Highly conserved and disease‐specific patterns of carboxyterminally truncated Aβ peptides 1–37/38/39 in addition to 1–40/42 in Alzheimer's disease and in patients with chronic neuroinflammation

Wiltfang, Jens; Esselmann, Hermann; Bibl, Mirko; Smirnov, Alexandr; Otto, Markus; Paul, Sabine; Schmidt, Bernhard; Klafki, Hans-Wolfgang; Maler, Manuel; Dyrks, Thomas; Bienert, Michael; Beyermann, Michael; Rüther, Eckart; Kornhuber, Johannes

doi:10.1046/j.1471-4159.2002.00818.x

Cited by 253 publications

(330 citation statements)

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“…Aβ peptide patterns were analysed by Aβ-SDS–PAGE/immunoblot (Wiltfang et al ., 2002) in the CSF of patients with Alzheimer's disease, DLB, PDD and non-demented disease controls (NDC). A total of 88 patients were divided into four diagnostic groups according to their clinical diagnosis and tested for significant differences in absolute and relative Aβ peptide values.…”

Section: Methodsmentioning

confidence: 99%

“…Pre-analytical concentration of CSF by immunoprecipitation (IP) was performed as recorded previously (Wiltfang et al ., 2002). The amino-terminal-selective mouse monoclonal antibodies 6E10 (Senetec Drug Delivery Technologies Inc, USA) and 1E8 were used in comparison with the carboxy-terminal-selective 13E9 and 6D5 directed against the carboxy-terminus of Aβ1–40 and Aβ1–42, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…For separation of Aβ peptides and subsequent detection, 10 μl of unconcentrated CSF was boiled in a sample buffer for SDS–PAGE, and Aβ-SDS–PAGE/immunoblot was conducted as published elsewhere (Wiltfang et al ., 1997, 2002). …”

Section: Methodsmentioning

confidence: 99%

“…The inter- and intra-assay coefficients of variation and sensitivity of detection of the Aβ-SDS–PAGE/immunoblot have been published elsewhere (Wiltfang et al ., 2002; Bibl et al ., 2004). …”

Section: Methodsmentioning

confidence: 99%

“…This Aβ peptide pattern displayed disease-specific variations in its absolute and relative quantities in the CSF of patients with Alzheimer's disease, Creutzfeldt–Jakob disease (CJD), chronic inflammatory diseases and other neuropsychiatric diseases (Wiltfang et al ., 2002, 2003). …”

Section: Introductionmentioning

confidence: 99%

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

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

186

146

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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 (Aβ) peptides, such as Aβ1–42. Absolute Aβ1–42 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 Aβ-sodium-dodecylsulphate–polyacrylamide-gel-electrophoresis with Western immunoblot (Aβ-SDS–PAGE/immunoblot) revealed a highly conserved Aβ peptide pattern of the carboxy-terminally truncated Aβ peptides 1–37, 1–38, 1–39 in addition to 1–40 and 1–42 in human CSF. We used the Aβ-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 Aβ 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 Aβ peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases—Alzheimer's disease, DLB and PDD. The Aβ peptide patterns displayed disease-specific variations and the ratio of the differentially altered Aβ1–42 to the Aβ1–37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Aβ-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 α-helical form of Aβ1–40 (Aβ1–40*). The increased abundance of Aβ1–40* probably reflects a disease-specific alteration of the Aβ1–40 metabolism in DLB. We conclude that Aβ peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Aβ 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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

186

146

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CSF beta‐amyloid 1–42 – what are we measuring in Alzheimer's disease?

Watts

Shaw

et al. 2014

Ann Clin Transl Neurol

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ObjectiveTo characterize biological and technical factors which influence cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, including the presence of apolipoprotein E (APOE) ε4 allele, AD diagnosis, Aβ-binding proteins, sample processing, and preanalytical handling.MethodsCSF was collected from 140 subjects with normal cognition, mild cognitive impairment, AD, and non-AD dementia. CSF levels of beta-amyloid 1–42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) were analyzed following the standard and modified protocols. CSF levels of apoJ, apoE, albumin, and α-synuclein were measured in a subgroup (n = 69), and their effects on measured AD biomarker levels were also determined in vitro using human CSF samples.ResultsCSF Aβ42 levels measured using the AD Neuro-imaging Initiative (ADNI) protocol (which we call suspended Aβ42 or susAβ) were lower than total measurable CSF Aβ42 in all groups, and on average represents 57% of the latter. Logistic regression analysis showed this proportion (% susAβ) to be directly correlated with CSF Aβ42 and apoJ levels, but inversely correlated with CSF t-Tau levels. Finally, we showed in vitro that increasing apoE and apoJ levels directly increased % susAβ.ConclusionCSF susAβ levels are influenced by biological and technical factors, and may represent a marker of Aβ susceptible to lipoprotein-mediated clearance. Clinical trials should include total measurable Aβ42 and susAβ to better inform outcomes.

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Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease

Liu

Lauro

et al. 2022

Alzheimer's & Dementia

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Introduction: Identifying CSF-based biomarkers for the β-amyloidosis that initiatesAlzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. Methods:We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation. Results:We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and(3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD.Discussion: We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γsecretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD.

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Highly conserved and disease‐specific patterns of carboxyterminally truncated Aβ peptides 1–37/38/39 in addition to 1–40/42 in Alzheimer's disease and in patients with chronic neuroinflammation

Cited by 253 publications

References 79 publications

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

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

CSF beta‐amyloid 1–42 – what are we measuring in Alzheimer's disease?

Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease

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