IC‐P1‐017: Evidence for transynaptic degeneration of fornix fibers in Alzheimer's disease

Alzheimer's disease (AD) is characterized by severe neurofibrillary pathology (NFT) in the pyramidal cells of the subiculum and CA1 regions of the hippocampus. Axons from these neurons form the major efferent pathway of the hippocampus extending from the fimbria through the fornix to the mamillary bodies. While degeneration of axons is hypothesized to occur with NFT pathology of these neurons, this phenomenon has yet to be detected in vivo and remains a controversial area of neurodegeneration research. To test this hypothesis, we examined the relationship between hippocampal radial distance and fractional anisotropy (FA) of the fornix in AD and cognitively normal individuals. Seventy-one individuals consisting of 23 AD and 48 cognitively normal (CN) subjects with mean age of 74.5 + 7.7 years were studied with MRI analysis of high-resolution T1 images and diffusion tensor imaging mapped to a mean deformation template. Hippocampal shape analysis was performed using radial distance measures according to Thompson et al (Neuroimage, 2004). Fornix FA was measured on a voxel by voxel basis based on fornix ROI delineated on the template image. Hippocampal radial distances were related to fornix FA as well as delayed episodic memory performance. Extensive differences in radial distance in the CA1/subiculum region were found between AD and CN (maximum t=6.9) which remained after permutation correction for multiple comparisons (p <0.0001; figure). Highly significant differences in voxel-level fornix FA values were also found. In addition, mean fornix FA values significantly and positively correlated with subicular and CA1 radial distances (p < 0.0001). Finally, subicular and CA1 radial differences were highly and positively associated with delayed memory performance after permutation correction (p <0.0001). Delayed memory also correlated significantly with fornix FA in the dorsal commissural area. We believe this is the first evidence for an association between focal hippocampal pathology and distal degeneration of efferent axons. We further believe that these results provide evidence for transynaptic degeneration, potentially resulting in disconnection of limbic system pathways. Degeneration of axons and disconnection of neural systems may play an important role in the cognitive consequences of focal AD pathology.