Abstract
While strong cross-sectional evidence supported the use of fornix microstructure as a marker for detecting Alzheimer’s disease (AD), longitudinal data remains inconclusive on the sequential nature of fornix microstructure abnormalities and AD progression. An unequivocal longitudinal relationship between fornix microstructure and markers of AD progression –memory impairment and hippocampal atrophy, must be established to validate fornix microstructure as a marker of AD progression. We included 115 participants from the Alzheimer’s Disease Neuroimaging Initiative across the non-demented AD spectrum— defined as those who had at least one AD risk marker at baseline (e.g., mild cognitive impairment (MCI) due to AD diagnosis, amyloid or ApoE4 positivity) and/or ‘cognitively normal individuals who converted to MCI due to AD or AD, with structural and diffusion tensor imaging scans at baseline and two years follow-up. Hippocampal volumes (HV), fractional anisotropy (FA) and mean diffusivity (MD) in the fornix were extracted. Memory was indexed via composite scores of verbal memory tests. Structural equation models tested the bidirectional cross-lagged effects of fornix microstructure, memory, and HV. Impaired memory and smaller HV at baseline significantly predicted worse fornix microstructure (decreased FA and increased MD) two years later. Baseline fornix microstructure was not associated with subsequent changes in memory and HV. Fornix microstructure is compromised likely at a later stage, where significant decline in memory and hippocampal atrophy have occurred. This limits the utility of fornix microstructure in the early detection of AD. Our findings inform the possible pathophysiology and refined the use of AD neural markers.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative condition characterized by progressive memory impairment
Within each of the cross-sectional time points, fornix fractional anisotropy (FA) and mean diffusivity (MD) were significantly associated with Hippocampal volumes (HV) and Alzheimer’s Disease Neuroimaging Initiative (ADNI)-MEM
There were significant changes in the HV (t = 7.78; p < .001) as well as fornix FA (t = 5.89; p < .001) and MD (t = 4.27; p < .001) in their expected directions, the decline in ADNI-MEM scores was marginally significant (t = 1.81; p < .073) the violin plots of these measures are shown in fig
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative condition characterized by progressive memory impairment. Detection and intervention are crucial to maximize prognostic outcomes. To this end, non-invasive neural markers have been suggested to facilitate early detection (Sperling et al 2011). The fornix is a bundle of WM fibers that connects the hippocampus to subcortical structures. Due to this structural association with the hippocampus — a region that is crucially implicated in both short-term and long-term memory, it has been widely studied in AD. Cross-sectional studies using DTI have revealed significantly altered WM microstructure in the fornix as indicated by decreased FA and increased
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