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Research Articles, Neurobiology of Disease

Medial Temporal Lobe Networks in Alzheimer's Disease: Structural and Molecular Vulnerabilities

Robin de Flores, Sandhitsu R. Das, Long Xie, Laura E. M. Wisse, Xueying Lyu, Preya Shah, Paul A. Yushkevich and David A. Wolk
Journal of Neuroscience 9 March 2022, 42 (10) 2131-2141; DOI: https://doi.org/10.1523/JNEUROSCI.0949-21.2021
Robin de Flores
1Department of Neurology, University of Pennsylvania, Philadelphia 19104, Pennsylvania
2Université de Caen Normandie, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche Scientifique (UMRS) Unité 1237, Caen 14000, France
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Sandhitsu R. Das
3Penn Image Computing and Science Laboratory (PICSL), University of Pennsylvania, Philadelphia 19104, Pennsylvania
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Long Xie
3Penn Image Computing and Science Laboratory (PICSL), University of Pennsylvania, Philadelphia 19104, Pennsylvania
4Department of Radiology, University of Pennsylvania, Philadelphia 19104, Pennsylvania
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Laura E. M. Wisse
3Penn Image Computing and Science Laboratory (PICSL), University of Pennsylvania, Philadelphia 19104, Pennsylvania
5Department of Diagnostic Radiology, Lund University, Lund 22185, Sweden
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Xueying Lyu
6Department of Bioengineering, University of Pennsylvania, Philadelphia 19104, Pennsylvania
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Preya Shah
6Department of Bioengineering, University of Pennsylvania, Philadelphia 19104, Pennsylvania
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Paul A. Yushkevich
3Penn Image Computing and Science Laboratory (PICSL), University of Pennsylvania, Philadelphia 19104, Pennsylvania
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David A. Wolk
1Department of Neurology, University of Pennsylvania, Philadelphia 19104, Pennsylvania
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Abstract

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n = 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n = 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n = 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD.

SIGNIFICANCE STATEMENT The current study provides further support for the notion that two distinct medial temporal lobe (MTL) networks, i.e., anterior-temporal (AT) and the posterior-medial (PM), display differential alterations in the context of Alzheimer's disease (AD). Importantly, neurodegeneration appears to occur within these networks in a dissociable manner marked by their covariance patterns. In addition, the AT and PM networks are also differentially associated with relative tau and amyloid burden, and perhaps differences in the relative burden of tau species [e.g., neurofibriliary tangles (NFTs) vs tau in neuritic plaques]. These findings, in the context of a growing literature consistent with the present results, have important implications for disease spread and the cognitive manifestations of AD in light of the differential cognitive processes ascribed to them.

  • Alzheimer's disease
  • medial temporal lobe
  • networks
  • neurodegeneration
  • proteinopathies

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The Journal of Neuroscience: 42 (10)
Journal of Neuroscience
Vol. 42, Issue 10
9 Mar 2022
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Medial Temporal Lobe Networks in Alzheimer's Disease: Structural and Molecular Vulnerabilities
Robin de Flores, Sandhitsu R. Das, Long Xie, Laura E. M. Wisse, Xueying Lyu, Preya Shah, Paul A. Yushkevich, David A. Wolk
Journal of Neuroscience 9 March 2022, 42 (10) 2131-2141; DOI: 10.1523/JNEUROSCI.0949-21.2021

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Medial Temporal Lobe Networks in Alzheimer's Disease: Structural and Molecular Vulnerabilities
Robin de Flores, Sandhitsu R. Das, Long Xie, Laura E. M. Wisse, Xueying Lyu, Preya Shah, Paul A. Yushkevich, David A. Wolk
Journal of Neuroscience 9 March 2022, 42 (10) 2131-2141; DOI: 10.1523/JNEUROSCI.0949-21.2021
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Keywords

  • Alzheimer's disease
  • medial temporal lobe
  • networks
  • neurodegeneration
  • proteinopathies

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