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.
Highlights
Progressive amnesia is the core feature of typical Alzheimer’s disease (AD) and can be assessed by different tests of episodic memory
Thirty-six patients with amnestic syndrome of the hippocampal type (ASHT) were enrolled according to the following criteria: (i) progressive episodic memory impairment characterized by a low free recall not normalized with semantic cueing (free recall score ≤ 17/48 and/or total recall score ≤ 42/48 at the Free and Cued Selective Reminding Test (FCSRT)) [26]; (ii) no other significant cognitive deficit than executive and social cognition impairments; (iii) a Clinical Dementia Rating (CDR) scale ≤1; (iv) no depression (MontgomeryAsberg Depression Rating Scale (MADRS) score
In a hypothesis-driven volumes of interest (VOI) analysis, we studied gray matter volumes in the following specific regions of interest: (1) the hippocampi and entorhinal cortices, whose atrophy is associated with amnestic syndromes (2) the amygdala, which are affected in non-AD pathologies, especially in LATE [13], (3) the insula, which has been associated with non-AD progressive amnesia [29]
Summary
Progressive amnesia is the core feature of typical Alzheimer’s disease (AD) and can be assessed by different tests of episodic memory. It is supposed to reflect the hippocampal dysfunction, which underlies the so-called amnestic syndrome of the hippocampal type (ASHT) [3]. The presence of an ASHT was proposed as a core clinical marker of typical AD in the recommendations of the International Working Group (IWG), but it must be supported by AD pathophysiological markers to make a diagnosis, especially at an early stage. Whether the amnestic syndrome of the hippocampal type is a signature of AD pathology has been questioned in a recent neuropathological study, showing that free and cued memory assessment lack accuracy to predict AD pathology [4]
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