in CSF (A?38MSDrS?=?0.44, p?=?0.001; A?40MSDrS?=?0.48, p?<?0.001; A?42MSDrS?=?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.

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.

Project description:BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid ?-peptide (A?) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A?1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A? pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA? pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A? pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.

Dataset Information

Dynamic changes of CSF sTREM2 in preclinical Alzheimer's disease: the CABLE study.

Publications

Dynamic changes of CSF sTREM2 in preclinical Alzheimer's disease: the CABLE study.

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