Diagnostic value of cerebrospinal fluid Aβ ratios in preclinical Alzheimer's disease

Katarzyna Adamczuk, Jolien Schaeverbeke, Hugo M J Vanderstichele, Johan Lilja, Natalie Nelissen, Koen Van Laere, Patrick Dupont, Kelly Hilven, Koen Poesen, Rik Vandenberghe, Katarzyna Adamczuk, Jolien Schaeverbeke, Hugo M J Vanderstichele, Johan Lilja, Natalie Nelissen, Koen Van Laere, Patrick Dupont, Kelly Hilven, Koen Poesen, Rik Vandenberghe

Abstract

Introduction: In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aβ ratios rather than Aβ42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET).

Methods: Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of Aβ1-42, Aβ1-40, Aβ1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %.

Results: Seven out of 38 subjects (18 %) were positive on amyloid PET. Aβ42/ttau, Aβ42/Aβ40, Aβ42/Aβ38, and Aβ42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aβ40 and Aβ38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aβ42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aβ42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively).

Conclusion: For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aβ42/ttau rather than using Aβ42 in isolation.

Figures

Fig. 1
Fig. 1
Distribution of 18F-flutemetamol SUVRcomp values and ROCs for different CSF analytes. a Distribution of 18F-flutemetamol SUVRcomp values according to age, sex, and APOE genotype. Solid line 1.57 SUVRcomp cutoff value; dashed line 1.57 SUVRcomp cutoff value ±1.5 % corresponding to a test–retest variability for SUVRcomp [20] (1.594 and 1.547). b ROCs for different CSF analytes, with 18F-flutemetamol positivity as classifier. Dots optimal cutoff values for each analyte, corresponding to the highest Youden index. Aβ Amyloid beta, SUVRcomp standardized uptake value ratios in composite cortical region, ttau total tau
Fig. 2
Fig. 2
Associations between the different CSF analytes and 18F-flutemetamol SUVRcomp. Black lines fitting of the model, shown only for the significant correlations. Aβ Amyloid beta, SUVRcomp standardized uptake value ratios in composite cortical region, ttau total tau

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