Accelerated Aging of White Matter in Late-Life Depression: Evidence From ¹⁸F-Flutemetamol Positron Emission Tomography Imaging

BACKGROUND: Late-life depression (LLD) is associated with white matter (WM) alterations. Current evidence indicates that amyloid positron emission tomography (PET) tracers are sensitive and reliable markers for evaluating normal-appearing WM (NAWM) on magnetic resonance imaging (MRI), showing an association between lower uptake and Alzheimer's disease pathology and higher uptake with age-related changes. Utilizing this novel and reliable technique, we aimed to distinguish between 2 hypothetical models for neurobiology of LLD, the pathological neurodegenerative model and the accelerated aging model. METHODS: In this monocentric cross-sectional study, a total of 103 participants, including 61 patients with LLD (age 73.8 ± 7.0 years; 41 female) and 42 healthy control (HC) participants (age 72.5 ± 7.6 years; 28 female), underwent PET imaging with ¹⁸F-flutemetamol, MRI, and clinical assessment. T2-weighted fluid-attenuated inversion recovery images were segmented into WM hyperintensities (WMHs) and NAWM. RESULTS: The ¹⁸F-flutemetamol standardized uptake value ratio (SUVR) in WMHs was significantly lower than that in NAWM (t₁₀₂ = 7.8, p < .001). Compared with HC participants, patients with LLD exhibited higher ¹⁸F-flutemetamol SUVR in both NAWM (p < .001, Cohen's d = 0.91) and WMHs (p = .005, d = 0.56), even after controlling for age and ¹⁸F-flutemetamol SUVR in cortical gray matter. CONCLUSIONS: Our result of elevated ¹⁸F-flutemetamol uptake in NAWM is not consistent with the pathological neurodegenerative aging pattern observed in Alzheimer's disease but is consistent with patterns of age-related changes. This distinction is crucial for the development of future targeted treatments.