Brain Advance Access originally published online on April 6, 2006
Brain 2006 129(5):1177-1187; doi:10.1093/brain/awl063
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CSF amyloid-ß-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia
1 Department of Psychiatry, University of Goettingen, Goettingen, 2 Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, 3 Bruker Daltronics, Leipzig, 4 Paracelsus-Elena Klinik, Kassel, 5 Department of Neurology, University of Ulm, Steinhövelstr, Ulm, Germany and 6 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Correspondence to: Professor Dr Jens Wiltfang, Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany E-mail: Jens.Wiltfang{at}psych.imed.uni-erlangen.de
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 (Aß) peptides, such as Aß1–42. Absolute Aß1–42 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 Aß-sodium-dodecylsulphate–polyacrylamide-gel-electrophoresis with Western immunoblot (Aß-SDS–PAGE/immunoblot) revealed a highly conserved Aß peptide pattern of the carboxy-terminally truncated Aß peptides 1–37, 1–38, 1–39 in addition to 1–40 and 1–42 in human CSF. We used the Aß-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 Aß 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 Aß peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases—Alzheimer's disease, DLB and PDD. The Aß peptide patterns displayed disease-specific variations and the ratio of the differentially altered Aß1–42 to the Aß1–37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Aß-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 
-helical form of Aß1–40 (Aß1–40*). The increased abundance of Aß1–40* probably reflects a disease-specific alteration of the Aß1–40 metabolism in DLB. We conclude that Aß peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Aß 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.
Key Words: Alzheimer's dementia; Lewy-body dementia; Parkinson's disease dementia; cerebrospinal fluid; amyloid-ß peptides
Abbreviations: Aß peptides = amyloid-beta peptides; Aß-SDS–PAGE/immunoblot = amyloid-beta-sodium-dodecyl-sulphate–polyacrylamide-gel-electrophoresis with Western immunoblot; APP = beta-amyloid precursor protein; bicine = N,N'-bis-[2-hydroxyethyl]glycine; C% = percentage of N,N'methylenebisacrylamide (bis) of the total of bis plus acrylamide; DLB = dementia with Lewy bodies; IP = immunoprecipitation; IPG = immobilized pH gradients; MALDI–TOF = matrix-assisted laser desorption ionization mass analysis–time-of-flight modus; MMSE = Mini-Mental-Status Examination; NINCDS–ADRDA = National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association; ND = non-demented; PDD: Parkinson's disease dementia; SKT = Syndrom-Kurz-Test; SPE = solid-phase extraction; T% = percentage of acrylamide of the total of bis plus acrylamide
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Received March 30, 2005. Revised February 14, 2006. Accepted February 20, 2006.
* These authors contributed equally to this work.
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