Dynamic white matter microstructure in anorexia nervosa: associations with neurofilament light and leptin across early weight restoration.

Longitudinal changes in white matter (WM) microstructure from acute underweight to early weight restoration in anorexia nervosa (AN), and their underlying mechanisms, remain largely unexplored. Thus, this study aims to examine the relationship between microstructural alterations across WM regions and neurofilament light (NF-L), a marker of axonal injury; brain-derived neurotrophic factor (BDNF), a neuroprotective molecule; and leptin, a neuroplasticity-promoting hormone, during acute underweight and following short-term weight restoration. Diffusion-weighted MRI scans from 101 predominantly adolescent female participants with acute AN before and after short-term weight restoration and from 147 female healthy participants were used. Alterations in microstructural WM integrity assessed by fractional anisotropy (FA) were tested using linear mixed-effects models across groups. Additional analyses were used to investigate relationships of FA with NF-L, BDNF, and leptin. We found a mixed, mostly elevated FA signature at the acutely underweight stage, followed by incomplete normalization with weight gain. Subsequent analyses identified that change in FA was positively associated with reductions in NF-L levels above and beyond the effect of weight gain in one WM tract. Leptin increase accompanying short-term weight restoration mediated the effect of weight gain on FA decrease across four WM tracts (estimated average causal mediation effects range: -0.0050 to -0.0026; confidence intervals within -0.01 to 0.0). The results suggest that a decrease in FA may indicate rehabilitation of WM integrity in acute AN. In addition to nutritional rehabilitation, the increase of leptin levels during weight gain may be relevant for the normalization of specific WM tracts.