Amanda Annettesdotter - Institutionen för kliniska vetenskaper, Lund

Title: A new look at the amygdala in neurodegenerative diseases

Main supervisor: Laura Wisse

Reviewers: Rosaleena Mohanty, Malin Wennström

Abstract

Background

Memory processes and neuropsychiatric symptoms are closely linked to the amygdala and other regions of the medial temporal lobe (MTL). Notably, both the amygdala and other MTL regions are also hotspots for different neuropathologies, including Alzheimer’s disease pathology, transactive response DNA-binding protein (TDP)-43, and α-synuclein pathology. Given their involvement in neurodegenerative diseases, magnetic resonance imaging (MRI) measures of the amygdala and MTL regions holds great potential for research on disease mechanisms and as biomarkers for clinical practice and trials. Nevertheless, despite its importance across different neurodegenerative disorders, the amygdala has received relatively little attention in previous studies.

Research questions

This PhD thesis addresses four main research questions across four planned projects: 

• Project I: Are neuropathological measures in the amygdala and MTL associated with whole and subregional amygdala volumes?
• Project II: Is the co-occurrence of multiple neuropathologies related to amygdala and MTL subregional MRI structural measures in an additive or synergistic manner?
• Project III: Which baseline predictors, including MTL structural measures, can best predict cognitive decline in amyloid beta-negative individuals with amnestic mild cognitive impairment?
• Project IV: Which neuropathological measures in different brain regions are associated with neuropsychiatric symptoms?

Preliminary results

In Project I, we found that tau pathology likely contributes to amygdala neurodegeneration through other MTL regions, whereas TDP-43 in the amygdala itself was directly associated with amygdala volume. Subregional analyses further revealed that tau and TDP-43 pathology were associated with widespread neurodegeneration in multiple amygdala subregions.

In Project III, using two independent cohorts, we found that MTL structures and cognitive measures consistently contributed to the prediction of cognitive decline in amyloid beta-negative individuals with amnestic mild cognitive impairment. However, the performance of the predictive models varied across datasets, and further validation is needed.

Significance

By investigating how different neuropathologies accumulate and contribute to neurodegeneration in the amygdala and surrounding MTL regions – and how these changes relate to cognitive and neuropsychiatric symptoms – this work aims to advance our understanding of underlying disease mechanisms. Such insights may inform the improvement of neuroimaging markers for diagnosis and monitoring progression in the early stages of neurodegenerative diseases.