Neurovascular Changes Associated with Olfactory Deficits in Early Parkinson s Disease
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by widespread impairments in motor and cognitive/behavioral functions. Currently, PD can only be confirmed through postmortem examinations of brain tissue, demonstrating Lewy bodies in remaining neurons. Clinical diagnosis relies primarily on the assessment of symptoms and signs such as rigidity, tremor, bradykinesia, and postural instability. To date, no effective disease-modifying therapy has been found for PD. A major hurdle for treatment development in PD has been the lack of reliable measures to evaluate the efficacy of experimental therapeutic strategies. The investigation of functional deficits and associated physiological abnormalities in the early stages of PD may advance our understanding of the disease and may provide quantitative measures that are suitable for assessing disease progression and evaluating outcomes in therapeutic trials. Olfactory deficits in PD are prevalent, can precede motor symptoms, and are associated with alpha-synuclein pathology, which is a major pathological hallmark of PD. Therefore, non-invasive and repeatable in vivo measures (such as neurovascular measures) associated with olfactory deficits may be excellent candidates as quantitative in vivo biomarkers in early PD for tracking disease progression and evaluating treatment outcomes. Such measures may provide more specific and sensitive information and may change earlier and faster with disease progression compared to commonly used olfactory tests in the clinic. Energy metabolism is crucial for maintenance of normal brain functions. As the supply of adequate oxygen and energy substrates for local metabolic demands is controlled by blood vessels in the brain, neurovascular abnormalities may contribute to the neuropathology and functional deficits in PD. In this study, we will use advanced magnetic resonance imaging (MRI) technologies developed at ultra-high field (7T) to investigate neurovascular changes related to the olfactory system in the brain and their relationship with the severity of olfactory deficits in early PD patients. We will investigate the progression of such neurovascular abnormalities by comparing them across different stages of PD patients. The enhanced sensitivity of ultra-high field (7T) MRI will allow us to detect subtle changes with unprecedented spatial specificity, and the advanced MRI methods developed by us will enable us to study physiological changes in specific types of blood vessels (arteriolar, capillary, and venous) and to detect subtle functional changes in brain regions close air cavities (resulting in large artifacts with conventional methods) such as the olfactory cortex. We expect that our findings here may have wider applicability even at sites without 7T scanners, as findings at 7T will provide more focused targets for studies conducted at more widely available 3T scanners, using the same spatial resolution but partial brain coverage with longer scan times (more repeats) to boost sensitivity. The proposed work directly addresses two of the Focus Areas of this program: (1) studies of the microvasculature in PD and (2) mechanisms in early PD involving the olfactory system. If successful, the proposed studies will reveal microvascular and metabolic abnormalities in the brain underlying olfactory deficits in PD patients. This will advance our understanding on the neurophysiology related to olfactory impairment in PD and may lead to new avenues of investigation. Our ultimate goal is to develop reliable quantitative in vivo biomarkers for assessing progression and treatment outcomes in early PD. Given the prevalence of olfactory impairment in early PD and its association with alpha-synucleinopathy, neurovascular changes in the olfactory system (if validated) may be excellent candidates as progression and/or treatment effect biomarkers in PD. These MRI-based measures are noninvasive, repeatable for follow-up
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710667
Entities
People
- Jun Hua
Organizations
- Kennedy Krieger Institute
- United States Army