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Project

Influence of chronic oligemia on neurovascular defects and their relation to the onset and development of neurodegeneration: in vivo evaluation of neurovascular response capacity and metabolism in an Alzheimer mouse model.

Alzheimer’s Disease (AD) is the most common cause of dementia, and the most common neurodegenerative disease. AD patients suffer from age-dependent accumulation of dysfunctional amyloid and tau proteins, leading to the deterioration of neurons.  As the disease progresses, cognitive faculties become impaired, eventually resulting in death 4-10 years after diagnosis. The most important risk factor is age, and to the increasing overall age of the Western population, it is becoming an increasingly important health issue.

Every year, substantial resources are used for research on AD. However, there has not been a breakthrough with regards to a definitive, curative treatment or even a diagnostic tool for sensitive early screening. Following several failures of promising novel drug candidates for AD, pharmaceutical giant Pfizer has recently even ceased research on AD altogether. Clearly, there is a large, unmet need for appropriate tools that may assist in the development of new drugs and diagnostic modalities.

In this thesis, we have approached this issue by developing several novel pipelines and image processing tools for the longitudinal in vivo follow-up of transgenic mouse models for AD. We made use of several models that address different aspects of AD, but in particular we focused on the biAT mouse model. This is a model that recapitulates many common hallmarks of AD, in particular the age-dependent accumulation of pathogenic amyloid plaques and tau tangles. We have also investigated the two parental strains of the biAT model, which exhibit only one of these two hallmarks, in order to elucidate whether the impairments we observed were caused by amyloid, tau, or an interaction of both.

Vascular dysfunction plays a substantial role in AD. Furthermore, there is substantial overlap between risk factors for cerebrovascular disease and AD. For this reason, we describe a novel pipeline for assessing the capacity of cerebral blood vessels to respond to vasodilatory stimuli, termed cerebrovascular response (CVR). This is a metric that provides information on how much blood, and by extension how much oxygen, the brain can mobilize in response to a sufficiently powerful vasodilatory stimulus. Rather than merely providing information on basal cerebral blood flow (CBF), which is heavily influenced by extraneous factors such as anesthesia level, CVR provides a robust measure of the brain’s capability of responding to e.g. stressors. Current methods for the assessment of CVR in mice are typically limited to cross-sectional studies due to ethical considerations regarding the anesthesia used. For this reason, we have described a novel acquisition paradigm for the acquisition of CVR data in mice. Furthermore, we were able to show that mice that develop amyloid pathology exhibit altered CVR even at a young, presymptomatic stage.

Next, we considered that cerebral perfusion and CVR provide functional but lack anatomical information. For this purpose, we developed a magnetic resonance angiography (MRA) pipeline, which allows for the semi-automatic assessment of the morphological characteristics of selected blood vessels. As a proof of concept, we applied this method in the context of a common carotid artery ligation model, which has severe vascular malformations. After indicating that we were able to reliably quantify the extent of these malformations, we applied it to the biAT mouse model, which we hypothesized might develop subtle morphological changes in larger blood vessels as a result of e.g. soluble amyloid or cerebral amyloid angiopathy. We were unable to identify such morphological impairments in transgenic animals, but we were able to map the age-related changes in vascular morphology, indicating that our method is sensitive enough to track subtle morphological alterations.

We also described the longitudinal changes in overall brain morphology, as well as magnetic resonance T2 relaxation times in biAT animals. We have applied an anatomical imaging protocol and processing pipeline and determined that biAT animals exhibit increased brain size compared to age-matched controls. Although we had hypothesized that amyloid deposition may influence T2 relaxation due to the presence of paramagnetic iron, we observed that parametric T2 maps were not sensitive enough to observe such changes at the ages of the mice we studied.

Finally, we applied the methods described before to the Tau.P301S model. These transgenic mice exhibit an aggressive pattern of neurodegeneration and have a maximum life span of only approximately 9 months. As the literature data is not as abundant for tau transgenic mice as for models for amyloid pathology, we set up a pilot study on a limited number of mice, in which we assessed the efficacy of several MRI modalities. We were able to establish that, in these mice, longitudinal atrophy monitoring based on anatomical imaging, as well as magnetic resonance spectroscopy (MRS), provided the most sensitive information on disease progression and to distinguish between control and Tau.P301S mice, possibly identifying early markers for onset of the disease.

Taken together, these results indicate that different animal models may require different imaging and processing approaches for their detailed and differential characterization. The methods we used link various different anatomical, functional and metabolic characteristics, and will therefore provide insights into the underlying mechanisms of AD. The various tools developed in this thesis will also prove helpful for future studies evaluating the progression of neurodegeneration in mouse models, as well as the response to newly developed treatments.

Date:1 Oct 2013 →  17 Sep 2019
Keywords:Influence of chronic oligemia
Disciplines:Medical imaging and therapy, Other paramedical sciences
Project type:PhD project