Cerebrospinal Fluid sTREM-2, GFAP, and β-S100 in Symptomatic Sporadic Alzheimer’s Disease: Microglial, Astrocytic, and APOE Contributions Along the Alzheimer’s Disease Continuum

Abstract

Background: Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer’s disease (AD), since amyloid-β (Aβ) deposition, tau pathology, and neuroinflammation influence each other. Objective: We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype. Methods: We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; β-S100) from 71 patients with AD (23 A+T–,48 A+T+; 38 APOE ɛ3, 33 APOE ɛ4) and 30 healthy controls (HC). With multivariate analyses we investigated associations between glial biomarkers, Aβ42, and p-tau in all subgroups. Results: CSF sTREM-2 was higher in A+T+ [1.437 (0.264)] and A+T– [1.355 (0.213)] than in HC [1.042 (0.198); both p < 0.001]; GFAP and β-S100 were comparable across groups. Considering all patients, sTREM-2 positively associated with Aβ 42 (p = 0.04) and p-tau (=0.016), with the first being present only in the A+T– subgroup (p = 0.023). GFAP positively associated with Aβ 42 in all patients (p = 0.020) and in the A+T+ subgroup (p = 0.04). Stratifying by APOE, a positive association of sTREM-2 and p-tau was confirmed selectively in carriers of ɛ4 (p = 0.018). Finally, sTREM-2 positively correlated with β-S100 in all subgroups, and with GFAP in A+T+ (p = 0.042). Conclusion: Our results confirm the increase of CSF sTREM-2 in AD, which associates with reduced amyloidopathy in A+T– patients. Moreover, microglial activation seems to increase CSF tau levels in carriers of APOE ɛ4, is associated with astrocytic reactivity (GFAP) in A+T+, and likely leads the acquisition of a more neurotoxic astrocytic phenotype (β-S100).

Soluble TREM2 Concentrations in the Cerebrospinal Fluid Correlate with the Severity of Neurofibrillary Degeneration, Cognitive Impairment, and Inflammasome Activation in Alzheimer’s Disease

“…Our findings demonstrate convincingly that CSF levels of sTREM2 are significantly greater in the AD group than in the MCI and HC groups. Apart from rare exceptions [ 34 , 43 ], the vast majority of previous studies [ 44 , 45 ] have, like the present study, found elevated concentrations of sTREM2 in CSF to be strongly associated with AD. Importantly, we found that concentrations of sTREM2 in CSF are substantially higher in the MCI group compared to the HC group, confirming previous suggestions that sTREM2 could be used as a biomarker to detect conversion from MCI to AD [ 45 ] and can indicate earlier changes in the MCI stage.…”

Peripheral Blood and Cerebrospinal Fluid Levels of YKL-40 in Alzheimer’s Disease: A Systematic Review and Meta-Analysis

“…In the neuropathological study of AD inflammation, CSF levels of sTREM-2 were significantly higher in AD patients than HCs [14]. However, the diagnostic performance of sTREM-2 is not entirely stable, and plasma levels of sTREM-2 showed no significant differences.…”

Clinical characteristics of unvaccinated or incompletely vaccinated children with neurological manifestations due to SARS‐CoV‐2 Omicron infection

“…RT-PCR was run in a LightCycler 480 ® Instrument II (Roche), with the thermocycling condition: 45°C for 10 min and 95°C for 5 min, followed by 45 cycles of 95°C for 5 s and 55°C for 30 s. As IL-6 and IL-8 levels had consistently been found to be perturbed in acute inflammatory response as well as MIS-C, 19,28 the blood and CSF levels of IL-6 and IL-8 were measured using ELISA MAX™ Deluxe Set Human IL-6 and ELISA MAX™ Deluxe Set Human IL-8 (BioLegend). Being markers of neuroinflammation 29 as well as biomarkers for Alzheimer's disease, 23,24 the blood and CSF chitinase-3 like-protein (CHI3L1) and sTREM-2 were measured using Human chitinase-3-like-1QUantikine ELISA Kit (R&D Systems) and Human TREM2 DuoSet ELISA kit (R&D Systems), respectively. Briefly, 96-well microplates were blocked with 1% bovine serum albumin and coated with the capture antibodies.…”

“…We hypothesized that the inflammatory markers in CSF rather than the level of cytokines in blood were better correlates of the disease severity and outcome of children with neuro‐COVID. In addition, as neuroinflammatory markers such as chitinase‐3 like‐protein‐1 (CHI3L1) and soluble triggering receptor expressed on myeloid cells 2 (sTREM‐2) are closely associated with neuroinflammation and neurodegenerative diseases such as Alzheimer's disease, 23,24 we investigated whether their blood or CSF levels were correlated with changes in neuronal activities manifested as seizures as well as neuronal damage in our patients. To better define the spectrum of clinical manifestations and to identify potential biomarkers associated with the clinical outcomes of children with Omicron‐related neurological complications, we recruited children who were hospitalized for Omicron‐related neurological manifestations during the Omicron wave in Hong Kong 25 .…”