We would like to thank the Vanderbilt University Institute of Imaging Science MRI technologists David Pennell, Leslie McIntosh, and Kristen George-Durrett, and the team of Vanderbilt University Medical Center PET/CT technologists led by Martha D. Shone. This work was supported by the following grants from the NIH: NCATS/NIH UL1 RR024975, NIDDK/NIH R21DK096282, NCI/NIH R25CA136440, and NIBIB/NIH T32EB014841.

NOTE: The local ethics committee of this institute approved this study, and all subjects provided written informed consent prior to participation. To be eligible for the study, subjects must fulfill the following requirements: no known diabetes mellitus; no use of beta blockers or anxiety medications, currently or in the past; does not smoke or chew tobacco products, currently or in the past; no more than 4 cups of caffeine each day; no more than 2 glasses of alcohol each day; and if female, not pregnant or breastfeeding...

The described study protocol is designed to use both thermoneutral and cold-activated PET/CT to automatically segment BAT depots on a subject specific basis. These automatically generated regions of interest can then be applied to both thermoneutral and cold-activated MRI scans which have been co-registered to the PET/CT scans of the same subject. To the best of our knowledge, this is the first research to perform both MRI and PET/CT after thermoneutral and cold-activated conditions on the same healthy adult human volunt...

Due to the marked rise in obesity worldwide, there is an increased interest in research areas aimed at understanding energy balance. Obesity can result in costly and devastating medical conditions such as diabetes, liver disease, cardiovascular disease and cancer, making it a significant area of concern for public health1. One area of research aimed at understanding the balance of energy intake versus energy expenditure is the study of brown adipose tissue or BAT. Although termed an adipose tissue, BAT differs from the more common white adipose tissue (WAT) in many ways2. The function of white adipocytes is to store triglycerides in a single large lipid vacuole per cell, and to release these triglycerides as a source of energy into the blood stream when needed. In a very different manner, the function of brown adipocytes is to produce heat. One mechanism by which this occurs is through exposure to cold. This causes an increase in sympathetic nervous system activity, which in turn activates BAT. When activated, brown adipocytes generate heat. To do so, they use the triglycerides contained in the many small lipid vacuoles per cell, and through the presence of uncoupling protein 1 (UCP1) in the abundant mitochondria, convert the triglycerides to metabolic substrates without the production of ATP, resulting in entropic loss as heat generation. As the triglycerides stored in the small lipid vacuoles are depleted, the adipocyte takes up both glucose and triglycerides present in the blood stream3.
Interest in studying BAT has dramatically increased in recent years due to its contribution to non-shivering thermogenesis, its role in modulating the body&#8217;s energy expenditure, and the potential inverse relationship between BAT and obesity3&#8211;9. In addition, recent animal studies indicate BAT plays a critical role in clearing triglycerides and glucose from the blood stream, especially following ingestion of a high fat meal10,11. However, most of what we know about BAT is a result of research in small mammals, which contain many depots of BAT4,9,12&#8211;15. Notwithstanding a few early studies16&#8211;18, the presence of BAT in humans was widely thought to diminish with age until recently when interest in studying human BAT has been renewed. Recent research suggests that relatively small amounts of BAT persist into adulthood19&#8211;24. An additional limiting factor to studying BAT is that apart from biopsy and histological staining, the currently accepted unequivocal method for detecting BAT is 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Modern PET scanners are typically combined with a computed tomography (CT) scanner. When activated by cold exposure, BAT takes up the 18F-FDG radiotracer, which is a metabolic analogue of glucose, and becomes visible on PET images, in comparison to the much lower level of 18F-FDG uptake when BAT is inactive20,21,23,25. CT images acquired during a PET exam on a PET-CT scanner help to differentiate between tissues with high 18F-FDG uptake by providing anatomical information. This use of PET-CT imaging exposes the subject to ionizing radiation (predominately from PET, though the dose from the CT scan is not negligible), and is therefore an undesirable method for BAT detection.
Although the number of studies on BAT in healthy adult humans is increasing, recent studies of human BAT have mainly been limited to retrospective PET-CT studies19,25, human infant cadavers26,27, human adolescents who have already been admitted to hospitals for other reasons27&#8211;30, and a few human studies of healthy adults31&#8211;35. One of the challenges with both studies of children and retrospective studies is the possibility of altered results when studying a patient population who is sick, which may affect BAT. Additionally, because glucose is not the preferred fuel source of BAT36, PET studies may not always detect activated BAT, and therefore may underrepresent the presence of BAT. Another difficulty in studying BAT with biomedical imaging is related to performing image segmentation to define the boundaries of tissue depots. Currently, segmentation of BAT in human studies often relies on some degree of manual image segmentation and is therefore vulnerable to misidentification of BAT depots, as well as inter-rater variability.
Because of these challenges, reliable spatial mapping techniques that can distinguish BAT from WAT distributions, along with automated segmentation methods, would provide investigators with a powerful new tool with which to study BAT. Magnetic resonance imaging (MRI) has the capability for identification, spatial mapping, and volumetric quantification of BAT, and unlike existing hybrid PET-CT imaging approaches that include a radioactive dose for the imaged subject, MRI involves no ionizing radiation and can be used safely and repeatedly. The ability to identify and quantify BAT using MRI can have a dramatic positive impact on clinical endocrinology and the pursuit of new avenues of obesity research. Previous fat-water MRI (FWMRI) studies of BAT in both mice and humans show that the fat-signal-fraction (FSF) of BAT is in the range of 40-80% fat, whereas WAT is above 90% fat15,26,27. We therefore hypothesize that this quantitative FWMRI metric, in conjunction with other quantitative MRI metrics, can be used in future work to visualize and quantify BAT depots in humans. This would provide the research community with a powerful tool with which to study BAT&#8217;s influence on metabolism and energy expenditure without the use of ionizing radiation.
Our research group has been studying BAT in adult humans for the past three years. Our first public presentation on the use of MRI to investigate suspected BAT in one adult human subject occurred in February 2012 at the International Society for Magnetic Resonance in Medicine (ISMRM) Fat-Water Separation Workshop in Long Beach, California37. Two months later, our group presented FSF values in suspected BAT in two adults at the 20th annual meeting of the ISMRM in April 2012 in Melbourne, Australia38. One year later at the 21st annual meeting of the ISMRM in April 2013 in Salt Lake City, Utah, the protocol described in this manuscript was used for the first (to the best of our knowledge) public presentation of MRI quantification of PET-confirmed BAT in adult human subjects39. Specifically, we presented evidence showing that the previously suspected BAT was confirmed to be activatable BAT using both cold-activated and thermoneutral 18F-FDG PET-CT imaging. Since 2013, our cohort of healthy adult human subjects imaged with both MRI and PET/CT under thermoneutral and cold-activated conditions has expanded to more than 20 subjects with results most recently presented in February 2014 at the workshop &#8220;Exploring the Role of Brown Fat in Humans&#8221; sponsored by the NIH NIDDK40. Specifically, we reported FWMRI FSF and R2* relaxation properties in regions of supraclavicular BAT confirmed by 18F-FDG PET-CT in adult humans, with the BAT ROIs delineated using automated segmentation algorithms based on the cold-activated and thermoneutral PET-CT scans. Most recently we presented results of temperature mapping in 18F-FDG PET-CT confirmed BAT in adult humans using advanced FWMRI thermometry41,42.
The procedure presented here acquires both MRI and 18F-FDG PET-CT scans on the same subject, each after exposure to both cold-activated and thermoneutral conditions. The cold-activated and thermoneutral 18F-FDG PET-CT scans are used to create automatically segmented BAT regions of interest (ROIs), on a subject specific basis. These BAT ROIs are then applied to the co-registered MRI scans to measure the MRI properties in the PET-CT confirmed BAT.
A limitation of this protocol is that the air temperature used when exposing subjects to either the warm or cold stimulus is consistent for every subject. This is a limitation because the temperature at which each subject experiences feeling warm or chilled can be different. Therefore, by running a trial session during which the air temperature is adjusted to fit the individual&#8217;s response, and then using these temperatures during the thermoneutral and cold-activation protocols, it could be possible to obtain better responses from the brown adipose tissue.

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			<td height="38" style="height:39px;width:363px;">MRI</td>
			<td style="width:392px;">Philips</td>
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			<td height="68" style="height:68px;width:363px;">MRI Torso-XL coil</td>
			<td style="width:392px;">Philips</td>
			<td style="width:375px;">Philips SENSE XL Torso coil 16-elements</td>
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			<td height="68" style="height:68px;width:363px;">MRI X-tend Table</td>
			<td style="width:392px;">X-Tend</td>
			<td style="width:375px;">X-tend table, Acieva 3T compatible</td>
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		<tr height="34">
			<td height="34" style="height:34px;width:363px;">X-tend armsupport</td>
			<td style="width:392px;">X-Tend</td>
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			<td height="34" style="height:34px;width:363px;">X-tend fabricsling</td>
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			<td style="width:375px;">Discovery STE</td>
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			<td height="38" style="height:39px;width:363px;">Portable A/C Unit</td>
			<td style="width:392px;">Soleus Air</td>
			<td style="width:375px;">XL-140, 14000 BTU</td>
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		<tr height="38">
			<td height="38" style="height:39px;width:363px;">Floor fan</td>
			<td style="width:392px;">Lasko Pedestal Fan</td>
			<td style="width:375px;">2527</td>
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		<tr height="38">
			<td height="38" style="height:39px;width:363px;">Portable Heater</td>
			<td style="width:392px;">Lasko Ceramic Air</td>
			<td style="width:375px;">5536</td>
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			<td height="38" style="height:39px;width:363px;">Chair</td>
			<td style="width:392px;">Winco Lifecare Recliner</td>
			<td style="width:375px;">585</td>
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			<td height="38" style="height:39px;width:363px;">Sublingual Thermometer</td>
			<td style="width:392px;">WelchAllyn</td>
			<td style="width:375px;">SureTemp Plus 690</td>
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			<td height="38" style="height:39px;width:363px;">Cold vest</td>
			<td style="width:392px;">Polar Products</td>
			<td style="width:375px;">Cool58 #PCVZ</td>
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		<tr height="38">
			<td height="38" style="height:39px;width:363px;">Thermal IR Camera</td>
			<td style="width:392px;">FLUKE</td>
			<td style="width:375px;">TIR-125</td>
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human brown adipose tissue depots automatically segmented by positron emission tomography/computed tomography and registered magnetic resonance images

Reliably differentiating brown adipose tissue (BAT) from other tissues using a non-invasive imaging method is an important step toward studying BAT in humans. Detecting BAT is typically confirmed by the uptake of the injected radioactive tracer 18F-Fluorodeoxyglucose (18F-FDG) into adipose tissue depots, as measured by positron emission tomography/computed tomography (PET-CT) scans after exposing the subject to cold stimulus. Fat-water separated magnetic resonance imaging (MRI) has the ability to distinguish BAT without the use of a radioactive tracer. To date, MRI of BAT in adult humans has not been co-registered with cold-activated PET-CT. Therefore, this protocol uses 18F-FDG PET-CT scans to automatically generate a BAT mask, which is then applied to co-registered MRI scans of the same subject. This approach enables measurement of quantitative MRI properties of BAT without manual segmentation. BAT masks are created from two PET-CT scans: after exposure for 2 hr to either thermoneutral (TN) (24 &#176;C) or cold-activated (CA) (17 &#176;C) conditions. The TN and CA PET-CT scans are registered, and the PET standardized uptake and CT Hounsfield values are used to create a mask containing only BAT. CA and TN MRI scans are also acquired on the same subject and registered to the PET-CT scans in order to establish quantitative MRI properties within the automatically defined BAT mask. An advantage of this approach is that the segmentation is completely automated and is based on widely accepted methods for identification of activated BAT (PET-CT). The quantitative MRI properties of BAT established using this protocol can serve as the basis for an MRI-only BAT examination that avoids the radiation associated with PET-CT.

Acquiring both MRI and PET-CT scans on the same subject, and performing co-registration on all scans enables reliable measurement of quantitative MRI metrics of BAT. Figure 1 shows the unprocessed warm (TN) and cold (CA) PET-CT and MRI scans from one subject. By acquiring both TN and CA PET-CT data, it is possible to clearly distinguish the cold-activated BAT depots by the increased 18F-FDG uptake. After co-registering all four scans (Figure 2 and 3), it is po...

Watch this Scientific Journal Video about Human Brown Adipose Tissue Depots Automatically Segmented by Positron Emission Tomography/Computed Tomography and Registered Magnetic Resonance Images at JoVE

Human Brown Adipose Tissue Depots Automatically Segmented by Positron Emission Tomography/Computed Tomography and Registered Magnetic Resonance Images

The method presented here uses 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET-CT) and fat-water separated magnetic resonance imaging (MRI), each scanned following 2 hr exposure to thermoneutral (24 &#176;C) and cold conditions (17 &#176;C) in order to map brown adipose tissue (BAT) in adult human subjects.

Reliably differentiating brown adipose tissue (BAT) from other tissues using a non-invasive imaging method is an important step toward studying BAT in ...

human-brown-adipose-tissue-depots-automatically-segmented-positron

Research

JoVE Journal

Medicine

12.1K ビュー.  Vanderbilt University. ここに提示された方法は、各々が温熱（24°Cに2時間暴露後にスキャンし、18 F-フルオロデオキシ（18 F-FDG）陽電子放出断層撮影/コンピュータ断層撮影法（PET-CT）および脂肪-水分離、磁気共鳴イメージング（MRI）を使用し）と成人のヒト対象における褐色脂肪組織（BAT）をマッピングするために冷たい条件（17℃）。 

ビデオ: Human Brown Adipose Tissue Depots Automatically Segmented by Positron Emission Tomography/Computed Tomography and Registered Magnetic Resonance Images