Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

Abstract

Objective:We assessed whether novelty-related fMRI activity in medial temporal lobe (MTL) regions and precuneus follows an inverted U-shape pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy.Methods:We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus and precuneus, as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, gender, study site, and education.Results:In the precuneus, we observed an inverted U-shape pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared to HC, but not in AD patients who showed relatively lower activity than MCI. This non-linear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to precuneus, hippocampal activity was reduced in AD dementia compared to all other groups and related to AD biomarkers.Conclusion:Novelty-related activity in the precuneus follows a non-linear pattern across the clinical spectrum of increased AD risk. While the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the non-linearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity.

Single-value scores of memory-related brain activity reflect dissociable neuropsychological and anatomical signatures of neurocognitive aging

“…Compatible with this finding, attenuated hippocampal novelty responses (E. Duzel et al, 2022) and reduced DMN deactivations during novelty processing (Billette et al, 2022) have been linked to lower memory performance in individuals at risk for AD.…”

“…J. Li et al, 2015). On the other hand, several authors discuss the role of the DMN as a potential cognitive resource in older adults (Billette et al, 2022; Colangeli et al, 2016), which should be further addressed in future studies (see Supplementary Discussion).…”

“…The reductionist single-value scores of age-related whole-brain fMRI activation (and deactivation) patterns described here may prove more reliable. In this context, it is of importance that in recent studies with older participants at risk for AD, researchers have often employed novelty rather than subsequent memory contrasts, owing to the lack of successfully encoded items in individuals with pronounced memory impairment (Billette et al, 2022; E. Duzel et al, 2018; E.…”

“…They may, for example, prove a useful tool in the assessment of cognitive impairment beyond the memory domain or in atypical presentations of pre-clinical dementia. The scores may also help to better understand and define "healthy aging" on a theoretical level and could facilitate the laborious screening of high-risk patients for pharmacological studies or may be combined with tau-or amyloid-PET (Billette et al, 2022) as a potential biomarker assessment at the clinical level.…”

“…Previous studies show that, compared to young individuals, older adults exhibited lower activations of inferior and medial temporal structures and reduced deactivations in the Default Mode Network (DMN) during novelty processing and successful long-term memory encoding (Maillet & Rajah, 2014; Soch et al, 2021a; Billette et al, 2022; E. Duzel et al, 2022).…”