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 (Abeta) peptides, such as Abeta1-42. Absolute Abeta1-42 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 Abeta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide pattern of the carboxy-terminally truncated Abeta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the Abeta-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 Abeta 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 Abeta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases--Alzheimer's disease, DLB and PDD. The Abeta peptide patterns displayed disease-specific variations and the ratio of the differentially altered Abeta1-42 to the Abeta1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Abeta-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 Abeta1-40 (Abeta1-40*). The increased abundance of Abeta1-40* probably reflects a disease-specific alteration of the Abeta1-40 metabolism in DLB. We conclude that Abeta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Abeta 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.
Bibl
Mirko
M
Department of Psychiatry, University of Goettingen, Goettingen, Germany.
Mollenhauer
Brit
B
Esselmann
Hermann
H
Lewczuk
Piotr
P
Klafki
Hans-Wolfgang
HW
Sparbier
Katrin
K
Smirnov
Alexandr
A
Cepek
Lukas
L
Trenkwalder
Claudia
C
Rüther
Eckart
E
Kornhuber
Johannes
J
Otto
Markus
M
Wiltfang
Jens
J
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003704:Dementia / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000209:etiology; D003937:Diagnosis, Differential; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; D015415:Biomarkers