Implementation and Assessment of Tau Thresholds in Non-Demented Individuals as Predictors of Cognitive Decline in Tau Imaging Studies

Article type: Research Article

Authors: Gogola, Alexandra^{a; *} | Cohen, Ann D.^{b; c} | Snitz, Beth^{c; d} | Minhas, Davneet^a | Tudorascu, Dana^{b; c} | Ikonomovic, Milos D.^{c; d; e} | Shaaban, C. Elizabeth^{c; f} | Doré, Vincent^{g; h} | Matan, Cristy^a | Bourgeat, Pierrick^h | Mason, N. Scott^a | Leuzy, Antoineⁱ | Aizenstein, Howard^{b; c} | Mathis, Chester A.^a | Lopez, Oscar L.^{c; d} | Lopresti, Brian J.^a | Villemagne, Victor L.^{b; c; g} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA | [b] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA | [c] Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA | [d] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA | [e] Geriatric Research Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA | [f] Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA | [g] Department of Molecular Imaging & Therapy, Austin Health, Melbourne, VIC, Australia | [h] Commonwealth Scientific and Industrial Research Organisation Health & Biosecurity, Melbourne, VIC, Australia | [i] Critical Path for Alzheimer’s Disease (CPAD) Consortium, Critical Path Institute, Tucson, AZ, USA

Correspondence: [*] Correspondence to: Alexandra Gogola, PET Facility, B-922 PUH, 200 Lothrop Street, Pittsburgh, PA 15213, USA. E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). The investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Tau accumulation in Alzheimer’s disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge. Objective:We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer’s disease where multiple levels of tau positivity are used to stage participants. Methods:18F-flortaucipir scans from 301 non-demented participants were processed and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging. Results:The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints. Conclusions:When using 18F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework.

Keywords: Alzheimer’s disease, ¹⁸F-flortaucipir, PET, tau

DOI: 10.3233/JAD-240543

Journal: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S75-S92, 2024