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.
The hippocampus within the medial temporal lobe is highly vulnerable to age- related pathology such as vascular disease. We examined hippocampal vascularization patterns by harnessing the ultra-high resolution of 7 Tesla MR angiography. Dual-supply hemispheres with a contribution of the anterior choroidal artery to hippocampal blood supply were distinguished from single-supply ones with a sole dependence on the posterior cerebral artery. A recent study indicated that a dual vascular supply is related to preserved cognition and structural hippocampal integrity in old age and vascular disease. Here, we examined regional specificity of these structural benefits at the level of medial temporal lobe sub- regions and hemispheres. In a cross-sectional study with an older cohort of 17 patients with cerebral small vessel disease (70.7±9.0 years, 35.5% female) and 27 controls (71.1±8.2 years, 44.4% female), we demonstrate that differences in grey matter volumes related to the hippocampal vascularization pattern were specifically observed in the anterior hippocampus and entorhinal cortex. These regions were especially bigger in dual-supply hemispheres, but also seemed to benefit from a contralateral dual supply. We further show that total grey matter volumes were greater in people with at least one dual-supply hemisphere, indicating that the hippocampal vascularization pattern has more far-reaching structural implications beyond the medial temporal lobe. A mediation analysis identified total grey matter as a mediator of differences in global cognition. However, our analyses on multiple neuroimaging markers for cerebral small vessel disease did not reveal any evidence that an augmented hippocampal vascularization conveys resistance nor resilience against vascular pathology. We propose that an augmented hippocampal vascularization might contribute to maintaining structural integrity in the brain and preserving cognition despite age-related degeneration. As such, the binary hippocampal vascularization pattern could have major implications for brain structure and function in aging and dementia independent of vascular pathology, while presenting a simple framework with potential applicability to the clinical setting.
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