Blood-based biomarkers of Alzheimer’s disease: Challenging but feasible

Laboratory of Personality & Cognition, Intramural Research Program, National Institue on Aging, NIH, USA.
Biomarkers in Medicine (Impact Factor: 2.86). 02/2010; 4(1):65-79. DOI: 10.2217/bmm.09.84
Source: PubMed

ABSTRACT Blood-based biomarkers present a considerable challenge: technically, as blood is a complex tissue and conceptually, as blood lacks direct contact with brain. Nonetheless, increasing evidence suggests that there is a blood protein signature, and possibly a transcript signature, that might act to increase confidence in diagnosis, be used to predict progression in either disease or prodromal states, and that may also be used to monitor disease progression. Evidence for this optimism comes partly from candidate protein studies, including those suggesting that amyloid-beta measures might have value in prediction and those studies of inflammatory markers that consistently show change in Alzheimer's disease, and partly from true proteomics studies that are beginning to identify markers in blood that replicate across studies and populations.

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Available from: Simon Lovestone, May 19, 2015
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    • "A recent study reported accurate detection of preclinical AD via lipid analysis [19]. However, most of these findings remain to be replicated in larger, prospective, population-based cohort studies, and to date no bloodbased biomarkers have been established or accepted as an aid to diagnosis [23] [24]. "
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    ABSTRACT: Abstract. Accurate blood-based biomarkers of Alzheimer’s disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.
    Journal of Alzheimer's disease: JAD 02/2015; DOI:10.3233/JAD-142925 · 4.15 Impact Factor
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    • "The potential reasons for failures are numerous [1] [2] [3]. Discussions center on several possibilities: (1) study design (e.g., trials are too short; include advanced patients, thus minimizing the possibility of demonstrating clinical impact), (2) study compounds (i.e., low efficacy, addressing incorrect target/ mechanism), and/or (3) lack of biomarkers to enroll the " right " patients into the trials (i.e., early-stage patients in whom disease modification is still possible) [2]. The latter notion is based on data that show pathology precedes clinical symptoms by years, and that currently available clinical outcomes , even ones used as clinical end points, show significant variation [2,4–10]. "
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    ABSTRACT: Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood–brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014; 10(1):115–131. DOI:10.1016/j.jalz.2013.01.013 · 17.47 Impact Factor
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    • "Category Analytes Biological fluid APP metabolism Beta-secretase 1, neuroserpin, S100A7, APP-b, sAPPs, SorLA CSF b-amyloid Ab15/16, Ab38, Ab oligomer(s), Ab40 oligomer. . . CSF/blood Ab-binding molecule b-2 microglobulin, cystatin C, gelsolin, transthyretin CSF Tau Tau hyperphosphorylated at different positions, truncated tau CSF Synapse loss/neurodegeneration Calbindin, calsyntenin 1, carboxypeptidase E, carnosinase I Chromogranin A and B, N-cadherin, NCAM-120, nectin-like molecule-1 CSF CSF Synapse loss/neurodegeneration Neurogranin, neuronal pentraxin receptor, NrCAM, S100A1 Secretogranin I, II and III CSF CSF Lipid metabolism Visinin-like protein 1, ApoJ/clusterin, other apolipoproteins ApoE Total serum cholesterol, oxysterols CSF CSF/Blood Blood (Neuro) inflammation a-1 antitrypsin, a-2-macroglobulin, complement C3 Complement C3a, complement C3a des-Arg, complement C4, complement C4a, complement C4a des-Arg, eotaxin-3/CCL-26, factor H, Fas, GFAP, GRO-a/CXCL1, MMP-2, MMP-3, MMP-10, MIF, MCP-1, MCP-2, neuroserpin, S100b, TACE, TECK, TRAIL-R3, chitinase 3, VEGF, GM-CSF, FABP, KIM-1, resistin, a-1 antichymotrypsin, MMP-9, CRP, homocystein CSF CSF CSF CSF CSF CSF CSF/Blood Blood Pro-inflammatory cytokines IL-1b, IL-1, R2 IL-2, IL-7, IL-8, IL-11, IL-12p70, IL-17E, sTNFR-1, sTNFR-2, TNF-a, IFN-g, TGF-b, CCL3, IL-6 CSF CSF CSF/Blood Oxidative stress a-aminobutyric acid, ammonia Oxidatively modified peroxiredoxin, total hydroxyoctadecadienoic acid, GSK-3, Dkk-3 3-nitrotyrosine adducts, advanced glycation end products, 8-OHG, isoprostanes CSF Blood Signal transduction GSK-3, Dkk-3 CSF Blood Small molecule/ metabolomics Cortisol, cysteine, dopamine norepinephrine, normetanephrine, citrulline, arginine, MHPG, ornithine, glutamate, threonine, urea, uridine CSF CSF Coagulation and fibrinolysis Fibrinogen, D-dimer, TAT and t-PA activity Blood Gene expression mRNA and miRNA profiling CSF/BloodP Adapted from (Fagan and Perrin, 2012, Thambisetty and Lovestone, 2010 "
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    ABSTRACT: A paradigm shift has occurred in the last ten years in the diagnostic field of Alzheimer's disease (AD). Scientific thought has enriched the concept of AD as a pathophysiological continuum and emphasized contribution of biological, morphological and functional brain imaging biomarkers for diagnosis, in particular during the early stages of the disease. We address here the present and the future of these biological biomarkers. Most of them are linked to the pathophysiological lesions of the Alzheimer process: aggregates of hyperphosphorylated tau proteins, also called neurofibrillary tangles (NFT), and extracellular deposit of amyloid-beta peptides (Aβ), also called senile plaques. The detection in the cerebrospinal fluid (CSF) of tau and Aβ represents the current diagnostic practice of AD. Improvement for a more accurate and earlier biological diagnosis is however expected using a new generation of biomarkers, mostly in relation with tau and Aβ metabolism.
    Revue Neurologique 09/2013; 169. DOI:10.1016/j.neurol.2013.07.012 · 0.60 Impact Factor
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