Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer's disease.

There 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. We 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. MIF 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). Inflammatory-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.

Hok-A-Hin YS ，Del Campo M ，Boiten WA ，Stoops E ，Vanhooren M ，Lemstra AW ，van der Flier WM ，Teunissen CE ... -  《Journal of Neuroinflammation》

Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease.

Henjum K ，Almdahl IS ，Årskog V ，Minthon L ，Hansson O ，Fladby T ，Nilsson LN ... -  《Alzheimers Research & Therapy》

Glial activation and inflammation along the Alzheimer's disease continuum.

Nordengen K ，Kirsebom BE ，Henjum K ，Selnes P ，Gísladóttir B ，Wettergreen M ，Torsetnes SB ，Grøntvedt GR ，Waterloo KK ，Aarsland D ，Nilsson LNG ，Fladby T ... -  《Journal of Neuroinflammation》

Cerebrospinal Fluid sTREM2 in Alzheimer's Disease Is Associated with Both Amyloid and Tau Pathologies but not with Cognitive Status.

Li TR ，Lyu DY ，Liu FQ ，Alzheimer’s Disease Neuroimaging Initiative ... -  《-》

Soluble TREM2 changes during the clinical course of Alzheimer's disease: A meta-analysis.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential and novel biomarker of neuroinflammation implicated in the onset and progression of Alzheimer's disease (AD). However, previous studies evaluating levels of sTREM2 in different clinical stages of AD have yielded inconsistent results. To clarify the dynamic change of sTREM2 in AD progression, we conducted a meta-analysis of case-control and cohort studies to determine the role of cerebral spinal fluid (CSF) and plasma sTREM2 levels in preclinical AD (pre-AD), mild cognitive impairment (MCI) and AD dementia. We searched PubMed, MEDLINE, EMBASE, the Cochrane Library for English articles and Sinomed, CNKI for Chinese. The associations between sTREM2 levels and AD continuum groups (pre-AD, MCI and AD) were analyzed. We further performed detailed subgroup analysis and meta-regression to detect the sources of heterogeneity. 17 reports comprising 82 patients with pre-AD, 159 with MCI, 598 with AD, as well as 754 controls were included in this analysis. Regarding the sTREM2 levels in CSF, the overall pooled standard mean difference (SMD) revealed significantly elevated sTREM2 levels in the whole AD continuum groups (SMD = 0.48; 95% CI: 0.23, 0.73; P < 0.001) compared with controls. The levels of sTREM2 significantly increased in pre-AD (SMD = 0.47; 95% CI: 0.21, 0.73; P < 0.001), the highest increase occurred in MCI group (SMD = 0.77; 95% CI: -0.05, 1.59; P = 0.066), and the effect size of AD group (SMD = 0.39; 95% CI: 0.13, 0.65; P = 0.004) was also higher compared with control. However, for sTREM2 levels measured in plasma, no significant differences were found (SMD = 0.11; 95% CI: -0.06, 0.27; P = 0.217). Therefore, our study showed that sTREM2 levels increased in the earlier course of AD, and slightly attenuated in dementia stage. The current results indicated that sTREM2 levels fluctuate as a function of clinical stage in AD and it might be a novel inflammatory biomarker involved in different stages of AD.

Liu D ，Cao B ，Zhao Y ，Huang H ，McIntyre RS ，Rosenblat JD ，Zhou H ... -  《-》