The authors wish to thank Dr. Uchino in Sousen hospital for all procedures. The authors also thank Adam Phillips from the Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

This study was performed in compliance with the institutional review board (approval No. 07-01) and adhered to the tenets of the Declaration of Helsinki. Informed consent for medical record and brain image use was obtained from the patients&#8217; legal representatives. The study was conducted after approval by the institutional ethics committee (2017-14). This protocol was made following the guidelines of the Japanese Society of Nuclear Medicine and European Association of Nuclear Medicine as a reference15,16.
1. Screening of the Participants
<ol>
	<li>Obtain informed consent to use the medical records and brain images of the patients from the patients&#8217; legal representatives. A Glasgow Coma Scale score &#8804; 8 at the time of accident must have been recorded in each patient&#8217;s medical record17,18,19.</li>
	<li>Hold neurology, psychology, and multi-disciplinary staff conferences every six months to assess clinical manifestations. 
	Note: Conference members should include medical staff such as medical doctors, nurses, physical therapists, occupational therapists, speech therapists, nutritionists, and medical social workers. Be sure to constantly check whether patients can communicate (verbally or nonverbally) and make decisions for themselves because arousal state and neurological status are typically unstable.</li>
	<li>Conduct clinical assessments of the auditory function, visual function, motor function, oromotor/verbal function, communication function, arousal state, facial expression, and other relevant functions, using standard assessment batteries such as the Coma Recovery Scale-Revised (CRS-R), the Nociception Coma Scale, and the Wessex Head Injury Matrix20,21,22.</li>
	<li>Schedule [18F]FDG-PET/CT scans for the patients who are medically stable and can safely participate in examinations. Only schedule those who have provided informed consent or whose legal representatives have provided informed consent, as stated in the informed consent form. Schedule [18F]FDG-PET/CT image acquisition near the day of clinical assessment.</li>
</ol>
2. Preparation of the [18F]FDG Tracer in the Hot Lab
<ol>
	<li>In the hot lab, begin to manufacture reagent kits for the automated production of FDG tailored to the FDG synthesizer (see Table of Materials). Be sure to use the automatic program to check the mobility of the pumping system in the FDG synthesizer and to ensure that air does not leak from the reagent kit. Sterilize the contact area of the machine (this is the start time). 
	Note: Be sure to check the radiation monitor in the hot lab and use the portable radiation dosimeters to check the radiation levels of each person before they enter the hot lab.</li>
	<li>Check the volume of [16O]-water and [18O]-water and the volume of helium, hydrogen, and nitrogen in the gas tank. Check whether the tap water temperature for primary cooling is under 25 &#176;C and that for secondary cooling is under 22 &#176;C. Use all water in the closed system (30 min after the start) for production.</li>
	<li>Begin the preliminary irradiation of [16O]-water in the cyclotron (1 h after the start). Check the monitor to be sure that 2 - 3 mL of [16O]-water is irradiated in optimal conditions (e.g., 20 &#181;A, 5 min) in the target area of the cyclotron. After irradiation, install the vial of [16O]-water into a radioisotope dose calibrator and measure the level of radioactivity (see Table of Materials). 
	Note: The radioactive decay should be calculated using the following formula. 
	<img alt="Equation" src="/files/ftp_upload/58641/58641eq1.jpg" /> 
	Here, 
	N(t) is the number radioactive nuclei at t = t seconds; 
	N(0) is the number radioactive nuclei at t = 0 seconds; 
	&#8203;T = the half-life.</li>
	<li>Begin the irradiation of [18O]-water in the cyclotron (1 h 30 min after the start). Set the bombardment time for up to 20 min and the energy of the impinging protons to 16.5 MeV.</li>
	<li>Start the FDG synthesizer according to the operator manual22 (2 h after the start). A modified procedure is given below.
	<ol>
		<li>After the irradiation, use helium gas to transfer 2 - 3 mL of the [18O]-water from the cyclotron to the polypropylene receiver of the FDG synthesizer.</li>
		<li>Hook syringes onto the corresponding syringe drivers, pressurize reagent vials, dissolve the 1,3,4,6-Tetra-O-acetyl-2-O-trifluoromethanesulfonyl-&#946;-D-mannopyranose in one vial (7 &#177; 0.2 mL) of acetonitrile (purity &#8805; 99.5%), and rinse the cassette with acetonitrile.</li>
		<li>After the bombardment, transfer the irradiated [16O]-water and [18O]-water to the FDG synthesizer. 
		Note: Once the synthesis has started, the irradiated [18O]-water moves through an anion exchange cartridge (see Table of Materials). Be sure to condition and convert the cartridge to the carbonate before the synthesis.</li>
		<li>After transferring the eluent containing the [18F]activity without liquid into the reaction vessels, allow the solvents to evaporate until dry. During the drying process, add small amounts of acetonitrile to the reaction vessel 3x (each time, add 80 &#181;L). Perform the evaporation at 95 &#176;C under nitrogen flow and vacuum.</li>
		<li>Add the mannose triflate precursor (25 mg) to the dry residue after dissolving it in about 3.5 mL of acetonitrile (with a purity of &#8805; 99.5%). A nucleophilic substitution reaction occurs at 85 &#176;C in the FDG synthesizer.</li>
		<li>As a preliminary purification, mix the labeled solution with 26 mL of distilled water. Send about 4 mL of the diluted labeling solution back to the reaction vessel to recover the remaining activity. Pass the solution through the reverse-phase cartridge (see Table of Materials). Rinse the cartridge containing the trapped labeled precursor 4x using 10 mL, 10 mL, 13 mL, and 13 mL of distilled water on the successive washes.</li>
		<li>Convert the acetylated compound (labeled precursor) into FDG within the cartridge via alkaline hydrolysis, using 750 &#181;L of 2 N NaOH for 2 min at room temperature.</li>
		<li>After hydrolysis, collect the alkaline FDG solution in 7 mL of water and mix it with the neutralization solution (5 mL of citrate buffer and 1 mL of 2 N HCl).</li>
		<li>Purify the resulting neutralized FDG solution.
		<ol>
			<li>Pass the neutralized FDG solution through a second reverse-phase cartridge (see Table of Materials), retaining the partially hydrolyzed compounds and nonpolar by-products.</li>
			<li>Pass it through an Alumina N cartridge (see Table of Materials), retaining the last traces of unreacted [18F]fluoride ions. Then, pass it through a 0.22-&#181;m filter.</li>
			<li>Rinse the cassette and cartridges, filter with 3 mL of water to recover the residual FDG that is left in the lines and, then, drain the FDG into the final vial, which contains 15 - 17 mL of liquid.</li>
		</ol>
		</li>
		<li>Perform a qualitative analysis of the [18F]FDG tracer (2 h 30 min after the start).
		<ol>
			<li>Visually observe the vial. Confirm that it is transparent and that it does not include any particles.</li>
			<li>Measure the amount of liquid using a Roberval&#8217;s balance (should be 15 - 17 mL).</li>
			<li>Measure the radioactivity and half-life using a radioisotope dose calibrator (the same as in step 2.3, see Table of Materials) (criterion: 105 - 115 min).</li>
			<li>Dispense 0.5 mL from the vial. Perform a radiochemical purity test via carbohydrate analysis. Use columns of 3.9 x 300 mm for high-performance liquid chromatography (see Table of Materials) to detect the peak radioactivity (over 95). 
			Note: A single peak means high purity.</li>
			<li>Measure the pH (pH 5.0 - 8.0) by using pH test paper (see Table of Materials). Measure the&#12288;residual 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (see Table of Materials) (&#60; 40 ppm) using test paper (see Table of Materials). Measure the endotoxins with the appropriate endotoxin-measuring device through absorbance measuring (see Table of Materials) (0.25 EU/mL). Do a test for sterility (finding no bacteria after 8 d at 37 &#176;C).</li>
		</ol>
		</li>
		<li>Fill the vial covered by lead and tungsten with the [18F]FDG tracer at a dosage of 5 MBq/kg body weight.</li>
		<li>Transfer the [18F]FDG tracer from the hot lab to the working room (3 h 25 min after the start).</li>
	</ol>
	</li>
</ol>
3. Time Course for the Acquisition of the [18F]FDG-PET/CT Brain Images
<ol>
	<li>Schedule the patients. Be sure to inform the staff to stop nutrition and feeding via gastrostomy. Do not stop providing water. The patients should fast starting 7 h before the image acquisition.</li>
	<li>Prepare the intravenous route for [18F]FDG tracer administration. Secure a 22- to 24-G needle with 5 mL of heparin sodium (10 units/mL) on one of the lower limbs before entering the radiation-controlled area.</li>
	<li>Have the patients lie down on a light stretcher before entering the radiation-controlled area. Bring the patients to the radiation-controlled area and wait for 30 min, in silence, while medical staff are on stand by.</li>
	<li>Recheck the patency of the intravenous route by drawing blood with a 10-mL syringe. Measure the blood-glucose levels with a glucose meter.</li>
	<li>After transferring the [18F]FDG tracer from the hot lab to the working room, set it up in the auto-dispensing and injection system (see Table of Materials).</li>
	<li>Recheck the following information (via the medical staff): patient ID number, name, birthday, height, and body weight; the name of the tracer, the amount of tracer (water with 3.5 mL of [18F]FDG tracer + 12 mL of saline), the programmed radioactivity (5 MBq/kg), the time of injection, the [18F]FDG tracer-lot number, the injection speed (normally, 0.3 mL/s), and the level of radioactivity that was measured in the hot lab.</li>
	<li>Record the automatic measurement of preinjected radioactivity that appears on the display of the auto-dispensing and injection system.</li>
	<li>Inject the [18F]FDG tracer via the intravenous route prepared in step 3.2 (3 h 30 min after the start).</li>
	<li>Record the residual volume of the [18F]FDG tracer, which is shown automatically on the display of the auto-dispensing and injection system.</li>
	<li>Have the patients wait in the waiting room of the radiation-controlled area for 50 min.</li>
	<li>Transfer the patients from the waiting room to the PET/CT machine (see Table of Materials). Record the brain images for 10 min (4 h 30 min after the start). 
	Note: The imaging parameters for [18F]FDG-PET/CT images are 10 min list mode. Reconstruct the data from 10-min bins. The data under 3 min are not used because the low-intensity signals are not adequate. Set the image reconstruction parameters: a block sequential regularized expectation maximization reconstruction algorithm (see Table of Materials); the matrix size = 192; the field of view = 25 cm; &#946;-value: 100 - 200; z-axis filter: none.</li>
	<li>After taking the images, check the injection area for extravasation. Discard all urine if the patient has a urinal catheter with urine bag.</li>
	<li>Remove the patient from the radiation-controlled area (4 h 50 min after the start). 
	Note: See Figure 1 for a schematic of the time schedule of events (patient procedure and synthesis of the [18F]FDG tracer).</li>
</ol>
4. Analysis of the [18F]FDG-PET/CT Images
<ol>
	<li>Evaluate all image data for a standardized uptake value (SUV) measurement using the imaging software (see Table of Materials).</li>
	<li>Select the patients.</li>
	<li>Assign the data to the MM oncology workflow.</li>
	<li>Click the button for Functional browsers.</li>
	<li>Click the VOI (volume of interest) threshold button.</li>
	<li>Set the VOI sphere to the three-dimensional browser. 
	Note: The maximum SUV (SUVmax) and mean SUV (SUVmean) are automatically measured for the VOI according to the chosen SUVmax threshold. Be sure to draw a border around the targeted VOI on the browser using the three-dimensional sphere, excluding other targets, extraocular muscles, and the scalp because they tend to disturb the set SUV threshold. Check the target area on axial, coronal, and sagittal slices.</li>
	<li>After selecting all the right settings, click the Edit the measure button.</li>
	<li>Change the threshold value (e.g., 50%) of the VOI and click OK.</li>
	<li>Record the SUVmax, SUVmean, target volume, and threshold of the target area, which are automatically measured.</li>
	<li>To sterically visualize the glucose metabolism of the whole-brain surface, use the software (see Table of Materials) to set a color map for the [18F]FDG-PET/CT images based on blood glucose.</li>
	<li>Finally, compare the clinical assessment with the [18F]FDG-PET/CT images.</li>
</ol>

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The authors have nothing to disclose.

This protocol provides the means to conduct a series of brain-glucose metabolic assessments with [18F]FDG-PET/CT using self-produced [18F]FDG tracer at a single institution.
The production of [18F]FDG tracer follows the procedure described in the FDG synthesizer operator manual; however, caution is necessary regarding three points. First, the bombardment time and energy (step 2.5) should be adjusted according to the number of patients. Second, attention should ...

Patients with sTBI are presented with unforeseeable neurological difficulties over the course of rehabilitation that include motor deficits, sensory deficits, and psychiatric instability1. Although clinical assessment is generally performed verbally, patients with sTBI such as unresponsive wakefulness syndrome or minimally conscious state have particular difficulty in knowing whether they are accurately expressing their thoughts and emotions because of disorders of consciousness, disrupted higher brain function, and verbal disturbances2,3. Family members, medical staff, and caregivers are sometimes confounded by unforeseeable neurological changes or the lack of response that can result from insufficient communicatory ability4,5.
Recently, multimodal brain imaging has been used to explore regional brain function6,7,8,9. The brain is the main consumer of glucose-derived energy, with glucose metabolism providing approximately 95% of the adenosine triphosphate (ATP) required for the brain to function10. The uptake of [18F]-fluorodeoxyglucose (FDG) is a marker for the uptake of glucose by brain tissue. [18F]FDG-PET/CT can detect [18F]FDG uptake and is, therefore, a useful tool for examining brain function11. In general, [18F]FDG image analysis is divided into two categories: ROI analysis and voxel-based analysis (VBA)12. Previous reports show that ROI analysis is preferred for studying specific regions of traumatic injury. This is because VBA (such as statistical parametric mapping [SPM]) requires coregistration and normalization to a standard brain, which does not work well in cases of TBI due to brain tissue deformation such as brain atrophy, swelling, enlargement, and shrinking of ventricular space7,12. Although various algorithms and software have been developed for analyzing magnetic resonance imaging (MRI) data, metals used in neurosurgical and orthopedic surgery generate noise artefacts7,12,13. Recently, the use of photomultipliers with PET/CT devices has improved the spatial resolution of PET/CT-derived brain images14. The current protocol focuses on semi-quantitatively measuring glucose uptake via ROI analysis in [18F]FDG-PET/CT using self-produced [18F]FDG tracers in patients with sTBI.

<table><tbody><tr><td>20ml syringe</td><td>Terumo</td><td>&lt;strong&gt;SS-20ESZ&lt;/strong&gt;</td><td></td></tr><tr><td>10ml syringe</td><td>Terumo</td><td>SS-10ESZ</td><td></td></tr><tr><td>1ml syringe</td><td>Terumo</td><td>SS-01T</td><td></td></tr><tr><td>Protective plug</td><td>Top</td><td>ML-KS</td><td></td></tr><tr><td>Three-way cock L type 180&amp;deg;</td><td>Terumo</td><td>TS-TL2K</td><td></td></tr><tr><td>Extension tube</td><td>Top</td><td>X1-50</td><td></td></tr><tr><td>Indwelling needle 22G or 24G</td><td>Terumo</td><td>SR-OT2225C</td><td></td></tr><tr><td>Tegaderm transparent dressing</td><td>3M</td><td>1624W</td><td></td></tr><tr><td>Hepaflash 10U/ml 10ml</td><td>Terumo</td><td>PF-10HF10UA</td><td></td></tr><tr><td>Auto dispensing and injection system</td><td>Universal Giken Co., Ltd.</td><td>UG-01</td><td></td></tr><tr><td>Fluid for auto dispensing and injection system</td><td>Universal Giken Co., Ltd.</td><td>UG-01-001</td><td></td></tr><tr><td>Millex-GS Syringe Filter Unit</td><td>Millipore</td><td>SLGSV255F</td><td></td></tr><tr><td>Air needle</td><td>Terumo</td><td>XX-MFA2038</td><td></td></tr><tr><td>Check valve</td><td>Hakko</td><td>23310100</td><td></td></tr><tr><td>Saline 500ml</td><td>HIKARI pharmaceutical Co., Ltd.</td><td>18610155-3</td><td></td></tr><tr><td>Yukiban 25x7mm</td><td>Nitto</td><td>3252</td><td></td></tr><tr><td>Elascot No.3</td><td>Alcare</td><td>44903221</td><td></td></tr><tr><td>Presnet No.3 27x20mm</td><td>Alcare</td><td>11674</td><td></td></tr><tr><td>Steri Cotto a 4x4cm</td><td>Kawamoto</td><td>023-720220-00</td><td></td></tr><tr><td>StatstripXp3</td><td>Nova Biomedical</td><td>11-110</td><td></td></tr><tr><td>Statstrip Glucose strips</td><td>Nova Biomedical</td><td>11-106</td><td></td></tr><tr><td>JMSsheet</td><td>JMS</td><td>JN-SW3X</td><td></td></tr><tr><td>Injection pad</td><td>Nichiban</td><td>No.30-N</td><td></td></tr><tr><td>Stepty</td><td>Nichiban</td><td>No.80</td><td></td></tr><tr><td>Advantage Workstation</td><td>GE Healthcare</td><td>Volume Share 7. version 4.7</td><td></td></tr><tr><td>Discovery MI PET/CT</td><td>GE Healthcare</td><td></td><td></td></tr><tr><td>EV Insite</td><td>PSP</td><td></td><td></td></tr><tr><td>GE TRACERlab MX&lt;sub&gt;FDG&lt;/sub&gt; synthesizer reagent kit</td><td>ABX</td><td>K-105TM</td><td></td></tr><tr><td>TRACERlab MX&lt;sub&gt;FDG&lt;/sub&gt; cassette</td><td>GE Healthcare</td><td>P5150ME</td><td></td></tr><tr><td>Extension tube</td><td>Universal Giken Co., Ltd</td><td>AT511-ST-001</td><td></td></tr><tr><td>TSK sterilized injection needle 18x100</td><td>Tochigiseiko</td><td>AT511-ST-004</td><td></td></tr><tr><td>TSK sterilized injection needle 18x60</td><td>Tochigiseiko</td><td>AT511-ST-002</td><td></td></tr><tr><td>TSK sterilized injection needle 21x65</td><td>Tochigiseiko</td><td>AT511-ST-003</td><td></td></tr><tr><td>Seal sterile vial -N 5ml</td><td>Mita Rika Kogyo Co., Ltd.</td><td>SSVN5CBFA</td><td></td></tr><tr><td>k222 TLC plate</td><td>Universal Giken Co., Ltd.</td><td>AT511-01-005</td><td></td></tr><tr><td>Anion-cation test paper</td><td>Toyo Roshi Kaisha</td><td>7030010</td><td></td></tr><tr><td>Endospecy ES-24S set</td><td>Seikagaku corporation</td><td>20170</td><td></td></tr><tr><td>Sterile evacuated vial</td><td>Gi phama</td><td>10214</td><td></td></tr><tr><td>5ml syringe</td><td>Terumo</td><td>SS-05SZ</td><td></td></tr><tr><td>Extension tube</td><td>Top</td><td>X-120</td><td></td></tr><tr><td>Finefilter F</td><td>Forte grow medical Co.Ltd.</td><td>F162</td><td></td></tr><tr><td>Millex FG</td><td>Merck</td><td>SLFG I25 LS</td><td></td></tr><tr><td>Vented Millex GS</td><td>Merck</td><td>SLGS V25 5F</td><td></td></tr><tr><td>Injection needle 18x38</td><td>Terumo</td><td>NN-1838R</td><td></td></tr><tr><td>Injection needle 21x38</td><td>Terumo</td><td>NN-2138R</td><td></td></tr><tr><td>Water-18O</td><td>Taiyo Nippon Sanso</td><td>F03-0027</td><td></td></tr><tr><td>Distilled water</td><td>Otsuka phrmaceutical</td><td></td><td></td></tr><tr><td>Hydrogen gas G1</td><td>Hosi Iryou Sanki</td><td></td><td></td></tr><tr><td>Helium gas G1</td><td>Hosi Iryou Sanki</td><td></td><td></td></tr><tr><td>Nitrogen G1</td><td>Hosi Iryou Sanki</td><td></td><td></td></tr><tr><td>TRACERlabMX&lt;sub&gt;FDG&lt;/sub&gt;</td><td>GE Healthcare</td><td></td><td></td></tr><tr><td>Sep-Pak Light Accell Plus QMA</td><td>WATERS</td><td></td><td></td></tr><tr><td>Sep-Pak Plus tC18</td><td>WATERS</td><td></td><td></td></tr><tr><td>Sep-Pak Plus Alumina N</td><td>WATERS</td><td></td><td></td></tr><tr><td>HPLC with 3.9 X 300 mm columns</td><td>WATERS</td><td></td><td></td></tr><tr><td>US-2000</td><td>Universal Giken CO. Ltd.</td><td></td><td></td></tr><tr><td>Kryptofix222</td><td>Merck</td><td></td><td></td></tr><tr><td>EG Reader SV-12</td><td>Seikagaku Corporation</td><td></td><td></td></tr><tr><td>UG-01</td><td>Universal Giken Co., Ltd.</td><td></td><td></td></tr><tr><td>syngo.via</td><td>Siemens Healthineers</td><td></td><td></td></tr><tr><td>Advantage Workstation Volume Share 7, version 4.7</td><td>GE Healthcare</td><td></td><td></td></tr><tr><td>Q clear</td><td>GE Healthcare</td><td></td><td></td></tr><tr><td>CRC-15PET dose calibrator</td><td>CAPINTEC, INC.</td><td></td><td></td></tr></tbody></table>

semi-quantitative assessment using [18f]fdg tracer in patients with severe brain injury

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of disorders of consciousness, disrupted higher brain function, and verbal disturbances. As a consequence of an insufficient ability to communicate, objective evaluations are needed from family members, medical staff, and caregivers. One such evaluation is the assessment of functioning brain areas. Recently, multimodal brain imaging has been used to explore the function of damaged brain areas. [18F]-fluorodeoxyglucose positron emission tomography-computed tomography ([18F]FDG-PET/CT) is a successful tool for examining brain function. However, the assessment of brain glucose metabolism based on [18F]FDG-PET/CT is not standardized and depends on several varying parameters, as well as the patient&#39;s condition. Here, we describe a series of semiquantitative assessment protocols for a region-of-interest (ROI) image analysis using self-produced [18F]FDG tracers in patients with sTBI. The protocol focuses on screening the participants, preparing the [18F]FDG tracer in the hot lab, scheduling the acquisition of [18F]FDG-PET/CT brain images, and measuring glucose metabolism using the ROI analysis from a targeted brain area.

A 63-year-old man who had been run over by a car while cycling was brought to the emergency room via ambulance. The examination revealed a Glasgow Coma Scale score of 7 (eye opening = 1, best verbal response = 2, best motor response = 4), anisocoria (right: 2 mm, and left: 3 mm), and a negative corneal response17. A CT of the head showed subarachnoid and intracranial hemorrhage and a skull fracture of the left zygoma, temporal bones, and parietal bones. Th...

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Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury

[18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography is useful for studying glucose metabolism related to brain function. Here, we present a protocol for an [18F]FDG tracer set-up and semiquantitative assessment of the region-of-interest analysis for targeted brain areas associated with clinical manifestations in patients with severe traumatic brain injury.

Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of ...

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7.5K Views.  Rehabilitation Center for Traumatic Apallics Chiba, National Agency for Automotive Safety and Victims' Aid. Deze lijst kan ons helpen met belangrijke vragen op het gebied van neuro-rehabilition. Met betrekking tot Niet-responsieve Wakefulness Syndroom en minimale bewuste staten na cerebrale traumatische hersenletsel. Het belangrijkste voordeel van deze techniek is dat patiënten met hersenweefselmisvorming zoals atrofie, zwelling, uitbreiding en krimp van ventriculaire ruimten kunnen worden geholpen in het chronische stadium.Demonstreren van de procedure zal Worden Tomoki Uchida, onze apothe...

Video: Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury

Non-invasive Imaging of Acute Allograft Rejection after Rat Renal Transplantation Using 18F-FDG PET

The number of patients with end-stage renal disease, and the number of kidney allograft recipients continuously increases. Episodes of acute cellular allograft rejection (AR) are a negative prognostic factor for long-term allograft survival, and its timely diagnosis is crucial for allograft function 1. At present, AR can only be definitely diagnosed by core-needle biopsy, which, as an invasive method, bares significant risk of graft injury or even loss. Moreover, biopsies are not feasible in patients taking anticoagulant drugs and the limited sampling site of this technique may result in false negative results if the AR is focal or patchy. As a consequence, this gave rise to an ongoing search for new AR detection methods, which often has to be done in animals including the use of various transplantation models.
Since the early 60s rat renal transplantation is a well-established experimental method for the examination and analysis of AR 2. We herein present in addition small animal positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) to assess AR in an allogeneic uninephrectomized rat renal transplantation model and propose graft FDG-PET imaging as a new option for a non-invasive, specific and early diagnosis of AR also for the human situation 3. Further, this method can be applied for follow-up to improve monitoring of transplant rejection 4.

Non-invasive Imaging of Acute Allograft Rejection after Rat Renal Transplantation Using 18F-FDG PET

We herein present a rat renal transplantation model to non-invasively assess acute allograft rejection using positron emission tomography with 18F-fluorodeoxyglucose.

The number of patients with end-stage renal  disease, and the number of kidney allograft recipients continuously increases.  Episodes of acute cellular ...

Driving Simulation in the Clinic: Testing Visual Exploratory Behavior in Daily Life Activities in Patients with Visual Field Defects

Patients suffering from homonymous hemianopia after infarction of the posterior cerebral artery (PCA) report different degrees of constraint in daily life, despite similar visual deficits. We assume this could be due to variable development of compensatory strategies such as altered visual scanning behavior. Scanning compensatory therapy (SCT) is studied as part of the visual training after infarction next to vision restoration therapy. SCT consists of learning to make larger eye movements into the blind field enlarging the visual field of search, which has been proven to be the most useful strategy1, not only in natural search tasks but also in mastering daily life activities2. Nevertheless, in clinical routine it is difficult to identify individual levels and training effects of compensatory behavior, since it requires measurement of eye movements in a head unrestrained condition. Studies demonstrated that unrestrained head movements alter the visual exploratory behavior compared to a head-restrained laboratory condition3. Martin et al.4 and Hayhoe et al.5 showed that behavior demonstrated in a laboratory setting cannot be assigned easily to a natural condition. Hence, our goal was to develop a study set-up which uncovers different compensatory oculomotor strategies quickly in a realistic testing situation: Patients are tested in the clinical environment in a driving simulator. SILAB software (Wuerzburg Institute for Traffic Sciences GmbH (WIVW)) was used to program driving scenarios of varying complexity and recording the driver's performance. The software was combined with a head mounted infrared video pupil tracker, recording head- and eye-movements (EyeSeeCam, University of Munich Hospital, Clinical Neurosciences).
The positioning of the patient in the driving simulator and the positioning, adjustment and calibration of the camera is demonstrated. Typical performances of a patient with and without compensatory strategy and a healthy control are illustrated in this pilot study. Different oculomotor behaviors (frequency and amplitude of eye- and head-movements) are evaluated very quickly during the drive itself by dynamic overlay pictures indicating where the subjects gaze is located on the screen, and by analyzing the data. Compensatory gaze behavior in a patient leads to a driving performance comparable to a healthy control, while the performance of a patient without compensatory behavior is significantly worse. The data of eye- and head-movement-behavior as well as driving performance are discussed with respect to different oculomotor strategies and in a broader context with respect to possible training effects throughout the testing session and implications on rehabilitation potential.

Patients with visual deficits after stroke report about different constraints in daily life most likely due to variable compensatory strategies, which are difficult to differentiate in clinical routine. We present a clinical set-up which allows measurement of different compensatory head- and eye-movement-strategies and evaluating their effects on driving performance.

Patients suffering from homonymous hemianopia after infarction of the posterior cerebral artery (PCA) report different degrees of constraint in daily ...

A Contusion Model of Severe Spinal Cord Injury in Rats

The translational potential of novel treatments should be investigated in severe spinal cord injury (SCI) contusion models. A detailed methodology is described to obtain a consistent model of severe SCI. Use of a stereotactic frame and computer controlled impactor allows for creation of reproducible injury. Hypothermia and urinary tract infection pose significant challenges in the post-operative period. Careful monitoring of animals with daily weight recording and bladder expression allows for early detection of post-operative complications. The functional results of this contusion model are equivalent to transection models. The contusion model can be utilized to evaluate the efficacy of both neuroprotective and neuroregenerative approaches.

A contusion model of severe spinal cord injury is described. Detailed pre-operative, operative and post-operative steps are described to obtain a consistent model.

The translational potential of novel treatments should be investigated in severe spinal cord injury (SCI) contusion models. A detailed methodology is ...

Evaluation of Respiratory Muscle Activation Using Respiratory Motor Control Assessment (RMCA) in Individuals with Chronic Spinal Cord Injury

During breathing, activation of respiratory muscles is coordinated by integrated input from the brain, brainstem, and spinal cord. When this coordination is disrupted by spinal cord injury (SCI), control of respiratory muscles innervated below the injury level is compromised1,2 leading to respiratory muscle dysfunction and pulmonary complications. These conditions are among the leading causes of death in patients with SCI3. Standard pulmonary function tests that assess respiratory motor function include spirometrical and maximum airway pressure outcomes: Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), Maximal Inspiratory Pressure (PImax) and Maximal Expiratory Pressure (PEmax)4,5. These values provide indirect measurements of respiratory muscle performance6. In clinical practice and research, a surface electromyography (sEMG) recorded from respiratory muscles can be used to assess respiratory motor function and help to diagnose neuromuscular pathology. However, variability in the sEMG amplitude inhibits efforts to develop objective and direct measures of respiratory motor function6. Based on a multi-muscle sEMG approach to characterize motor control of limb muscles7, known as the voluntary response index (VRI)8, we developed an analytical tool to characterize respiratory motor control directly from sEMG data recorded from multiple respiratory muscles during the voluntary respiratory tasks. We have termed this the Respiratory Motor Control Assessment (RMCA)9. This vector analysis method quantifies the amount and distribution of activity across muscles and presents it in the form of an index that relates the degree to which sEMG output within a test-subject resembles that from a group of healthy (non-injured) controls. The resulting index value has been shown to have high face validity, sensitivity and specificity9-11. We showed previously9 that the RMCA outcomes significantly correlate with levels of SCI and pulmonary function measures. We are presenting here the method to quantitatively compare post-spinal cord injury respiratory multi-muscle activation patterns to those of healthy individuals.

Evaluation of Respiratory Muscle Activation Using Respiratory Motor Control Assessment RMCA in Individuals with Chronic Spinal Cord Injury

The purpose of this publication is to present our original work on a multi-muscle surface electromyographic approach to quantitatively characterize respiratory muscle activation patterns in individuals with chronic spinal cord injury using vector-based analysis.

During breathing, activation of respiratory muscles is coordinated by integrated input from the brain, brainstem, and spinal cord. When this coordination ...

Computerized Dynamic Posturography for Postural Control Assessment in Patients with Intermittent Claudication

Computerized dynamic posturography with the EquiTest is an objective technique for measuring postural strategies under challenging static and dynamic conditions. As part of a diagnostic assessment, the early detection of postural deficits is important so that appropriate and targeted interventions can be prescribed. The Sensory Organization Test (SOT) on the EquiTest determines an individual&#39;s use of the sensory systems (somatosensory, visual, and vestibular) that are responsible for postural control. Somatosensory and visual input are altered by the calibrated sway-referenced support surface and visual surround, which move in the anterior-posterior direction in response to the individual&#39;s postural sway. This creates a conflicting sensory experience. The Motor Control Test (MCT) challenges postural control by creating unexpected postural disturbances in the form of backwards and forwards translations. The translations are graded in magnitude and the time to recover from the perturbation is computed.
Intermittent claudication, the most common symptom of peripheral arterial disease, is characterized by a cramping pain in the lower limbs and caused by muscle ischemia secondary to reduced blood flow to working muscles during physical exertion. Claudicants often display poor balance, making them susceptible to falls and activity avoidance. The Ankle Brachial Pressure Index (ABPI) is a noninvasive method for indicating the presence of peripheral arterial disease and intermittent claudication, a common symptom in the lower extremities. ABPI is measured as the highest systolic pressure from either the dorsalis pedis or posterior tibial artery divided by the highest brachial artery systolic pressure from either arm. This paper will focus on the use of computerized dynamic posturography in the assessment of balance in claudicants.

Individuals with intermittent claudication exhibit poor balance compared to healthy controls. Computerized dynamic posturography is an objective method for measuring an individual's postural responses to balance disturbances. This provides an objective reflection of the person&#x2019;s ability to respond to situations under which sensory stimuli are altered and unexpected perturbations occur.

Computerized dynamic posturography with the EquiTest is an objective technique for measuring postural strategies under challenging static and dynamic ...

Assessment of Vascular Function in Patients With Chronic Kidney Disease

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA, aPWV, and vascular endothelial cell protein expression.

The degree of vascular dysfunction and contributing physiological mechanisms can be assessed in patients with chronic kidney disease by measuring brachial artery flow-mediated dilation, aortic pulse-wave velocity, and vascular endothelial cell protein expression.

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this ...

Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG

Stroke is the third leading cause of death among Americans 65 years of age or older1. The quality of life for patients who suffer from a stroke fails to return to normal in a large majority of patients2, which is mainly due to current lack of clinical treatment for acute stroke. This necessitates understanding the physiological effects of cerebral ischemia on brain tissue over time and is a major area of active research. Towards this end, experimental progress has been made using rats as a preclinical model for stroke, particularly, using non-invasive methods such as 18F-fluorodeoxyglucose (FDG) coupled with Positron Emission Tomography (PET) imaging3,10,17. Here we present a strategy for inducing cerebral ischemia in rats by middle cerebral artery occlusion (MCAO) that mimics focal cerebral ischemia in humans, and imaging its effects over 24 hr using FDG-PET coupled with X-ray computed tomography (CT) with an Albira PET-CT instrument. A VOI template atlas was subsequently fused to the cerebral rat data to enable a unbiased analysis of the brain and its sub-regions4. In addition, a method for 3D visualization of the FDG-PET-CT time course is presented. In summary, we present a detailed protocol for initiating, quantifying, and visualizing an induced ischemic stroke event in a living Sprague-Dawley rat in three dimensions using FDG-PET.

Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG

Brain damage resulting from cerebral ischemia may be non-invasively imaged and studied in rats using pre-clinical positron emission tomography coupled with the injectable radioactive probe, 18F-fluorodeoxyglucose. Further, the use of modern software tools that include volume of interest (VOI) brain templates dramatically increase the quantitative information gleaned from these studies.

Stroke is the third leading cause of death among Americans 65 years of age or older1. The quality of life for patients who suffer from a stroke fails to ...

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity.

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations ...

Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT

This paper describes the use of 18F-FDG and micro-PET/CT imaging to determine in vivo glucose metabolism kinetics in mice (and is transferable to rats). Impaired uptake and metabolism of glucose in multiple organ systems due to insulin resistance is a hallmark of type 2 diabetes. The ability of this technique to extract an image-derived input function from the vena cava using an iterative deconvolution method eliminates the requirement of the collection of arterial blood samples. Fitting of tissue and vena cava time activity curves to a two-tissue, three compartment model permits the estimation of kinetic micro-parameters related to the 18F-FDG uptake from the plasma to the intracellular space, the rate of transport from intracellular space to plasma and the rate of 18F-FDG phosphorylation. This methodology allows for multiple measures of glucose uptake and metabolism kinetics in the context of longitudinal studies and also provides insights into the efficacy of therapeutic interventions.

Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT

This study describes a protocol that uses 18F-FDG and positron emission tomography/computed tomography (PET/CT) imaging, together with kinetic modelling, to quantify the in vivo, real-time uptake of 18F-FDG into tissues.

This paper describes the use of 18F-FDG and micro-PET/CT imaging to determine in vivo glucose metabolism kinetics in mice (and is transferable to rats). ...

Severe Burn Injury in a Swine Model for Clinical Dressing Assessment

Wound healing is a dynamic repair process and is the most complex biological process in human life. In response to burn injury, alterations in biological pathways impair the inflammation response, resulting in delayed wound healing. Impaired wound healing frequently occurs in patients with diabetes leading to unfavorable outcomes such as amputation. Hence, dressings having beneficial effect in promoting burn wound repair are needed. However, studies on burn wound treatment are limited due to lack of proper animal models. Our previous study demonstrated wound-healing performance in rat and swine models using a minimally invasive surgical technique. This study aimed to demonstrate a swine model of severe burn injury that eliminates wound contraction and more closely approximates the human processes of re-epithelialization and new tissue formation. This protocol provides a detailed procedure for creating consistent burn wounds and examining the wound-healing performance under the treatment of an experimental dressing in a swine model. Six burn wounds were created symmetrically on the dorsum, which were covered with a clinical dressing composed of four layers: an inner contact layer of experimental materials, an inner intermediate layer of waterproof film, an outer intermediate layer of gauze, and an outer layer of adhesive plaster. Upon the completion of experiments, wound closure, wound area, and Vancouver Scar Scale score were examined. The samples of skin resected from each animal post-sacrifice were histologically prepared and stained using hematoxylin and eosin staining. Antibacterial activity of each dressing in the context of wound healing was also examined. The application of the clinical dressing to the wounds in swine model mimics the biological processes of human wound healing with respect to the processes of epithelialization, cellular proliferation, and angiogenesis. Therefore, this swine model provides an easy-to-learn, cost-effective, and robust method to assess the effect of clinical dressings in severe burn injury.

To closely mimic the mode of burn injuries requires the interplay between clinical observation and studies in animal models. In this study, a swine model of severe burn injury was established to assess an experimental dressing in physiological and pathophysiological settings.

Wound healing is a dynamic repair process and is the most complex biological process in human life. In response to burn injury, alterations in biological ...

Semi-quantitative Assessment Using [¹⁸F]FDG Tracer in Patients with Severe Brain Injury

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