Neurochemical diagnosis of Alzheimer’s dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau

Lewczuk, Piotr; Esselmann, Hermann; Otto, Markus; Maler, Juan Manuel; Henkel, Andreas; Henkel, Maria Kerstin; Eikenberg, Oliver; Antz, Christof; Krause, Wolf-Rainer; Reulbach, Udo; Kornhuber, Johannes; Wiltfang, Jens

doi:10.1016/s0197-4580(03)00086-1

Cited by 280 publications

(248 citation statements)

References 25 publications

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“…Thus, the actual differential diagnostic value of Aβ peptide patterns can be considered to be as relevant as the established ELISAs for tau and Aβ1–42. Moreover, since multiparametric approaches are gaining increasing importance in the early and differential diagnosis of dementias (Lewczuk et al ., 2004; Wiltfang et al ., 2005), the evaluation of Aβ peptide patterns may aid neurochemical dementia diagnosis in combination with other biomarkers (e.g. tau and phospho-tau) (Wiltfang et al ., 2005).…”

Section: Discussionmentioning

confidence: 99%

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

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

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186

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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: Discussionmentioning

confidence: 99%

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

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

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186

146

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“…The early AD group fulfilled the NINCDS-ADRDA criteria for probable AD and the diagnosis was supported by cerebrospinal fluid (CSF)-based neurochemical dementia diagnostics using commercially available enzyme-linked immunosorbent assay kits to assess Ab1-40, Ab1-42, tau and phospho-tau proteins (The Genetics Company, Zurich, Switzerland; Innogenetics, Ghent, Belgium). 10,11 Spouses or caregivers served as non-demented age, sex and environmentally matched controls.…”

Section: Methodsmentioning

confidence: 99%

Decreased circulating CD34+ stem cells in early Alzheimer's disease: evidence for a deficient hematopoietic brain support?

et al. 2006

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Hematopoietic stem cells contribute to mammalian brain tissue regeneration by transdifferentiation processes. We found decreased counts of circulating CD34 þ cells in early Alzheimer's dementia (AD; P = 0.01), which significantly correlated with age (r = À0.661; P = 0.001), cerebrospinal fluid b-amyloid (Ab)1-42 (r = À0.467; P = 0.025) and most pronounced the Ab42/40 ratio (r = À0.688; P = 0.005). Our data suggest a deficient regenerative hematopoietic support for the central nervous system in early AD.

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“…In the second categorization, patients were divided according to the neurochemical findings in the CSF: the group with pathologic results of neurochemical dementia diagnosis (NDD þ ; n = 103) characterized by decreased CSF amyloidb (Ab) x-42/x-40 concentration ratio (Ab ratio; cutoff, 0.11 21 ) accompanied by increased CSF concentration of phospho-Tau181 (pTau181; cutoff 70 pg ml À1 ), and the group with normal results of neurochemical dementia diagnosis (NDDÀ; n = 48) characterizing with normal amyloidb ratio (that is higher than 0.11) accompanied by normal pTau181 (below 50 pg ml À1 ). Note that n = 37 patients with 'borderline' CSF pTau181 concentration (50-70 pg ml À1 ) were not considered for this categorization.…”

Section: Patients and Lumbar Puncturesmentioning

confidence: 99%

“…21,23 Briefly, with the assay of the Genetics Co. (Zü rich, Switzerland) Abx-42 peptide was measured, as the capturing antibody of this assay is not N terminus specific, and with the assay of Innogenetics (Ghent, Belgium), Ab1-42 peptide was measured, as the capturing antibody of this assay shows N terminus specificity. In both assays, the detecting antibodies are specific for the position 42.…”

Section: Assaysmentioning

confidence: 99%

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

et al. 2008

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In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins a and b (sAPPa and sAPPb) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examinationX20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloidb peptides, Tau and phospho-Tau. sAPPa and sAPPb were measured with multiplexing method based on electrochemiluminescence. sAPPa and sAPPb CSF concentrations correlated with each other with very high correlation ratio (R = 0.96, P < 0.001). We observed highly significantly increased sAPPa and sAPPb CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPPa and sAPPb highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPPa: cutoff, 117.4 ng ml À1 , sensitivity, 68%, specificity, 85%, P < 0.001; sAPPb: cutoff, 181.8 ng ml À1 , sensitivity, 75%, specificity, 85%, P < 0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPPa and sAPPb might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

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Neurochemical diagnosis of Alzheimer’s dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau

Cited by 280 publications

References 25 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

Decreased circulating CD34+ stem cells in early Alzheimer's disease: evidence for a deficient hematopoietic brain support?

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

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