Author ORCID Identifier

https://orcid.org/0000-0003-1809-0879

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Engineering

Department

Biomedical Engineering

First Advisor

Dr. Guoqiang Yu

Abstract

Objective: Cerebrovascular disease (CVD) is the fifth most common cause of mortality in the United States. Diagnosis of CVD at an early stage is critical for optimal intervention designed to prevent ongoing and future brain injury. CVD is commonly associated with abnormalities of the cerebral microvasculature leading to tissue dysfunction, neuronal injury and death, and resultant clinical symptoms, which in turn, further impacts cerebral autoregulation (CA). This series of studies aims to test the hypothesis that white matter hyperintensities (WMH) and cerebral hemodynamics (quantified by magnetic resonance imaging (MRI) and an by innovative hybrid near-infrared diffuse optical instrument) can be used as biomarkers to distinguish cognitively healthy older subjects with high or low risk for developing CVD.

Methods: Using functional MRI, WMH and cerebral blood flow (CBF) were quantified in 26 cognitively healthy older subjects (age: 77.8 ± 6.8 years). In a follow-up study, significant variability in WMH quantification methodology was addressed, with sources of variability identified in selecting image center of gravity, software compatibility, thresholding techniques, and manual editing procedures.

Accordingly, post-acquisition processing methods were optimized to develop a standardized protocol with less than 0.5% inter-rater variance. Using a novel laboratory-made hybrid near-infrared spectroscopy/diffuse correlation spectroscopy (NIRS/DCS) and a finger plethysmograph, low-frequency oscillations (LFOs) of CBF, cerebral oxygenation, and main arterial pressure (MAP) were simultaneously measured before, during, and after 70° head-up-tilting (HUT). Gains (associated with CAs) to magnify LFOs were determined by transfer function analyses with MAP as the input and cerebral hemodynamic parameters as the outputs. In a follow-up study, a fast software correlator for DCS and a parallel detection technique for NIRS/DCS were adapted to improve the sampling rate of hybrid optical measurements. In addition, a new DCS probe was developed to measure CBF at the occipital lobe, which represents a novel application of the NIRS/DCS technique.

Results: MRI measurements demonstrate that deep WMH (dWMH) and periventricular WMH (pWMH) volumetric measures are associated with reduced regional cortical CBF in patients at high-risk of CVD. Moreover, CBF in white matter (WM) was reduced in regions demonstrating both pWMH and dWMHs. NIRS/DCS optical measurements demonstrate that at resting baseline, LFO gains in the high-risk group were relatively lower compared to the low-risk group. The lower baseline gains in the high-risk group may be attributed to compensatory mechanisms that allow the maintenance of a stronger steady-state CA. However, HUT resulted in smaller gain reductions in the high-risk group compared to the low-risk group, suggesting weaker dynamic CA in association with increased CVD risks. A noteworthy finding in these experiments was that CVD risk more strongly influenced CBF than cerebral oxygenation.

Conclusions: Regional WMH volumes, cortical and WM CBF values, and LFO gains of cerebral hemodynamics demonstrate specific associations with CA and may serve as important potential biomarkers for early diagnosis of CVD. The high spatial resolution, large penetration depth, and variety of imaging-sequences afforded by MRI make it an appealing imaging modality for evaluation of CVD, although MRI is costly, time-limited, and requires transfer of subjects from bed to imaging facility. In contrast, low-cost, portable, mobile diffuse optical technologies provide a complementary alternative for early screening of CVD, that can further allow continuous monitoring of disease attenuation or progression at the subject’s bedside. Thus, development of both methodologies is essential for progress in our future understanding of CVD as a major contributor to the morbidity and mortality associated with CVD today.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.140

Funding Information

Higher Committee for Education Development in Iraq (HCED). and National Institutes of Health (NIH): UH2-NS100606 (2016 - 2018), R01-NR014189 (2012 - 2017), R01-AG042419 (2013 - 2016), P30-AG028383 (2017), 5P30-AG028383 (2013 - 2014), 1R21-HD091118-01A1 (2018 - 2020), 3R21-HD091118-02S1 (2019 - 2021), 1R21-AR062356 (2012), and 1R01-AG062480 (2019 - 2024), American Heart Association (AHA): 16GIA30820006 (2016 - 2019) and National Science Foundation (NSF): EPSCoR-1539068 (2015 - 2020).

Available for download on Thursday, November 12, 2020

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