Multi-scale functional connectivity in preclinical models of Parkinson's disease

PROJECT SUMMARY / ABSTRACT: Parkinson’s disease is a progressive neurodegenerative disorder and is associated with significant motor and non-motor symptoms, traceable to the loss of nigral dopamine neurons in addition to widespread circuit dysfunction extending beyond the dying nigrostriatal tract. Imaging-based biomarkers play a critical role in assessing Parkinson’s-related pathological changes, but current biomarkers are limited in their diagnostic and prognostic ability, particularly in early disease stages when intervention would be most beneficial. Functional magnetic resonance imaging (fMRI) enables the study of brain activation and has been widely used to study global functional network changes in Parkinson’s disease. However, standard fMRI is limited in its ability to robustly measure subtle changes with disease, in part due to low sensitivity and specificity; furthermore, interpretation of standard fMRI is challenging due to the indirect link between neuronal function and MRI signal change. This lack of robust direct biomarkers is a critical gap that ultimately limits our ability to understand the underlying pathological changes, as well as evaluate emerging therapies. To overcome these limitations, we propose to leverage an advanced multi-contrast fMRI method that provides high contrast sensitivity, as well as distinct microvascular sensitivity. By coupling this method with pharmacological and chemogenetic manipulations, a direct link between fMRI-based functional networks and underlying neuronal function can be inferred. More specifically, this project aims to a) characterize multi-contrast (total vascular and microvascular) functional connectivity networks in two complementary preclinical models that recapitulate classic hallmarks of Parkinson’s disease - the progressive PFF synucleinopathy model and the acute 6-OHDA model; b) assess the effect of pharmacological dopamine modulation on functional networks, using both acute and chronic treatment paradigms, analogous to the standard treatment paradigm; and c) investigate the effect of endogenous modulation of the dorsal raphe serotonergic circuit and the locus coeruleus noradrenergic circuit – both of which are proposed to be involved in certain non-motor symptomology – on functional networks using chemogenetic methods. These studies will provide insight into functional network changes that occur over different vascular scales and via different neurotransmitter populations. The development of robust MRI biomarkers that relate to dopaminergic, serotonergic, and noradrenergic circuit function and dysfunction may also provide insight into the multifaceted nature of Parkinson’s disease that contributes to both motor and non-motor symptoms. As functional brain network dysfunction is widely observed in Parkinson’s disease, this integrative approach will enable the development of robust biomarkers of Parkinson’s disease with well-characterized pathophysiological origins, which is a critical shortcoming of current technologies.