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

Abstract

IntroductionIn 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).MethodsThirty-eight community-recruited cognitively intact older adults (mean age 73, range 65–80 years) underwent 18F-flutemetamol PET and CSF measurement of Aβ1-42, Aβ1-40, Aβ1-38, and total tau (ttau). 18F-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 18F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %.ResultsSeven 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).ConclusionFor 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.

Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer’s Disease

“…This discrepancy is likely due to the differences in the cohorts (higher numbers of cognitively normal individuals expected to be in the preclinical period in the current cohort) and/or different methodological issues. Another study reported no significant differences in concordances between Aβ 42/40 and Aβ 42 with amyloid PET, although the AUC for Aβ 42/40 was slightly larger than that for Aβ 42 alone [37]. This lack of significance might be attributed to the lower statistical power (a much smaller cohort, n  = 38) and/or the use of different ELISAs and PET tracer ( 18 F-flutemetamol) in that study.…”

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

“…The cut‐off for CSF Aβ 1–42 to predict amyloid‐PET positivity was 745 pg/mL and was previously defined on the same cohort (Adamczuk et al . ). The CSF Aβ 1–42 cut‐off of 745 pg/mL was derived by calculating the area under the curve in a receiver operating characteristics approach for which the Youden criterium was applied to select the optimal cut‐off, i.e.…”

“…the best compromise between high sensitivity and high specificity (area under the curve: 0.908, 100% sensitivity and 74.19% specificity) (Adamczuk et al . ). The standard of truth for the receiver operating characteristics analysis in that study was amyloid‐positivity based on an autopsy validated amyloid‐PET SUVRcomp cut‐off of 1.57 (Adamczuk et al .…”

“…The standard of truth for the receiver operating characteristics analysis in that study was amyloid‐positivity based on an autopsy validated amyloid‐PET SUVRcomp cut‐off of 1.57 (Adamczuk et al . ).…”

“…1). This CSF cohort (n = 38) is identical to that from a previous study comparing CSF AD biomarkers and [ 18 F]-flutemetamol (Adamczuk et al 2015). All participants are currently receiving a 2 yearly neuropsychological assessment for a 10 years period.…”