The Impact of Age on Gray Matter Volume Reduction in Anorexia Nervosa: A Systematic Review.

Objective: This study examines the relationship between gray matter (GM) volume reduction and age in individuals with Anorexia Nervosa (AN). Specifically, it investigates whether the magnitude and direction of GM volume differences between AN and healthy controls remain consistent across a range of age groups. Additionally, we reviewed regional GM alterations reported in the literature to characterize unique regional brain profiles observed in AN. By synthesizing neuroimaging studies and mean-age stratified analysis, this work provides insights into the possible impact aging can have on GM reduction in patients with AN. Methods: Systematic review and meta-analysis were conducted using MRI-based neuroimaging studies assessing GM volume in AN patients and controls. A primary meta-analysis was run for all feasible studies combined, followed by a stratified analysis approach examining "younger mean-age" studies and "older mean-age" studies separately. Random effects models were used for the meta-analysis. Meta-regression was used to determine the influence of age on GM volume differences and was controlled for the body mass index to minimize the confounding effect recovery status has on the GM differences between groups. Regional GM alterations were reviewed and discussed. Results: 44 studies, including 1391 individuals with AN and 1566 healthy controls, were included in the primary meta-analysis. No substantial heterogeneity was found across studies. Compared to their respective control groups, the younger-age studies, defined by studies with AN subject of mean age less than 18, exhibited greater significant GM volume loss (-5.39, 95% CI: -7.76 to -3.01, p<0.05) compared to older-age studies (-3.09, 95% CI: -4.16 to -2.03, p<0.05). Meta-regression subgroup results suggest that having older age in AN subjects is linked to less severe GM reduction relative controls. Our review of the regional GM literature reveals that alterations in the hippocampus, amygdala, and precuneus of the medial parietal lobe were more frequently reported than other brain regions in AN. In these regions, we also noticed that younger individuals with AN had more consistent volume reductions across studies, whereas studies with older AN showed greater variability. Conclusion: Grey matter volume loss in AN is more pronounced in younger patients even after controlling for the effect of the recovery status. Having older age appears to contribute to less deficit in brain volume loss in AN, suggesting a protective mechanism underlying GM alteration in older AN patients. These findings reinforce the need for early intervention and prolonged recovery support and emphasize the need to develop lifespan-specific disorder management approaches. Future research should explore long-term GM recovery trajectories and the aging effect on GM alteration for older patients to refine strategies for neuroprotection in AN.