title: Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.
abstract: BACKGROUND
  Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD.
  
  
  RESULTS
  Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181)-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A.
  
  
  CONCLUSIONS
  The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.
authors: Department of Psychiatry, University Hospital Hamburg-Eppendorf, Hamburg, Germany. jahn@uke.uni-hamburg.de
authors: Holger
authors: H
authors: Jahn
authors: Stefan
authors: S
authors: Wittke
authors: Petra
authors: P
authors: Zürbig
authors: Thomas J
authors: TJ
authors: Raedler
authors: Sönke
authors: S
authors: Arlt
authors: Markus
authors: M
authors: Kellmann
authors: William
authors: W
authors: Mullen
authors: Martin
authors: M
authors: Eichenlaub
authors: Harald
authors: H
authors: Mischak
authors: Klaus
authors: K
authors: Wiedemann
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D001185:Artificial Intelligence; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D019075:Electrophoresis, Capillary; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis*; D010449:Peptide Mapping; D040901:Proteomics / Q000379:methods; D012680:Sensitivity and Specificity; D013569:Synapses / Q000737:chemistry*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D009419:Nerve Tissue Proteins