Challenges in Alzheimer's Disease Diagnostic Work-Up: Amyloid Biomarker Incongruences.

ABSTRACT

BACKGROUND: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. OBJECTIVES: 1) To verify that cerebrospinal fluid (CSF) Aß42/Aß40 ratio (AßR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aß42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AßR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. METHOD: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. RESULTS: CSF AßR better agreed with Amy-PET compared to CSF Aß42 (Cohen's K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AßR values and negative Amy-PET (CSF AßR+/AmyPET-). FDG-PET and all CSF markers (Aß42, AßR, p-Tau, t-Tau) were suggestive of Alzheimer's disease (AD) in 5 of these 6 cases. CONCLUSION: 1) CSF AßR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAßR+/Amy-PET-discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AßR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD.