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Background and ObjectivesThe goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.MethodsThe FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)–positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.ResultsParticipants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.DiscussionPresence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.Trial Registration InformationClinicalTrials.gov identifier: NCT02008357.Classification of EvidenceThis study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.

The cognitive efficacy of the M1-selective muscarinic agonist xanomeline in mild-to-moderate Alzheimer disease (AD) was measured using the Computerized Neuropsychological Test Battery (CNTB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) in this 17-center, double-blind, placebo-controlled study. Three hundred forty-three patients were randomly assigned to receive 25, 50, or 75 mg xanomeline tartrate or placebo three times daily (t.i.d.) for 24 weeks, followed by placebo for 4 weeks in a single-blind washout phase. Cognitive function was assessed at randomization and after 4, 8, 12, 24, and 28 weeks. Three hundred nineteen patients were included in an intent-to-treat (ITT) analysis; 209 completers had evaluable data at week 24. ITT analysis showed a significant (por = 0.05) dose-response trend and a significant (por = 0.05) between-group comparison favoring 75 mg t.i.d. over placebo for the CNTB summary score but not for the ADAS-cog. In the completer analysis, however, the ADAS-cog showed a significant (por = 0.05) dose-response trend and between-group comparison, whereas the CNTB Summary Score did not. The ADAS-cog was less sensitive to treatment effects in mildly impaired patients (ADAS-cog21) than in moderately impaired patients (ADAS-cogor = 21), whereas the CNTB was sensitive in the entire study population (mean ADAS-cog = 22.5+/-9.6). Significant (por = 0.05) beneficial treatment effects were seen in measures of simple reaction time and delayed verbal recall, which are included in the CNTB but not in the ADAS-cog. During the single-blind placebo washout period, the ADAS-cog score of the placebo group worsened dramatically (change of 2.63 points; por = 0.001), whereas the CNTB score remained stable (change of 1.04 points; p=0.694). Thus, the CNTB appears to be more objective than the ADAS-cog.