Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins

A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2–6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

[1]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[2]  P. Eikelenboom,et al.  Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-1 family , 1989, Neuroscience Letters.

[3]  R. Cacabelos,et al.  Interleukin-1 in Alzheimer's disease and multi-infarct dementia: neuropsychological correlations. , 1991, Methods and findings in experimental and clinical pharmacology.

[4]  M. Viitanen,et al.  Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type , 1993, Journal of neural transmission. Parkinson's disease and dementia section.

[5]  L. Fernández-Novoa,et al.  Serum tumor necrosis factor (TNF) in Alzheimer's disease and multi-infarct dementia. , 1994, Methods and findings in experimental and clinical pharmacology.

[6]  P. Wesseling,et al.  Accumulation of intercellular adhesion molecule-1 in senile plaques in brain tissue of patients with Alzheimer's disease. , 1994, The American journal of pathology.

[7]  E. Masliah,et al.  PDGF is associated with neuronal and glial alterations of Alzheimer's disease , 1995, Neurobiology of Aging.

[8]  L. Fernández-Novoa,et al.  Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease. , 1996, Molecular and chemical neuropathology.

[9]  L. Fernández-Novoa,et al.  Blood levels of histamine, IL-1β, and TNF-α in patients with mild to moderate alzheimer disease , 1996 .

[10]  W. Tourtellotte,et al.  Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Smith,et al.  Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. , 1998, Alzheimer disease and associated disorders.

[12]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  B T Hyman,et al.  Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease. , 1999, Journal of neurovirology.

[14]  B. Pedersen,et al.  A high plasma concentration of TNF-alpha is associated with dementia in centenarians. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[15]  G. Murphy,et al.  Expression of macrophage colony-stimulating factor receptor is increased in the AbetaPP(V717F) transgenic mouse model of Alzheimer's disease. , 2000, The American journal of pathology.

[16]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Miller,et al.  CME Practice parameter : Diagnosis of dementia ( an evidence-based review ) Report of the Quality Standards Subcommittee of the American Academy of Neurology , 2001 .

[18]  Manjit,et al.  Neurology , 1912, NeuroImage.

[19]  R. Schliebs,et al.  β-Amyloid-associated expression of intercellular adhesion molecule-1 in brain cortical tissue of transgenic Tg2576 mice , 2002, Neuroscience Letters.

[20]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J Philip Miller,et al.  Rates of progression in mild cognitive impairment and early Alzheimer’s disease , 2002, Neurology.

[22]  E. Porreca,et al.  Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild–moderate Alzheimer's disease patients , 2002, Experimental Gerontology.

[23]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[24]  K. Blennow,et al.  Intrathecal inflammation precedes development of Alzheimer’s disease , 2003, Journal of neurology, neurosurgery, and psychiatry.

[25]  George Karypis,et al.  Clustering in life sciences. , 2003, Methods in molecular biology.

[26]  Lawrence Steinman,et al.  Elaborate interactions between the immune and nervous systems , 2004, Nature Immunology.

[27]  M. Inglese,et al.  Plasma levels of amyloid β-protein 42 are increased in women with mild cognitive impairment , 2004, Neurology.

[28]  W. Markesbery,et al.  Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  K. Blennow,et al.  Intracerebral Production of Tumor Necrosis Factor-α, a Local Neuroprotective Agent, in Alzheimer Disease and Vascular Dementia , 1999, Journal of Clinical Immunology.

[30]  S Miyano,et al.  Open source clustering software. , 2004, Bioinformatics.

[31]  M. Michalopoulou,et al.  Serum Levels of Soluble Intercellular Adhesion Molecule-1 and Soluble Endothelial Leukocyte Adhesion Molecule-1 in Alzheimer’s Disease , 2004, Journal of geriatric psychiatry and neurology.

[32]  Alok J. Saldanha,et al.  Java Treeview - extensible visualization of microarray data , 2004, Bioinform..

[33]  Ruo-Pan Huang Cytokine protein arrays. , 2004, Methods in molecular biology.

[34]  Satoru Miyano,et al.  Open source clustering software , 2004 .

[35]  John D. Storey,et al.  A network-based analysis of systemic inflammation in humans , 2005, Nature.

[36]  P. Lewczuk,et al.  Decline of immune responsiveness: a pathogenetic factor in Alzheimer's disease? , 2005, Journal of psychiatric research.

[37]  A. LeBlanc,et al.  The role of apoptotic pathways in Alzheimer's disease neurodegeneration and cell death. , 2005, Current Alzheimer research.

[38]  Bing Zhang,et al.  WebGestalt: an integrated system for exploring gene sets in various biological contexts , 2005, Nucleic Acids Res..

[39]  P. Grammas,et al.  Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: implications for disease pathogenesis. , 2006, Journal of Alzheimer's disease : JAD.

[40]  J. Julien,et al.  Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer's Disease , 2006, Neuron.

[41]  N. Bresolin,et al.  Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. , 2006, Archives of neurology.

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

[43]  K. Blennow,et al.  Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study , 2006, The Lancet Neurology.

[44]  Kiyoko F. Aoki-Kinoshita,et al.  From genomics to chemical genomics: new developments in KEGG , 2005, Nucleic Acids Res..

[45]  Hyman M. Schipper,et al.  Transcriptional profiling of Alzheimer blood mononuclear cells by microarray , 2007, Neurobiology of Aging.

[46]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[47]  J. Fries,et al.  Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines , 2006, Annals of the rheumatic diseases.

[48]  Bruce L. Miller,et al.  Appendix B: Practice parameter: Diagnosis of dementia (an evidence-based review): Report of the quality standards subcommittee of the American academy neurology , 2007 .

[49]  J. Growdon,et al.  Molecular markers of early Parkinson's disease based on gene expression in blood , 2007, Proceedings of the National Academy of Sciences.

[50]  T. Wyss-Coray,et al.  Systemic and acquired immune responses in Alzheimer's disease. , 2007, International review of neurobiology.