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. 2024 Feb;46(1):769-782.
doi: 10.1007/s11357-023-01031-w. Epub 2023 Dec 16.

Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy

Aftab Bakhtiari  1   2   3   4 , Krisztina Benedek  5 , Ian Law  6 , Birgitte Fagerlund  7   8 , Erik Lykke Mortensen  9 , Merete Osler  9   10 , Martin Lauritzen  11   12   13 , Henrik B W Larsson  14   15 , Mark B Vestergaard  14
Affiliations

Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy

Aftab Bakhtiari et al. Geroscience. 2024 Feb.

Abstract

Aims: Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) in the brain. The deposition of Aβ is believed to initiate a detrimental cascade, including cerebral hypometabolism, accelerated brain atrophy, and cognitive problems-ultimately resulting in AD. However, the timing and causality of the cascade resulting in AD are not yet fully established. Therefore, we examined whether early Aβ accumulation affects cerebral glucose metabolism, atrophy rate, and age-related cognitive decline before the onset of neurodegenerative disease.

Methods: Participants from the Metropolit 1953 Danish Male Birth Cohort underwent brain positron emission tomography (PET) imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) (N = 70) and [18F]Fluorodeoxyglucose (FDG) (N = 76) to assess cerebral Aβ accumulation and glucose metabolism, respectively. The atrophy rate was calculated from anatomical magnetic resonance imaging (MRI) scans conducted presently and 10 years ago. Cognitive decline was examined from neurophysiological tests conducted presently and ten or 5 years ago.

Results: Higher Aβ accumulation in AD-critical brain regions correlated with greater visual memory decline (p = 0.023). Aβ accumulation did not correlate with brain atrophy rates. Increased cerebral glucose metabolism in AD-susceptible regions correlated with worse verbal memory performance (p = 0.040).

Conclusions: Aβ accumulation in known AD-related areas was associated with subtle cognitive deficits. The association was observed before hypometabolism or accelerated brain atrophy, suggesting that Aβ accumulation is involved early in age-related cognitive dysfunction. The association between hypermetabolism and worse memory performance may be due to early compensatory mechanisms adapting for malfunctioning neurons by increasing metabolism.

Keywords: Aging; Amyloid; Atrophy; Cerebral glucose metabolism; Cognition; PET imaging.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Flowchart illustrating experiment setup, including age of participants at each timepoint and each included imaging modality
Fig. 2
Fig. 2
Illustration of brain regions examined in the PiB AD-ROI and hippocampus and examples of corresponding PiB SUVr images in two representative subjects. The included brain were the precuneus, isthmus cingulate cortex, posterior cingulate cortex, and caudal anterior cingulate cortex (all demonstrated in A and C. The hippocampus is not included in the AD-ROI, but is illustrated in panel B. The top row shows a PiB-positive subject, and the bottom row shows an PiB-negative subject. Aβ accumulation is clearly visible in the PiB positive subject in regions belonging to the AD-ROI. PCC; posterior cingulate cortex, ICC; isthmus cingulate cortex, CACC; caudal anterior cingulate cortex
Fig. 3
Fig. 3
Illustration of brain regions examined in the FDG AD-ROI and examples of corresponding FDG SUVr images in two representative subjects. The included regions were the inferior parietal and superior parietal cortex (demonstrated in A, D, and E), superior parietal cortex (B, D, E), precuneus, and posterior cingulate cortex (C, D, and E). The top row shows FDG SUVr in a PiB positive subject, and the bottom row shows an PiB-negative subject. PCC; posterior cingulate cortex
Fig. 4
Fig. 4
Summary of main findings. A Trajectory of total brain volume atrophy in a 10-year period. B Plots illustrating the correlation between cognition and PET SUVr. The first two scatterplots show that worse performance and increased decline in PAL 8 Shapes are associated with higher PiB SUVr in the AD-ROI. Similarly, the third scatterplot shows how worse performance on VPA Retention is correlated with higher FDG SUVr in the AD-ROI. C Results from the surface-based cortical analysis, showing regions where worse PAL 8 Shapes performance is associated with increased PiB SUVr. D Results from the surface-based cortical analysis, showing regions where increased decline in PAL 8 Shapes performance is associated with increased PiB SUVr
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