Structure–function coupling using fixel-based analysis and functional magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment Open Access

Functional MRI (fMRI) and diffusion-weighted imaging (DWI) help explore correlations between structural connectivity (SC) and functional connectivity (FC; SC–FC coupling). Studies on mild cognitive impairment (MCI) and Alzheimer’s disease (AD) observed coupling disruptions, co-occurring with cognitive decline. Advanced “fixel-based” analyses improved DWI’s accuracy in assessing microstructural and macrostructural features of white matter (WM), but previous aging coupling studies commonly defined SC via tensor-based tractography and streamline counts, thereby missing fiber-specific information. We investigated different types of fixel-FC coupling and their relation to cognition in 392 participants (Age_mean = 73; 207F) from the ADNI. Two hundred twenty-five controls, 142 MCI, and 25 AD with diffusion-weighted and resting-state fMRI scans were analyzed. Structural connectomes were constructed using average fixel metrics (fiber density (FD), fiber-bundle cross-section log, and combined [FDC]) as edges. SC–FC coupling for each SC metric was calculated at overall network, edge, and node levels. Overall DMN, node- and edge-specific coupling differences were found across SC measures and groups. DMN nodal coupling significantly predicted Mini-Mental Status Examination score and verbal memory. In conclusion, different types of fixel-based coupling alterations can be observed across the neurocognitive aging spectrum, in particular, FD–FC and FDC–FC coupling between DMN regions are associated with cognitive functioning.

Structure–function coupling is the correlation between white matter structures connecting pairs of brain regions (structural connectivity) and their concomitant brain activity (functional connectivity). “fixel-based” diffusion-weighted imaging techniques improve the accuracy of white matter structure estimation and provide information on microstructural and macrostructural changes to brain networks. Using structural connectomes based on fixel-based weights, coupling was found to be altered in Alzheimer’s disease and mild cognitive impairment, especially in the default mode network. Default mode network coupling may be relevant to verbal memory and cognitive decline across aging, particularly for coupling driven by microstructural features of white matter.