Plasma Proteomics for the Identification of Alzheimer Disease

Less-invasive biomarkers for early Alzheimer disease (AD) are urgently needed. The present study aimed to establish a panel of plasma proteins that accurately distinguishes early AD from physiological aging and to compare the findings with previous reports. Fifty-eight healthy controls (CON) and 109 patients with AD dementia were randomly split into a training (40%) and a test (60%) sample. Significant proteins to differentiate between the CON and AD dementia groups were identified in a comprehensive panel of 107 plasma analytes in the training sample; the accuracy in differentiating these 2 groups was explored in the test sample. A set of 5 plasma proteins was identified, which differentiated between the CON group and the AD dementia group with a sensitivity of 89.36% and a specificity of 79.17%. A biological pathway analysis showed that 4 of 5 proteins belonged to a common network with amyloid precursor protein and tau. Apolipoprotein E was the only protein that was both significant in the present report and in a previous proteomic study. The study provides a piece of evidence in support of the feasibility of a blood-based biomarker approach in AD diagnostics; however, further research is required because of issues with replicability.

[1]  Henrik Zetterberg,et al.  Low Incidence of Post-Lumbar Puncture Headache in 1,089 Consecutive Memory Clinic Patients , 2010, European Neurology.

[2]  S. Lovestone,et al.  Proteome-based plasma biomarkers for Alzheimer's disease. , 2006, Brain : a journal of neurology.

[3]  P. Visca,et al.  Hemoglobin and heme scavenging , 2005, IUBMB life.

[4]  Monique Breteler,et al.  Identifying Early Markers of Alzheimer's Disease using Quantitative Multiplex Proteomic Immunoassay Panels , 2009, Annals of the New York Academy of Sciences.

[5]  J. Szaflarski,et al.  Human blood genomics: distinct profiles for gender, age and neurofibromatosis type 1. , 2004, Brain research. Molecular brain research.

[6]  M. Riemenschneider Diagnosis of Alzheimer's disease with cerebrospinal fluid tau protein and aspartate aminotransferase , 1998, The Lancet.

[7]  H. Schluesener,et al.  Expression of interleukin-16 by microglial cells in inflammatory, autoimmune, and degenerative lesions of the rat brain , 2004, Journal of Neuroimmunology.

[8]  A. Hofman,et al.  Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. , 2004, Archives of neurology.

[9]  C. Rowe,et al.  Plasma apolipoprotein E and Alzheimer disease risk , 2011, Neurology.

[10]  H. Hampel,et al.  Total and Phosphorylated Tau Proteins: Evaluation as Core Biomarker Candidates in Frontotemporal Dementia , 2004, Dementia and Geriatric Cognitive Disorders.

[11]  Yuan Qi,et al.  Identifying Neuroimaging and Proteomic Biomarkers for MCI and AD via the Elastic Net , 2011, MBIA.

[12]  E. Umlauf,et al.  The role of proteomics in dementia and Alzheimer’s disease , 2009, Acta Neuropathologica.

[13]  Hirotoshi Watanabe,et al.  Clinical impression of brain natriuretic peptide levels in demented patients without cardiovascular disease , 2009, Geriatrics & gerontology international.

[14]  J. Broderick,et al.  Effects of Gender on Gene Expression in the Blood of Ischemic Stroke Patients , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  G. Siest,et al.  Apolipoprotein E Polymorphism and Serum Concentration in Alzheimer's Disease in Nine European Centres: the ApoEurope Study , 2000, Clinical chemistry and laboratory medicine.

[16]  Giuseppe Banfi,et al.  Metabolic markers in sports medicine. , 2012, Advances in clinical chemistry.

[17]  Werner Zolg,et al.  The Proteomic Search for Diagnostic Biomarkers , 2006, Molecular & Cellular Proteomics.

[18]  K. Rufibach,et al.  Modeling of Pathological Traits in Alzheimer's Disease Based on Systemic Extracellular Signaling Proteome* , 2011, Molecular & Cellular Proteomics.

[19]  Yi Zhang,et al.  Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease , 2011, PloS one.

[20]  R. Tibshirani,et al.  Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins , 2007, Nature Medicine.

[21]  A. Smilde,et al.  Statistical data processing in clinical proteomics. , 2008, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[22]  P. Moscato,et al.  Differences in Abundances of Cell-Signalling Proteins in Blood Reveal Novel Biomarkers for Early Detection Of Clinical Alzheimer's Disease , 2011, PloS one.

[23]  Christoph Laske,et al.  Identification of a blood-based biomarker panel for classification of Alzheimer's disease. , 2011, The international journal of neuropsychopharmacology.

[24]  Eileen Daly,et al.  Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer’s disease , 2008, Journal of Neurology.

[25]  F. Jessen,et al.  Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease , 2012, Neurology.

[26]  Guanghua Xiao,et al.  A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI , 2011, PloS one.

[27]  P. Lewczuk,et al.  Neurochemical approaches of cerebrospinal fluid diagnostics in neurodegenerative diseases. , 2008, Methods.

[28]  A. Kurz,et al.  Apolipoprotein E epsilon 4 allele, cognitive decline, and deterioration of everyday performance in Alzheimer's disease , 1996, Neurology.

[29]  A. Roses,et al.  The discovery and early validation of novel plasma biomarkers in mild-to-moderate Alzheimer's disease patients responding to treatment with rosiglitazone. , 2008, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[30]  S. Bunge,et al.  Blood gene expression correlated with tic severity in medicated and unmedicated patients with Tourette Syndrome. , 2010, Pharmacogenomics.

[31]  Thomas Arendt,et al.  Synaptic degeneration in Alzheimer’s disease , 2009, Acta Neuropathologica.

[32]  D. Holtzman,et al.  Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance , 2009, Neuron.

[33]  Katharina Buerger,et al.  Biological Marker Candidates of Alzheimer's Disease in Blood, Plasma, and Serum , 2009, CNS neuroscience & therapeutics.

[34]  P. Deyn,et al.  Improved discrimination of AD patients using β-amyloid(1-42) and tau levels in CSF , 1999, Neurology.

[35]  Guanghua Xiao,et al.  A serum protein-based algorithm for the detection of Alzheimer disease. , 2010, Archives of neurology.

[36]  Min Shi,et al.  Biomarker discovery in neurodegenerative diseases: A proteomic approach , 2009, Neurobiology of Disease.

[37]  Wei Li,et al.  The mechanism for heme to prevent Aβ1–40 aggregation and its cytotoxicity , 2011, JBIC Journal of Biological Inorganic Chemistry.

[38]  Vincenzo Savarino,et al.  Liver enzyme alteration: a guide for clinicians , 2005, Canadian Medical Association Journal.

[39]  Kevin Taddei,et al.  Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease , 1997, Neuroscience Letters.

[40]  G. Fisher,et al.  Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients , 2005, Neuroscience Letters.

[41]  Nick C Fox,et al.  The clinical use of structural MRI in Alzheimer disease , 2010, Nature Reviews Neurology.

[42]  M. Martini,et al.  Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer's disease , 1999, Neuroscience Letters.

[43]  S. Potkin,et al.  Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort , 2010, Neurology.

[44]  Hans Förstl,et al.  CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease , 2011, Neurology.

[45]  Tony Wyss-Coray,et al.  Inflammation in Alzheimer disease: driving force, bystander or beneficial response? , 2006, Nature Medicine.

[46]  J. Rockstroh,et al.  Biomarkers of fibrosis and impaired liver function in chronic hepatitis C: how well do they predict clinical outcomes? , 2010, Current opinion in HIV and AIDS.

[47]  F. Nicoletti,et al.  Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementia , 2006, The European journal of neuroscience.

[48]  Xiaojing Sui,et al.  Cerebrospinal fluid biomarkers of Alzheimer’s disease , 2014, Neuroscience Bulletin.

[49]  A. Ortqvist,et al.  Pneumocystis carinii pneumonia in Stockholm, Sweden: treatment, outcome, one-year-follow-up and pyrimethamine prophylaxis. , 1989, Scandinavian journal of infectious diseases.

[50]  K. Dietz,et al.  Expression of interleukin-16 by tumor-associated macrophages/activated microglia in high-grade astrocytic brain tumors , 2007, Archivum Immunologiae et Therapiae Experimentalis.

[51]  M. Weiner,et al.  Cerebrospinal fluid and plasma biomarkers in Alzheimer disease , 2010, Nature Reviews Neurology.

[52]  A. Passaro,et al.  Markers of endothelial dysfunction in older subjects with late onset Alzheimer's disease or vascular dementia , 2008, Journal of the Neurological Sciences.

[53]  Madhav Thambisetty,et al.  Blood-based biomarkers of Alzheimer's disease: challenging but feasible. , 2010, Biomarkers in medicine.

[54]  P. Liao,et al.  Proteomics analysis of plasma for potential biomarkers in the diagnosis of Alzheimer's disease , 2007, Proteomics. Clinical applications.

[55]  A. Wu Cardiac markers: from enzymes to proteins, diagnosis to prognosis, laboratory to bedside. , 1999, Annals of clinical and laboratory science.

[56]  Markus Schwaiger,et al.  Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease , 2008, NeuroImage.

[57]  Georg Kemmler,et al.  Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease , 2011, Neurobiology of Aging.

[58]  J. Morris,et al.  Validation of clinical diagnostic criteria for Alzheimer's disease , 1988, Annals of neurology.

[59]  C. Schaefer,et al.  Analysis of the human serum proteome , 2004, Clinical Proteomics.

[60]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .