Validation of amyloid-beta 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-beta (Ab) peptide patterns, using the quantitative A beta-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on A beta 1-38. The main outcome measures were a striking decrease of A beta 1-42 in AD ( P = 7.4 x 10(-19)), and most interestingly a pronounced decrease of A beta 1-38 in FTD ( P = 9.6 x 1 0(-7)). Moreover, a novel peptide that most probably represents an oxidized alpha-helical form of A beta 1-40 (A beta 1-40(ox)) displayed a highly significant increase in DLB ( P = 3.7 x 10(-3)) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Ab peptide abundances (A beta 1-X%) was clearly superior to absolute CSF Ab levels. A beta 1-42% and A beta 1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. A beta 1-40(ox)% 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 A beta 1-38 levels as measured by the A beta-SDS-PAGE/immunoblot and MSD, respectively. CSF A beta peptides may reflect disease-specific impact of distinct neurodegenerative processes on A beta peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.