Amyotrophic Lateral Sclerosis (ALS): Sporadic Amyotrophic lateral sclerosis (SALS) is a neurodegenerative disease that targets upper and lower motor neurons and causes motor unit loss; severe, progressive muscle atrophy; and almost inevitably, death. Multiple lines of evidence, derived primarily from animal models of ALS, suggest that reduced skeletal muscle oxidative ATP-synthesis (“mitochondrial dysfunction”) manifests itself early in the disease process and may contribute to these neurodegenerative processes. However, whether or not skeletal muscle mitochondrial dysfunction is present in human ALS patients and what role it may play in neurdegeneration remains equivocal. A limitation to testing the hypothesis of skeletal muscle mitochondrial dysfunction in human SALS patients is the primary technique used to date is muscle biopsy followed by histochemical analysis. The biopsy technique is prone to false negatives, due to the small sampling volume, and the invasive nature of the technique makes it inappropriate for use in a disease marked by muscle wasting. However, phosphorus magnetic resonance spectroscopy (31P-MRS) provides a powerful alternative for assessing mitochondrial function in vivo, has been used successfully to study mitochondrial function in other pathological conditions involving muscle, can acquire data from localized anatomical regions, and is non-invasive and non-destructive. Therefore, the overall goal of this project is to use 31P-MRS to explore the presence and whole-body energetic consequences of skeletal muscle mitochondrial dysfunction in SALS patients and to relate these measures of mitochondrial function to clinical measures of disease state.
Collaborators: Chris Lee: https://www.mc.vanderbilt.edu/root/vumc.php?site=neurology&doc=26240 and Amanda Peltier: https://www.mc.vanderbilt.edu/root/vumc.php?site=neurology&doc=26254
Brown Adipose Tissue:Human BAT was believed to diminish with age and to be essentially undetectable in adults. However, recent studies using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and fat-water MRI suggest that small but metabolically significant amounts of hBAT persist into adulthood. It is estimated that between 41% and 96% of healthy adult human subjects have detectable BAT. Recent studies further suggest an inverse relationship between hBAT and obesity, although it remains unclear whether reduced hBAT amount and/or activity promotes or results from obesity. The most popular technique for assessing hBAT mass and activity is PET, which has come under scrutiny because it only detects activated hBAT and therefore may underreport the prevalence of hBAT. The almost exclusive use of PET may explain the large variation in the reported presence of hBAT (41% to 96%). Furthermore, radioactive tracers are incompatible with studies designed to assess longitudinal changes in hBAT mass and activity following pharmacological or lifestyle interventions. Recently we have developed robust MRI-based techniques to assess hBAT mass and activity. These techniques will provide an accurate assessment of the prevalence of hBAT as well as the role of physical activity, sex, age, and body composition on hBAT mass and activity. The purpose of this project is to measure the presence and metabolic activity of hBAT in a broad range of adult human subjects and to learn how hBAT impacts metabolism and energy balance when activated.
Collaborator: Brian Welch: https://medschool.mc.vanderbilt.edu/facultydata/php_files/show_faculty…
Skeletal Muscle BOLD imaging at Ultra-High Field: Blood oxygenation-level dependent (BOLD) contrast in skeletal muscle was first described more than 15 years ago. Since that time, the applications of muscle BOLD (mBOLD) contrast have been advanced in several ways. For example, function-based mBOLD contrast has been used to infer small vessel function following isometric contractions, arterial occlusion in patients with peripheral artery disease patients, and the infusion of vasoactive compounds. Also, the dependence of the rate of RF-reversible dephasing on blood deoxyhemoglobin content has allowed the use of mBOLD-based methods to estimate blood O2 extraction during exercise.
When compared to studies at lower field strength, mBOLD studies at ultra-high fields may differ in several fundamental ways. One advantage to 7T MRI is an improved signal-to-noise ratio (SNR) due to greater spin polarization, which may be used in imaging studies to improve spatial and/or temporal resolution. Another potential advantage is improved contrast, including an improved contrast-to-noise ratio (CNR) and/or new or more physiologically specific sources of contrast. In particular, the rapid transverse relaxation of blood at 7T is expected to favor BOLD contrast from extravascular (EV) sources. EV BOLD contrast refers to the effects of hemoglobin content and oxygen saturation on the relaxation of extravascular spins. A final general advantage is improved SNR and spectral dispersion for MR spectroscopy studies. These possibilities have promoted the use of 7T MRI for studies of human brain structure and function. However, during this same period, there have been very few musculoskeletal MRI studies at 7T and even fewer have been dedicated to skeletal muscle. The goals of our mBOLD projects are to develop and implement protocol to understand the biophysical basis of mBOLD at ultra-high magnetic field strengths.
Collaborator: Bruce Damon: https://medschool.mc.vanderbilt.edu/facultydata/php_files/part_dept/sho…