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sTREM 2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early ‐ stage Alzheimer's disease and associate with neuronal injury markers

View Article: PubMed Central - PubMed

ABSTRACT

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type‐1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

No MeSH data available.


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Association of CSF sTREM2 with the AD CSF core biomarkersA–FScatter plots representing association of CSF sTREM2 with T‐tau (A, B), P‐tau181P (C, D), and Aβ1–42 (E, F) in the control and AD continuum groups. Each point depicts the value of CSF sTREM2 of a subject, and the solid lines indicate the regression line for each of the groups calculated by a linear mixed‐effects model adjusted by age and gender (fixed effects) and center (random effects). The standardized regression coefficients (β) and the P‐values are also shown. The sample contained some extreme values of T‐tau and P‐tau181P. We did not exclude any value, but we performed a bootstrapping for each association in order to ensure that the associations were not driven by these extreme values.
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emmm201506123-fig-0003: Association of CSF sTREM2 with the AD CSF core biomarkersA–FScatter plots representing association of CSF sTREM2 with T‐tau (A, B), P‐tau181P (C, D), and Aβ1–42 (E, F) in the control and AD continuum groups. Each point depicts the value of CSF sTREM2 of a subject, and the solid lines indicate the regression line for each of the groups calculated by a linear mixed‐effects model adjusted by age and gender (fixed effects) and center (random effects). The standardized regression coefficients (β) and the P‐values are also shown. The sample contained some extreme values of T‐tau and P‐tau181P. We did not exclude any value, but we performed a bootstrapping for each association in order to ensure that the associations were not driven by these extreme values.

Mentions: We studied the relationship between CSF sTREM2 and the core AD CSF biomarkers using linear mixed‐effects models, controlled for age, gender, and center. In the whole sample of subjects including the controls and all the AD continuum groups, increased CSF sTREM2 was associated with higher levels of T‐tau (β = +0.336, P = 0.001) (Fig 3A and B) and P‐tau181P (β = +0.370, P = 0.001) (Fig 3C and D), and lower levels of Aβ1–42 (β = −0.098, P = 0.014) (Fig 3E and F). Within each diagnostic group, the positive association between CSF sTREM2 and T‐tau or P‐tau181P was present (Fig 3A–D), except for the association between CSF sTREM2 and T‐tau in the MCI‐AD group (β = +0.184, P = 0.098). On the other hand, higher CSF sTREM2 levels showed a tendency to be associated with higher Aβ1–42 in the control group (β = +0.159, P = 0.060), but with lower Aβ1–42 in the MCI‐AD group (β = −0.291, P = 0.002) (Fig 3E and F). We conclude that higher CSF sTREM2 correlates with higher levels of markers of neuronal injury and tau pathology (i.e. T‐tau and P‐tau181P) suggesting an early response of TREM2 to first symptoms of neurodegeneration.


sTREM 2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early ‐ stage Alzheimer's disease and associate with neuronal injury markers
Association of CSF sTREM2 with the AD CSF core biomarkersA–FScatter plots representing association of CSF sTREM2 with T‐tau (A, B), P‐tau181P (C, D), and Aβ1–42 (E, F) in the control and AD continuum groups. Each point depicts the value of CSF sTREM2 of a subject, and the solid lines indicate the regression line for each of the groups calculated by a linear mixed‐effects model adjusted by age and gender (fixed effects) and center (random effects). The standardized regression coefficients (β) and the P‐values are also shown. The sample contained some extreme values of T‐tau and P‐tau181P. We did not exclude any value, but we performed a bootstrapping for each association in order to ensure that the associations were not driven by these extreme values.
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Related In: Results  -  Collection

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emmm201506123-fig-0003: Association of CSF sTREM2 with the AD CSF core biomarkersA–FScatter plots representing association of CSF sTREM2 with T‐tau (A, B), P‐tau181P (C, D), and Aβ1–42 (E, F) in the control and AD continuum groups. Each point depicts the value of CSF sTREM2 of a subject, and the solid lines indicate the regression line for each of the groups calculated by a linear mixed‐effects model adjusted by age and gender (fixed effects) and center (random effects). The standardized regression coefficients (β) and the P‐values are also shown. The sample contained some extreme values of T‐tau and P‐tau181P. We did not exclude any value, but we performed a bootstrapping for each association in order to ensure that the associations were not driven by these extreme values.
Mentions: We studied the relationship between CSF sTREM2 and the core AD CSF biomarkers using linear mixed‐effects models, controlled for age, gender, and center. In the whole sample of subjects including the controls and all the AD continuum groups, increased CSF sTREM2 was associated with higher levels of T‐tau (β = +0.336, P = 0.001) (Fig 3A and B) and P‐tau181P (β = +0.370, P = 0.001) (Fig 3C and D), and lower levels of Aβ1–42 (β = −0.098, P = 0.014) (Fig 3E and F). Within each diagnostic group, the positive association between CSF sTREM2 and T‐tau or P‐tau181P was present (Fig 3A–D), except for the association between CSF sTREM2 and T‐tau in the MCI‐AD group (β = +0.184, P = 0.098). On the other hand, higher CSF sTREM2 levels showed a tendency to be associated with higher Aβ1–42 in the control group (β = +0.159, P = 0.060), but with lower Aβ1–42 in the MCI‐AD group (β = −0.291, P = 0.002) (Fig 3E and F). We conclude that higher CSF sTREM2 correlates with higher levels of markers of neuronal injury and tau pathology (i.e. T‐tau and P‐tau181P) suggesting an early response of TREM2 to first symptoms of neurodegeneration.

View Article: PubMed Central - PubMed

ABSTRACT

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type‐1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

No MeSH data available.


Related in: MedlinePlus