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Differential medial temporal lobe and default-mode network functional connectivity and morphometric changes in Alzheimer's disease.

ABSTRACT: We 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 subcortical and hippocampal subfield volumes and cortical thinning. 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, bilaterally symmetric spatial organization of affected medial temporal lobe regions; b) mutual hyperconnectivity involving ventral medial temporal lobe structures (temporal pole, uncus); c) dorsal medial temporal lobe hypoconnectivity with anterior and posterior midline default-mode network nodes; and d) a complex pattern of transient and persistent changes in hypo- and hyper-connectivity across Alzheimer's Disease stages. 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.

SUBMITTER: Grajski KA

PROVIDER: S-EPMC6545401 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Differential medial temporal lobe and default-mode network functional connectivity and morphometric changes in Alzheimer's disease.

Grajski Kamil A KA Bressler Steven L SL

NeuroImage. Clinical 20190518

We 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 subcortical and hippocampal subfi ...[more]

PMID: 31158694

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Project description:Human episodic memory critically depends on subregions of the medial temporal lobe, which are part of functional brain systems such as the anterior-temporal and the posterior-medial system. Here we analysed how Alzheimer's pathology affects functional connectivity within these systems. Data from 256 amyloid-β-negative cognitively unimpaired, 103 amyloid-β-positive cognitively unimpaired, and 83 amyloid-β-positive individuals with mild cognitive impairment were analysed. Amyloid-β and tau pathology were measured using the CSF amyloid-β42/40 ratio and phosphorylated tau, respectively. We found that amyloid-β-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the medial temporal lobe and regions in the anterior-temporal system, most prominently between left perirhinal/entorhinal cortices and medial prefrontal cortex. Furthermore, correlation analysis in this group revealed decreasing functional connectivity between bilateral perirhinal/entorhinal cortices, anterior hippocampus and posterior-medial regions with increasing levels of phosphorylated tau. The amyloid-β-positive individuals with mild cognitive impairment mostly exhibited reduced connectivity between the medial temporal lobe and posterior-medial regions, predominantly between the anterior hippocampus and posterior cingulate cortex. In addition, they showed hyperconnectivity within the medial temporal lobe and its immediate proximity. Lower medial temporal-cortical functional connectivity networks resulting from the group comparisons of cognitively unimpaired individuals were associated with reduced memory performance and more rapid longitudinal memory decline as shown by linear mixed-effects regression analysis. Finally, we found that reduced medial temporal-cortical connectivity in mildly cognitively impaired individuals was related to reduced entorhinal thickness and white matter integrity of the parahippocampal cingulum and the fornix. No such relationships were found in cognitively unimpaired individuals. In conclusion, our findings show that the earliest changes in preclinical Alzheimer's disease might involve decreased connectivity within the anterior-temporal system, and early changes in connectivity might be related to memory impairment, but not to structural changes. With disease progression and increased tau pathology, medial temporal functional connectivity with posterior-medial regions seems to be increasingly impaired. In individuals with mild cognitive impairment, reduced functional connectivity is associated with structural brain changes as well as the emergence of locally increased connectivity patterns. Thus, functional connectivity between the medial temporal lobe and the anterior-temporal and posterior-medial system could serve as stage-specific functional markers in early Alzheimer's disease.

Project description:SEE BIGLER DOI101093/AWW277 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-traumatic amnesia is very common immediately after traumatic brain injury. It is characterized by a confused, agitated state and a pronounced inability to encode new memories and sustain attention. Clinically, post-traumatic amnesia is an important predictor of functional outcome. However, despite its prevalence and functional importance, the pathophysiology of post-traumatic amnesia is not understood. Memory processing relies on limbic structures such as the hippocampus, parahippocampus and parts of the cingulate cortex. These structures are connected within an intrinsic connectivity network, the default mode network. Interactions within the default mode network can be assessed using resting state functional magnetic resonance imaging, which can be acquired in confused patients unable to perform tasks in the scanner. Here we used this approach to test the hypothesis that the mnemonic symptoms of post-traumatic amnesia are caused by functional disconnection within the default mode network. We assessed whether the hippocampus and parahippocampus showed evidence of transient disconnection from cortical brain regions involved in memory processing. Nineteen patients with traumatic brain injury were classified into post-traumatic amnesia and traumatic brain injury control groups, based on their performance on a paired associates learning task. Cognitive function was also assessed with a detailed neuropsychological test battery. Functional interactions between brain regions were investigated using resting-state functional magnetic resonance imaging. Together with impairments in associative memory, patients in post-traumatic amnesia demonstrated impairments in information processing speed and spatial working memory. Patients in post-traumatic amnesia showed abnormal functional connectivity between the parahippocampal gyrus and posterior cingulate cortex. The strength of this functional connection correlated with both associative memory and information processing speed and normalized when these functions improved. We have previously shown abnormally high posterior cingulate cortex connectivity in the chronic phase after traumatic brain injury, and this abnormality was also observed in patients with post-traumatic amnesia. Patients with post-traumatic amnesia showed evidence of widespread traumatic axonal injury measured using diffusion magnetic resonance imaging. This change was more marked within the cingulum bundle, the tract connecting the parahippocampal gyrus to the posterior cingulate cortex. These findings provide novel insights into the pathophysiology of post-traumatic amnesia and evidence that memory impairment acutely after traumatic brain injury results from altered parahippocampal functional connectivity, perhaps secondary to the effects of axonal injury on white matter tracts connecting limbic structures involved in memory processing.

Dataset Information

Differential medial temporal lobe and default-mode network functional connectivity and morphometric changes in Alzheimer's disease.

Publications

Differential medial temporal lobe and default-mode network functional connectivity and morphometric changes in Alzheimer's disease.

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