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Identification of longitudinally dynamic biomarkers in Alzheimer's disease cerebrospinal fluid by targeted proteomics.

Wildsmith KR, Schauer SP, Smith AM, Arnott D, Zhu Y, Haznedar J, Kaur S, Mathews WR, Honigberg LA - Mol Neurodegener (2014)

Bottom Line: Four of 28 quantifiable CSF proteins were significantly different between aged, cognitively-normal controls and AD subjects including chitinase-3-like protein 1, reproducing published results.Four CSF markers demonstrated significant longitudinal change in AD: Amyloid precursor protein, Neuronal pentraxin receptor, NrCAM and Chromogranin A.Using a targeted proteomics approach, we confirmed previous findings for a subset of markers, defined longitudinal performance of our panel of markers, and established a flexible proteomics method for robust multiplexed analyses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Phamacodynamic Biomarkers within Development Sciences, Genentech, Inc, (a member of the Roche Group), 1 DNA Way, South San Francisco, CA 94080, USA. wildsmith.kristin@gene.com.

ABSTRACT

Background: Alzheimer's disease (AD) is the leading cause of dementia affecting greater than 26 million people worldwide. Although cerebrospinal fluid (CSF) levels of Aβ42, tau, and p-tau181 are well established as diagnostic biomarkers of AD, there is a need for additional CSF biomarkers of neuronal function that continue to change during disease progression and could be used as pharmacodynamic measures in clinical trials. Multiple proteomic discovery experiments have reported a range of CSF biomarkers that differ between AD and control subjects. These potential biomarkers represent multiple aspects of the disease pathology. The performance of these markers has not been compared with each other, and their performance has not been evaluated longitudinally.

Results: We developed a targeted-proteomic, multiple reaction monitoring (MRM) assay for the absolute quantitation of 39 peptides corresponding to 30 proteins. We evaluated the candidate biomarkers in longitudinal CSF samples collected from aged, cognitively-normal control (n = 10), MCI (n = 5), and AD (n = 45) individuals (age > 60 years). We evaluated each biomarker for diagnostic sensitivity, longitudinal consistency, and compared with CSF Aβ42, tau, and p-tau181. Four of 28 quantifiable CSF proteins were significantly different between aged, cognitively-normal controls and AD subjects including chitinase-3-like protein 1, reproducing published results. Four CSF markers demonstrated significant longitudinal change in AD: Amyloid precursor protein, Neuronal pentraxin receptor, NrCAM and Chromogranin A. Robust correlations were observed within some subgroups of proteins including the potential disease progression markers.

Conclusion: Using a targeted proteomics approach, we confirmed previous findings for a subset of markers, defined longitudinal performance of our panel of markers, and established a flexible proteomics method for robust multiplexed analyses.

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Related in: MedlinePlus

Potential longitudinal biomarkers in established AD patients. Black-line mean slope. Control, green-circle, MCI blue-square, AD red-triangle. Closed symbols, decliners. A. Amyloid precursor protein peptide (A4_117), B. Neuronal pentraxin receptor (NPTXR), C. Chromogranin A (CMGA), D. NrCAM.
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Figure 4: Potential longitudinal biomarkers in established AD patients. Black-line mean slope. Control, green-circle, MCI blue-square, AD red-triangle. Closed symbols, decliners. A. Amyloid precursor protein peptide (A4_117), B. Neuronal pentraxin receptor (NPTXR), C. Chromogranin A (CMGA), D. NrCAM.

Mentions: It is estimated that levels of Aβ42 and tau change 1–2 decades prior to AD onset [4,5]. However, both markers demonstrate limited to no annual change in established AD patients [59-63]. One of the primary goals of our study was to evaluate the longitudinal stability of the candidate biomarkers. We estimated the annualized rates of change via a linear mixed-effects model using three time points collected repeatedly from the same patients (baseline, 3–8 mo., 11–16 mo.) including age and sex as covariates [64]. As expected, both Aβ42 and tau remained stable in the AD subjects’ samples analyzed in this study (Figure 2) (% annual change for Aβ42 = −0.1%, 95% CI = −7.3 - 7.7% annual change for tau = −5.4, 95% CI = −16.1-6.6). P-tau trended toward a decrease in AD, but the change from baseline did not reach significance (% annual change for p-tau = −10.8%, 95% CI = −21.4-1.3). The annual rate of yearly change was estimated for all peptides in AD subjects (Figure 3). The majority of peptides were stable over time, however, four peptides demonstrated significant decreases over time in AD as indicated by the 95% confidence interval error bars (~10% per year) (amyloid precursor protein, A4_117; neuronal pentraxin receptor, NPTXR; Chromogranin A, CMGA; and NrCAM) (Figure 3). The individual trajectories and the mean group slope are shown in Figure 4 for the four potential longitudinal biomarkers. There was no significant change from baseline observed in a smaller set of aged control and MCI patients (Figure 4).


Identification of longitudinally dynamic biomarkers in Alzheimer's disease cerebrospinal fluid by targeted proteomics.

Wildsmith KR, Schauer SP, Smith AM, Arnott D, Zhu Y, Haznedar J, Kaur S, Mathews WR, Honigberg LA - Mol Neurodegener (2014)

Potential longitudinal biomarkers in established AD patients. Black-line mean slope. Control, green-circle, MCI blue-square, AD red-triangle. Closed symbols, decliners. A. Amyloid precursor protein peptide (A4_117), B. Neuronal pentraxin receptor (NPTXR), C. Chromogranin A (CMGA), D. NrCAM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061120&req=5

Figure 4: Potential longitudinal biomarkers in established AD patients. Black-line mean slope. Control, green-circle, MCI blue-square, AD red-triangle. Closed symbols, decliners. A. Amyloid precursor protein peptide (A4_117), B. Neuronal pentraxin receptor (NPTXR), C. Chromogranin A (CMGA), D. NrCAM.
Mentions: It is estimated that levels of Aβ42 and tau change 1–2 decades prior to AD onset [4,5]. However, both markers demonstrate limited to no annual change in established AD patients [59-63]. One of the primary goals of our study was to evaluate the longitudinal stability of the candidate biomarkers. We estimated the annualized rates of change via a linear mixed-effects model using three time points collected repeatedly from the same patients (baseline, 3–8 mo., 11–16 mo.) including age and sex as covariates [64]. As expected, both Aβ42 and tau remained stable in the AD subjects’ samples analyzed in this study (Figure 2) (% annual change for Aβ42 = −0.1%, 95% CI = −7.3 - 7.7% annual change for tau = −5.4, 95% CI = −16.1-6.6). P-tau trended toward a decrease in AD, but the change from baseline did not reach significance (% annual change for p-tau = −10.8%, 95% CI = −21.4-1.3). The annual rate of yearly change was estimated for all peptides in AD subjects (Figure 3). The majority of peptides were stable over time, however, four peptides demonstrated significant decreases over time in AD as indicated by the 95% confidence interval error bars (~10% per year) (amyloid precursor protein, A4_117; neuronal pentraxin receptor, NPTXR; Chromogranin A, CMGA; and NrCAM) (Figure 3). The individual trajectories and the mean group slope are shown in Figure 4 for the four potential longitudinal biomarkers. There was no significant change from baseline observed in a smaller set of aged control and MCI patients (Figure 4).

Bottom Line: Four of 28 quantifiable CSF proteins were significantly different between aged, cognitively-normal controls and AD subjects including chitinase-3-like protein 1, reproducing published results.Four CSF markers demonstrated significant longitudinal change in AD: Amyloid precursor protein, Neuronal pentraxin receptor, NrCAM and Chromogranin A.Using a targeted proteomics approach, we confirmed previous findings for a subset of markers, defined longitudinal performance of our panel of markers, and established a flexible proteomics method for robust multiplexed analyses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Phamacodynamic Biomarkers within Development Sciences, Genentech, Inc, (a member of the Roche Group), 1 DNA Way, South San Francisco, CA 94080, USA. wildsmith.kristin@gene.com.

ABSTRACT

Background: Alzheimer's disease (AD) is the leading cause of dementia affecting greater than 26 million people worldwide. Although cerebrospinal fluid (CSF) levels of Aβ42, tau, and p-tau181 are well established as diagnostic biomarkers of AD, there is a need for additional CSF biomarkers of neuronal function that continue to change during disease progression and could be used as pharmacodynamic measures in clinical trials. Multiple proteomic discovery experiments have reported a range of CSF biomarkers that differ between AD and control subjects. These potential biomarkers represent multiple aspects of the disease pathology. The performance of these markers has not been compared with each other, and their performance has not been evaluated longitudinally.

Results: We developed a targeted-proteomic, multiple reaction monitoring (MRM) assay for the absolute quantitation of 39 peptides corresponding to 30 proteins. We evaluated the candidate biomarkers in longitudinal CSF samples collected from aged, cognitively-normal control (n = 10), MCI (n = 5), and AD (n = 45) individuals (age > 60 years). We evaluated each biomarker for diagnostic sensitivity, longitudinal consistency, and compared with CSF Aβ42, tau, and p-tau181. Four of 28 quantifiable CSF proteins were significantly different between aged, cognitively-normal controls and AD subjects including chitinase-3-like protein 1, reproducing published results. Four CSF markers demonstrated significant longitudinal change in AD: Amyloid precursor protein, Neuronal pentraxin receptor, NrCAM and Chromogranin A. Robust correlations were observed within some subgroups of proteins including the potential disease progression markers.

Conclusion: Using a targeted proteomics approach, we confirmed previous findings for a subset of markers, defined longitudinal performance of our panel of markers, and established a flexible proteomics method for robust multiplexed analyses.

Show MeSH
Related in: MedlinePlus