Dataset Information

CSF protein biomarkers predicting longitudinal reduction of CSF ?-amyloid42 in cognitively healthy elders.

ABSTRACT: ?-amyloid (A?) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide A?1-42 (A?42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and A? metabolism predict the development of A? plaques, assessed by longitudinal CSF A?42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in A?42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal A?42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for A? metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal A?42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal A?42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with A?42 reduction only in subjects with normal baseline A?42, and not in subjects with reduced baseline A?42. We conclude that baseline CSF proteins related to A? metabolism, microglia activity or synapses predict longitudinal A?42 reduction in cognitively healthy elders. The finding that some proteins only predict A?42 reduction in subjects with normal baseline A?42 suggest that they predict future development of the brain A? pathology at the earliest stages of AD, prior to widespread development of A? plaques.

SUBMITTER: Mattsson N

PROVIDER: S-EPMC3756294 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders.

Mattsson N N Insel P P Nosheny R R Zetterberg H H Trojanowski J Q JQ Shaw L M LM Tosun D D Weiner M M

Translational psychiatry 20130820

β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with ...[more]

PMID: 23962923

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Project description:Cerebrospinal fluid (CSF) YKL40 and sTREM2 are astroglial and microglial activity biomarkers, respectively. We assessed whether CSF YKL40 and sTREM2 baseline levels are associated with longitudinal brain volume and diffusivity changes in cognitively unimpaired adults. Two brain MRI scans of 36 participants (57 to 78-years old, 12 male) were acquired in a 2-year interval. Aβ42, p-tau, YKL40 and sTREM2 concentrations in CSF were determined at baseline. We calculated gray and white matter volume changes per year maps (ΔGM and ΔWM, respectively) by means of longitudinal pairwise registration, and mean diffusivity variation per year (ΔMD) by subtraction. We checked voxel-wise for associations between ΔGM, ΔWM and ΔMD and baseline CSF level of YKL40 and sTREM2 and verified to what extent these associations were modulated by age (YKL40xAGE and sTREM2xAGE interactions). We found a positive association between ΔGM and YKL40 in the left inferior parietal region and no association between sTREM2 and ΔGM. Negative associations were also observed between ΔGM and YKL40xAGE (bilateral frontal areas, left precuneus and left postcentral and supramarginal gyri) and sTREM2xAGE (bilateral temporal and frontal cortex, putamen and left middle cingulate gyrus). We found negative associations between ΔWM and YKL40xAGE (bilateral superior longitudinal fasciculus) and sTREM2xAGE (bilateral superior longitudinal fasciculus, left superior corona radiata, retrolenticular external capsule and forceps minor, among other regions) but none between ΔWM and neither YKL40 nor sTREM2. ΔMD was positively correlated with YKL40 in right orbital region and negatively with sTREM2 in left lingual gyrus and precuneus. In addition, significant associations were found between ΔMD and YKL40xAGE (tail of left hippocampus and surrounding areas and right anterior cingulate gyrus) and sTREM2xAGE (right superior temporal gyrus). Areas showing statistically significant differences were disjoint in analyses involving YKL40 and sTREM2. These results suggest that glial biomarkers exert a relevant and distinct influence in longitudinal brain macro- and microstructural changes in cognitively unimpaired adults, which appears to be modulated by age. In younger subjects increased glial markers (both YKL40 and sTREM2) predict a better outcome, as indicated by a decrease in ΔGM and ΔWM and an increase in ΔMD, whereas in older subjects this association is inverted and higher levels of glial markers are associated with a poorer neuroimaging outcome.

Dataset Information

CSF protein biomarkers predicting longitudinal reduction of CSF ?-amyloid42 in cognitively healthy elders.

Publications

CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders.

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