Decoupling of Neurochemical and White Matter Microstructural Integrity in Posterior Cingulate Cortex Predicts Early Alzheimer's Disease Progression.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by early metabolic and structural brain changes. These alterations are often detectable during mild cognitive impairment due to AD (AD-MCI), a prodromal stage of the disease. The posterior cingulate cortex (PCC), a critical brain region involved in memory and self-referential processing, is particularly vulnerable to these changes. We recruited 21 healthy controls (HC) and 20 AD-MCI patients to participate in this study. Point-Resolved Echo Spin Spectroscopy (PRESS) combined with MEGA-PRESS was employed to accurately measure levels of Gamma-Aminobutyric Acid (GABA) and Glx (Combination of Glutamate and Glutamine) in the PCC. Additionally, diffusion tensor imaging (DTI) was utilized to assess white matter (WM) microstructure integrity. Key metabolites, including N-acetylaspartate (NAA), choline (Cho), and myo-inositol (mI), were quantified to provide insights into neuronal health and metabolic status, while WM integrity was evaluated using fractional anisotropy (FA) and mean diffusivity (MD) metrics. In the PCC, AD-MCI patients exhibited a significant reduction in tNAA/tCr (1.22 ± 0.09 vs. HC 1.32 ± 0.07, p < 0.001) and NAA/mI (1.22 ± 0.12 vs. HC 1.44 ± 0.12, p < 0.001), along with an increase in mI/Cr (1.84 ± 0.28 vs. HC 1.60 ± 0.29, p = 0.012) and decreased GABA+/water (2.23 ± 0.78 vs. HC 2.98 ± 0.73, p = 0.003). Diffusion metrics revealed higher mean diffusivity in PCC-connected gray matter (GM_MD: 10.40 ± 0.79 vs. 9.53 ± 0.80 × 10⁻⁴ mm²/s, p < 0.01) and white matter (WM_MD: 0.09 ± 0.01 vs. 0.08 ± 0.01 × 10⁻² mm²/s, p < 0.01). Notably, in AD-MCI, NAA/mI was negatively correlated with WM_MD (r = - 0.462, p = 0.047), and tNAA/tCr was positively correlated with WM_FA (r = 0.580, p = 0.009). PCC neurochemical-microstructural decoupling (NAA/mI-MD dissociation with preserved tNAA/tCr-FA coupling) marks early AD progression. This dissociation pattern, reflecting concurrent neuronal dysfunction and compensatory glial responses, proposes a novel multimodal biomarker for tracking axonal degeneration prior to overt cognitive decline.