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

Article type: Research Article

Authors: Lombardi, Gemma^{a; b; *} | Pupi, Alberto^b | Bessi, Valentina^c | Polito, Cristina^d | Padiglioni, Sonia^a | Ferrari, Camilla^a | Lucidi, Giulia^e | Berti, Valentina^d | De Cristofaro, Maria Teresa^f | Piaceri, Irene^a | Bagnoli, Silvia^a | Nacmias, Benedetta^{a; e} | Sorbi, Sandro^{a; e}

Affiliations: [a] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy | [b] Fondazione Filippo Turati, Pistoia, Italy | [c] Neurology Unit AOU Careggi, Florence, Italy | [d] Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Nuclear Medicine Unit, University of Florence, Florence, Italy | [e] Fondazione IRCCS Don Carlo Gnocchi, Florence, Italy | [f] Nuclear Medicine Unit, AOU Careggi, Florence, Italy

Correspondence: [*] Correspondence to: Dr. Gemma Lombardi, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Tel.: +39 055 7948910; Fax: +390552758265; E-mail: [email protected].

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) Aβ42/Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR 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 AβR better agreed with Amy-PET compared to CSF Aβ42 (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 AβR values and negative Amy-PET (CSF AβR+/AmyPET–). FDG-PET and all CSF markers (Aβ42, AβR, p-Tau, t-Tau) were suggestive of Alzheimer’s disease (AD) in 5 of these 6 cases. Conclusion:1) CSF AβR 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 CSFAβR+/Amy-PET–discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR 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.

Keywords: Aging, Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, diagnosis, PET scan

DOI: 10.3233/JAD-200119

Journal: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 203-217, 2020