Peptides and Proteins in Plasma and Cerebrospinal Fluid as Biomarkers for the Prediction, Diagnosis, and Monitoring of Therapeutic Efficacy of Alzheimer's Disease

Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 09/2008; 1782(10):549-58. DOI: 10.1016/j.bbadis.2008.07.008
Source: PubMed


Alzheimer's disease (AD) affects millions of persons worldwide. Earlier detection and/or diagnosis of AD would permit earlier intervention, which conceivably could delay progression of this dementing disorder. In order to accomplish this goal, reliable and specific biomarkers are needed. Biomarkers are multidimensional and have the potential to aid in various facets of AD such as diagnostic prediction, assessment of disease stage, discrimination from normally cognitive controls as well as other forms of dementia, and therapeutic efficacy of AD drugs. To date, biomarker research has focused on plasma and cerebrospinal fluid (CSF), two bodily fluids believed to contain the richest source of biomarkers for AD. CSF is the fluid surrounding the central nervous system (CNS), and is the most indicative obtainable fluid of brain pathology. Blood plasma contains proteins that affect brain processes from the periphery, as well as proteins/peptides exported from the brain; this fluid would be ideal for biomarker discovery due to the ease and non-invasive process of sample collection. However, it seems reasonable that biomarker discovery will result in combinations of CSF, plasma, and other fluids such as urine, to serve the aforementioned purposes. This review focuses on proteins and peptides identified from CSF, plasma, and urine that may serve as biomarkers in AD.

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    • "Biomarkers are usually analyzed in bodily fluids such as blood, urine, or the cerebrospinal fluid (CSF), but data collected with brain imaging methods are also considered as biomarkers (4-6). To be accepted as such, a new marker of AD must fulfill two conditions: it must be evaluated in at least two independent peer-reviewed cross-sectional clinical studies and be confirmed neuropathologically at autopsy (7). "
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    ABSTRACT: Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.
    Croatian Medical Journal 08/2014; 55(4):347-365. DOI:10.3325/cmj.2014.55.347 · 1.31 Impact Factor
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    • "In the last two decades, there have been intensive efforts to develop disease-modifying drugs to counteract the progression of AD. Because initiating treatment with these agents early in the disease continuum is expected to provide the greatest long-term benefits, there is a critical need for further progress in the development and validation of diagnostic tools to accurately identify patients with early AD dementia (and especially prodromal AD) for inclusion in clinical trials [14]. Aside from the need for biomarkers to identify patients for inclusion in registration trials of disease-modifying agents, once these drugs are approved for widespread use, diagnostic tools will also be required to recognize prodromal AD patients and provide appropriate treatments in routine clinical practice. "
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    ABSTRACT: Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 05/2014; 11(1). DOI:10.1016/j.jalz.2014.02.004 · 12.41 Impact Factor
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    • "Herein, we report additions to the released reference database based on results obtained from the analysis of plasma samples in our laboratory analyzed by a dual depletion shotgun proteomics technique. Quantitative proteomics analyses of plasma are useful for identifying clinically relevant biomarkers [4] or in understanding disease mechanisms such as Alzheimer's disease [11]. "
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    ABSTRACT: Robust platforms for determining differentially expressed proteins in biomarker and discovery studies using human plasma are of great interest. While increased depth in proteome coverage is desirable, it is associated with costs of experimental time due to necessary sample fractionation. We evaluated a robust quantitative proteomics workflow for its ability (1) to provide increased depth in plasma proteome coverage and (2) to give statistical insight useful for establishing differentially expressed plasma proteins. The workflow involves dual-stage immunodepletion on a multiple affinity removal system (MARS) column, iTRAQ tagging, offline strong-cation exchange chromatography, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Independent workflow experiments were performed in triplicate on four plasma samples tagged with iTRAQ 4-plex reagents. After stringent criteria were applied to database searched results, 689 proteins with at least two spectral counts (SC) were identified. Depth in proteome coverage was assessed by comparison to the 2010 Human Plasma Proteome Reference Database in which our studies reveal 399 additional proteins which have not been previously reported. Additionally, we report on the technical variation of this quantitative workflow which ranges from ±11 to 30%.
    02/2013; 2013(11):654356. DOI:10.1155/2013/654356
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