Brain function and structure during accelerated and pathological ageing, an in vivo MRI approach in rodents
18 September 2018
UAntwerp, Campus Drie Eiken, Building O, Auditorium O5 - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
3:00 PM - 5:00 PM
Annemie Van der Linden, Marleen Verhoye
PhD defence Cynthia Anckaerts - Department of Biomedical Sciences
Due to an increasing life expectancy, age-related disorders pose a growing economic and social burden. Although many efforts are being made to unravel processes leading to neurodegeneration and cognitive decline, the key mechanisms orchestrating brain ageing remain largely unknown. A proper understanding of brain alterations during various age-related processes is therefore pivotal to enable the identification and discovery of potential diagnostic or therapeutic targets. This thesis focusses on improving our knowledge concerning (i) accelerated ageing due to endocrine alterations and (ii) pathological ageing in Alzheimer’s Disease (AD). For this, highly translational neuroimaging techniques were used: resting state functional MRI (rsfMRI), diffusion tensor imaging (DTI), 3 dimensional (3D) anatomical imaging, and magnetic resonance spectroscopy (MRS). Further complementary ex vivo analyses were added to fully unravel the underlying changes in the brain.
First, the impact of disturbances of the hypothalamus-pituitary-gonadal (HPG) axis on the brain was extensively explored. This neuroendocrine system is crucial for reproduction, however, increasing evidence points towards a significant role in brain ageing and neurodegeneration as well. However, so far no clear consensus exists regarding the potential of targeting this system to prevent or even cure cognitive deficits. In this thesis, two complementary models were used to unravel the impact on the brain induced by either peripheral HPG disturbances (driven by estrogen depletion upon ovariectomization) or central HPG disturbances (driven by GnRH deficiency). In the first model, aberrant long-range functional connectivity was coincident with cognitive deficits and alterations in cellular aging, myelination and dopaminergic neurotransmission. The second model presented an adult phenotype entailing hyperleptinemia, overweight and sensory hyperconnectivity. This model further showed evidence of a possible compensatory mechanism involving the hypothalamic excitatory/inhibitory balance.
In a second part, pathological brain ageing was examined in a promising rat model of AD recapitulating all hallmarks of human AD, in contrast to most existing (mouse) models. The importance of this study is highlighted by the fact that today most AD patients remain undiagnosed and still no cure exists. The obtained MRI results revealed that vast functional hypoconnectivity was already present at early stages of the disease, before plaque load, clear structural changes or known cognitive impairment.
In conclusion, this thesis highlights the potential of these translational neuroimaging methods to detect early signs of accelerated and pathological ageing. These results hold great significance for future studies aimed at the early diagnosis or modulation of age-related disease processes by e.g. targeting the endocrine system.