Abstract
We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer’s disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury.
Highlights
Neuropathological changes associated with Alzheimer’s disease (AD) begin in medial temporal structures including the hippocampus (Ball, 1977; Braak and Braak, 1991)
Because the subiculum and CA1 hippocampal subfields are believed to be principal sources of hippocampal efferent fibers passing through the fornix (Rosene and Van Hoesen, 1977; Krayniak et al, 1979; Thierry et al, 2000; Aggleton et al, 2005; Cenquizca and Swanson, 2007), these findings may suggest that damage to axons connected to early sites of neuronal injury in AD may play a prominent role in the AD pathological process
We began with a global approach of associating total hippocampal volume with overall fornix fractional anisotropy (FA); we examined whether hippocampal subregion atrophy was associated with reduced fornix FA in the predicted topographical manner
Summary
Neuropathological changes associated with Alzheimer’s disease (AD) begin in medial temporal structures including the hippocampus (Ball, 1977; Braak and Braak, 1991). A number of AD studies have observed injury to the fornix, the main axonal output pathway from the hippocampus to the mammillary body (Brodal, 1981; Aggleton and Brown, 1999; Aggleton et al, 2005) Several such studies have used fractional anisotropy (FA) derived from diffusion tensor imaging (DTI) as a measure of anisotropic water diffusion, which is believed to reflect the microstructural integrity of white matter fibers including the axon and surrounding myelin (Assaf and Pasternak, 2008; Mielke et al, 2009; Pievani et al, 2010; Agosta et al, 2011). Because the subiculum and CA1 hippocampal subfields are believed to be principal sources of hippocampal efferent fibers passing through the fornix (Rosene and Van Hoesen, 1977; Krayniak et al, 1979; Thierry et al, 2000; Aggleton et al, 2005; Cenquizca and Swanson, 2007), these findings may suggest that damage to axons connected to early sites of neuronal injury in AD may play a prominent role in the AD pathological process
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