Abstract
In the diagnosis of Alzheimer’s disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha β-amyloid (Aβ) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several “confounding” factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient’s variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV<20%, AUC>0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p<0.01) of Apo A-1 levels in AD, together with a specific dysregulation of Apo A-1 proteoforms was observed. The profiling of CSF and serum of the same patients, suggests that the decrement of total Apo A-1 occurs specifically in CSF. Serum and CSF of AD shows a characteristic Apo A-1 proteoform pattern suggesting it as potential marker which can support the clinical workflow adopted for AD diagnosis and progression.
Highlights
Dementia is one of the biggest global public health challenges facing our generation
Idiopathic normal-pressure hydrocephalus were selected as possible reference. These patients are characterized by reversible symptoms of dementia related to an increased production of cerebrospinal fluid (CSF) leading to a pressure overload causing transient symptoms [28]
CSF followed by MALDI profiling has been utilized as preliminary screening to identify peptides or proteoforms associated to Alzheimer’s disease (AD), to supplement the panel of already existing biomarkers to improve diagnostic sensitivity and accuracy
Summary
Dementia is one of the biggest global public health challenges facing our generation. Total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 aminoacid isoform of alpha β-amyloid (Aβ42) dysregulated levels are a characteristic of AD patients and are used to support clinical diagnosis Their concentration depends on several “confounding” factors related to pre-analytical variables like sample collection modality, material of diagnostic tubes, CSF handling and storage. Beside the principal aim of identifying new candidates for AD diagnosis and monitoring, this study deals with the intra and inter-individual variability and the low sample number availability This was addressed by performing the proteome profiling of low molecular weight proteins for CSF and low abundant low molecular weight proteins for serum to detect discrepancies of specific proteoforms [6] between blood and CSF in AD patients compared to controls. Patient clusterization was based on tau, p-tau, and Aβ levels
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