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

Mattsson N, Insel P, Nosheny R, Zetterberg H, Trojanowski JQ, Shaw LM, Tosun D, Weiner M, Alzheimer's Disease Neuroimaging Initiati - Transl Psychiatry (2013)

Bottom Line: 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).There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years.We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA 94121, USA. niklas.mattsson@neuro.gu.se

ABSTRACT
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 three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. 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 Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques.

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Longitudinal measurements of CSF Aβ42, T-tau and P-tau. CSF Aβ42, T-tau and P-tau in cognitively healthy controls followed up to 4 years, with three to four samples each. Thick lines are regression curves calculated using linear mixed effect models, adjusted for age, sex, education and APOE. The changes over time (in years) were significant for Aβ42 (β=−4.11, s.e.=0.77, P<0.0001), T-tau (β=2.34, s.e.=0.51, P<0.0001) and P-tau (β=2.76, s.e.=0.49, P<0.0001).
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fig1: Longitudinal measurements of CSF Aβ42, T-tau and P-tau. CSF Aβ42, T-tau and P-tau in cognitively healthy controls followed up to 4 years, with three to four samples each. Thick lines are regression curves calculated using linear mixed effect models, adjusted for age, sex, education and APOE. The changes over time (in years) were significant for Aβ42 (β=−4.11, s.e.=0.77, P<0.0001), T-tau (β=2.34, s.e.=0.51, P<0.0001) and P-tau (β=2.76, s.e.=0.49, P<0.0001).

Mentions: The main goal of the study was to test the prediction by baseline proteins of longitudinal CSF Aβ42 (predictions of CSF T-tau and P-tau were also tested, presented below). See Figure 1 for plots of longitudinal CSF Aβ42, T-tau and P-tau. We tested the prediction by baseline proteins of longitudinal CSF Aβ42 in two ways. First, we used linear mixed effect models with longitudinal Aβ42 as a continuous variable, including all subjects. Second, we used ROC statistics as described in the Patients and methods section, dichotomizing the study population based on relative change in Aβ42 from baseline to 4-year follow-up (using estimated rates from the linear mixed effect model). To clearly separate the subjects compared in the ROC statistics, we only compared subjects with the most and the least Aβ42 change (1st and 4th quartiles of subjects ranked by relative Aβ42 change).


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

Mattsson N, Insel P, Nosheny R, Zetterberg H, Trojanowski JQ, Shaw LM, Tosun D, Weiner M, Alzheimer's Disease Neuroimaging Initiati - Transl Psychiatry (2013)

Longitudinal measurements of CSF Aβ42, T-tau and P-tau. CSF Aβ42, T-tau and P-tau in cognitively healthy controls followed up to 4 years, with three to four samples each. Thick lines are regression curves calculated using linear mixed effect models, adjusted for age, sex, education and APOE. The changes over time (in years) were significant for Aβ42 (β=−4.11, s.e.=0.77, P<0.0001), T-tau (β=2.34, s.e.=0.51, P<0.0001) and P-tau (β=2.76, s.e.=0.49, P<0.0001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756294&req=5

fig1: Longitudinal measurements of CSF Aβ42, T-tau and P-tau. CSF Aβ42, T-tau and P-tau in cognitively healthy controls followed up to 4 years, with three to four samples each. Thick lines are regression curves calculated using linear mixed effect models, adjusted for age, sex, education and APOE. The changes over time (in years) were significant for Aβ42 (β=−4.11, s.e.=0.77, P<0.0001), T-tau (β=2.34, s.e.=0.51, P<0.0001) and P-tau (β=2.76, s.e.=0.49, P<0.0001).
Mentions: The main goal of the study was to test the prediction by baseline proteins of longitudinal CSF Aβ42 (predictions of CSF T-tau and P-tau were also tested, presented below). See Figure 1 for plots of longitudinal CSF Aβ42, T-tau and P-tau. We tested the prediction by baseline proteins of longitudinal CSF Aβ42 in two ways. First, we used linear mixed effect models with longitudinal Aβ42 as a continuous variable, including all subjects. Second, we used ROC statistics as described in the Patients and methods section, dichotomizing the study population based on relative change in Aβ42 from baseline to 4-year follow-up (using estimated rates from the linear mixed effect model). To clearly separate the subjects compared in the ROC statistics, we only compared subjects with the most and the least Aβ42 change (1st and 4th quartiles of subjects ranked by relative Aβ42 change).

Bottom Line: 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).There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years.We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA 94121, USA. niklas.mattsson@neuro.gu.se

ABSTRACT
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 three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. 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 Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques.

Show MeSH
Related in: MedlinePlus