CSF amyloid-beta-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (A beta) peptides, such as A beta 1-42. Absolute A beta 1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based A beta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (A beta-SDS-PAGE/immunoblot) revealed a highly conserved A beta peptide pattern of the carboxy-terminally truncated A beta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the A beta-SDS-PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the A beta peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of A beta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases-Alzheimer's disease, DLB and PDD. The A beta peptide patterns displayed disease-specific variations and the ratio of the differentially altered A beta 1-42 to the A beta 1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with A beta-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized alpha-helical form of A beta 1-40 (A beta 1-40( )). The increased abundance of A beta 1-40( ) probably reflects a disease-specific alteration of the A beta 1-40 metabolism in DLB. We conclude that A beta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although A beta peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.