Correction to: Cerebrospinal fluid amyloid-ß 2-42 is decreased in Alzheimer's, but not in frontotemporal dementia.

The respective first and last authors of this article, Mirko Bibl and Jens Wiltfang, would like to clarify the issue of the seeming duplicate publication of a figure in two articles.

Plasma amyloid-beta peptides in acute cerebral ischemia: a pilot study.

BACKGROUND: Blood-based tests for a rapid and valid diagnosis as well as outcome prognosis of acute stroke are desirable. Recently, plasma Aß40 was suggested as an independent cerebrovascular risk factor candidate. METHODS: We investigated eight plasma samples of patients with clinical signs of acute cerebral ischemia for derangements of plasma amyloid-beta (Aß) peptide patterns as compared to 13 patients with other neuropsychiatric diseases. For the analysis of plasma, we used immunoprecipitation followed by the quantitative Aß-SDS-PAGE/immunoblot. RESULTS: The major outcome was a striking decrease of Aß1-40 in plasma paralleled by an increase in the ratio of Aß1-38/Aß1-40 in two patients with acute stroke. Interestingly, these patients had an onset of symptoms within only 2-4 hr before venous puncture and there was a strong correlation of Aß1-38/Aß1-40 levels with the time span between onset of symptoms and venous puncture. CONCLUSION: From these results, we suggest the ratio of plasma Aß1-38/Aß1-40 as a possible biomarker for the early diagnosis of acute stroke.

Characterization of cerebrospinal fluid aminoterminally truncated and oxidized amyloid-ß peptides.

PURPOSE: Carboxyterminally elongated and aminoterminally truncated Aß peptides as well as their pyroglutamate and oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to characterize aminoterminally truncated or oxidized Aß38, Aß40, and Aß42 peptide species in immunoprecipitated human cerebrospinal fluid (CSF). EXPERIMENTAL DESIGN: We invented a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and used the Aß-SDS-PAGE/immunoblot for subsequent analysis of CSF Aß peptide patterns. RESULTS: In the present study, we identified the aminoterminally truncated Aß peptides 2-40 and 2-42 as well as oxidized forms of Aß1-38 and Aß1-42 in CSF. Our protocol allowed the quantification of a pattern of Aß peptides 1-38(ox), 2-40, and 2-42 in addition to the well known panel of Aß 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1-42 in a group of seven patients with peripheral polyneuropathy. CONCLUSIONS AND CLINICAL RELEVANCE: In the present approach, we could broaden the range of quantifiable Aß peptides described in previous studies (i.e., 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1-42) by Aß 1-38(ox), 2-40, and 2-42. An exact analysis of CSF Aß peptides regarding their carboxy- and aminoterminus as well as posttranslational modification seems promising with respect to diagnostic and pathogenic aspects.

Cerebrospinal fluid amyloid-ß 2-42 is decreased in Alzheimer's, but not in frontotemporal dementia.

Alzheimer's dementia (AD) and frontotemporal dementias (FTD) are common and their clinical differential diagnosis may be complicated by overlapping symptoms, which is why biomarkers may have an important role to play. Cerebrospinal fluids (CSF) Aß2-42 and 1-42 have been shown to be similarly decreased in AD, but 1-42 did not display sufficient specificity for exclusion of other dementias from AD. The objective of the present study was to clarify the diagnostic value of Aß2-42 peptides for the differential diagnosis of AD from FTD. For this purpose, 20 non-demented disease controls (NDC), 22 patients with AD and 17 with FTD were comparatively analysed by a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol with subsequent Aß-SDS-PAGE/immunoblot, allowing the quantification of peptides 1-38(ox), 2-40 and 2-42 along with Aß 1-37, 1-38, 1-39, 1-40, 1-40(ox) and 1-42. CSF Aß1-42 was decreased in AD as compared to NDC, but not to FTD. In a subgroup of the patients analyzed, the decrease of Abeta2-42 in AD was evident as compared to both NDC and FTD. Aß1-38 was decreased in FTD as compared to NDC and AD. For differentiating AD from FTD, Aß1-42 demonstrated sufficient diagnostic accuracies only when combined with Aß1-38. Aß2-42 yielded diagnostic accuracies of over 85 % as a single marker. These accuracy figures could be improved by combining Aß2-42 to Aß1-38. Aß2-42 seems to be a promising biomarker for differentiating AD from other degenerative dementias, such as FTD.

Aminoterminally truncated and oxidized amyloid-ß peptides in the cerebrospinal fluid of Alzheimer's disease patients.

Carboxyterminally elongated and aminoterminally truncated amyloid-ß (Aß) peptides and their oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to clarify the diagnostic impact of the Aß peptides 1-38ox, 2-40, and 2-42 peptides on the neurochemical cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD). For this purpose, 22 patients with AD and 20 non-demented disease controls (NDC) were comparatively analyzed for their cerebrospinal fluid pattern of Aß1-38ox, Aß2-40, and Aß2-42 along with Aß1-37, Aß1-38, Aß1-39, Aß1-40, Aß1-40ox, and Aß1-42 using a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and subsequent analysis in the Aß-SDS-PAGE/immunoblot. The Aß peptides 1-38ox, 2-40, and 2-42 could not be consistently detected in the investigated CSF samples, which applied to samples from AD and NDC patients alike. Otherwise, our approach revealed a striking decrease of Aß1-42 and Aß2-42, but not of Aß1-38ox and Aß2-40 in AD. Both Aß1-42 and Aß2-42 reached reasonable accuracies for diagnosing AD alone as well as in relation to Aß1-40, Aß1-38, or the sum of all measured Aß peptides. Aß1-38ox was negatively correlated to the Mini-Mental Status Examination score of AD patients, indicating that this peptide to linked to disease severity. We conclude that an exact analysis of CSF Aß peptides regarding their carboxy- and aminoterminus as well as posttranslational modification may be a promising approach for diagnosing and tracking AD.

Stability of amyloid-ß peptides in plasma and serum.

Plasma amyloid-ß peptide (Aß) levels have been suggested as a biomarker candidate for detecting incipient AD. Aß peptides are known to be sensitive to distinct preanalytical sample handling, which calls for standardised preanalytical procedures. We investigated serum and plasma samples of 19 patients with no clinical signs of dementia for different preanalytical sample handlings. Both serum and plasma were analysed by the one-dimensional Aß-SDS-PAGE/immunoblot, either immediately or after storage at room temperature for 24 and 48 h, respectively. The panel of Aß1-37/38/39/40/42 and Aß2-40 was evaluated. In both analytical matrices, sample storage led to a significant loss of measurable peptide levels. This effect was most pronounced during the first 24 h of storage and stronger in serum than in plasma. There were no significant differences between the distinct analysed Aß peptide species regarding these results. The ratios of peptides (e.g. Aß1-42/Aß1-40 and Aß1-42/Aß1-38) displayed a higher stability under the influence of storage than each single peptide. In conclusion, plasma may be more appropriate than serum for analysing Aß peptides for routine application. At least, the analysis should be done within 24 h and peptide ratios should be created to minimise artificial results.

Combined CSF tau, p-tau181 and amyloid-beta 38/40/42 for diagnosing Alzheimer's disease.

Cerebrospinal fluid (CSF) concentrations of amyloid-beta (Abeta) 1-38, 1-40, 1-42, total-tau and phospho-tau in samples from 156 patients with Alzheimer's disease (AD) (n = 44), depressive cognitive complainers (DCC, n = 25) and various other forms of non-Alzheimer dementias (NAD, n = 87) were analyzed by electrochemiluminescence and enzyme linked immunosorbent assay, respectively. A significant decrease of CSF Abeta1-42 was the most powerful single marker for differentiation of AD from DCC, yielding accuracies of beyond 85%. Increased p-tau and the ratio Abeta1-42/Abeta1-38 yielded accuracies of beyond 80 and 85%, respectively, to discriminate AD versus NAD. Combining p-tau with Abeta1-42/Abeta1-38 resulted in a sensitivity of 94% for detection of AD and 85% specificity for excluding NAD. Decreased CSF Abeta1-42 represents a core biomarker for AD. The lack of specificity for exclusion of NAD can be most effectively compensated by the ratio Abeta1-42/Abeta1-38. The ratio Abeta1-42/Abeta1-38/p-tau powerfully discriminates AD versus NAD and fulfils the accuracy requirements for an applicable screening and differential diagnostic AD biomarker.

Cerebrospinal fluid neurochemical phenotypes in vascular dementias: original data and mini-review.

BACKGROUND/AIMS: The study evaluated the patterns of cerebrospinal fluid (CSF), amyloid-beta (Abeta) peptides, total tau and phospho-tau among Alzheimer's disease (AD) and vascular dementias (VAD). METHODS: Abeta-SDS-PAGE immunoblot and commercially available ELISAs were applied to the CSF analysis of 52 patients with probable (n = 21) and possible (n = 16) VAD, AD with cerebrovascular disease (n = 15), 30 patients with probable AD and 30 nondemented disease controls. RESULTS: AD and AD with cerebrovascular disease displayed a similar neurochemical phenotype in contrast to nondemented disease controls and probable VAD with regard to tau, p-tau, Abeta1-40(ox) and Abeta1-42%. Possible VAD displayed AD-like changes only for Abeta1-40(ox) and Abeta1-42%. CONCLUSION: CSF neurochemical phenotypes sufficiently discriminate probable AD and VAD from each other, but their diagnostic value is limited in case of no clear-cut clinical appearance, such as possible VAD. Conversely, CSF Abeta peptides and p-tau levels may help estimate the involvement of AD-like pathophysiological pathways in VAD subgroups.

CSF amyloid-ß 1-38 and 1-42 in FTD and AD: Biomarker performance critically depends on the detergent accessible fraction.

Cerebrospinal fluid (CSF) Aß1-38, Aß1-40, and Aß1-42 were comparatively analyzed by amyloid-beta SDS-PAGE with Western immunoblot (Aß-SDS-PAGE/immunoblot), electrochemiluminescence detection and ELISA (MSD/ELISA) in patients with Alzheimer's disease (AD, n = 40), frontotemporal dementia (FTD, n = 30), and other dementias (n = 50) and nondemented disease controls (n = 30). CSF Aß-peptide concentrations were higher and selective decreases of CSF Aß1-38 in FTD and Aß1-42 in AD were more evident as measured after SDS-denaturizing of samples by Aß-SDS-PAGE/immunoblot. The SDS-accessible pool of CSF Aß1-38 and Aß1-42, represented by the individual gain of Aß-peptide yield using Aß-SDS-PAGE/immunoblot, was reduced in both FTD and AD. Accordingly, biomarker accuracies of Aß1-38 and Aß1-42 for detection of FTD and AD, respectively declined as determined by MSD/ELISA. We conclude that a pool of CSF Aß1-38 and Aß1-42, which shows disease-specific reductions in FTD and AD, may be bound to carriers and can be released by SDS. Assessing this SDS-accessible Aß-peptide pool may crucially enhance the accuracy of CSF biomarker tests. Identifying disease-specific binding properties of affected Aß carriers may elucidate pathogenic aspects and open up a novel field for therapeutic approaches.

Blood-based neurochemical diagnosis of vascular dementia: a pilot study.

Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.