Abstract
BackgroundToday, 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.Methods and FindingsCerebrospinal 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 phospho181-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.ConclusionsThe 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.
Highlights
In an aging population dementias are a serious threat
The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient Alzheimer’s disease (AD) in patients suffering from mild cognitive impairment (MCI)
Different new analytical proteomic technologies like mass spectrometry coupled with protein separation or protein microarrays that can be applied on cerebrospinal fluid (CSF) have been developed to study proteins in neuroscience [7]
Summary
In an aging population dementias are a serious threat. Currently 30 million people worldwide suffer from Alzheimer’s disease (AD) and the World Health organization projects that this number will triple over the 20 years [1]. An enormous wealth of information regarding pathological processes should be present in the less abundant CSF-proteins and the identification of changes in CSF composition at that level beside the current disease models would promote the understanding of the various dementias and their fundamental pathological processes. Such valid new biomarkers for AD could serve as surrogate markers in detecting treatment effects while any earlier identification of AD patients is another goal to enable the development of treatments that stop or postpone the disease processes. 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
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