AbstractWe report group level differential detection of medial temporal lobe resting-state functional connectivity disruption and morphometric changes in the transition from cognitively normal to early mild cognitive impairment in an age-, education- and gender-matched 105 subjects Alzheimer’s Disease Neuroimaging Initiative dataset. In mild Alzheimer’s Disease, but not early mild cognitive impairment, characteristic brain atrophy was detected in FreeSurfer estimates of cortical thickness and subcortical and hippocampal subfield volumes. By contrast, functional connectivity analysis detected earlier significant changes. In early mild cognitive impairment these changes involved medial temporal lobe regions of transentorhinal, perirhinal and entorhinal cortices (associated with the earliest stages of neurofibrillary changes in Alzheimer’s Disease), hippocampus, parahippocampal gyrus and temporal pole, and cortical regions comprising or co-activated with the default-mode network, including rostral and medial prefrontal cortex, anterior cingulate cortex, precuneus and inferior temporal cortex. Key findings include: a) focal and bilaterally symmetric spatial organization of affected medial temporal lobe regions; b) mutual hyperconnectivity bilaterally involving ventral medial temporal lobe structures (temporal pole, uncus); and c) dorsal medial temporal lobe hypoconnectivity with anterior and posterior midline default-mode network nodes. These findings position medial temporal lobe resting state functional connectivity as a candidate biomarker of an Alzheimer’s Disease pathophysiological cascade, potentially in advance of clinical biomarkers, and coincident with biomarkers of the earliest stages of Alzheimer’s neuropathology. Our results indicate that medial temporal lobe resting-state functional connectivity should be further investigated as a potential biomarker in the diagnosis of Alzheimer’s Disease.HighlightsFunctional connectivity change seen before structural change in Alzheimer’s DiseaseMedial temporal lobes mutually hyper-connect in mild cognitive impairmentMedial temporal lobe and default mode network decouple in mild cognitive impairmentLoci of functional change in hippocampi are focal with bilaterally symmetric featuresNonmonotonic functional connectivity changes in Alzheimer’s Disease progression
Primary Disruption of the Memory-Related Subsystems of the Default Mode Network in Alzheimer’s Disease: Resting-State Functional Connectivity MRI Study
