9 research outputs found
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Brain-Blood Partition Coefficient and Cerebral Blood Flow in Canines Using Calibrated Short TR Recovery (CaSTRR) Correction Method.
The brain-blood partition coefficient (BBPC) is necessary for quantifying cerebral blood flow (CBF) when using tracer based techniques like arterial spin labeling (ASL). A recent improvement to traditional MRI measurements of BBPC, called calibrated short TR recovery (CaSTRR), has demonstrated a significant reduction in acquisition time for BBPC maps in mice. In this study CaSTRR is applied to a cohort of healthy canines (n = 17, age = 5.0 - 8.0 years) using a protocol suited for application in humans at 3T. The imaging protocol included CaSTRR for BBPC maps, pseudo-continuous ASL for CBF maps, and high resolution anatomical images. The standard CaSTRR method of normalizing BBPC to gadolinium-doped deuterium oxide phantoms was also compared to normalization using hematocrit (Hct) as a proxy value for blood water content. The results show that CaSTRR is able to produce high quality BBPC maps with a 4 min acquisition time. The BBPC maps demonstrate significantly higher BBPC in gray matter (0.83 ± 0.05 mL/g) than in white matter (0.78 ± 0.04 mL/g, p = 0.006). Maps of CBF acquired with pCASL demonstrate a negative correlation between gray matter perfusion and age (p = 0.003). Voxel-wise correction for BBPC is also shown to improve contrast to noise ratio between gray and white matter in CBF maps. A novel aspect of the study was to show that that BBPC measurements can be calculated based on the known Hct of the blood sample placed in scanner. We found a strong correlation (R 2 = 0.81 in gray matter, R 2 = 0.59 in white matter) established between BBPC maps normalized to the doped phantoms and BBPC maps normalized using Hct. This obviates the need for doped water phantoms which simplifies both the acquisition protocol and the post-processing methods. Together this suggests that CaSTRR represents a feasible, rapid method to account for BBPC variability when quantifying CBF. As canines have been used widely for aging and Alzheimer's disease studies, the CaSTRR method established in the animals may further improve CBF measurements and advance our understanding of cerebrovascular changes in aging and neurodegeneration
Adipose-Derived Autotaxin Regulates Inflammation and Steatosis Associated with Diet-Induced Obesity
Autotaxin (ATX) is a secreted enzyme that generates the bioactive lipid lysophosphatidic acid (LPA). We generated mice with global inducible post-natal inactivation or adipose-specific loss of the Enpp2 gene encoding ATX. The animals are phenotypically unremarkable and exhibit differences in adipocyte size and adipose tissue expression of inflammatory genes after high fat feeding without gross differences in fat distribution or body mass. Surprisingly, both models of Enpp2- deficiency exhibited marked protection from high fat diet-induced hepatic steatosis. This phenotype was not associated with differences in dietary fat absorption but may be accounted for by differences in hepatic expression of genes involved in de novo synthesis of triglycerides. These findings suggest that pharmacological inhibition of ATX might be protective against hepatic steatosis
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Brain-Blood Partition Coefficient and Cerebral Blood Flow in Canines Using Calibrated Short TR Recovery (CaSTRR) Correction Method.
The brain-blood partition coefficient (BBPC) is necessary for quantifying cerebral blood flow (CBF) when using tracer based techniques like arterial spin labeling (ASL). A recent improvement to traditional MRI measurements of BBPC, called calibrated short TR recovery (CaSTRR), has demonstrated a significant reduction in acquisition time for BBPC maps in mice. In this study CaSTRR is applied to a cohort of healthy canines (n = 17, age = 5.0 - 8.0 years) using a protocol suited for application in humans at 3T. The imaging protocol included CaSTRR for BBPC maps, pseudo-continuous ASL for CBF maps, and high resolution anatomical images. The standard CaSTRR method of normalizing BBPC to gadolinium-doped deuterium oxide phantoms was also compared to normalization using hematocrit (Hct) as a proxy value for blood water content. The results show that CaSTRR is able to produce high quality BBPC maps with a 4 min acquisition time. The BBPC maps demonstrate significantly higher BBPC in gray matter (0.83 ± 0.05 mL/g) than in white matter (0.78 ± 0.04 mL/g, p = 0.006). Maps of CBF acquired with pCASL demonstrate a negative correlation between gray matter perfusion and age (p = 0.003). Voxel-wise correction for BBPC is also shown to improve contrast to noise ratio between gray and white matter in CBF maps. A novel aspect of the study was to show that that BBPC measurements can be calculated based on the known Hct of the blood sample placed in scanner. We found a strong correlation (R 2 = 0.81 in gray matter, R 2 = 0.59 in white matter) established between BBPC maps normalized to the doped phantoms and BBPC maps normalized using Hct. This obviates the need for doped water phantoms which simplifies both the acquisition protocol and the post-processing methods. Together this suggests that CaSTRR represents a feasible, rapid method to account for BBPC variability when quantifying CBF. As canines have been used widely for aging and Alzheimer's disease studies, the CaSTRR method established in the animals may further improve CBF measurements and advance our understanding of cerebrovascular changes in aging and neurodegeneration
Satellite Cell Depletion Does Not Inhibit Adult Skeletal Muscle Regrowth Following Unloading-induced Atrophy
Resident muscle stem cells, known as satellite cells, are thought to be the main mediators of skeletal muscle plasticity. Satellite cells are activated, replicate, and fuse into existing muscle fibers in response to both muscle injury and mechanical load. It is generally well-accepted that satellite cells participate in postnatal growth, hypertrophy, and muscle regeneration following injury; however, their role in muscle regrowth following an atrophic stimulus remains equivocal. The current study employed a genetic mouse model (Pax7-DTA) that allowed for the effective depletion of \u3e90% of satellite cells in adult muscle upon the administration of tamoxifen. Vehicle and tamoxifen-treated young adult female mice were either hindlimb suspended for 14 days to induce muscle atrophy or hindlimb suspended for 14 days followed by 14 days of reloading to allow regrowth, or they remained ambulatory for the duration of the experimental protocol. Additionally, 5-bromo-2\u27-deoxyuridine (BrdU) was added to the drinking water to track cell proliferation. Soleus muscle atrophy, as measured by whole muscle wet weight, fiber cross-sectional area, and single-fiber width, occurred in response to suspension and did not differ between satellite cell-depleted and control muscles. Furthermore, the depletion of satellite cells did not attenuate muscle mass or force recovery during the 14-day reloading period, suggesting that satellite cells are not required for muscle regrowth. Myonuclear number was not altered during either the suspension or the reloading period in soleus muscle fibers from vehicle-treated or satellite cell-depleted animals. Thus, myonuclear domain size was reduced following suspension due to decreased cytoplasmic volume and was completely restored following reloading, independent of the presence of satellite cells. These results provide convincing evidence that satellite cells are not required for muscle regrowth following atrophy and that, instead, the myonuclear domain size changes as myofibers adapt
Satellite cell depletion does not inhibit adult skeletal muscle regrowth following unloading-induced atrophy
Resident muscle stem cells, known as satellite cells, are thought to be the main mediators of skeletal muscle plasticity. Satellite cells are activated, replicate, and fuse into existing muscle fibers in response to both muscle injury and mechanical load. It is generally well-accepted that satellite cells participate in postnatal growth, hypertrophy, and muscle regeneration following injury; however, their role in muscle regrowth following an atrophic stimulus remains equivocal. The current study employed a genetic mouse model (Pax7-DTA) that allowed for the effective depletion of >90% of satellite cells in adult muscle upon the administration of tamoxifen. Vehicle and tamoxifen-treated young adult female mice were either hindlimb suspended for 14 days to induce muscle atrophy or hindlimb suspended for 14 days followed by 14 days of reloading to allow regrowth, or they remained ambulatory for the duration of the experimental protocol. Additionally, 5-bromo-2'-deoxyuridine (BrdU) was added to the drinking water to track cell proliferation. Soleus muscle atrophy, as measured by whole muscle wet weight, fiber cross-sectional area, and single-fiber width, occurred in response to suspension and did not differ between satellite cell-depleted and control muscles. Furthermore, the depletion of satellite cells did not attenuate muscle mass or force recovery during the 14-day reloading period, suggesting that satellite cells are not required for muscle regrowth. Myonuclear number was not altered during either the suspension or the reloading period in soleus muscle fibers from vehicle-treated or satellite cell-depleted animals. Thus, myonuclear domain size was reduced following suspension due to decreased cytoplasmic volume and was completely restored following reloading, independent of the presence of satellite cells. These results provide convincing evidence that satellite cells are not required for muscle regrowth following atrophy and that, instead, the myonuclear domain size changes as myofibers adapt
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APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease
The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (Aβ) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aβ retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE ε3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine Aβ retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for Aβ transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers