The medial temporal lobe in aging and Alzheimer’s disease: A deep dive into anatomy, methodology, and clinical characterization
Wuestefeld, Anika LU
(2025)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Alzheimer’s disease, the most common form of dementia, is characterized by progressive cognitive decline and the accumulation of amyloid-beta (Aβ) and tau neurofibrillary tangle (NFT) pathology. The medial temporal lobe (MTL) is one of the earliest sites of NFT pathology, crucial for memory functioning, and is made up of cytoarchitectonic and functionally different subregions. These subregions are hypothesized to be differentially vulnerable to various neurodegenerative pathologies,
such as NFTs. This thesis focuses on the MTL in aging and Alzheimer’s disease. The two overarching objectives of this thesis were to (i) contribute to the methodological advancements of in vivo measures of MTL subregions and (ii) characterize MTL... (More) - Alzheimer’s disease, the most common form of dementia, is characterized by progressive cognitive decline and the accumulation of amyloid-beta (Aβ) and tau neurofibrillary tangle (NFT) pathology. The medial temporal lobe (MTL) is one of the earliest sites of NFT pathology, crucial for memory functioning, and is made up of cytoarchitectonic and functionally different subregions. These subregions are hypothesized to be differentially vulnerable to various neurodegenerative pathologies,
such as NFTs. This thesis focuses on the MTL in aging and Alzheimer’s disease. The two overarching objectives of this thesis were to (i) contribute to the methodological advancements of in vivo measures of MTL subregions and (ii) characterize MTL subregional atrophy and contributions to cognitive decline in aging and Alzheimer’s disease.
In paper I, the variability in annotations of cortical MTL subregions on postmortem histology sections of different neuroanatomical laboratories were compared and characterized. The results increase our understanding of why differences in annotations arise, setting a crucial foundation for improved measurements and to study the MTL cortex with in vivo neuroimaging data. In paper II – part 1, a segmentation protocol for the whole amygdala on commonly used T1-weighted magnetic resonance images was developed.
In paper III, Aβ-independent age-related tau pathology in normal aging was characterized. This study indicated that NFT pathology occurs in aging in MTL, frontal, and parietal regions, independent of Aβ, contributing to downstream effects of neurodegeneration and cognitive decline. In paper IV, specific structural measures were found to partially mediate the association between NFT pathology and cognitive subdomain associations, providing a nuanced understanding of region-specific macrostructural atrophy as one pathway of tau-induced cognitive changes. In paper II – part 2, MTL subregional atrophy patterns in amnestic early-onset versus late-onset Alzheimer’s disease were investigated. The results showed that subtle MTL atrophy differences exist between these two groups. However, the patterns were not as distinct as previously reported, suggesting a largely shared pathophysiology for early- and late-onset Alzheimer’s disease. In paper V, the relative contribution of
NFT and TDP-43 pathology to MTL atrophy was reviewed. The findings were summarized to provide hypotheses on the interplay, synergism, and timing of the pathologies as well as future directions for research.
In summary, by developing and applying refined methodologies to characterize MTL subregions, this thesis contributes to a more detailed characterization of the complex factors driving MTL atrophy in aging and Alzheimer’s disease. This will aid in the early detection and progression of Alzheimer’s disease and allow fine-grained tracking of treatment outcomes in clinical trials. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/877ea8a4-4d85-4ccd-90af-d492a3962f9b
- author
- Wuestefeld, Anika
LU
- supervisor
- opponent
-
- Professor Schott, Jonathan, University College London, United Kingdom
- organization
- publishing date
- 2025
- type
- Thesis
- publication status
- published
- subject
- keywords
- Alzheimer's disease, aging, Medial temporal lobe, MRI, amyloid-beta, tau-PET imaging, neurofibrillary tangles, PART, neuroanatomy
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2025:75
- pages
- 124 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/67494217991
- defense date
- 2025-06-19 08:30:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-728-6
- language
- English
- LU publication?
- yes
- id
- 877ea8a4-4d85-4ccd-90af-d492a3962f9b
- date added to LUP
- 2025-05-15 09:25:29
- date last changed
- 2025-06-18 08:16:06
@phdthesis{877ea8a4-4d85-4ccd-90af-d492a3962f9b,
abstract = {{Alzheimer’s disease, the most common form of dementia, is characterized by progressive cognitive decline and the accumulation of amyloid-beta (Aβ) and tau neurofibrillary tangle (NFT) pathology. The medial temporal lobe (MTL) is one of the earliest sites of NFT pathology, crucial for memory functioning, and is made up of cytoarchitectonic and functionally different subregions. These subregions are hypothesized to be differentially vulnerable to various neurodegenerative pathologies,<br/>such as NFTs. This thesis focuses on the MTL in aging and Alzheimer’s disease. The two overarching objectives of this thesis were to (i) contribute to the methodological advancements of in vivo measures of MTL subregions and (ii) characterize MTL subregional atrophy and contributions to cognitive decline in aging and Alzheimer’s disease.<br/>In paper I, the variability in annotations of cortical MTL subregions on postmortem histology sections of different neuroanatomical laboratories were compared and characterized. The results increase our understanding of why differences in annotations arise, setting a crucial foundation for improved measurements and to study the MTL cortex with in vivo neuroimaging data. In paper II – part 1, a segmentation protocol for the whole amygdala on commonly used T1-weighted magnetic resonance images was developed. <br/>In paper III, Aβ-independent age-related tau pathology in normal aging was characterized. This study indicated that NFT pathology occurs in aging in MTL, frontal, and parietal regions, independent of Aβ, contributing to downstream effects of neurodegeneration and cognitive decline. In paper IV, specific structural measures were found to partially mediate the association between NFT pathology and cognitive subdomain associations, providing a nuanced understanding of region-specific macrostructural atrophy as one pathway of tau-induced cognitive changes. In paper II – part 2, MTL subregional atrophy patterns in amnestic early-onset versus late-onset Alzheimer’s disease were investigated. The results showed that subtle MTL atrophy differences exist between these two groups. However, the patterns were not as distinct as previously reported, suggesting a largely shared pathophysiology for early- and late-onset Alzheimer’s disease. In paper V, the relative contribution of<br/>NFT and TDP-43 pathology to MTL atrophy was reviewed. The findings were summarized to provide hypotheses on the interplay, synergism, and timing of the pathologies as well as future directions for research.<br/>In summary, by developing and applying refined methodologies to characterize MTL subregions, this thesis contributes to a more detailed characterization of the complex factors driving MTL atrophy in aging and Alzheimer’s disease. This will aid in the early detection and progression of Alzheimer’s disease and allow fine-grained tracking of treatment outcomes in clinical trials.}},
author = {{Wuestefeld, Anika}},
isbn = {{978-91-8021-728-6}},
issn = {{1652-8220}},
keywords = {{Alzheimer's disease; aging; Medial temporal lobe; MRI; amyloid-beta; tau-PET imaging; neurofibrillary tangles; PART; neuroanatomy}},
language = {{eng}},
number = {{2025:75}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{The medial temporal lobe in aging and Alzheimer’s disease: A deep dive into anatomy, methodology, and clinical characterization}},
url = {{https://lup.lub.lu.se/search/files/219232397/Avhandling_Anika_W_LUCRIS.pdf}},
year = {{2025}},
}