sTREM2 Mediates the Correlation Between BIN1 Gene Polymorphism and Tau Pathology in Alzheimer's Disease.

Background: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc = 0.017; 0.010, respectively) and total-tau (T-tau) (pc = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.

The interrelationships of CSF sTREM2, AD pathology, minimal depressive symptoms, and cognition in non-demented adults.

BACKGROUND: Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition. METHODS: A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition. RESULTS: Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (PFDR = 0.012) and amyloid biomarkers (PFDR < 0.05), as well as cognitive scores (PFDR < 0.05) and hippocampal volume (PFDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2. CONCLUSIONS: MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.

Associations between Microglia and Astrocytic Proteins and Tau Biomarkers across the Continuum of Alzheimer's Disease.

Recent investigations implicate neuroinflammatory changes, including astrocyte and microglia activation, as crucial in the progression of Alzheimer's disease (AD) Thus, we compared selected proteins reflecting neuroinflammatory processes to establish their connection to AD pathologies. Our study, encompassing 80 subjects with (n = 42) AD, (n = 18) mild cognitive impairment (MCI) and (n = 20) non-demented controls compares the clinical potential of tested molecules. Using antibody-based methods, we assessed concentrations of NGAL, CXCL-11, sTREM1, and sTREM2 in cerebrospinal fluid (CSF). Proinflammatory proteins, NGAL, and CXCL-11 reached a peak in the early stage of the disease and allowed for the identification of patients with MCI. Furthermore, the concentration of the anti-inflammatory molecule sTREM2 was highest in the more advanced stage of the disease and permitted differentiation between AD and non-demented controls. Additionally, sTREM2 was biochemically linked to tau and pTau in the AD group. Notably, NGAL demonstrated superior diagnostic performance compared to classical AD biomarkers in discriminating MCI patients from controls. These findings suggest that proteins secreted mainly through microglia dysfunction might play not only a detrimental but also a protective role in the development of AD pathology.

Association between Cerebrospinal Fluid sTREM2 Levels and Depression: The Alzheimer's Disease Neuroimaging Initiative Study.

OBJECTIVE: Previous studies demonstrated a significant protective effect of elevated cerebrospinal fluid (CSF) sTREM2 levels on brain structure and cognitive decline. Nonetheless, the role of sTREM2 in the depression progression remains unclear. This study aimed to investigate the association between CSF sTREM2 levels and longitudinal trajectories of depression. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study were used. CSF sTREM2 levels and depression were measured using an ELISA-based assay and the Geriatric Depression Scale (GDS-15), respectively. Linear mixed-effect models were employed to assess the relationships between CSF sTREM2 levels and GDS scores. RESULTS: A total of 1,017 participants were enrolled at baseline, with a mean follow-up time of 4.65 years. Baseline CSF sTREM2 levels were negatively correlated with GDS scores (ß=-0.21, P=0.022) after adjustment for age, gender, race/ethnicity, education, APOE ε4 carrier status, TREM2 rare variant carrier status, marital status, smoking, and clinical cognitive status. CONCLUSION: Our findings suggested that a higher level of CSF sTREM2 was associated with a lower risk of depression.

Association between sTREM2, an immune biomarker of microglial activation, and frontal lobe function in community-dwelling older adults: a cross-sectional study.

Objective: Identifying the peripheral biomarkers related to the prevention or modification of unhealthy mental conditions in older adults is extremely beneficial. This study aimed to evaluate the serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble form of an innate immune receptor expressed on microglia, in older adults living in a rural community, and their association with cognitive function. Materials and Methods: This survey was conducted between November 2016 and September 2017 in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged ≥65 years. Blood samples were collected from the participants for serum sTREM2 level analysis using a peptide enzyme immunoassay. The participants underwent cognitive function assessments, including the Mini-Mental State Examination, Clinical Dementia Rating, and Frontal Assessment Battery. Therefore, we examined the association between serum sTREM2 levels and cognitive function. Results: Of the 95 participants, 25 were men and 70 were women with a mean age 78.24 ± 3.85 years and 77.96 ± 5.52 years, respectively. Serum sTREM2 levels were negatively associated with Frontal Assessment Battery scores, even after adjusting for age, sex, years of education, and serum high-sensitivity C-reactive protein levels. Conclusion: Serum sTREM2 levels may be associated with frontal lobe function in adults aged ≥65 years.

Decoding sTREM2: its impact on Alzheimer's disease - a comprehensive review of mechanisms and implications.

Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). This review comprehensively examines sTREM2's involvement in AD, focusing on its regulatory functions in microglial responses, neuroinflammation, and interactions with key pathological processes. We discuss the dynamic changes in sTREM2 levels in cerebrospinal fluid and plasma throughout AD progression, highlighting its potential as a therapeutic target. Furthermore, we explore the impact of genetic variants on sTREM2 expression and its interplay with other AD risk genes. The evidence presented in this review suggests that modulating sTREM2 activity could influence AD trajectory, making it a promising avenue for future research and drug development. By providing a holistic understanding of sTREM2's multifaceted role in AD, this review aims to guide future studies and inspire novel therapeutic strategies.

The longitudinal trajectory of CSF sTREM2: the alzheimer's disease neuroimaging initiative.

BACKGROUND: The 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. METHODS: A 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. RESULTS: CSF 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 (ß = 0.146, P = 0.002). CONCLUSION: Our 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.

Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology.

Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aß40, worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aß40 (ß = -0.44, p-value = 0.017) and replicated this interaction in ADNI (ß = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aß peptides in brain (Aß total ß = -0.14, p = 0.629; Aß1-38, ß = 0.11, p = 0.200). In contrast to the effects on Aß, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (ß = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aß levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

Evidence for reduced anti-inflammatory microglial phagocytic response in late-life major depression.

Major depressive disorder (MDD) is associated with Alzheimer's disease (AD) but the precise mechanisms underlying this relationship are not understood. While it is well established that cerebrospinal fluid (CSF) soluble levels of triggering receptor expressed on myeloid cells 2 (sTREM2) increase during early stages of AD, how sTREM2 levels behave in subjects with MDD is not known. In a longitudinal study, we measured CSF sTREM2 levels in 27 elderly cognitively intact individuals with late-life major depression (LLMD) and in 19 healthy controls. We tested the hypothesis that, similarly to what happens in early stages of AD, CSF sTREM2 would be elevated in MDD. In addition, we compared the associations of CSF sTREM2, pro- and anti- inflammatory, and AD biomarkers in LLMD and control subjects. Surprisingly, we found that mean CSF sTREM2 levels were significantly reduced in LLMD compared to controls. This reduction was no longer significant at the 3-year follow-up visit when depression severity improved. In addition, we found that CSF sTREM2 was associated with AD biomarkers and proinflammatory cytokines in controls but not in LLMD. These findings suggest that impaired microglia phagocytic response to AD pathology may be a novel link between MDD and AD.

sTREM2 Differentially Affects Cytokine Expression in Myeloid-Derived Cell Models via MAPK-JNK Signaling Pathway.

TREM2 is a critical innate immune receptor primarily expressed on myeloid-derived cells, such as microglia and macrophages. Mutations in TREM2 are linked to several neurodegenerative diseases including Alzheimer's disease (AD). TREM2 can be cleaved from the cell membrane and released as soluble TREM2 (sTREM2). sTREM2 levels are shown to peak prior to AD, with its levels fluctuating throughout disease progression. However, the mechanism by which sTREM2 may affect innate immune responses is largely uncharacterized. In this study, we investigated whether sTREM2 can induce inflammatory response in myeloid-derived THP-1 monocytes and macrophages and characterized the signaling mechanisms involved. Our results show that sTREM2 was capable of stimulating the expression of several inflammatory cytokines in THP-1 cells throughout the time course of 2 h to 8 h but inducing anti-inflammatory cytokine expression at later time points. A TREM2 antibody was capable of inhibiting the expression of some cytokines induced by sTREM2 but enhancing others. The complex of sTREM2/TREM2 antibody was shown to enhance IL-1ß expression, which was partially blocked by an NLRP3 specific inhibitor, indicating that the complex activated the NRLP3 inflammasome pathway. sTREM2 was also shown to have differential effects on cytokine expression in M0, M1, and M2 macrophages differentiated from THP-1 cells. sTREM2 has a more stimulating effect on cytokine expression in M0 macrophages, less of an effect on M2 macrophages, and some inhibitory effects on cytokine expression in M1 macrophages at early time points. Analyses of several signaling pathways revealed that sTREM2-induced expression of cytokines occurs mainly through MAPK-JNK signaling. Our work reveals differential effects of sTREM2 on cytokine expression profiles of THP-1 cells and macrophages and demonstrates that the MAPK-JNK signaling pathway is mainly responsible for sTREM2-induced cytokine expression.

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment.

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients. To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3 T-MRI scans and signature inflammatory markers in n = 120 participants comprising healthy never-infected controls (n = 30), healthy COVID-19 survivors (n = 29), and subgroups of long-COVID patients with (n = 26) and without (n = 35) cognitive impairment according to screening with Montreal Cognitive Assessment. Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry. We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p < 0.05, FWE-corrected). Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNγ, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment. We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Association between sTREM2, an immune biomarker of microglial activation, and frontal lobe function in community-dwelling older adults: a cross-sectional study / Journal of Rural Medicine

Objective: Identifying the peripheral biomarkers related to the prevention or modification of unhealthy mental conditions in older adults is extremely beneficial. This study aimed to evaluate the serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble form of an innate immune receptor expressed on microglia, in older adults living in a rural community, and their association with cognitive function.Materials and Methods: This survey was conducted between November 2016 and September 2017 in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged ≥65 years. Blood samples were collected from the participants for serum sTREM2 level analysis using a peptide enzyme immunoassay. The participants underwent cognitive function assessments, including the Mini-Mental State Examination, Clinical Dementia Rating, and Frontal Assessment Battery. Therefore, we examined the association between serum sTREM2 levels and cognitive function.Results: Of the 95 participants, 25 were men and 70 were women with a mean age 78.24 ± 3.85 years and 77.96 ± 5.52 years, respectively. Serum sTREM2 levels were negatively associated with Frontal Assessment Battery scores, even after adjusting for age, sex, years of education, and serum high-sensitivity C-reactive protein levels.Conclusion: Serum sTREM2 levels may be associated with frontal lobe function in adults aged ≥65 years.

14-3-3 [Formula: see text]-reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2.

INTRODUCTION: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. METHODS: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. RESULTS: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. CONCLUSIONS: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.

Serum soluble TREM2 is an independent biomarker associated with coronary heart disease.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear. METHODS: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC). RESULTS: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB). CONCLUSION: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. FINDINGS: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031). CONCLUSION: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein ß (S100ß), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1ß, and S100ß levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.

Effects of soluble TREM2 on motor progression in Parkinson's disease.

OBJECTIVES: To determine whether sTREM2 is changed during the pathogenesis of PD and reflect motor decline in PD individuals. METHODS: The cerebrospinal fluid (CSF) from PD and healthy individuals were obtained to measure the expression of sTREM2 and further to evaluate the motor function at baseline and after four years of follow-up using the Parkinson's Progression Markers Initiative (PPMI) database. The relationship between motor disease progression at baseline and longitudinal CSF sTREM2 was evaluated by linear mixed-effects (LME) and multiple linear regression (MLR) models. The change rates of the motor symptoms and sTREM2 level in CSF were further rigorously analyzed using the LME model. Cox proportional-hazards regression models were used to evaluate the predictive values of sTREM2 in CSF for motor progression. The regulatory role of CSF α-syn and Tau between sTREM2 and motor assessments was evaluated by Mediating effect analysis. RESULTS: We found no significant difference in CSF sTREM2 levels between the PD and HC groups (p = 0.155). However, late-onset PD patients had higher CSF sTREM2 levels than early-onset PD patients (p = 0.044). The basal levels of sTREM2 could predict motor progression over the four years of follow-up. The change rate of CSF sTREM2 was correlated with the progressive deterioration of motor function in PD individuals. Our observations also showed that CSF Tau was a significant mediator of the association between CSF sTREM2 and total UPDRS scores and UPDRS III and tremor at baseline with 26.5% and 33.5%, and 28.7% mediation, respectively. CONCLUSION: Our results indicated that CSF sTREM2 was associated with the prognosis of PD motor symptoms. Besides, CSF Tau could effectively mediate the association of sTREM2 with motor progression.

sTREM2 and GFAP Mediated the Association of IGF-1 Signaling Biomarkers with Alzheimer's Disease Pathology.

Defects in insulin-like growth factor 1 (IGF-1) signaling is a key contributor to Alzheimer's disease (AD). However, the mechanism of how IGF-1 signaling relates to AD remained unclear. Here, we investigated the association of IGF-1 signaling associated biomarkers with AD pathology, sTREM2, and GFAP. Finally, insulin-like growth factor binding protein 2 (IGFBP-2) was associated with AD pathology, and the association was partly medicated by sTREM2 (Aß42, ß= 0.794, p = 0.016; T-tau, ß= 0.291, p < 0.001; P-tau181, ß= 0.031, p < 0.001) and GFAP (T-tau, ß= 0.427, p < 0.001; P-tau181, ß= 0.044, p < 0.001). It suggested that sTREM2 and GFAP mediated the relationship between IGF-1 signaling and AD pathology.

Association of rs2062323 in the TREM1 gene with Alzheimer's disease and cerebrospinal fluid-soluble TREM2.

INTRODUCTION AND AIMS: Genetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD and TREM1 gene polymorphisms (SNPs) remained lacking. We sought to examine the associations between TREM1 SNPs and AD. METHODS: Based on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in the TREM1 gene. AD cases (1081) and healthy control subjects (870) were collected and genotyped, and the associations between candidate SNPs and AD risk were analyzed. We explored the associations between target SNP and AD biomarkers. Moreover, 842 individuals from ADNI were selected to verify these results. Linear mixed models were used to estimate associations between the target SNP and longitudinal cognitive changes. RESULTS: The rs2062323 was identified to be associated with AD risk in the Han population, and rs2062323T carriers had a lower AD risk (co-dominant model: OR, 0.67, 95% CI, 0.51-0.88, p = 0.0037; additive model: OR, 0.82, 95% CI, 0.72-0.94, p = 0.0032). Cerebrospinal fluid (CSF) sTREM2 levels were significantly increased in middle-aged rs2062323T carriers (additive model: ß = 0.18, p = 0.0348). We also found significantly elevated levels of CSF sTREM2 in the ADNI. The rate of cognitive decline slowed down in rs2062323T carriers. CONCLUSIONS: This study is the first to identify significant associations between TREM1 rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD.

Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study.

BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer's disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aß1-42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aß1-42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.