Distinct amyloid and tau PET signatures are associated with diverging clinical and imaging trajectories in patients with amnestic syndrome of the hippocampal type

Abstract

We aimed to investigate the amyloid and tau PET imaging signatures of patients with amnestic syndrome of the hippocampal type (ASHT) and study their clinical and imaging progression according to their initial PET imaging status. Thirty-six patients with a progressive ASHT and 30 controls underwent a complete neuropsychological assessment, 3 T brain MRI, [¹¹C]-PiB and [¹⁸F]-Flortaucipir PET imaging. Subjects were clinically followed-up annually over 2 years, with a second 3 T MRI (n = 27 ASHT patients, n = 28 controls) and tau-PET (n = 20 ASHT patients) at the last visit. At baseline, in accordance with the recent biological definition of Alzheimer's disease (AD), the AD PET signature was defined as the combination of (i) positive cortical amyloid load, and (ii) increased tau tracer binding in the entorhinal cortices and at least one of the following regions: amygdala, parahippocampal gyri, fusiform gyri. Patients who did not meet these criteria were considered to have a non-AD pathology (SNAP). Twenty-one patients were classified as AD and 15 as SNAP. We found a circumscribed tau tracer retention in the entorhinal cortices and/or amygdala in 5 amyloid-negative SNAP patients. At baseline, the SNAP patients were older and had lower ApoE ε4 allele frequency than the AD patients, but both groups did not differ regarding the neuropsychological testing and medial temporal lobe atrophy. During the 2-year follow-up, the episodic memory and language decline, as well as the temporo-parietal atrophy progression, were more pronounced in the AD sub-group, while the SNAP patients had a more pronounced progression of atrophy in the frontal lobes. Longitudinal tau tracer binding increased in AD patients but remained stable in SNAP patients. At baseline, distinct amyloid and tau PET signatures differentiated early AD and SNAP patients despite identical cognitive profiles characterized by an isolated ASHT and a similar degree of medial temporal atrophy. During the longitudinal follow-up, AD and SNAP patients diverged regarding clinical and imaging progression. Among SNAP patients, tau PET imaging could detect a tauopathy restricted to the medial temporal lobes, which was possibly explained by primary age-related tauopathy.