Validation of amyloid-β peptides in CSF diagnosis of neurodegenerative dementias

Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-β (Aβ) peptide patterns, using the quantitative Aβ-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Aβ1-38. The main outcome measures were a striking decrease of Aβ1-42 in AD (P=7.4 × 10−19), and most interestingly a pronounced decrease of Aβ1-38 in FTD (P=9.6 × 10−7). Moreover, a novel peptide that most probably represents an oxidized α-helical form of Aβ1-40 (Aβ1-40ox) displayed a highly significant increase in DLB (P=3.7 × 10−3) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Aβ peptide abundances (Aβ1-X%) was clearly superior to absolute CSF Aβ levels. Aβ1-42% and Aβ1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Aβ1-40ox% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Aβ1-38 levels as measured by the Aβ-SDS-PAGE/immunoblot and MSD, respectively. CSF Aβ peptides may reflect disease-specific impact of distinct neurodegenerative processes on Aβ peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.