Neurochemical diagnosis of Alzheimer’s dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau
Introduction
Alzheimer’s disease (AD) is the major cause of memory impairment and dementia in the elderly, and is one of the most severe causes of health problems in this group. Meanwhile, the advent of new therapeutic avenues call for an improved early and differential diagnosis of AD. Since cerebrospinal fluid (CSF) is in direct contact with the central nervous system (CNS), several potentially promising CSF biomarkers have been tested alone or in combinations [4], [24].
Among these biomarkers, amyloid β peptides (Aβ peptides) and tau protein(s) fulfill the criteria for good AD diagnostic tests, as recently summarized by an expert review [1]. This is not surprising since these factors are directly involved in pathologic events of the disease, namely deposition of senile plaques and formation of neurofibrillary tangles. CSF concentration of amyloid β peptide ending at amino acid position 42 (Aβ42) was reported to be decreased in AD [8], [20], [25], [26], and reports have been published demonstrating that a combination of Aβ42 and tau protein can increase the accuracy of the neurochemical diagnosis of AD [3], [6], [8]. Interestingly, although the concentration of another amyloid β peptide species, Aβ40, was reported to be unaltered in AD, the ratio of Aβ42 to Aβ40 was suggested to be superior to the concentration of Aβ42 alone in discriminating patients with AD [21]. This effect was even more prominent for a recently published quantitative Aβ-SDS-PAGE/immunoblot [26].
In the present study, we used receiver operating characteristic (ROC) analysis to compare sensitivities, specificities and percentages of correctly classified patients for Aβ42 as compared to the ratio Aβ42/Aβ40, investigating patients with AD, other types of dementia (nAD) and controls. Moreover, we determined whether the combination of the Aβ peptide ratio 42/40 and the concentration of total tau (tTau) protein in the CSF further improved the percentage of correctly classified patients. Since possessing the apolipoprotein E allele ε4 (ApoE ε4) is a major risk factor of AD and the presence of ε4 was shown to influence the CSF concentration of Aβ42 [6], [8], [26], evaluation of our results was performed with regard to the ApoE ε4 allele of the patients.
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Patients
The study was approved by the ethics committee of the University of Goettingen. All patients gave their informed consent. CSF was obtained from all patients by a lumbar puncture as a part of a routine diagnostic procedure. CSF was aliquoted, immediately frozen and stored at −80 °C until assay. The demographic data of subjects are presented in Table 1. The following groups of patients were investigated:
The group of AD patients (n=22) consisted of patients diagnosed according to the criteria of
CSF Aβ peptides and tTau
The concentrations of Aβ42, Aβ40 and tTau protein in the CSF as well as the percentage ratio of the two Aβ peptides are presented in Fig. 1. The concentration of Aβ42 was significantly lower in the AD group (370.5, 296–447 pg/ml) as compared to the controls (865, 599–1111 pg/ml, P<0.001) as well as to nAD (650, 508–1223 pg/ml, P<0.001).
Similarly to Aβ42 concentration, the Aβ42/Aβ40 ratio was significantly decreased in AD (6.37, 5.29–8.45) compared to the controls (14.26, 11.71–15.98, P<0.001) and
Discussion
In this study, we compared the power of the CSF Aβ42 concentration and the Aβ peptide ratio to distinguish patients with AD from subjects with other dementias and controls. Our results indicate that the value of Aβ peptide ratio is slightly increased as compared to the Aβ42 alone for the neurochemical diagnosis of AD, however, this effect fails the level of significance. The accuracy of neurochemical dementia diagnosis was further improved when we combined the two Aβ biomarkers and tTau.
The
Acknowledgements
The authors gratefully acknowledge routine CSF/serum analysis and tTau measurements performed in Neurochemistry Laboratory, University of Goettingen (Head, Professor Dr. H. Reiber).
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