Reproducibility of Alzheimer’s Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions

Abstract

Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer’s disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Aβ42, p < 0.001), 0.5739 (Aβ40, p < 0.001), and 0.4308 (Aβ42/40, p < 0.001). However, the diagnostic classifications of the Aβ42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40, instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure.

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…The superior performance of these ratios may be due to several reasons. Aβ42 in ratio with Aβ40 appears to compensate for between laboratory variations in the way CSF is processed [ 27 , 199 ] and also for interindividual differences in Aβ production levels [ 200 , 201 ]. The superiority of Aβ42 in ratio with either P-tau or T-tau may be due to the combination of two different pathological processes into one measure [ 26 ].…”

Higher Level of Mismatch in APOEε4 Carriers for Amyloid-Beta Peptide Alzheimer’s Disease Biomarkers in Cerebrospinal Fluid

“…Within the biomaterial bank of the Department of Psychiatry and Psychotherapy of the University Medical Center Goettingen, we identified 126 samples from patients between 45 and 90 years where AD-relevant CSF biomarkers were measured in two independent, clinically certified laboratories during routine clinical diagnostic procedures, as described recently (Vogelgsang et al., 2018). CSF biomarkers were measured according to the local standard operating procedures (SOPs), and both laboratories were not informed prior to the study to ensure routine procedures were maintained.…”

“…We have recently shown that CSF biomarkers measured in different clinically validated and certified laboratories are interpreted discordantly in up to 31.5% of cases for Aβ 42 (Vogelgsang et al., 2018), whereas Aβ 42/40 seems to be less prone to pre-analytical factors (Gervaise-Henry et al., 2017). It is not clear whether these findings are caused by pre-analytical or analytical interferences.…”

S1 guidelines “lumbar puncture and cerebrospinal fluid analysis” (abridged and translated version)

“…Several studies have shown that the concentration ratio of Aβ1-42 to Aβ1-40 (Aβ1-42/1-40) [ 192 ] shows much better correlation with prognosis of the development of dementia, compares better with amyloid β-PET, and correlates better with postmortem validation than Aβ1-42. Therefore, it is recommended to use the Aβ42/40 ratio instead of Aβ1-42 alone [ 11 , 12 , 41 , 106 , 108 , 129 , 181 ].…”