External Hardware and Sensors, for Improved MRI.

Complex engineered systems are often equipped with suites of sensors and ancillary devices that monitor their performance and maintenance needs. MRI scanners are no different in this regard. Some of the ancillary devices available to support MRI equipment, the ones of particular interest here, have the distinction of actually participating in the image acquisition process itself. Most commonly, such devices are used to monitor physiological motion or variations in the scanner's imaging fields, allowing the imaging and/or reconstruction process to adapt as imaging conditions change. "Classic" examples include electrocardiography (ECG) leads and respiratory bellows to monitor cardiac and respiratory motion, which have been standard equipment in scan rooms since the early days of MRI. Since then, many additional sensors and devices have been proposed to support MRI acquisitions. The main physical properties that they measure may be primarily "mechanical" (eg acceleration, speed, and torque), "acoustic" (sound and ultrasound), "optical" (light and infrared), or "electromagnetic" in nature. A review of these ancillary devices, as currently available in clinical and research settings, is presented here. In our opinion, these devices are not in competition with each other: as long as they provide useful and unique information, do not interfere with each other and are not prohibitively cumbersome to use, they might find their proper place in future suites of sensors. In time, MRI acquisitions will likely include a plurality of complementary signals. A little like the microbiome that provides genetic diversity to organisms, these devices can provide signal diversity to MRI acquisitions and enrich measurements. Machine-learning (ML) algorithms are well suited at combining diverse input signals toward coherent outputs, and they could make use of all such information toward improved MRI capabilities. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study.

BACKGROUND: The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown. AIMS: To determine the effects of RTD on brain 5-HT(2) receptors using positron emission tomography (PET) and (18)F-labelled setoperone. METHOD: Ten healthy women under went two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days. RESULTS: The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT(2) receptor binding in various cortical regions following the RTD session. CONCLUSIONS: When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT(2) receptors, these findings suggest that a decrease in 5-HT(2) binding following RTD might be an adaptive response that provides protection against depressive symptoms.

Brain serotonin2 receptors in major depression: a positron emission tomography study.

BACKGROUND: Postmortem and brain imaging studies that measured brain serotinin(2) (5-HT(2)) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT(2) receptors in 20 depressed patients (mean +/- SD age, 40.1 +/- 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 +/- 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([(18)F]setoperone). METHODS: Patients with DSM-IV major depression and healthy controls underwent scanning with [(18)F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT(2) binding images were created using region-to-cerebellum ratios. The differences in 5-HT(2) receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis. RESULTS: There was a significant negative correlation between 5-HT(2) receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT(2) receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT(2) receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels. CONCLUSION: This study suggests that brain 5-HT(2) receptors are decreased in patients with major depression.

Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18-labeled setoperone.

BACKGROUND: The neuroreceptor changes involved in therapeutic efficacy of various antidepressants remain unclear. Preclinical studies have shown that long-term administration of various antidepressants causes down-regulation of brain serotonin 2 (5-HT2) receptors in rodents, but it is unknown if similar changes occur following antidepressant treatment in depressed patients. Our purpose, therefore, was to assess the effects of treatment with desipramine hydrochloride on brain 5-HT2 receptors in depressed patients using positron emission tomography (PET) and fluorine-18 (18F)-labeled setoperone. METHODS: Eleven patients who met DSM-IV criteria for major depression as determined by a structured clinical interview for DSM-III-R diagnosis and suitable for treatment with desipramine were recruited. Ten patients underwent a PET scan before and another after 3 to 4 weeks of treatment with desipramine. RESULTS: Eight of the 10 patients responded to desipramine treatment as indicated by more than 50% decrease in Hamilton Depression Rating Scale scores. Depressed patients showed a significant decrease in 5-HT2 receptor binding as measured by setoperone binding in frontal, temporal, parietal, and occipital cortical regions following desipramine treatment. The decrease in 5-HT2 receptor binding was observed bilaterally and was particularly prominent in frontal cortex. CONCLUSIONS: Depressed patients showed a significant reduction in available 5-HT2 receptors in the brain following desipramine treatment, but it is unknown if this change in 5-HT2 receptors is due to clinical improvement or an effect of desipramine that is unrelated to clinical status.

Pulmonary nodules: differential diagnosis using 18F-fluorodeoxyglucose single-photon emission computed tomography.

OBJECTIVE: The objective of this study was to prospectively evaluate the feasibility and efficacy of single-photon emission computed tomography (SPECT) with 18F-fluorodeoxyglucose (FDG) for differentiating malignant from benign pulmonary nodules. SUBJECTS AND METHODS: Twenty-six patients with 28 radiologically indeterminate focal pulmonary lesions were examined. Fasting patients were injected with 5 MBq/kg of FDG (maximum dose, 370 MBq). Imaging was performed with dual-head SPECT cameras equipped with 511-keV collimators. RESULTS: Seventeen of 21 pathologically malignant nodules showed FDG uptake on SPECT imaging (sensitivity, 81%). None of the seven benign modules showed uptake (specificity, 100%). SPECT imaging with FDG was positive in all 16 malignant nodules that were larger than or equal to 2 cm in diameter. However, only one (20%) of five nodules smaller than 2 cm in diameter showed positive on SPECT imaging. CONCLUSION: Using current technology, we found FDG SPECT imaging useful for distinguishing benign from malignant pulmonary nodules that were larger than or equal to 2 cm in diameter. However, because of the relatively low sensitivity of SPECT, smaller malignant nodules were not adequately revealed.

In vivo inhibition of beta-glucosidase and beta-mannosidase activity in rats by 2-deoxy-2-fluoro-beta-glycosyl fluorides and recovery of activity in vivo and in vitro.

2-Deoxy-2-fluoro-beta-glucosyl and -beta-mannosyl fluorides administered to rats in a single dose (10 mg/kg) inhibited beta-glucosidase and beta-mannosidase activity respectively after 1 h in brain, spleen, liver and kidney tissues. This inhibition, presumably caused by accumulation of 2-deoxy-2-fluoroglycosyl-enzyme intermediates, indicates that intact 2-deoxy-2-fluoroglycosyl fluorides are distributed to these organs and, in the case of brain, that they cross the blood/brain barrier. beta-Glucosidase activity recovered completely or partially in brain, spleen, liver and kidney by 20-48 h. beta-Mannosidase activity partially recovered in all tissues by 48 h. beta-Galactosidase activity in brain and kidney was not significantly affected by administration of either the gluco or manno compounds at this dosage, indicating that these inhibitors are directed towards specific glycosidases. Observation of similar relatively rapid rates of beta-glycosidase re-activation in vivo and in tissue homogenates in vitro at 37 degrees C suggests that hydrolysis or transglycosylation of 2-deoxy-2-fluoroglycosyl-enzymes, not protein synthesis, are the primary mechanisms involved in the recovery of glycosidase activity inhibited by this class of compounds in vivo.

Syntheses of 2-deoxy-2-fluoro mono- and oligo-saccharide glycosides from glycals and evaluation as glycosidase inhibitors.

Several fluorinated oligosaccharides, including 2-deoxy-2-fluoro derivatives of cellobiose, maltose, and maltotriose were synthesized by the action of fluorine or acetyl hypofluorite on the corresponding glycal peracetates. Temperature effects on the stereoselectivities of these reactions were examined. Addition of acetyl hypofluorite to several 2-substituted glycals in the gluco or galacto series gave 2,2-disubstituted arabino- or lyxo-hexose derivatives; 3,4,6-tri-O-acetyl-2-fluoro-D-glucal or the analogous galactal yielded 2-deoxy-2,2-difluoro arabino- or lyxo-hexose peracetates, whereas 2-acetoxy-3,4,6-tri-O-acetyl-D-glucal or the analogous galactal gave 2(R)-2-acetoxy-2-fluoro-arabino- or lyxo-hexose peracetates, respectively. 2-Acetamido-3,4,6-tri-O-acetyl-D-glucal gave 2(R)-2-acetamido-2-acetoxy-3,4,6-tri-O-acetyl-alpha-D-arabino-hexopyrano syl fluoride. 2,4-Dinitrophenyl 2-deoxy-2-fluoro-beta-cellobioside was an inactivator of the exoglucanase from Cellulomonas fimi while 2-deoxy-2-fluoro-alpha-maltosyl and alpha-maltotriosyl fluorides were slow substrates of human pancreatic alpha-amylase and rabbit muscle glycogen debranching enzyme, respectively.

Binding energy and catalysis. Fluorinated and deoxygenated glycosides as mechanistic probes of Escherichia coli (lacZ) beta-galactosidase.

Kinetic parameters for the hydrolysis of a series of deoxy and deoxyfluoro analogues of 2',4'-dinitrophenyl beta-D-galactopyranoside by Escherichia coli (lacZ) beta-galactosidase have been determined and rates found to be two to nine orders of magnitude lower than that for the parent compound. These large rate reductions result primarily from the loss of transition-state binding interactions due to the replacement of sugar hydroxy groups, and such interactions are estimated to contribute at least 16.7 kJ (4 kcal).mol-1 to binding at the 3, 4 and 6 positions and more than 33.5 kJ (8 kcal).mol-1 at the 2 position. The existence of a linear free-energy relationship between log(kcat./Km) for these compounds and the logarithm of the first-order rate constant for their spontaneous hydrolysis demonstrates that electronic effects are also important and provides direct evidence for oxocarbonium ion character in the enzymic transition state. A covalent intermediate which turns over only extremely slowly (t1/2 = 45 h) accumulates during hydrolysis of the 2-deoxyfluorogalactoside, and kinetic parameters for its formation have been determined. This intermediate is nonetheless catalytically competent, since it re-activates much more rapidly in the presence of the transglycosylation acceptors methanol or glucose, thereby providing support for the notion of a covalent intermediate during hydrolysis of the parent substrates.

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies.

A batch-contact alumina-extraction method has been used to separate [18F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[18F]-6-fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique developed in this laboratory. In 60 human subjects including normal healthy volunteers and patients diagnosed as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio (metabolites/FD) versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore necessary for each PET-FD study conducted.

Positron emission tomography in manganese intoxication.

We employed 6-fluorodopa to study the integrity of the nigrostriatal dopaminergic projection by positron emission tomography in 4 subjects with clinical features of mild parkinsonism caused by exposure to manganese. The 6-fluorodopa scans were normal. This finding suggests that in early manganism sufficient to cause parkinsonian deficits, damage may occur in pathways postsynaptic to the nigrostriatal system, probably involving striatal or pallidal neurons. Fluorodeoxyglucose scans showed decreased cortical glucose metabolism, the significance of which is discussed.

PET studies of parkinsonian patients treated with autologous adrenal implants.

Transplantation of autologous adrenal medulla tissue into the striatum has recently been proposed as a treatment for Parkinson's disease. We report the use of positron emission tomography (PET) to evaluate patients who had adrenal implants placed into the right caudate. 6-[18F] fluoro-L-dopa (6-FD) scans were performed to study the integrity and activity of the implant, and the nigrostriatal dopamine system before and six weeks after transplantation surgery. [68Ga] Gallium-ethylenediaminetetraacetate (Ga) scans were also performed to assess the blood brain barrier. The Ga scans performed on two patients showed increased permeability of the blood brain barrier at the surgical site. 6-FD PET scans in five patients did not show a consistent change in striatal uptake following adrenal medullary implantation after six weeks. Further assessment of implant viability with 6-FD PET scans after longer follow up may provide useful information if the blood-brain barrier becomes re-established with the passage of time.

An improved HPLC system for the analysis and purification of organic amine radiopharmaceuticals.

This paper describes the separation of lipophilic amine radiopharmaceuticals on normal phase silica using a reversed phase type eluant. This class of compound usually gives very poor peak symmetry on reversed phase columns. However, excellent separation of a number of amines of interest to Positron Emission Tomography, such as spiperone and its derivatives, has been achieved on this system.

Asymptomatic striatal dopamine depletion: PET scans in unilateral MPTP monkeys.

In cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces irreversible clinical, chemical, and pathological alterations that are similar to those found in Parkinson's disease. Unilateral carotid injections of this toxin produce ipsilateral nigrostriatal dopamine depletion while sparing the contralateral dopaminergic pathways. In order to study the damage to the nigrostriatal dopamine system in asymptomatic animals after unilateral MPTP administration, positron emission tomography (PET) scans were performed with [18F]fluoro-L-dopa (6-FD). This study demonstrates that clinically asymptomatic MPTP lesions may be assessed in vivo using 6-FD and PET.

Kinetics of in vitro decarboxylation and the in vivo metabolism of 2-18F- and 6-18F-fluorodopa in the hooded rat.

The metabolisms of L-18F-2-fluoro-DOPA (L-2-18F-DOPA) and L-18F-6-fluoro-DOPA (L-6-18F-DOPA) were compared in vitro and in vivo in the carbidopa-pretreated male hooded rat. In vivo, the sole metabolites in plasma were O-methylated derivatives. The peripheral formation of the O-methylated derivative of L-2-18F-DOPA was approximately twice as great as that for the 6-isomer. Animals were killed at 10 and 60 min after administration of the 18F-DOPAs, and samples of striatum and vermis were analyzed by HPLC. L-2-18F-DOPA passed less readily into brain than did L-6-18F-DOPA. Whereas significant amounts of 6-18F-fluorodopamine and metabolites were formed in the striatum, no decarboxylated derivatives of L-2-18F-DOPA were found. Determination of the Michaelis-Menten kinetic constants for aromatic amino acid decarboxylase AADC, EC 4.1.1.26) indicated that the Km for L-2-18F-DOPA (982 +/- 115 microM) was considerably higher than that for L-6-18F-DOPA (101 +/- 22 microM). The low substrate affinity for AADC and the relatively more rapid rate of O-methylation in the periphery account for the lack of formation of 2-18F-fluorodopamine in vivo. The ratio of total radioactivity between striatum and other brain regions is related to the decarboxylation of radiolabeled tracer and the relative persistence of the decarboxylated derivatives in the striatum. Since L-2-18F-DOPA is not decarboxylated in rat striatum, it is not a promising agent for the study of cerebral DOPA metabolism in humans by means of positron emission tomography.

Routine synthesis of carbon-11-carboxyl-labeled L-dopa.

Carbon-11-carboxyl-labeled L-dopa has been synthesized by the modified Bucherer-Strecker method. The reaction mixture was first purified by chiral HPLC followed by deprotection using hydriodic acid. The entire procedure was performed in a remotely operated system which gave the product in 28% radiochemical yield (decay corrected) in an overall synthesis time of 55-60 min.

Lesions of the putamen: their relevance to dystonia.

Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.

Routine synthesis of L-[18F]6-fluorodopa with fluorine-18 acetyl hypofluorite.

The synthesis of L-[18F]6-fluorodopa (2.4-10.6 mCi) was done by passing gaseous [18F]acetyl hypofluorite through a solution of L-methyl-N- acetyl-[beta-(3-methoxy-4-acetoxyphenyl)]alaninate in acetic acid at room temperature followed by the hydrolysis of the intermediate products with concentrated hydriodic acid. The desired fluorodopa isomer was isolated in 8% EOB radiochemical yield by high performance liquid chromatography in an overall synthesis time of 100 min.