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LETTER TO THE EDITOR |
Departments of 1 Neurology
2 Geriatric Medicine
3 Alzheimer Centre Nijmegen
4 Laboratory of Pediatrics and Neurology Radboud University Nijmegen Medical Centre The Netherlands
Address correspondence to Marcel M. Verbeek, MSc, PhD, Radboud University Nijmegen Medical Centre, Laboratory of Pediatrics and Neurology (830 LKN), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: m.verbeek{at}cukz.umcn.nl
To the Editor:
We thank Dr. Le Bastard and colleagues for their interest in our study, and their additional investigations based on our findings. Similar to our study (1), they calculated the ratio of cerebrospinal fluid (CSF) levels of amyloid ß42 and tau phosphorylated at threonine 181 (Q Aß42/p-tau181) in patients with Alzheimer's disease (AD), and vascular dementia (VaD). These diagnoses were established after post mortem examination, which is an important addition to our study in which we used a clinical diagnosis. In contrast to our findings, they found unexpectedly low specificity levels (38% to 52%) when applying our proposed Q Aß42/p-tau181 cutoff levels to differentiate between AD and VaD. This discrepancy thus needs further attention and clarification.
Critical review of the data provided by Le Bastard and colleagues revealed several striking findings. Mean CSF Aß42 levels were lower in both AD and VaD patients compared to our study (Table 1), and compared to other studies using the same methods (2–5). Furthermore, the minimum CSF Aß42 concentration they reported was 67 pg/ml in the AD group, and 46 pg/ml in the VaD group, which is surprisingly low since the analytical range of the enzyme-linked immunosorbent assay (ELISA) was reported to be 125–2000 pg/ml. There are a few possible explanations for the low CSF Aß42 levels. First, the method of storage of CSF samples: It is recommended to store CSF samples at –80 °C, and it is known that in CSF samples stored at 4°C, Aß42 decreases by approximately 20% during the first 2 days compared with the baseline value (–80 °C) (6). The authors stored their CSF samples at a higher temperature (–20°C or lower) than recommended. Second, the type of test tubes used to collect and store CSF: The authors provided no information about the material of which the test tubes were produced, although previous investigations have shown that this affects results, particularly those of Aß42. When CSF is collected in glass or polystyrene tubes, the measured concentration of Aß42 decreases. Therefore, nonadsorbing plastic (polypropylene) tubes should be used (7).
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As a result of the above-mentioned discrepancies, the outcome of the calculations of Q Aß42/p-tau181, sensitivity, and specificity were also different, and our proposed cutoff levels could not be applied. Therefore, although we acknowledge the importance of autopsy confirmation of clinical studies, we encourage that investigators take great care in the preanalytical and analytical conditions required for optimal CSF analysis of Aß42, and p-tau181. Furthermore, the diagnosis of patients with out-of-range levels of CSF biomarkers should be carefully reevaluated.
References
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