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Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease

Berron, David LU ; van Westen, Danielle LU orcid ; Ossenkoppele, Rik LU ; Strandberg, Olof LU and Hansson, Oskar LU orcid (2020) In Brain 143(3). p.1233-1248
Abstract

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-b-negative cognitively unimpaired, 103 amyloid-b-positive cognitively unimpaired, and 83 amyloid-b-positive individuals with mild cognitive impairment were analysed. Amyloid-b and tau pathology were measured using the CSF amyloid-b42/40 ratio and phosphorylated tau, respectively. We found that amyloid-b-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the... (More)

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-b-negative cognitively unimpaired, 103 amyloid-b-positive cognitively unimpaired, and 83 amyloid-b-positive individuals with mild cognitive impairment were analysed. Amyloid-b and tau pathology were measured using the CSF amyloid-b42/40 ratio and phosphorylated tau, respectively. We found that amyloid-b-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-b-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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Fluid biomarkers, Functional connectivity, Medial temporal lobe, PMAT systems
in
Brain
volume
143
issue
3
pages
16 pages
publisher
Oxford University Press
external identifiers
  • scopus:85088885117
  • pmid:32252068
ISSN
0006-8950
DOI
10.1093/brain/awaa068
language
English
LU publication?
yes
id
e37ad3f2-61fa-427b-8a5f-dc085e4f6717
date added to LUP
2021-01-13 09:42:04
date last changed
2024-06-14 07:29:38
@article{e37ad3f2-61fa-427b-8a5f-dc085e4f6717,
  abstract     = {{<p>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-b-negative cognitively unimpaired, 103 amyloid-b-positive cognitively unimpaired, and 83 amyloid-b-positive individuals with mild cognitive impairment were analysed. Amyloid-b and tau pathology were measured using the CSF amyloid-b<sub>42/40</sub> ratio and phosphorylated tau, respectively. We found that amyloid-b-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-b-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.</p>}},
  author       = {{Berron, David and van Westen, Danielle and Ossenkoppele, Rik and Strandberg, Olof and Hansson, Oskar}},
  issn         = {{0006-8950}},
  keywords     = {{Alzheimer's disease; Fluid biomarkers; Functional connectivity; Medial temporal lobe; PMAT systems}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{1233--1248}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1093/brain/awaa068}},
  doi          = {{10.1093/brain/awaa068}},
  volume       = {{143}},
  year         = {{2020}},
}