Microstructural Neurodegeneration of the Entorhinal-Hippocampus Pathway along the Alzheimer’s Disease Continuum

BACKGROUND: Conventional neuroimaging biomarkers for the neurodegeneration of Alzheimer’s disease (AD) are not sensitive enough to detect neurodegenerative alterations during the preclinical stage of AD individuals. OBJECTIVE: We examined whether neurodegeneration of the entorhinal-hippocampal pathway could be detected along the AD continuum using ultra-high-field diffusion tensor imaging and tractography for ex vivo brain tissues. METHODS: Postmortem brain specimens from a cognitively unimpaired individual without AD pathological changes (non-AD), a cognitively unimpaired individual with AD pathological changes (preclinical AD), and a demented individual with AD pathological changes (AD dementia) were scanned with an 11.7T diffusion magnetic resonance imaging. Fractional anisotropy (FA) values of the entorhinal layer II and number of perforant path fibers counted by tractography were compared among the AD continuum. Following the imaging analyses, the status of myelinated fibers and neuronal cells were verified by subsequent serial histological examinations. RESULTS: At 250μm (zipped to 125μm) isotropic resolution, the entorhinal layer II islands and the perforant path fibers could be identified in non-AD and preclinical AD, but not in AD dementia, followed by histological verification. The FA value of the entorhinal layer II was the highest among the entorhinal laminae in non-AD and preclinical AD, whereas the FA values in the entorhinal laminae were homogeneously low in AD dementia. The FA values and number of perforant path fibers decreased along the AD continuum (non-AD>preclinical AD > AD dementia). CONCLUSION: We successfully detected neurodegenerative alterations of the entorhinal-hippocampal pathway at the preclinical stage of the AD continuum.