Faculty Bibliography

Contraction of the heart is central to its purpose of pumping blood around the body. While simple global function measures (such as the ejection fraction) are most commonly used in the clinical assessment of cardiac function, MRI also provides a range of approaches for quantitatively characterizing regional cardiac function, including the local deformation (or strain) within the heart wall. While they have been around for some years, these methods are still undergoing further technical development, and they have had relatively little clinical evaluation. However, they can provide potentially useful new ways to assess cardiac function, which may be able to contribute to better classification and treatment of heart disease. This article provides some basic background on the physical and physiological factors that determine the motion of the heart, in health and disease and then reviews some of the ways that MRI methods are being developed to image and quantify strain within the myocardium. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) alpha. We examined behavioral alterations related to obsessive-compulsive disorder (OCD) and the role of TNFalpha and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFalpha in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFalpha. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor kappaB (NF-kappaB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-kappaB activation in microglia and elevated TNFalpha signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

Eukaryotic translation initiation factor 2B (eIF2B) is a master regulator of protein synthesis under normal and stress conditions. Mutations in any of the five genes encoding its subunits lead to vanishing white matter (VWM) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. In this study we used fibroblasts, which are not involved in the disease, to demonstrate the involvement of eIF2B in mitochondrial function and abundance. Mass spectrometry of total proteome of mouse embryonic fibroblasts (MEFs) isolated from Eif2b5R132H/R132H mice revealed unbalanced stoichiometry of proteins involved in oxidative phosphorylation and of mitochondrial translation machinery components, among others. Mutant MEFs exhibit 55% decrease in oxygen consumption rate per mtDNA content and 47% increase in mitochondrial abundance (p < 0.005), reflecting adaptation to energy requirements. A more robust eIF2B-associated oxidative respiration deficiency was found in mutant primary astrocytes, which exhibit > 3-fold lower ATP-linked respiration per cell despite a 2-fold increase in mtDNA content (p < 0.03). The 2-fold increase in basal and stimulated glycolysis in mutant astrocytes (p