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Credentials

Education ?

Medical School
University Of Toronto Faculty Of Medicine (1979)
Foreign school

Awards & Distinctions ?

Appointments
Univ. Of Toronto (1986 - 2000)
New York-presbyterian Hospital
Harvard Med. School (2005 - Present)
Associations
American College of Radiology
American Board of Radiology
Royal College of Physicians and Surgeons of Canada

Affiliations ?

Dr. Ichise is affiliated with 6 hospitals.

Hospital Affiliations

Score

Rankings

  • New York Presbyterian Hospital / Columbia
    630 W 168th St, New York, NY 10032
    •  
    Top 25%
  • New York Presbyterian Hospital - Presby Campus
  • New York Presbyterian / Westchester
    21 Bloomingdale Rd, White Plains, NY 10605
  • NewYork-PresbyterianColumbia
  • New York Presbyterian Hospital Columbia Presbyterian Ctr
  • NewYork-Presbyterian/Columbia
  • Publications & Research

    Dr. Ichise has contributed to 90 publications.
    Title F-18 Fdg Pet Imaging of Chronic Traumatic Brain Injury in Boxers: a Statistical Parametric Analysis.
    Date January 2011
    Journal Nuclear Medicine Communications
    Excerpt

    The participation in concussive susceptible sports such as boxing may cause chronic traumatic brain injury. The objective of this study was to determine whether there are unique patterns of reduced brain glucose metabolism in professional and amateur boxers.

    Title Epilepsy Duration Impacts on Brain Glucose Metabolism in Temporal Lobe Epilepsy: Results of Voxel-based Mapping.
    Date June 2010
    Journal Epilepsy & Behavior : E&b
    Excerpt

    [(18)F]Fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [(18)F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE).

    Title Procedure Guideline for Brain Perfusion Spect Using (99m)tc Radiopharmaceuticals 3.0.
    Date October 2009
    Journal Journal of Nuclear Medicine Technology
    Title 11c-dihydrotetrabenazine Pet of the Pancreas in Subjects with Long-standing Type 1 Diabetes and in Healthy Controls.
    Date June 2009
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Type 2 vesicular monoamine transporter (VMAT2), found in the brain, is also expressed by beta-cells of the pancreas in association with insulin. Preclinical experiments suggested that (11)C-dihydrotetrabenazine PET-measured VMAT2 binding might serve as a biomarker of beta-cell mass. We evaluated the feasibility of (11)C-dihydrotetrabenazine PET quantification of pancreatic VMAT2 binding in healthy subjects and patients with long-standing type 1 diabetes.

    Title Vmat2 Quantitation by Pet As a Biomarker for Beta-cell Mass in Health and Disease.
    Date December 2008
    Journal Diabetes, Obesity & Metabolism
    Excerpt

    The common pathology underlying both type 1 and type 2 diabetes (T1DM and T2DM) is insufficient beta-cell mass (BCM) to meet metabolic demands. An important impediment to the more rapid evaluation of interventions for both T1DM and T2DM lack of biomarkers of pancreatic BCM. A reliable means of monitoring the mass and/or function of beta-cells would enable evaluation of the progression of diabetes as well as the monitoring of pharmacologic and other interventions. Recently, we identified a biomarker of BCM that is quantifiable by positron emission tomography (PET). PET is an imaging technique which allows for non-invasive measurements of radioligand uptake and clearance, is sensitive in the pico- to nanomolar range and of which the results can be deconvoluted into measurements of receptor concentration. For BCM estimates, we have identified VMAT2 (vesicular monoamine transporter type 2) as a biomarker and [(11)C] DTBZ (dihydrotetrabenazine) as the transporter's ligand. VMAT2 is highly expressed in beta-cells of the human pancreas relative to other cells of the endocrine and exocrine pancreas. Thus measurements of [(11)C] DTBZ in the pancreas provide an indirect measurement of BCM. Here we summarize our ongoing efforts to validate the clinical utility of this non-invasive approach to real-time BCM measurements.

    Title In Vivo Imaging of Microglial Activation Using a Peripheral Benzodiazepine Receptor Ligand: [11c]pk-11195 and Animal Pet Following Ethanol Injury in Rat Striatum.
    Date August 2008
    Journal Annals of Nuclear Medicine
    Excerpt

    OBJECTIVE: To investigate whether [(11)C]PK-11195, a specific peripheral benzodiazepine receptors (PBRs) ligand for positron emission tomography (PET), can show activated microglia in a rat brain injury model. METHODS: On day 1, ethanol was injected into the rat's right striatum (ST) using a stereotaxic operative procedure. On day 3, head magnetic resonance imaging (MRI) scans for surgically treated rats were performed to evaluate ethanol injury morphologically. On day 4, dynamic PET scans (17 injured rats and 7 non-injured controls) were performed for 60 min with an animal PET scanner under chloral hydrate anesthesia following a bolus injection of [(11)C]PK-11195 through tail vein. Because PBRs are present throughout the brain, there is no suitable receptor-free reference region. The reference tissue model may not be applicable because of low target to background ratio for low affinity of [(11)C]PK-11195 to PBRs. We evaluated the PBRs binding with regions of interest (ROIs)-based approach to estimate total distribution volume (V). We used an integral from 0 min to 60 min (V (60)) as an estimate of V. On the coronal PET image, ROIs were placed on bilateral ST. Differences in right/left ST V (60) ratios between lesioned and unlesioned control rats were compared using unpaired t tests. Immunohistochemical staining was performed for confirming the presence of activated microglia following decapitation on the PET experiment day. RESULTS: The right/left ST V (60) ratios in lesioned rats (1.07 +/- 0.08) were significantly higher than those in unlesioned control rats (1.00 +/- 0.06, P < 0.05). On immunohistochemical staining, activated microglia were exclusively observed in the injured right ST but not in the noninjured left ST of the injury rats and the bilateral ST of the non-injured control rats. CONCLUSIONS: These results suggest that [(11)C]PK-11195 PET imaging would be a useful tool for evaluating microglial activation in a rat brain injury model.

    Title Noninvasive Estimation of Normalized Distribution Volume: Application to the Muscarinic-2 Ligand [(18)f]fp-tztp.
    Date April 2008
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    Reference tissue methods to estimate neuroreceptor binding are not applicable to [(18)F]FP-TZTP (a muscarinic-2 cholinergic receptor ligand), because there is no suitable receptor-free reference region. We evaluated a new method to estimate, without using arterial data or a receptor-free reference region, a receptor parameter called the normalized distribution volume, V(T)(*), using a region containing receptors as the input tissue. V(T)(*) is defined as V(T)/K'(1) (distribution volume (V(T)) normalized by K'(1) of the input region). We used a two-parameter multilinear reference tissue model (MRTM2) to generate parametric images of V(T)(*) and R(1) (R(1)=K(1)/K'(1)) from [(18)F]FP-TZTP PET data of healthy aged subjects (10 with apolipoprotein E-epsilon4 alleles (APOE-epsilon4(+)) and nine without (APOE-epsilon4(-)). V(T)(*) and V(T) were normalized by plasma-free fraction, f(P). By one-tissue kinetic analysis (1TKA) with metabolite-corrected plasma data, V(T) was previously reported as higher in the APOE-epsilon4(+) group. The noise magnitude of MRTM2 V(T)(*) and R(1) images were nearly identical to those of 1TKA V(T) and K(1) images. K'(1) or f(P) was not different between the two groups. V(T)(*) (mins) (1,659+/-497) and V(T) (mL/cm(3)) (701+/-99) in APOE-epsilon4(+) were higher by 38 and 22% than those (1,209+/-233 and 577+/-112) in APOE-epsilon4(-), respectively. The statistical significance for V(T)(*) (0.041) was lower than that for V(T) (0.025), due to the higher intersubject variability of V(T)(*) (25%) than that of V(T) (17%). We conclude that MRTM2 V(T)(*) allows detection of group differences in receptor binding without arterial blood or a receptor-free reference region.

    Title Synthesis and Initial Evaluation of [11c](r)-rway in Monkey-a New, Simply Labeled Antagonist Radioligand for Imaging Brain 5-ht1a Receptors with Pet.
    Date February 2008
    Journal European Journal of Nuclear Medicine and Molecular Imaging
    Excerpt

    PURPOSE: We aimed to fulfill a need for a radioligand that may be simply labeled with carbon-11 for effective positron emission tomography (PET) imaging of brain 5-HT(1A) receptors. METHODS: Racemic RWAY (2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylbutyryl]-1H-azepine) has high affinity for 5-HT(1A) receptors. The enantiomers of RWAY and O-desmethyl-RWAY, synthesized from commercially available materials, were each labeled with carbon-11 by treating the respective O-desmethyl precursor with [(11)C]iodomethane, and injected into rhesus monkey for measurement of regional brain uptake. The 5-HT(1A) selectivity of (R)-[(11)C]RWAY was checked by administering WAY-100635, before and after radioligand administration. Radiometabolites of (R)-[(11)C]RWAY in blood and urine were analyzed by HPLC with partial elucidation of their structures by LC-MS-MS. RESULTS: (R)-[(11)C]RWAY was a 5-HT(1A) receptor antagonist exhibiting high brain uptake with regional distribution consistent with specific binding to 5-HT(1A) receptors. The similar affinity, (S)-[(11)C]RWAY was a weak partial agonist at 5-HT(1A) receptors exhibiting similar brain peak uptake with much less 5-HT(1A) receptor-specific binding. The maximal ratio in receptor-rich cingulate gyrus to receptor-devoid cerebellum reached 6.4 at 87.5 min after injection of (R)-[(11)C]RWAY. After treatment with WAY-100635 before or after (R)-[(11)C]RWAY administration, radioactivity levels in 5-HT(1A) receptor-rich regions were reduced almost to that in cerebellum. Blood and urine radiometabolites were less lipophilic than parent and were not due to hydrolysis but to ring hydroxylations, oxidation, and dephenylation. CONCLUSION: (R)-[(11)C]RWAY is simply prepared and an effective antagonist for imaging brain 5-HT(1A) receptors. This radioligand resists hydrolysis in vivo, gives less lipophilic radiometabolites, and warrants further PET studies in human subjects.

    Title Elevated Serotonin Transporter Binding in Major Depressive Disorder Assessed Using Positron Emission Tomography and [11c]dasb; Comparison with Bipolar Disorder.
    Date November 2007
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.

    Title Consensus Nomenclature for in Vivo Imaging of Reversibly Binding Radioligands.
    Date October 2007
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

    Title Identification and Regional Distribution in Rat Brain of Radiometabolites of the Dopamine Transporter Pet Radioligand [11c]pe2i.
    Date September 2007
    Journal European Journal of Nuclear Medicine and Molecular Imaging
    Excerpt

    PURPOSE: We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [(11)C]PE2I. METHODS: PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [(11)C]PE2I. Carrier-added [(11)C]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [(11)C]PE2I was assessed in rat brain homogenates. RESULTS: After peak brain uptake of no-carrier-added [(11)C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [(11)C]PE2I represented 10.9 +/- 2.9% of the radioactivity in plasma, 67.1 +/- 11.0% in cerebellum, and 92.5 +/- 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [(11)C]PE2I was stable in rat brain homogenate for at least 1 h at 37 degrees C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442-->424 transition due to H(2)O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [(11)C]PE2I, [(11)C]1, and [(11)C]2 in striata to their cognates in cerebellum were 6.1 +/- 3.4, 3.7 +/- 2.2 and 1.33 +/- 0.38, respectively, showing binding selectivity of metabolite [(11)C]1 to striata. CONCLUSION: Radiometabolites [(11)C]1 and [(11)C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [(11)C]PE2I, respectively. The presence of the pharmacologically active [(11)C]1 and the inactive [(11)C]2 is a serious impediment to successful biomathematical analysis.

    Title Persistent Dopamine Functions of Neurons Derived from Embryonic Stem Cells in a Rodent Model of Parkinson Disease.
    Date July 2007
    Journal Stem Cells (dayton, Ohio)
    Excerpt

    The derivation of dopamine neurons is one of the best examples of the clinical potential of embryonic stem (ES) cells, but the long-term function of the grafted neurons has not been established. Here, we show that, after transplantation into an animal model, neurons derived from mouse ES cells survived for over 32 weeks, maintained midbrain markers, and had sustained behavioral effects. Microdialysis in grafted animals showed that dopamine (DA) release was induced by depolarization and pharmacological stimulants. Positron emission tomography measured the expression of presynaptic dopamine transporters in the graft and also showed that the number of postsynaptic DA D(2) receptors was normalized in the host striatum. These data suggest that ES cell-derived neurons show DA release and reuptake and stimulate appropriate postsynaptic responses for long periods after implantation. This work supports continued interest in ES cells as a source of functional DA neurons.

    Title Pet Imaging of Neurokinin-1 Receptors with [(18)f]spa-rq in Human Subjects: Assessment of Reference Tissue Models and Their Test-retest Reproducibility.
    Date April 2007
    Journal Synapse (new York, N.y.)
    Excerpt

    [(18)F]SPA-RQ (substance P antagonist receptor quantifier) labels the substance P-preferring (NK(1)) receptor in human brain. A prior study showed that [(18)F]SPA-RQ brain uptake can be quantified with a reference tissue method and thereby avoid invasive blood sampling. The purposes of this study were to compare three different reference tissue methods and to assess test-retest reproducibility. Eight healthy subjects underwent two [(18)F]SPA-RQ scans. We calculated the binding potential (BP), which is proportional to receptor density, from both regional volume of interest and voxel-wise data. We compared three reference tissue methods: simplified reference tissue model, multilinear reference tissue model (MRTM), and its two-parameter version (MRTM2). The three methods generated equivalent values of regional BP, but MRTM2 was the most resistant to noise. Temporally stable values of BP were obtained with 240 min of imaging data. MRTM2 had excellent test-retest reproducibility, with high reliability (intraclass correlation > 0.9) and low variability (< 10%). In addition to regional volume of interest analysis, we also created parametric images of BP, variability, and reliability based on voxel-wise time-activity data. The reproducibility of parametric BP was also good, with variability < 20% and reliability > 0.7 in gray matter regions. In conclusion, a two-parameter reference tissue method (MRTM2) provided reproducible and reliable measurements of [(18)F]SPA-RQ brain uptake using 240 min of both regional and voxel-wise data.

    Title Pet [11c]dasb Imaging of Serotonin Transporters in Patients with Alcoholism.
    Date March 2007
    Journal Alcoholism, Clinical and Experimental Research
    Excerpt

    OBJECTIVE: Alcoholism and aggression have each been associated with neurochemical measurements suggestive of decreased serotonin synaptic transmission. We measured densities of the serotonin transporter (SERT) in a moderate-sized sample of alcoholic patients who were assessed for aggressive characteristics. METHODS: Thirty alcoholic inpatients and 18 healthy controls received a PET scan with [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile. The alcoholic inpatients were classified as aggressive or nonaggressive based on a comparison between the top third and bottom third scores on the Buss-Durkee Hostility Index. RESULTS: Using a pixel-wise comparison, no brain region showed significant alterations in SERT binding among the 3 groups of subjects (aggressive alcoholic subjects, nonaggressive alcoholic subjects, and healthy controls) or between the combined alcoholic group and healthy controls. None of the clinical measures (including measures of aggression) correlated with SERT binding in the alcoholic subjects. CONCLUSION: Contrary to prior imaging reports using the nonselective ligand [(123)I]beta-CIT, we found no significant alterations of SERT density in alcoholic patients.

    Title Quantification of Serotonin 5-ht1a Receptors in Monkey Brain with [11c](r)-(-)-rway.
    Date December 2006
    Journal Synapse (new York, N.y.)
    Excerpt

    [11C](R)-(-)-RWAY ([11C]2, 3, 4, 5, 6, 7-hexahydro-1{4-[1[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylbutyry}-1H-azepine) is a new radioligand for imaging brain 5-HT1A receptors with positron emission tomography. In [11C](R)-(-)-RWAY, the direction of the amide bond is expected to reduce metabolism by hydrolysis while allowing easy 11C-labeling at the methoxy position. The purposes of this study were to evaluate different tracer kinetic models in nonhuman primates to quantify 5-HT1A receptors with [11C](R)-(-)-RWAY and to test for the possible action of P-glycoprotein (P-gp), one of the known efflux pumps at the blood-brain barrier. The brain uptake of radioactivity from [11C](R)-(-)-RWAY into 5-HT1A receptor-rich brain regions was severalfold greater than for its antipode ([11C](S)-(+)-RWAY) and could be displaced by receptor saturating doses of the selective 5-HT1A antagonist, WAY-100635. Pretreatment with tariquidar, a potent inhibitor of P-gp, increased brain uptake of [11C](R)-(-)-RWAY about 1.5-fold and the plasma free fraction about 1.8-fold. Thus, the effect of tariquidar on brain uptake may have been caused by displacement of the radioligand binding to plasma proteins. Mathematical modeling showed that the estimated values of regional binding potential were correlated strongly between two-tissue compartment model and multilinear reference tissue model, and thus, supported the use of the cerebellum as a reference region.

    Title Pet Imaging of Serotonin Transporters with [11c]dasb: Test-retest Reproducibility Using a Multilinear Reference Tissue Parametric Imaging Method.
    Date November 2006
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Parametric imaging of serotonin transporters (SERT) with 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([11C]DASB) PET is a useful data analysis tool. The purpose of this study was to evaluate the reproducibility of measurements of SERT binding potential (BP) and relative blood flow (R1) by a 2-parameter multilinear reference tissue parametric imaging method (MRTM2) for human [11C]DASB studies. METHODS: Eight healthy subjects (3 men, 5 women; age, 26 +/- 9 y) underwent 2 [11C]DASB PET scans separated by 1 h on the same day (dose, 703 +/- 111 MBq). Parametric images of BP and R1 were generated by MRTM2 using the cerebellum as a reference region. The k'2 (clearance rate constant from the reference region) required by MRTM2 was estimated by the 3-parameter MRTM. Reproducibility of BP and R1 measurements was evaluated by calculating bias (100 x (retest - test/test), variability (SD of the bias), and reliability (intraclass correlation coefficient = rho) for several representative regions of interest (ROIs). BP and R1 were estimated for ROI time-activity curves fitted by MRTM2 and were compared with those based on the parametric images. RESULTS: The test-retest (0.066 +/- 0.013/0.06 +/- 0.011 min(-1)) MRTM k'2 reproducibility was excellent with small bias (3%) and variability (6%) and high reliability (0.95). Retest BP values were consistently lower than those of test BP values in all regions (a mean negative bias of approximately 6%; P < 0.001). The test-retest BP variability was relatively small, ranging from 4% to 13%, with rho ranging from 0.44 to 0.85. In contrast to BP, test-retest R1 values were similar with negligible bias of < or =0.1%. The test-retest R1 variability was excellent and smaller than that of BP ranging from 3% to 6%, with rho ranging from 0.58 to 0.95. BP and R1 values estimated by the ROI time-activity curve-fitting method were slightly lower ( approximately 3% and approximately 1%, respectively) than those by the parametric imaging method (P < 0.001). However, the test-retest bias and variability of BP and R1 were very similar for both ROI and parametric methods. CONCLUSION: Our results suggest that [11C]DASB parametric imaging of BP and R1 with the noninvasive MRTM2 method is reproducible and reliable for PET studies of SERT.

    Title Pet Imaging of Brain 5-ht1a Receptors in Rat in Vivo with 18f-fcway and Improvement by Successful Inhibition of Radioligand Defluorination with Miconazole.
    Date November 2006
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities. METHODS: PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis. RESULTS: PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment. CONCLUSION: Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.

    Title Serotonin Transporter Binding in Bipolar Disorder Assessed Using [11c]dasb and Positron Emission Tomography.
    Date September 2006
    Journal Biological Psychiatry
    Excerpt

    BACKGROUND: Evidence from neuroimaging post-mortem, and genetic studies suggests that bipolar disorder (BD) is associated with abnormalities of the serotonin-transporter (5-HTT) system. Because of various limitations of these studies, however, it has remained unclear whether 5-HTT binding is abnormal in unmedicated BD-subjects. This study used PET and [(11)C]DASB, a radioligand that afforded higher sensitivity and specificity for the 5-HTT than previously available radioligands, to compare 5-HTT binding between BD and control subjects. METHODS: The 5-HTT binding-potential (BP) was assessed in 18 currently-depressed, unmedicated BD-subjects and 37 healthy controls using PET and [(11)C]DASB. RESULTS: In BD, the mean 5-HTT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex and insula and decreased in the brainstem at the level of the pontine raphe-nuclei. Anxiety ratings correlated positively with 5-HTT BP in insula and DCC, and BP in these regions was higher in subjects manifesting pathological obsessions and compulsions relative to BD-subjects lacking such symptoms. Subjects with a history of suicide attempts showed reduced 5-HTT binding in the midbrain and increased binding in anterior cingulate cortex versus controls and to BD-subjects without attempts. CONCLUSIONS: This is the first study to report abnormalities in 5-HTT binding in unmedicated BD-subjects. The direction of abnormality in the brainstem was opposite to that found in the cortex, thalamus, and striatum. Elevated 5-HTT binding in the cortex may be related to anxiety symptoms and syndromes associated with BD.

    Title Development of New Brain Imaging Agents Based Upon Nocaine-modafinil Hybrid Monoamine Transporter Inhibitors.
    Date August 2006
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

    Title Effects of Early Life Stress on [11c]dasb Positron Emission Tomography Imaging of Serotonin Transporters in Adolescent Peer- and Mother-reared Rhesus Monkeys.
    Date May 2006
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Excerpt

    Peer-reared (PR) rhesus monkeys with early maternal separation later exhibit aggressiveness, impaired impulse control, alcohol abuse, and low CSF 5-hydroxyindoleacetic acid. This study compared regional brain serotonin transporter (SERT) binding between nine PR and seven mother-reared rhesus monkeys with [11C]DASB positron emission tomography (PET) imaging. Parametric images of binding potential (BP) (which is proportional to Bmax/KD, in which Bmax is transporter density and KD is dissociation constant) and relative blood flow (R1) were generated by the two-parameter multilinear reference tissue model. R1 images were used for coregistration and normalization of PET parametric data to the magnetic resonance imaging template space. Group BP differences were analyzed voxelwise by Student's t test in SPM2. Region of interest-based parameter values were also calculated to obtain the magnitude of regional BP differences between the two groups. For the PR group, SERT BP was decreased by 10-23% across a range of brain areas consisting of the raphe, thalamus, hypothalamus, caudate and putamen, globus pallidum, anterior cingulate gyrus, and medial temporal regions, including amygdala and hippocampus (cluster-level corrected p = 0.002). For the latter three regions, BP was decreased in the right hemisphere. These results agree with the hypothesis that early maternal deprivation affects the development of the serotonergic system and suggest that decreased serotonergic innervations in the critical brain regions may explain some of the behavioral and biochemical abnormalities in PR monkeys.

    Title Pet Imaging of the Dopamine Transporter with 18f-fecnt: a Polar Radiometabolite Confounds Brain Radioligand Measurements.
    Date April 2006
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.

    Title Widespread Decrease of Nicotinic Acetylcholine Receptors in Parkinson's Disease.
    Date March 2006
    Journal Annals of Neurology
    Excerpt

    OBJECTIVE: Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects. METHODS: Nicotinic acetylcholine receptors were imaged in 10 nondemented Parkinson's disease patients and 15 age-matched healthy subjects using a single-photon emission computed tomography ligand [(123)I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus nondisplaceable), as well as the delivery (K(1)). RESULTS: Parkinson's disease showed a widespread significant decrease (approximately 10%) of V in both cortical and subcortical regions without a significant change in K(1). INTERPRETATION: These results indicate the importance of extending the study to demented patients.

    Title Pet Imaging of Brain with the Beta-amyloid Probe, [11c]6-oh-bta-1, in a Transgenic Mouse Model of Alzheimer's Disease.
    Date October 2005
    Journal European Journal of Nuclear Medicine and Molecular Imaging
    Excerpt

    PURPOSE: The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). METHODS: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. RESULTS: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. CONCLUSION: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

    Title Reproducibility of Dopamine Transporter Density Measured with 123i-fpcit Spect in Normal Control and Parkinson's Disease Patients.
    Date March 2005
    Journal Annals of Nuclear Medicine
    Excerpt

    The objective of this study was to evaluate the reproducibility of 123I-FPCIT SPECT by using whole striatal region of interest (ROI) and subdivided ROI in normal controls (NC) and Parkinson's disease (PD) patients. METHODS: Ten NC and 6 PD received a SPECT scan for 6 hours postinjection of FPCIT. The distribution volume ratio (R(V)) and specific-nonspecific tissue activity ratio (RT) were measured as an outcome measure. The test/retest reproducibility of R(V) and R(T) was evaluated by calculating the test/retest difference, variability, and reliability. RESULTS: There were no significant test/retest differences for any regions in either the NC or PD. The test/retest variability/reliability of Rv was 5.53+/-4.12%/0.89 in NC, 4.50+/-5.31%/0.99 in PD with whole striatal ROI, 4.29+/-0.78%/ 0.94+/-0.03 in NC, and 6.87+/-1.23 %/0.98+/-0.01 in PD with subdivided ROI. The test/retest variability/reliability of RT was 11.1+/-10.4%/0.59 in NC, 7.84+/-8.94%/0.95 in PD with whole striatal ROI, 11.9+/-1.22%/0.65+/-0.06 in NC, and 12.2+/-4.00%/0.95+/-0.03 in PD with subdivided ROI. CONCLUSION: R(V) is highly reproducible and reliable compared with RT in both NC and PD as an outcome measure.

    Title Evaluation of Anesthesia Effects on [18f]fdg Uptake in Mouse Brain and Heart Using Small Animal Pet.
    Date November 2004
    Journal Nuclear Medicine and Biology
    Excerpt

    This study evaluates effects of anesthesia on (18)F-FDG (FDG) uptake in mouse brain and heart to establish the basic conditions of small animal PET imaging. Prior to FDG injection, 12 mice were anesthetized with isoflurane gas; 11 mice were anesthetized with an intraperitoneal injection of a ketamine/xylazine mixture; and 11 mice were awake. In isoflurane and ketamine/xylazine conditions, FDG brain uptake (%ID/g) was significantly lower than in controls. Conversely, in the isoflurane condition, %ID/g in heart was significantly higher than in controls, whereas heart uptake in ketamine/xylazine mice was significantly lower. Results suggest that anesthesia impedes FDG uptake in mouse brain and affects FDG uptake in heart; however, the effects in the brain and heart differ depending on the type of anesthesia used.

    Title Biodistribution and Radiation Dosimetry of the Serotonin Transporter Ligand 11c-dasb Determined from Human Whole-body Pet.
    Date October 2004
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    11C-Labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) is a selective radioligand for the in vivo quantitation of serotonin transporters (SERTs) using PET. The goal of this study was to provide dosimetry estimates for 11C-DASB based on human whole-body PET. METHODS: Dynamic whole-body PET scans were acquired for 7 subjects after the injection of 669 +/- 97 MBq (18.1 +/- 2.6 mCi) of 11C-DASB. The acquisition for each subject was obtained at 14 time points for a total of 115 min after injection of the radioligand. Regions of interest were placed over compressed planar images of source organs that could be visually identified to generate time-activity curves. Radiation burden to the body was calculated from residence times of these source organs using the MIRDOSE3.1 program. RESULTS: The organs with high radiation burden included the lungs, urinary bladder wall, kidneys, gallbladder wall, heart wall, spleen, and liver. The activity peaked within 10 min after the injection of 11C-DASB for all these organs except two--the excretory organs gallbladder and urinary bladder wall, which had peak activities at 32 and 22 min, respectively. Monoexponential fitting of activity overlying the urinary bladder suggested that approximately 12% of activity was excreted via the urine. Simulations in which the urinary voiding interval was decreased from 4.8 to 0.6 h produced only modest effects on the dose to the urinary bladder wall. With a 2.4-h voiding interval, the calculated effective dose was 6.98 microGy/MBq (25.8 mrem/mCi). CONCLUSION: The estimated radiation burden of 11C-DASB is relatively modest and would allow multiple PET examinations of the same research subject per year.

    Title Quantification of Nicotinic Acetylcholine Receptors in Human Brain Using [123i]5-i-a-85380 Spet.
    Date October 2004
    Journal European Journal of Nuclear Medicine and Molecular Imaging
    Excerpt

    The purpose of this study was to assess the utility of a new single-photon emission tomography ligand, [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), to measure regional nAChR binding in human brain. Six healthy nonsmoker subjects (two men and four women, age 33 +/- 15 years) participated in both a bolus (dose: 317 +/- 42 MBq) and a bolus plus constant infusion (dose of bolus: 98 +/- 32 MBq, B/I=6.7 +/- 2.6 h, total dose: 331 +/- 55 MBq) study. The study duration was 5-8 h and 14 h in the former and the latter, respectively. Nonlinear least-squares compartmental analysis was applied to bolus studies to calculate total (VT') and specific (VS') distribution volumes. A two-tissue compartment model was applied to identify VS'. VT' was also calculated in B/I studies. In bolus studies, VT' was well identified by both one- and two-tissue compartment models, with a coefficient of variation of less than 5% in most regions. The two-compartment model gave VT' values of 51, 22, 27, 32, 20, 19, 20, and 17 ml cm(-3) in thalamus, cerebellum, putamen, pons, and frontal, parietal, temporal, and occipital cortices, respectively. The two-compartment model did not identify VS' well. B/I studies provided poor accuracy of VT' measurement, possibly due to deviations from equilibrium conditions. These results demonstrate the feasibility of quantifying high-affinity type nAChRs using [123I]5-I-A-85380 in humans and support the use of VT' measured by bolus studies.

    Title Absolute Quantification of Regional Cerebral Glucose Utilization in Mice by 18f-fdg Small Animal Pet Scanning and 2-14c-dg Autoradiography.
    Date September 2004
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice by use of (18)F-FDG and a small animal PET scanner. rCMR(glc) determined with (18)F-FDG PET was compared with values determined simultaneously by the autoradiographic 2-(14)C-DG method. In addition, we compared the rCMR(glc) values under isoflurane, ketamine and xylazine anesthesia, and awake states. METHODS: Immediately after injection of (18)F-FDG and 2-(14)C-DG into mice, timed arterial samples were drawn over 45 min to determine the time courses of (18)F-FDG and 2-(14)C-DG. Animals were euthanized at 45 min and their brain was imaged with the PET scanner. The brains were then processed for 2-(14)C-DG autoradiography. Regions of interest were manually placed over cortical regions on corresponding coronal (18)F-FDG PET and 2-(14)C-DG autoradiographic images. rCMR(glc) values were calculated for both tracers by the autoradiographic 2-(14)C-DG method with modifications for the different rate and lumped constants for the 2 tracers. RESULTS: Average rCMR(glc) values in cerebral cortex with (18)F-FDG PET under normoglycemic conditions (isoflurane and awake) were generally lower (by 8.3%) but strongly correlated with those of 2-(14)C-DG (r(2) = 0.95). On the other hand, under hyperglycemic conditions (ketamine/xylazine) average cortical rCMR(glc) values with (18)F-FDG PET were higher (by 17.3%) than those with 2-(14)C-DG. Values for rCMR(glc) and uptake (percentage injected dose per gram [%ID/g]) with (18)F-FDG PET were significantly lower under both isoflurane and ketamine/xylazine anesthesia than in the awake mice. However, the reductions of rCMR(glc) were markedly greater under isoflurane (by 57%) than under ketamine and xylazine (by 19%), whereas more marked reductions of %ID/g were observed with ketamine/xylazine (by 54%) than with isoflurane (by 37%). These reverse differences between isoflurane and ketamine/xylazine may be due to competitive effect of (18)F-FDG and glucose uptake to the brain under hyperglycemia. CONCLUSION: We were able to obtain accurate absolute quantification of rCMR(glc) with mouse (18)F-FDG PET imaging as confirmed by concurrent use of the autoradiographic 2-(14)C-DG method. Underestimation of rCMR(glc) by (18)F-FDG in normoglycemic conditions may be due to partial-volume effects. Computation of rCMR(glc) from (18)F-FDG data in hyperglycemic animals may require, however, alternative rate and lumped constants for (18)F-FDG.

    Title Radiation Dosimetry Estimates for the Pet Serotonin Transporter Probe 11c-dasb Determined from Whole-body Imaging in Non-human Primates.
    Date September 2004
    Journal Nuclear Medicine Communications
    Excerpt

    The radiotracer 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile labelled in the N-methyl position (11C-DASB) is a selective radioligand for the in vivo quantification of serotonin transporters (SERTs) using positron emission tomography (PET). The current study quantified the distribution of activity in two rhesus monkeys after the injection of approximately 333 MBq (9 mCi) 11C-DASB. Whole-body images were acquired at 22 time points for a total of 120 min following injection of the radioligand. Source organs were identified at each time point from both tomographic images (using multiple regions of interest on each tomograph for each organ) and a single planar image (using a single region of interest for each organ). The peak activities in planar images in the five identified source organs (expressed as per cent injected dose (ID)) were lungs (24% ID at 1.5 min), kidneys (6.5% ID at 4 min), liver (8% ID at 3 min), brain (4% ID at 5 min) and spleen (0.42% ID at 3 min). Mono-exponential fitting of activity overlying the bladder suggested that approximately 14% of activity was excreted via the urine. The radiation burden to the body was calculated from residence times of these source organs and then scaled to corresponding human values. The calculated effective dose from tomographic and planar images was 6.0 and 6.4 microGy x MBq(-1) (22.3 and 23.7 mrad x mCi(-1)), respectively. The planar analysis was much easier to perform, and generally yielded slightly higher (i.e., more conservative) estimates of radiation burden than the tomographic analysis. The estimated radiation burden of 11C-DASB is relatively modest and would allow multiple scans per research subject per year.

    Title Synthesis and Evaluation of Two 18f-labeled 6-iodo-2-(4'-n,n-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives As Prospective Radioligands for Beta-amyloid in Alzheimer's Disease.
    Date May 2004
    Journal Journal of Medicinal Chemistry
    Excerpt

    This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

    Title Evaluation of 2 Scatter Correction Methods Using a Striatal Phantom for Quantitative Brain Spect.
    Date March 2004
    Journal Journal of Nuclear Medicine Technology
    Excerpt

    OBJECTIVE: Scatter correction is an important factor in quantitative SPECT. In this study, we evaluated 2 methods of scatter correction for brain SPECT. The first is based on thresholding the energy spectrum (ES), and the second is based on a modification of the transmission-dependent convolution subtraction (TDCS) method. METHODS: SPECT imaging of a skull striatal phantom was performed using a triple-head camera with and without scatter correction. The striatal compartments were filled with (123)I, and the brain shell cavity (background) was filled with varying concentrations of (123)I to obtain striatal-to-background ratios of 2, 5, 10, 15, 20, and 25 to 1, respectively, which were considered to be the expected ratios. SPECT-measured ratios of striatal-to-background counts were determined with scatter correction (both ES and TDCS methods) and without scatter correction and were then compared with the expected ratios. RESULTS: Without scatter correction, measured striatal-to-background ratios were underestimated by an average of 41.7%, compared with the expected ratios. The ES method of scatter correction underestimated the striatal-to-background ratios by an average of 27.4%, a significant improvement (P < 0.04) over those without scatter correction. With the TDCS method of scatter correction, the ratios were underestimated by only 3.3% (P < 0.03). TDCS ratios were significantly (P < 0.04) higher than ES ratios and were nearly identical to the expected ratios. CONCLUSION: These results suggest that scatter correction significantly improves the striatal-to-background ratios. The TDCS method appears to correct scatter more effectively than does the ES method for the striatal phantom, thus providing more accurate quantification.

    Title Pharmacological and Genetic Characterization of Two Selective Serotonin Transporter Ligands: 2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine (afm) and 3-amino-4-[2-(dimethylaminomethyl-phenylthio)]benzonitrile (dasb).
    Date March 2004
    Journal The Journal of Pharmacology and Experimental Therapeutics
    Excerpt

    The expression and function of the serotonin transporter (SERT) is important in the regulation of mood and emotion. Determination of SERT alterations in physiological and pathological states is essential for understanding the role of SERT in mood regulation, and in the etiology and therapy of psychiatric disorders. Two SERT ligands, AFM ([(3)H]2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine) and DASB ([(3)H]3-amino-4-[2-(dimethylaminomethylphenylthio)]benzonitrile), have recently been developed for positron emission tomography (PET) imaging. The aim of the present study was to determine the selectivity of these compounds for SERT. Autoradiography of AFM or DASB binding was compared in the brains of mice with genetically normal, diminished, or absent SERT. In addition, the pharmacodynamic profile of [(3)H]AFM was examined in the mouse brain. The distribution of [(3)H]AFM and [(3)H]DASB binding in the normal brains was consistent with that of previously studied serotonin reuptake inhibitors. Both ligands had negligible binding in the brain of SERT knockout mice, and binding was reduced approximately 50% in heterozygote SERT mice. The K(d) of [(3)H]AFM binding in the cortex and midbrain was 1.6 and 1.0 nM, respectively. Competition studies showed that [(3)H]AFM has very low affinity for norepinephrine and dopamine transporters as well as 5-HT receptors, including 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(2C) receptors. In addition, fenfluramine showed a low capability to compete with [(3)H]AFM. The present results suggest that both AFM and DASB are highly selective SERT ligands potentially suitable for use in human PET studies of SERT.

    Title Linearized Reference Tissue Parametric Imaging Methods: Application to [11c]dasb Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain.
    Date October 2003
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    SUMMARY: The authors developed and applied two new linearized reference tissue models for parametric images of binding potential (BP) and relative delivery (R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTM(O)) was modified (MRTM) and used to estimate a clearance rate (k'2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k'2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k'2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTM(O) from 12-70% to 1-4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.

    Title Strategies to Improve Neuroreceptor Parameter Estimation by Linear Regression Analysis.
    Date November 2002
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    In an attempt to improve neuroreceptor distribution volume (V) estimates, the authors evaluated three alternative linear methods to Logan graphical analysis (GA): GA using total least squares (TLS), and two multilinear analyses, MA1 and MA2, based on mathematical rearrangement of GA equation and two-tissue compartments, respectively, using simulated and actual PET data of two receptor tracers, [(18)F]FCWAY and [(11)C]MDL 100,907. For simulations, all three methods decreased the noise-induced GA bias (up to 30%) at the expense of increased variability. The bias reduction was most pronounced for MA1, moderate to large for MA2, and modest to moderate for TLS. In addition, GA, TLS, and MA1, methods that used only a portion of the data (T > t*, chosen by an automatic process), showed a small underestimation for [(11)C]MDL 100,907 with its slow kinetics, due to selection of t* before the true point of linearity. These noniterative methods are computationally simple, allowing efficient pixelwise parameter estimation. For tracers with kinetics that permit t* to be accurately identified within the study duration, MA1 appears to be the best. For tracers with slow kinetics and low to moderate noise, however, MA2 may provide the lowest bias while maintaining computational ease for pixelwise parameter estimation.

    Title Combination of Dopamine Transporter and D2 Receptor Spect in the Diagnostic Evaluation of Pd, Msa, and Psp.
    Date May 2002
    Journal Movement Disorders : Official Journal of the Movement Disorder Society
    Excerpt

    It is often difficult to differentiate clinically between Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP).The objective of this work was to investigate whether combined pre- and postsynaptic dopaminergic single photon emission computed tomography (SPECT) scanning can reliably demonstrate changes in the nigrostriatal dopaminergic system and help differentiate between normal controls, PD, MSA, and PSP patients. We performed SPECT evaluation of the dopamine transporter (DAT) and dopamine D2 receptors (D2). SPECT scans using [123I]beta-CIT (for DAT) and [123I]IBF (for D2) were performed in 18 patients with PD (12 dopa-naïve and 6 on levodopa and/or dopamine agonists), 7 with MSA of the striatonigral degeneration type, 6 with PSP, and 29 normal controls. Antiparkinsonian drugs were withheld for at least 12 hours before the scans. DAT and D2 binding potentials (Rv = V3/V2) were measured for caudate, anterior, and posterior putamen on the sides ipsilateral and contralateral to the worst motor symptoms. DAT binding in the posterior putamen was markedly reduced in all patients. However, D2 binding in posterior putamen was significantly increased in dopa-untreated PD, being greater than the normal range in 4 of 12 (33%), and it was significantly reduced in MSA, being below the normal range in 5 of 7 (71%). None of the patients with PD showed reduced D2 binding below the normal range in posterior putamen. The degree of DAT binding could not discriminate between the patient groups. The ratio of posterior putamen to caudate percentage D2 Rv compared with the controls showed an opposite pattern between PD or PSP and MSA; the caudate was greater in 16 of 18 with PD and 6 of 6 with PSP, whereas caudate was less in 5 of 7 with MSA. These findings suggest that DAT SPECT may be useful in differentiating parkinsonism from controls and D2 SPECT in further differentiating MSA from Parkinson's disease and possibly PSP.

    Title Simple and Low-cost Tele-nuclear Medicine Conference System with the E-mail Protocol.
    Date May 2002
    Journal Annals of Nuclear Medicine
    Excerpt

    PURPOSE: Because of the recent innovative growth in computer technology, digital imaging, and the Internet, we can take advantage of these facilities for education and clinical work in nuclear medicine. We developed a tele-nuclear medicine conference system with electronic mail (e-mail) on the Internet. METHODS: Twenty-one physicians (20 radiologists, 1 neurologist), 6 technologists and 2 medical students in six university hospitals (Japan 5, Canada 1), 5 local hospitals in Japan participated in this project. We used digital still cameras (330 k pixels) equipped with a floppy disk drive and 10 x optical zoom to digitize images with JPEG compression (640 x 480 matrix). The images were attached to e-mail messages (containing a brief description of each case). The mail was sent simultaneously to all members on the mailing list. Scintigram and SPECT images as well as other radiological images were sent by e-mail. Reply mails about each case were sent to all members via the mailing list. RESULTS: During a period of 6 months, 18 cases (tumor/infection: 7, bone: 6, cardiovascular: 1, neurology; 3, endocrine: 1) with 144 e-mails (average 5.6/case) were submitted to the conference. The average period of discussion was 15.6 days. The number of attached images was 1 to 9 (average, 4.2/e-mails). JPEG compression rate was 1/10 to 1/20. The quality of the images was good enough for discussion. Some cases required additional images for further discussion. CONCLUSION: Our tele-nuclear medicine conference with an electronic mailing list and digital camera was simple and low-cost. The conference system was useful for education and clinical work.

    Title Single Photon Emission Ct and Positron Emission Tomography in the Evaluation of Neurologic Disease.
    Date October 2001
    Journal Radiologic Clinics of North America
    Excerpt

    Widely available SPECT allows imaging of certain critical components of neurotransmission, providing clinically and experimentally significant information. Future efforts may be directed toward developing innovative techniques to delineate dynamic neurochemical changes in vivo.

    Title An Introduction to Pet and Spect Neuroreceptor Quantification Models.
    Date August 2001
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    PET and SPECT using appropriate radioligands allow imaging of certain critical components of neurotransmission such as presynaptic transporters and postsynaptic receptors in living human brains. PET and SPECT data are commonly analyzed by applying tracer kinetic models. These modeling approaches assume a compartmental system and derive the outcome measure called the binding potential, which reflects the densities of transporters or receptors in a brain region of interest. New models are often noninvasive in that they do not require arterial blood sampling. In this review, the concept and principles of tracer kinetic modeling are introduced and commonly used PET and SPECT neuroreceptor quantification models are discussed.

    Title Comparison of the Accumulation and Efflux Kinetics of Technetium-99m Sestamibi and Technetium-99m Tetrofosmin in an Mrp-expressing Tumour Cell Line.
    Date March 2001
    Journal European Journal of Nuclear Medicine
    Excerpt

    The potential clinical use of technetium-99m labeled sestamibi (Tc-MIBI) and tetrofosmin (Tc-Tfos) to image tumours is currently being evaluated. In this study. the accumulation and efflux of Tc-MIBI and Tc-Tfos in the nasopharyngeal carcinoma cell line CNE-1 were examined in the presence or absence of various inhibitors of P-glycoprotein (PGP) and/or multidrug resistance associated protein (MRP) activity [GG918, PSC833, verapamil (Vrp), cyclosporin A (CsA) and buthionine sulfoximine (BSO)]. Reverse-transcriptase polymerase chain reaction analysis and immunodetection of the CNE-1 cells detected expression of MRP, MRPI and MRP2 but not PGP. Tc-MIBI and Tc-Tfos accumulation was increased (P < 0.0001) and efflux decreased (P < 0.05) in the presence of BSO, CsA, Vrp and PSC833 but not GG918, which is a specific inhibitor of PGP. The absolute accumulation of Tc-MIBI was approximately twofold higher than that seen with Tc-Tfos, whereas the addition of inhibitors caused a much greater suppression of Tc-Tfos transport (>2 times greater than for Tc-MIBI). However, no qualitative differences in inhibitors were seen between Tc-MIBI and Tc-Tfos. These results suggest that both Tc-MIBI and Tc-Tfos are substrates for the MRP transporter and that PSC833, Vrp, CsA and BSO but not GG918 can inhibit MRP activity. These results indicate that Tc-MIBI and Tc-Tfos may be suitable imaging agents for detecting MRP-mediated drug resistance in human cancers.

    Title Modeling of Receptor Ligand Data in Pet and Spect Imaging: a Review of Major Approaches.
    Date February 2001
    Journal Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging
    Excerpt

    Over the past decade, a number of new kinetic modeling techniques have been developed for PET and SPECT ligands. This article will review commonly used modeling solutions for reversible positron-emission tomography (PET) and single photon emission computed tomography (SPECT) radioligands, with an emphasis on noninvasive methods. All of the modeling approaches in PET and SPECT assume a compartmental system and derive parameters that describe the compartmental system. These parameters will be defined, and their relationship to analogous parameters in pharmacology will be discussed. Then the major approaches are presented under the categories of graphical or mathematical as well as invasive or noninvasive.

    Title Normal Patterns on 99mtc-ecd Brain Spect Scans in Adults.
    Date October 2000
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Normative ethyl cysteinate dimer (ECD) SPECT data must be available to successfully apply ECD SPECT to clinical studies. The purpose of this study was to determine ECD SPECT scan patterns of healthy adults. METHODS: Forty-eight healthy volunteers (22 men, 26 women; age range, 22-95 y; mean age, 47.6 +/- 19.2 y) underwent high-resolution ECD SPECT. For visual analysis of regional brain ECD uptake, we used a scale of +3 to -3, in which +3 and -3 indicated highest ECD uptake and deficit, respectively. For quantitative analysis, we measured the region-to-cerebellum ratio (R/CE) and the region-to-cerebral cortex ratio (R/CO) for 17 regions (13 cortical, 3 subcortical, and 1 cerebellar). RESULTS: On visual analysis, no subject had a score of -3. All subjects had a score of -2 for the hippocampus and a score of +3 for the medial occipital cortex, except for 2 subjects who had a score of +3 for the striatum and thalamus. A frontal eye field and posterior parieto-occipital junction were identified in 60% of subjects with a score of +1 and 79% of subjects with a score of +2. On quantitative analysis, a significant regional variation (ANOVA, P < 0.0001) was seen in R/CE, ranging from 0.709 (hippocampus) to 1.26 (medial occipital cortex). However, regional right-to-left differences and intersubject variability of R/CE were small (asymmetry index, 3.6% +/- 0.8%; coefficient variation, 6.6% +/- 0.7%). R/CE declined significantly with age in 6 regions, including the anterior and posterior cingulate cortex, superior prefrontal and parietal cortex, striatum, and hippocampus (1.0%-2.0% per decade, P < 0.05), whereas R/CO in the cerebellum increased significantly with age (1.0% per decade, P < 0.05). CONCLUSION: Although regional ECD brain perfusion patterns vary significantly, including variability caused by the age-related effect, intersubject variability is small. Recognition of these normal patterns is important for clinical interpretation of ECD SPECT studies.

    Title Stilbene Oligomers in Roots of Sophora Davidii.
    Date August 2000
    Journal Phytochemistry
    Excerpt

    Three stilbene oligomers, davidiols A-C were isolated from the roots of Sophora davidii in addition to the seven known phenols, leachianone A, sophoraflavanones G, H and I, miyabenol C, alpha-viniferin and epsilon-viniferin. Their structures and relative configurations were established by means of 2D-NMR spectroscopy including COLOC and PSNOESY.

    Title The Use of Spect in the Diagnosis of Parkinson's Disease.
    Date August 2000
    Journal Canadian Association of Radiologists Journal = Journal L'association Canadienne Des Radiologistes
    Excerpt

    This article looks briefly at the latest efforts to develop an objective diagnostic marker for Parkinson's disease on single-photon emission computed tomography (SPECT). Traditionally, the diagnosis of idiopathic Parkinson's disease has been based on clinical criteria. However, these predict the pathologic diagnosis in only 80% of patients suspected of having the disease. Since a correct diagnosis is essential for prognosis, effective treatment and research, the search has continued for objective markers. The latest developments in nuclear medicine have come the closest in making such a marker clinically available. These developments are based on SPECT and positron-emission tomographic imaging of the basal ganglia using specific radio-labelled dopaminergic-receptor tracers. SPECT radiotracers target either the pre- or postsynaptic component of the dopaminergic system in the basal ganglia. These techniques show great promise in the early diagnosis of PD as well as in measuring its progression.

    Title Periprosthetic Bone Remodelling Around a Prosthesis for Distal Femoral Tumours. Measurement by Dual-energy X-ray Absorptiometry (dexa).
    Date March 2000
    Journal The Journal of Bone and Joint Surgery. British Volume
    Excerpt

    We used dual-energy x-ray absorptiometry (DEXA) to evaluate the extent of periprosthetic bone remodelling around a prosthesis for distal femoral reconstruction, the Kotz modular femoral tibial replacement (KMFTR; Howmedica, Rutherford, New Jersey). A total of 23 patients was entered into the study which had four parts: 1) 17 patients were scanned three times on both the implant and contralateral legs to determine whether the precision of DEXA measurements was adequate to estimate bone loss surrounding the anchorage piece of the KMFTR; 2) in 23 patients the bone mineral density (BMD) in different regions of interest surrounding the diaphyseal anchorage was compared with that of the contralateral femur at the same location to test whether there was consistent evidence of loss of BMD adjacent to the prosthetic stem; 3) in 12 patients sequential studies were performed about one year apart to compare bone loss; and 4) bone loss was compared in ten patients with implants fixed by three screws and in 13 without screws. The mean coefficients of variation (SD/mean) for the 17 sets of repeated scans ranged from 2.9% to 7.8% at different regions of interest in the KMFTR leg and from 1.4% to 2.5% in the contralateral leg. BMD was decreased in the KMFTR leg relative to the contralateral limb and the percentage of BMD loss in general increased as the region of interest moved distally in the femur. Studies done after one year showed no consistent pattern of progressive bone loss between the two measurements. The ten patients with implants fixed by screws were found to have a mean loss of BMD of 42% in the most distal part of the femur, while the 13 without screw fixation had a mean loss of 11%. DEXA was shown to have adequate precision to evaluate loss of BMD around the KMFTR. This was evident relative to the contralateral leg in all patients and generally increased in the most distal part of the femur. In general, it stabilised between two measurements taken one year apart and was greater surrounding implants fixed by cross-locking screws.

    Title Graphical Analysis and Simplified Quantification of Striatal and Extrastriatal Dopamine D2 Receptor Binding with [123i]epidepride Spect.
    Date December 1999
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The purpose of this study was to extend the graphical analysis of reversible tracer binding to account for labeled lipophilic metabolites (metabolites) in quantifying [123I]epidepride binding to striatal and extrastriatal D2 receptors and, additionally, to evaluate the feasibility of simplified analysis to measure the specific volume of distribution (V3') using single-sample blood data because the tissue ratio (RT) may be a less reliable measure of D2 binding in the presence of metabolites. METHODS: Multilinear regression analysis (MLRA) and graphical analysis (GA) using plasma parent (P) plus metabolite (M) activities as input and time activities of receptor-free (RF, cerebellum) and receptor-containing regions (RR, striatum and temporal cortex) derived V3' = (alpha(RR)(P) - alpha(RF)(P)), V3' = (1 + delta) (alpha(RR) - alpha(RF)) and RT = V3'/(V2P' + deltaV2M'), where alpha is a regression coefficient, delta is the equilibrium area ratio of M and P, and (V2P'/V2M') are the corresponding nondisplaceable distribution volumes. V3' by simplified analysis (SA) was calculated from RT determined without blood data and (V2P' + deltaV2M') with single-blood sample data. The accuracy of these three V3' values was assessed relative to the metabolite-accounted kinetic analysis (KA) for [123I]epidepride SPECT studies of 11 healthy volunteers, in which each participant had 27 scans and 30 plasma samples drawn during the 14 h after injection. RESULTS: All three V3' values (mL/g) significantly correlated with those by KA (r > or = 0.90) (striatum/temporal cortex: MLRA, 77.8 +/- 36.6/2.35 +/- 1.16; GA, 98.8 +/- 34.2/4.61 +/- 1.77; SA, 83.9 +/- 24.8/4.26 +/- 1.74; KA, 107.6 +/- 34.4/5.61 +/- 1.84). However, the correlation between RT and V3' was only moderate (r < or = 0.65) because of significant intersubject variability (23%) in (V2P' + deltaV2M'). CONCLUSION: The graphical analysis can be extended to account for metabolites in measuring D2 binding with [123I]epidepride SPECT for both high and low D2 density regions. Additionally, simplified V3' measurements with single blood sampling are feasible and may be a practical alternative to the tissue ratio RT because RT suffers as a measure of D2 binding from significant intersubject variability in the metabolite-contributed distribution volume of the nondisplaceable compartment.

    Title Kinetic and Equilibrium Analyses of [(123)i]epidepride Binding to Striatal and Extrastriatal Dopamine D(2) Receptors.
    Date November 1999
    Journal Synapse (new York, N.y.)
    Excerpt

    Quantitative SPECT measures of dopamine D(2) like receptors with [(123)I]epidepride is complicated by its high affinity and lipophilic metabolites. The purpose of this study was to use both parent (P) and lipophilic metabolites (M) as input functions in a kinetic paradigm and in comparison to the results of equilibrium studies. Kinetic studies on eleven healthy human subjects, ages 32+/- 10 were performed following i.v. injection of approximately 370 MBq of [(123)I]epidepride. Images were acquired for 13.5+/-1.0 hours. Equilibrium studies were done on seven of eleven subjects with a bolus injection of approximately 140 MBq, bolus/infusion ratio of 10 hours, and infusion for 30-32 hours. High (striatum) and low (temporal cortex) density regions were studied. Two (P and M) and one (P) input function models were applied in the kinetic studies. In receptor-rich regions, the distribution volumes in nondisplaceable compartments were fixed to those in cerebellum. In addition, in the two input function model, K(1)(P)/K(1)(M) was fixed to the values in the cerebellum. The one input function model provided V'(3) values (=f(1)*B'(max)/K(D)) which were consistent with those obtained in equilibrium studies in both receptor-rich regions, while the two input function model provided consistent values only in striatum. Poor identifiability of the rate constants of metabolites seemed to be the source of errors in the two input function model. These results suggest that correct V'(3) values can be obtained with the one input function model both in high- and low-density regions.

    Title Evaluation of Differential Magnification During Brain Spect Acquisition.
    Date October 1999
    Journal Journal of Nuclear Medicine Technology
    Excerpt

    OBJECTIVE: We developed a modification of the acquisition zoom technique, referred to as differential magnification (DM), to improve the pixel resolution with fanbeam collimators. This study evaluated the effects of DM on brain SPECT image quality. METHODS: SPECT imaging was performed using a triple-head camera with and without DM for a line source in air, Jaszczak and Hoffman phantoms, and 15 clinical patients having regional cerebral blood-flow scans with 99mTc ECD. Full width at half maximum (FWHM) and contrast ratios were measured on the line source and Jaszczak phantom data, respectively. Visual image evaluation was performed by 2 independent, blinded observers for the Hoffman brain phantom images and clinical patient studies. RESULTS: FWHM improved on the fanned axis (transverse plane) by 0.05 mm (P < 0.001), and the unfanned axis (longitudinal plane) by 0.66 mm (P < 10(-6)), when DM was used. The mean improvement of contrast ratios for the spheres on the Jaszczak phantom with DM was 11.4% (P < 0.004). The images with DM were rated superior to those without, for the Hoffman brain phantom and the clinical patients. CONCLUSION: This study has demonstrated that SPECT acquisition with fanbeam collimators and DM significantly improves both FWHM and image contrast, resulting in superior image quality. DM techniques may be useful in improving clinical brain SPECT images.

    Title Brain Perfusion Imaging in Asymptomatic Patients Receiving Cyclosporin.
    Date July 1999
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    BACKGROUND AND PURPOSE: Cyclosporin has neurotoxic effects in a significant number of transplant patients that are associated with characteristic findings on MR images. Focal abnormalities in cerebral perfusion have been implicated in the pathophysiology of cyclosporin neurotoxicity. In the clinically asymptomatic patient, however, it is not known whether any imaging evidence of cyclosporin's effect on the brain is demonstrable. Our hypothesis was that conventional MR imaging, perfusion MR imaging, and single-photon emission CT (SPECT) could enable detection of subclinical lesions in asymptomatic patients. The ability to detect such lesions might aid in the identification of persons most at risk for clinical neurotoxicity. METHODS: Ten posttransplant patients being treated with cyclosporin were recruited prospectively. Imaging studies were performed within 3 weeks of transplantation. Patients were examined with MR imaging, using standard spin-echo and dynamic contrast-enhanced perfusion techniques, and SPECT scanning. Postprocessing of MR perfusion data was performed to obtain pixel-by-pixel maps of regional cerebral blood volume, peak height, and time-to-peak parameters. RESULTS: The mean age of the patients was 45 +/- 11 years. At the time of imaging, three patients had minor neurologic manifestations commonly associated with cyclosporin (ie, mild tremor, headache), but no patient had clinical neurotoxicity. Findings on conventional MR images, MR perfusion maps, and SPECT perfusion scans were normal in all patients. CONCLUSION: Conventional MR imaging, dynamic perfusion MR imaging, and SPECT do not depict any lesions in asymptomatic patients on cyclosporin. Therefore, it may not be possible for imaging methods to aid in the identification of patients at risk for neurotoxicity. Our findings support previously published conclusions that the lesions visible in patients with clinical neurotoxicity are due to cyclosporin effects and not to preexisting coincidental abnormalities.

    Title External Radioactive Reference Markers in Spect Imaging of the Dopamine System.
    Date July 1999
    Journal Journal of Nuclear Medicine Technology
    Excerpt

    OBJECTIVE: External radioactive reference markers have been used to localize the canthomeatal (CM) line and correct for head rotation in perfusion brain SPECT. This ensures that regardless of the subject's head position or rotation under the SPECT camera, reconstructed transaxial slices are reoriented parallel to the CM line. This study was undertaken to demonstrate the value of external radioactive reference markers in dopamine SPECT imaging. METHODS: We compared visual and marker methods of reorienting the transaxial slices between dopamine and perfusion brain SPECT studies, respectively. These consisted of imaging normal controls and patients with Alzheimer's or Parkinson's disease using a triple-head camera. Intra- and interoperator variability of the visual and marker methods of reorientation was determined for both perfusion and dopamine studies. RESULTS: In both intra- and interoperator studies, the variability of image reorientation was significantly reduced (P = 0.0066 and 0.014, respectively) by using the marker method on dopamine images. The variability of reorientation using the marker method for a single operator with dopamine images was 3.0% coefficient of variation (CV), and for the interoperator study (5 different operators) this was 7.0% CV. CONCLUSION: This study demonstrated that SPECT imaging of the dopamine system with external radioactive reference markers significantly reduced the variability of determining the angle of reorientation. This resulted in a standardized and consistent method of reorienting transaxial slices, allowing comparison within and between subjects of pre- and postsynaptic dopamine SPECT studies.

    Title Spect Imaging of Pre- and Postsynaptic Dopaminergic Alterations in L-dopa-untreated Pd.
    Date May 1999
    Journal Neurology
    Excerpt

    BACKGROUND: In PD, presynaptic dopamine transporters are known to be decreased, whereas postsynaptic striatal D2 receptors are proposed to be upregulated. However, the relationship between these alterations is not clear. OBJECTIVE: To evaluate the ability of SPECT to detect both the pre- and postsynaptic dopaminergic alterations of the striatum in patients with L-dopa-untreated PD. METHODS: We studied 10 L-dopa-untreated patients with clinically mild PD and 21 age-matched normal controls. Individuals had both presynaptic [123I]beta-CIT dopamine transporter and postsynaptic [123I]IBF D2 SPECT studies 1 week apart. RESULTS: In PD patients, the dopamine transporter binding potential Rv ipsilateral/contralateral to the most affected limbs was 30%/41%, 41%/50%, and 59%/68% lower than controls for caudate, anterior putamen, and posterior putamen, respectively. These bilateral Rv decreases showed a lateralized difference more reduced in the contralateral striatum as well as intrastriatal differences most reduced in the posterior putamen. In contrast, in PD patients the D2 binding potential Rv ipsilateral/contralateral was 15%/16% higher for caudate, 18%/14% higher for anterior putamen, and 28%/31% higher for posterior putamen. These bilateral Rv increases showed no lateralized differences and less marked intrastriatal differences. The motor Unified Parkinson's Disease Rating Scale scores negatively correlated with dopamine transporter Rv but not with D2 Rv. CONCLUSIONS: SPECT imaging can detect characteristic dopaminergic alterations in the striatum of dopa-untreated PD patients including the upregulation of postsynaptic D2 receptors (denervation supersensitivity). SPECT is widely available and is a promising clinical tool to evaluate PD patients.

    Title Functional Morphometry of the Striatum in Parkinson's Disease on Three-dimensional Surface Display of 123i-beta-cit Spect Data.
    Date May 1999
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The purpose of this study was to evaluate whether striatal morphology on a three-dimensional surface display of 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (123I-beta-CIT) SPECT data can be used as a diagnostic index for Parkinson's disease. METHODS: We studied 11 patients with mild Parkinson's disease and 21 age-matched controls. Triple-head SPECT scans were acquired for 30 min at 20 h after injection of 123I-beta-CIT. We measured the vertical height of the caudate head (H) and the length of the long axis of the striatum (L) on the three-dimensional surface display generated from SPECT data. The morphometric index of the striatum was defined as L/H. The power of L/H to discriminate Parkinson's disease and control groups was evaluated by discriminant function analysis and was compared with that of region of interest (ROI)-based 123I-beta-CIT binding measurements (V"3) and their ratios. RESULTS: The mean L/H ratios (ipsilateral/contralateral) to the most affected limbs were (33%/45%) lower in the Parkinson's disease group compared with the control group, respectively. All other ROI-based measures confirmed that dopamine transporter reductions were most severe in the contralateral posterior putamen (a 68% reduction in V"3). In 1 patient with a subsequent clinical diagnosis of drug-induced parkinsonism, all SPECT measures were normal. The contralateral putamen contributed most to the discriminatory power, and the contralateral L/H showed the best discriminatory power of all SPECT measures. CONCLUSION: These results suggest that striatal morphology on a three-dimensional display of 123I-beta-CIT SPECT data provides information of diagnostic significance for Parkinson's disease. This morphometry can be done without requiring technically demanding ROI analysis, and thus this technique may be suitable for routine clinical use.

    Title Characterization of Neuronal Damage by Iomazenil Binding and Cerebral Blood Flow in an Ischemic Rat Model.
    Date February 1999
    Journal Annals of Nuclear Medicine
    Excerpt

    I-123-iomazenil is a SPECT probe for central benzodiazepine receptors (BZR) which may reflect intact cortical neuron density after ischemic insults. We evaluated whether neuronal damage in rats could be characterized by iomazenil as compared with cerebral blood flow (CBF). Serial changes in I-125-iomazenil for BZR and I-123-IMP for CBF were analyzed after the unilateral middle cerebral artery occlusion in rats by using an in vivo dualtracer technique. Uptake ratios of affected to contralateral regions were calculated. The iomazenil as well as IMP were decreased in all regions except for the cerebellum (remote area). Both iomazenil and IMP increased over time except in the temporal region (ischemic core). The iomazenil uptake was higher than IMP except in the ischemic core between 1 and 3-4 wk when iomazenil was lower than IMP. Iomazenil showed a moderate decrease in the proximal and middle parietal regions (peri-infarct areas) at 3-4 wk. The triphenyl-tetrazolium-chloride (TTC) stain at 1 wk demonstrated unstained tissue in the temporal region indicating tissue necrosis. With hematoxylin-eosin (HE) stain at 1 wk, widespread neuronal necrosis with occasional intact neurons were found in the proximal parietal region, and isolated necrotic neurons were represented in the distal parietal region. Iomazenil correlated well with the neuron distribution and the finding of a discrepancy between iomazenil and IMP might be useful in evaluating the neuronal damage.

    Title Age-related Changes in D2 Receptor Binding with Iodine-123-iodobenzofuran Spect.
    Date October 1998
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The purpose of this study was to evaluate the effects of age on D2 receptor binding with 123I-iodobenzofuran (IBF) SPECT. METHODS: Subjects were 40 healthy volunteers (age 19-83 yr), including 6 who had test/retest studies. Scans were acquired with a triple-head SPECT camera 3 hr postinjection of IBF (300 MBq). Striatal regions (caudate and putamen) were defined by two different region-of-interest (ROI) sets consisting of large volumes [(CLVs), 2.2 and 6.6 m] and small volumes [(SVs), 0.6 and 1.3 ml]. D2 binding (Rv=V3/V2) was quantified using our previously proposed multilinear regression technique. Effects of age on D2 binding were evaluated by fitting linear, exponential and logarithmic models. RESULTS: The mean Rvs were 26% lower than LV for both putamen and caudate than the corresponding values from the SV due to the partial-volume effect. Although the identifiability of Rv using SV deteriorated slightly, the test/retest reproducibility of Rv measurements was equally excellent for LV and SV. The mean Rvs were 11% higher for putamen compared with those for caudate. D2 binding declined significantly with age (p < 10(-5)) for all three models. The nonlinear models were slightly superior to the linear model in describing the relationship between Rv and age. In these models, D2 binding declined with age, equally for caudate and putamen at 7%-13% per decade; the decline was progressively smaller with age. CONCLUSION: IBF SPECT permitted reliable measurements of D2 binding in the caudate or putamen separately using small ROI volumes that significantly improved the quantitation loss from the partial-volume effect. Our results agreed with previous PET and postmortem findings of D2 binding losses with age. However, these age effects may be nonlinear. Age-related changes in D2 binding must be taken into consideration in clinical IBF SPECT investigations.

    Title Procedure Guideline for Brain Perfusion Spect Using Technetium-99m Radiopharmaceuticals. Society of Nuclear Medicine.
    Date June 1998
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Title Off-site Determinations of Effective Renal Plasma Flow Using Technetium-99m-mag3 and Single Blood Sampling.
    Date June 1998
    Journal Journal of Nuclear Medicine Technology
    Excerpt

    This study evaluated the feasibility of determining effective renal plasma flow (ERPF) at an off-site central laboratory by transferring blood samples from the on-site laboratory. METHODS: Blood samples were obtained from 66 patients referred for renal imaging with 99mTc-MAG3. ERPF values were determined using the single blood sample method (BSM) at both on- and off-site laboratories. The ERPF values were classified clinically as normal or abnormal. Both the ERPF values and clinical classification were compared between on- and off-site laboratories. RESULTS: The off-site ERPF overestimated those on-site by 2.8% (paired Student's t-test p < 10(-5)). However, off-site ERPF values highly correlated with the values obtained on-site (r = 0.99; p < 10(-5)). In addition, the clinical classification for each patient determined at each site was identical. CONCLUSION: ERPF can be determined accurately off-site. This method should allow many nuclear medicine departments access to the ERPF determination by the BSM at a central off-site laboratory.

    Title Fully Automated Establishment of Stereotaxic Image Orientation in Six Degrees of Freedom for Technetium-99m-ecd Brain Spect.
    Date April 1998
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Anatomical localization requires establishing an anatomical space within the image matrix. We developed a fast, fully automated method to establish the image orientation for 99mTc-ethylcysteinate dimer (ECD) brain SPECT images. METHODS: The image orientation of ECD brain SPECT images was established in four stages. First, the brain surface was edge-detected as an isosurface at an adaptive threshold. Second, a "convex hull" was determined for the isosurface to minimize regional variability in brain shape. A principal axis transformation and a symmetry vector analysis were applied to the convex hull to resolve the craniocaudal direction and to estimate the midsagittal plane. Third, the brain orientation was refined from this estimate by location of the interhemispheric fissure, the tentorial groove and the frontotemporal groove on the isosurface. Last, the intercommissural (anterior commissure-posterior commissure, or AC-PC) line was detected on the midsagittal slice, and the Talairach grid was scaled to fit the maximal brain dimensions from the AC-PC line. RESULTS: The average absolute errors were 2.3 degrees +/- 1.5 degrees and 1.08 mm +/- 1.11 mm for the midsagittal plane (n = 24) and 2.04 degrees +/- 0.80 degrees, 2.0% +/- 1.8% of the brain length and 2.3% +/- 2.2% of the brain height for the AC-PC line (n = 8). In addition, this program successfully established the image orientation in 94 of 100 clinical ECD brain SPECT studies. Processing time was <40 sec for 128 x 128 x 50 matrices on a DEC Alpha workstation. CONCLUSION: We have developed a fast, robust and fully automated method that determines the orientation of ECD brain SPECT images. This objective method of standardizing the image orientation should be useful for anatomical localization and clinical interpretation of these images.

    Title Noncutaneous Cavernous Hemangiomas of the Head and Neck.
    Date March 1998
    Journal American Journal of Otolaryngology
    Title Pre-operative Assessment of Axillary Lymph Node Status in Patients with Breast Adenocarcinoma Using Intravenous 99mtechnetium Mab-170h.82 (tru-scint Ad).
    Date January 1998
    Journal Breast Cancer Research and Treatment
    Excerpt

    Immunoscintigraphy of the axilla has potential utility for the diagnostic and prognostic assessment of patients with breast adenocarcinoma. mAb-170H.82 is a murine monoclonal antibody (mAb) derived against synthetic Thomsen-Friedenreich (TF) antigen. Tru-Scint AD, a 99mTc-mAb-170H.82 immunoconjugate, has previously been shown to localize in various human adenocarcinomas. The purpose of this study was to evaluate the accuracy of this immunoconjugate in the pre-operative assessment of axillary lymph nodes in patients with known breast adenocarcinoma. Sixteen patients with documented primary breast cancer were injected intravenously with 1 mg of immunoconjugate (radioactivity 1.8 GBq) and imaged 22-24 hrs post-injection. Both planar and single photon emission computed tomographic (SPECT) images were obtained and reviewed in a blinded fashion. Imaging results were compared with surgical and pathological findings. Seven of 16 patients were found to have histologically positive axillary nodes: 5 of these sites were detected by immunoscintigraphy (sensitivity = 71%). Nine patients had pathologically disease-free axillary nodes: only 1 of these was misidentified as positive by immunoscintigraphy (specificity = 89%). These results suggest that immunoscintigraphy with 99mTc-mAb-170H.82 has promise in the detection of axillary lymph node involvement in patients with breast cancer. Further studies are warranted to define the role of immunoscintigraphy in axillary staging.

    Title Accumulation of 99mtc-hmpao and 99mtc-ecd in Rodent and Human Breast Tumor Cell Lines in Vitro.
    Date September 1997
    Journal Annals of Nuclear Medicine
    Excerpt

    The accumulation of 99mTc-HMPAO and 99mTc-ECD was studied in rat (MatB) and human (MCF-7) breast tumor cell lines in vitro as a function of incubation time. The general pattern was the same for both tracers and both cell lines: the tracer rapidly and extensively accumulated in the cells but a plateau was reached in 15-30 minutes. Accumulation of HMPAO was higher than that of ECD, did not show a difference between rat and human cells, and correction of HMPAO data for intracellular sequestration and extracellular metabolism resulted in a linear increase in accumulation with time. In contrast, accumulation of ECD was approximately 2-fold higher in human cells than in rat cells but after correction for sequestration and metabolism a plateau remained. These experiments show differences between HMPAO and ECD in their accumulation and retention in breast cancer cells in vitro and support that the need for further work on the potential clinical role for HMPAO in tumor characterization.

    Title Regional Differences in Technetium-99m-ecd Clearance on Brain Spect in Healthy Subjects.
    Date September 1997
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The aim of this study was to evaluate the in vivo stability of ECD brain SPECT. METHODS: Twenty normal volunteers (35.4 +/- 9.1 yr) each had six ECD scans at 30, 60, 120, 240, 360 and 480 min postinjection. Each scan was acquired for 24 min using a triple-head SPECT system. Average counts per pixel were measured from frontal, temporal, parietal, occipital, cerebellum, basal ganglia, thalamus and white matter regions. ECD clearance rates were calculated by fitting regional time activity data to a monoexponential equation. Regional gray-to-white matter (G/W) and gray-to-cerebellum (G/C) ratios were calculated for each scan. Analysis of variance was used to compare regional ECD clearance and ratio measurements. RESULTS: The average ECD clearance was 4.3%/hr. There was a significant regional variation in the ECD clearance, being higher for occipital (6.34%/hr) but lower for both white matter (2.39%/hr) and thalamus (2.45%/hr). Both G/W and G/C ratios showed a significant regional variation with time. The overall G/W ratio was 2.13 at 30 min and became progressively lower after 2 hr, reaching 1.78 at 8 hr. All regional G/W ratios declined with time except for thalamus where it remained constant at 2.15. The overall G/C ratio was 0.984 at 30 min but it declined after 4 hr, reaching 0.955 at 8 hr. All regional G/C ratios declined with time except for thalamus where it increased progressively from 0.955 to 1.120 at 8 hr. CONCLUSION: ECD clears from normal brain slowly and shows a significant regional variation. As a result, G/W contrast begins to decrease after 2 hr and the gray-matter activity pattern becomes significantly different after 4 hr. Therefore, the optimal imaging time may be between 30-120 min. However, images obtained up to 4 hr still maintain the initial gray-matter activity pattern.

    Title Physiologic Modeling of Pet Data: Quantitative Conflict and Challenge.
    Date September 1997
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Title Neuropsychologic Deficits and Clinical Features of Posttraumatic Temporomandibular Disorders.
    Date May 1997
    Journal Journal of Orofacial Pain
    Excerpt

    Previous studies have shown that characteristics of posttraumatic temporomandibular disorders (pTMD) differ considerably from those of nontraumatic or idiopathic temporomandibular disorders (iTMD). Both the rate of recovery and the amount of treatment required appear to be different for both groups. In this blinded study, 14 patients with iTMD and 13 patients with pTMD were examined. Patients submitted to a variety of reaction-time tests and neuropsychologic assessments to test their ability to cope with simple and more complex tasks with and without a variety of cognitive interferences. Clinical examination was used to assess signs of TMD. Eleven of the subjects (six iTMD, five pTMD) consented to a second phase of the investigation, whereby the patients were studied with single-photon emission computerized tomography (SPECT) using 99mTc-hexamethylpropyleneamineoxime (HMPAO). For simple and complex reaction-time tests, the pTMD group was significantly slower than the iTMD group (P < .05 to P < .001). Other neuropsychologic assessment tools such as the Consonant Trigram Test and the California Verbal Learning Test indicated that pTMD patients were more affected by both proactive and retroactive interferences and were more likely to perseverate on a single thought. In clinical examination, pTMD patients demonstrated greater reaction to muscle palpation than did iTMD patients (P < .05). The SPECT results suggested that there were mild differences between the two populations, and further ther studies are required to confirm this finding. The results lend support to the concept that there are differences between pTMD and iTMD populations. It is suggested that although patients with pTMD may have some similarities to those with iTMD, the former population may benefit from being handled somewhat differently and should be assessed and treated using a more broad, multidisciplinary treatment paradigm. These results must be confirmed in studies of larger populations.

    Title Simplified Quantification and Reproducibility Studies of Dopamine D2-receptor Binding with Iodine-123-ibf Spect in Healthy Subjects.
    Date February 1997
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The purpose of this study was to assess the feasibility of a simplified SPECT scan protocol to quantify D2-receptor binding using [123I]iodobenzofuran (IBF) and to evaluate reproducibility of quantitative IBF-SPECT imaging without blood data. METHODS: Twenty healthy volunteers participated in the study, six had test/retest studies separated by 1 wk. Scans were acquired every 5 min for 180 min using a triple-headed SPECT camera after a bolus injection of IBF (292 MBq). The receptor parameter was determined by using our previously proposed variation of graphical analysis that derives the distribution volume ratio (Rv = V3/V2) from multiple scan data without blood data. Rv' was determined from three 20-min scan data obtained at 0-20, 50-70 and 160-180 min postinjection and compared with Rv as determined from scans obtained at 0-180 min. RESULTS: The mean Rv' (2.93 +/- 0.59) underestimated the mean Rv (3.10 +/- 0.50) by 5%. The mean variability (mean percent absolute difference) between Rv' and Rv was low (10%) with excellent reliability (intraclass correlation coefficient, p = 0.90). The relationship between Rv' and Rv was linear (r = 0.95, p < 10(-5)). The mean test/retest Rv and mean test/retest Rv' were (3.19 +/- 0.70/3.18 +/- 0.80) and (3.16 +/- 0.81/3.01 +/- 0.94), respectively, and these measures were not significantly different between test/retest studies. The mean test/retest variability of Rv was low (5%) with excellent reliability (p = 0.98). In addition, the mean test/retest variability of Rv' was low (10%) with excellent reliability (p = 0.94). CONCLUSION: Three short (20 min) IBF-SPECT scans allowing for rest periods between scans permit reliable measurements of the dopamine D2-receptor parameter V3/V2. Quantitative IBF-SPECT imaging without blood data is reliable and reproducible.

    Title Evaluation of Single Isotope Technetium 99m-sestamibi in Localization Efficiency for Hyperparathyroidism.
    Date January 1997
    Journal American Journal of Surgery
    Excerpt

    BACKGROUND: Regardless of surgical effectiveness, ongoing activity in parathyroid localization in hyperparathyroidism (HPT) is an established enterprise. Sestamibi (MIBI), the most recent new modality, is being assessed in this regard. METHODS: Twenty mCI of 99 TC Sestamibi was administered intravenously in patients with prospective HPT. Images were assessed by pinhole and full-field gamma camera at 20 minutes and 2 hours. Dual-phase one isotope only was utilized. Patients were then studied for pathology and MIBI correlation. RESULTS: Sixty-three cases underwent MIBI scanning, 50, or 79%, of which were due to a single adenoma. Sensitivity showed in 41 of 50 adenomas and was 82% correct. Quadrant localization was 97%. Eleven patients showed hyperplasia with MIBI sensitivity of 82% on a case basis but only 31% for multiglandular disease. Overall MIBI sensitivity is 80%. One false-positive and one true-negative case were observed. All patients achieved eucalcemia. No operative morbidity of significance occurred. CONCLUSION: Scanning with 99M Sestamibi dual-phase technique is the preferred mode of parathyroid localization in current practice. It is of assistance in primary HPT, essential in recurrent HPT, and of use in ectopic gland detection. It can support surgical intervention in the marginal HPT patient. Scanning still requires bilateral exploration for complete assessment.

    Title Noninvasive Quantification of Dopamine D2 Receptors with Iodine-123-ibf Spect.
    Date January 1997
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Iodine-123-iodobenzofuran (IBF) is a potent dopamine D2 receptor ligand suited for quantitative receptor studies. The purpose of this study was to evaluate three noninvasive methods of estimating the receptor parameter k3/k4 in humans with IBF-SPECT. METHODS: Scans were acquired every 5 min for 180 min using a triple-headed SPECT system following a bolus injection of IBF (296 +/- 37 MBq) in 14 normal volunteers. k3/k4 was estimated by the peak equilibrium ratio (RPE) method and two proposed methods: a variation of the graphic method that derives the ratio of ligand distribution volumes (RV) and area ratio (RA) method, in which the ratio is calculated from the areas under the specific binding and nondisplaceable activity curves. RESULTS: The mean RPE, RV and RA were 2.74 +/- 0.40, 3.06 +/- 0.42 and 2.26 +/- 0.28, respectively. Both RPE and RA underestimated RV. The relationship between RPE or RA and RV was linear (p < or = 10(-5), RA showed higher correlation (r = 0.94) with RV than did RPE (r = 0.90). Simulations based on a tracer kinetic model showed that RV, unlike RPE or RA, is affected by neither regional cerebral blood flow (rCBF) nor peripheral clearance rate (CR) of IBF. All three measures showed a significant decline with increasing age (r = 0.54-0.58, p < 0.05). CONCLUSION: RV is preferred because it provides a theoretically valid estimate of k3/k4, independently of rCBF or CR. Alternatively, RA might be preferred to RPE because the former is simpler than the latter to implement yet the former provides a measure that equally well correlates with k3/k4.

    Title From Graphical Analysis to Multilinear Regression Analysis of Reversible Radioligand Binding.
    Date December 1996
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Title Spect Imaging of Dopamine Receptors.
    Date November 1996
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Title Usefulness of Follow-up Regional Cerebral Blood Flow Measurements by Single-photon Emission Computed Tomography in the Differential Diagnosis of Dementia.
    Date February 1996
    Journal Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging
    Excerpt

    The aim of this study was to evaluate whether follow-up measurements of regional cerebral blood flow (rCBF) by single-photon emission computed tomography (SPECT) provide additional information in the differential diagnosis of dementia. Thirty-six patients (70 +/- 14 yr) with suspected dementia who had two technetium 99m-hexamethylpropyleneamineoxime SPECT scans over 18 +/- 7 months were included in this retrospective study. The patients comprised three groups based on the final clinical diagnosis: (1) neurodegenerative disorder (NDD) including Alzheimer's disease (AD) (n = 13), frontotemporal lobe dementia (n = 2), progressive supranuclear palsy (n = 1), and mixed dementia (AD plus multiinfarct dementia [MID]) (n = 3); (2) MID (n = 8); and (3) psychiatric disorders (depression [n = 7], psychosis [n = 1], and anxiety [n = 1]). Blinded to the clinical diagnosis and using visual analysis, the nuclear medicine physicians compared the second scan with the first scan for each patient to characterize temporal changes in rCBF. SPECT findings were categorized into three patterns of rCBF change: worsened, improved, and unchanged. Of the worsened rCBF group, 17 (85%) belonged to the NDD group whereas 2 (10%) and 1 (5%) belonged to the MID and psychiatric disorders groups, respectively. All 5 (100%) of the improved rCBF patients belonged to the psychiatric disorders group. Thus, worsening of rCBF favors the diagnosis of NDD whereas improvement in rCBF may mitigate against the diagnosis of NDD or MID. Follow-up rCBF measurements by SPECT thus provided additional information on the possible cause of dementia. A prospective study to further evaluate the usefulness of follow-up rCBF measurements by SPECT appears warranted.

    Title A Method of Two-dimensional Mapping of Cortical Perfusion by Cylindrical Transformation of Hmpao Spet Data.
    Date October 1995
    Journal Nuclear Medicine Communications
    Excerpt

    In order to synthesize three-dimensional information on relative regional blood flow (rCBF) from the cortical grey matter in 99Tcm-hexamethylpropyleneamine oxime (HMPAO) single photon emission tomographic (SPET) images into a single two-dimensional 'cortical peel' (CP) image, we developed a program that performs cylindrical transformation of SPET data. A sub-routine of this program performs measurements of cortex-to-cerebellum rCBF ratios for 54 cortical regions in the CP image. This program was used to establish a normative database derived from 30 young normal control subjects aged 28.7 +/- 6.9 years. The database was then used to express cortex-to-cerebellum rCBF ratios in four colour-coded ranges of normal standard deviation of the mean rCBF ratio across the cortical regions in the CP image. This CP method was implemented for 30 clinical HMPAO SPET studies in patients (n = 30, aged 71.8 +/- 4.2 years) with suspected dementia as well as several studies in aged healthy subjects (n = 8, aged 67 +/- 9.8 years). In 25/30 (83%) patients, all abnormalities seen on the tomographic display were evident on the corresponding CP image. No aged healthy subjects showed abnormalities on either the tomographic display or the corresponding CP image. An advantage of this technique is that the extent and severity of rCBF abnormalities are readily appreciated in one single image. This technique, in conjunction with the conventional multi-slice tomographic display, was a useful tool in identifying various patterns of rCBF abnormalities in the patients with clinically suspected dementia.

    Title [in Vivo Characteristics of Ibzm in Rat Brains: an Agent for Quantitative Spect Imaging of D2 Dopamine Receptors--a Basis for Semiquantitative Measurement of the Receptor Density Using Equilibrium Analysis]
    Date December 1994
    Journal Kaku Igaku. The Japanese Journal of Nuclear Medicine
    Excerpt

    To establish a basis for semiquantitative SPECT measurements of the D2 dopamine receptor density using equilibrium analysis, we evaluated in vivo kinetic properties of 125I-IBZM in rat brains. We measured percent uptakes (% dose/g) of 125I-IBZM in the striatum, frontal cortex, and cerebellum. We made these regional measurements at 15, 30, 45, 60, 90, and 120 minutes after injection, respectively. The specific striatal uptake, which is the uptake difference between striatum and frontal cortex or cerebellum, showed a transient equilibrium phase at 60 min. Theoretically, with these 'reversible' D2 receptor binding ligands, the tracer-uptake ratio of the striatum-to-frontal cortex or cerebellum during the equilibrium phase provides an estimate of binding potential (Bound/Free = Bmax/Kd). Our experiment showed that these ratio increased with time after bolus injection of the tracer. Striatum to frontal cortex or cerebellum ratios which were calculated with pooled data (n = 12) at 60 minutes in equilibrium phase showed nearly constant values (C.V. = 12.3% and 13.5%, respectively). Although measuring the striatum to frontal cortex or cerebellum ratios near equilibrium phase by bolus injection of the tracer which are widely used in human SPECT study could not exactly signify the binding potential, those ratios at fixed time after injection would be reliable for semiquantitative index.

    Title Scintigraphic Flare in Skeletal Lymphoma.
    Date December 1994
    Journal Clinical Nuclear Medicine
    Excerpt

    The authors describe the bone scan flare phenomenon in a patient with treated skeletal lymphoma. This was confirmed by both gallium scanning and computed tomography. If serial bone scintigraphy is used for assessing the treatment response of lymphoma, the flare phenomenon must be recognized.

    Title Spect for Differential Diagnosis of Dementia and Correlation of Rcbf with Cognitive Impairment.
    Date October 1994
    Journal The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques
    Excerpt

    99mTc-HM-PAO single photon emission computed tomography (SPECT) was used to image 30 patients referred for the assessment of dementia. SPECT images revealed various patterns of regional cerebral perfusion (rCBF) in the subgroups of patients with the clinical diagnoses of Alzheimer's disease (AD, n = 14), Pick's disease (n = 1), and multi-infarct dementia (n = 7). In three patients, SPECT clarified the clinical differential diagnostic possibilities. Using a relative rCBF quantification technique, the relationship between specific cognitive impairments and rCBF in the AD patients was determined. There was a significant correlation between language impairment and left hemisphere hypoperfusion, whereas, apraxia correlated with hypoperfusion in the left parietal region. Thus, HM-PAO SPECT is useful as an aid in the differential diagnosis of dementia and the technique of relative rCBF quantification with SPECT may contribute to the understanding of the clinico-anatomical relations of cognitive deficits in dementia.

    Title [in Vivo Characteristics of Ibzm in Rat Brains: an Agent for Quantitative Spect Imaging of Dopamine D2 Receptors. Preparation of 125i-ibzm and Its Biodistribution and Kinetic Properties]
    Date August 1994
    Journal Kaku Igaku. The Japanese Journal of Nuclear Medicine
    Excerpt

    123I-(S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]-benzamide (IBZM) is a CNS dopamine D2 receptor imaging agent for SPECT and has already been used clinically in the United States, Canada and Europe. However, methods of quantitative SPECT measurement of the D2 receptor density have not been well established. We performed in vivo biodistribution studies of 125I-IBZM in rat brains as the first step toward establishment of a basis for quantitative SPECT imaging of D2 receptors in humans. 125I-IBZM was prepared by the chloramine-T method. Radiochemical yields were 80 to 90% and radiochemical purity was 94.7% on day 81 after labeling. At 10, 30, 60 and 120 min after injection of the radiopharmaceutical, the percent uptakes (% dose/g) in the rat striatum were 2.9, 1.9, 1.7 and 1.0, respectively. These kinetic data were considered suitable for SPECT imagings. Pretreatment with haloperidol (1 mg/kg) blocked specific striatal uptake and there was a significant reduction in the uptake to 40.9% of the unblocked uptake at 60 min after injection (p = 0.006). The regional IBZM uptake ratio of striatum-to-cerebellum increased steadily from 1.7 at 10 min to 5.7 at 120 min. This suggests that SPECT imaging must be done during fixed time after tracer injection for the semiquantitative ratio to be meaningful.

    Title Technetium-99m-hmpao Spect, Ct and Mri in the Evaluation of Patients with Chronic Traumatic Brain Injury: a Correlation with Neuropsychological Performance.
    Date March 1994
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The purposes of this study were: (1) to compare 99mTc-hexamethylpropyleneamineoxime (HMPAO) SPECT with CT and MRI in chronic traumatic brain injury (TBI) patients and (2) to correlate both functional and structural neuroimaging measurements of brain damage with neuropsychological (NP) performance. METHODS: Twenty-nine patients (minor TBI, n = 15 and major TBI, n = 14) and 17 normal controls (NC) underwent HMPAO SPECT, CT, MRI and NP testing. Imaging data were analyzed both visually and quantitatively. RESULTS: Nineteen (66%) patients showed 42 abnormalities on SPECT images, whereas 13 (45%) and 10 (34%) patients showed 29 abnormalities on MRI and 24 abnormalities on CT. SPECT detected relatively more abnormalities than CT or MRI in the minor TBI subgroup. The TBI group showed impairment on 11 tests for memory, attention and executive function. Of these, the anterior-posterior ratio (APR) correlated with six tests, whereas the ventricle-to-brain ratio (VBR), a known structural index of a poor NP outcome, correlated with only two tests. CONCLUSION: In evaluating chronic TBI patients, HMPAO SPECT, as a complement to CT or MRI, may play a useful role by demonstrating brain dysfunction in morphologically intact brain regions and providing objective evidence for some of the impaired NP performance.

    Title Post-infectious Neuromyasthenia (chronic Fatigue Syndrome): a Summary of Ongoing Studies.
    Date January 1994
    Journal Canada Diseases Weekly Report = Rapport Hebdomadaire Des Maladies Au Canada
    Title Iodine-123-ibzm Dopamine D2 Receptor and Technetium-99m-hmpao Brain Perfusion Spect in the Evaluation of Patients with and Subjects at Risk for Huntington's Disease.
    Date August 1993
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Huntington's disease (HD) is pathologically characterized by neuronal loss and neuroreceptor alterations in the striatum, including a reduction in dopamine receptor density. We evaluated the clinical usefulness of 123I-iodobenzamide (IBZM) D2 receptor SPECT imaging and 99mTc-hexamethylpropyleneamineoxime (HMPAO) brain perfusion SPECT imaging by studying four early symptomatic HD patients, 20 asymptomatic subjects at risk for HD and 22 controls. Striatal D2 receptor binding and perfusion were measured semiquantitatively by calculating striatum-to-frontal cortex IBZM and HMPAO uptake ratios, respectively. The control IBZM ratio (1.58 +/- 0.06) declined with age at 1.5% per decade (r = -0.58, p < 0.005), whereas the HMPAO ratio (1.15 +/- 0.05) did not. All four symptomatic patients had decreased IBZM ratios and three patients also had decreased HMPAO ratios. Five of 20 at-risk subjects had decreased IBZM ratios and two subjects also had decreased HMPAO ratios. Three of the five at-risk subjects showed subtle nonchoreic neurological abnormalities. Decreased striatal D2 receptor binding thus may be detected by IBZM-SPECT in the asymptomatic as well as symptomatic groups, and these changes were more marked than perfusion deficits detected by HMPAO-SPECT. IBZM-SPECT thus appears to be a promising method for early diagnosis and preclinical detection of HD.

    Title Dopamine D2 Receptor Spect Imaging: Basic in Vivo Characteristics and Clinical Applications of 123i-ibzm in Humans.
    Date May 1993
    Journal Annals of Nuclear Medicine
    Excerpt

    The purposes of this study are to evaluate the utility of kit formulation, the basic in vivo characteristics, and clinical usefulness of dopamine D2 receptor imaging with 123I-(S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrodinyl)m ethyl]- benzamide (123I-IBZM). We studied 22 normal controls, 3 early symptomatic Huntington's disease patients, and 1 patient with visual hallucination on and off neuroleptics. 123I-IBZM could be conveniently prepared with a high degree of purity from a kit, but with relatively low radiochemical yield. We demonstrated 123I-IBZM receptor binding equilibrium by performing serial SPECT scanning in a normal volunteer. The basal ganglia/frontal cortex (BG/FC) ratios plateaued after the specific binding reached equilibrium approximately 60 minutes after injection. The BG/FC ratio declined significantly with age. The ratios for the Huntington's disease patients were significantly lower than those for normal controls. The images of the patient off neuroleptic therapy showed dramatically increased BG activity compared with those obtained while on therapy. The BG/FC ratio provides an estimate of Bmax/Kd and hence the receptor density. It appears important to perform SPECT early in the equilibrium phase and at a fixed time after injection to obtain significantly high signal to noise ratios. 123I-IBZM is an ideal tracer for SPECT including a rotating gamma camera type which can provide estimates of the receptor density objectively by calculating the BG/FC ratio, and is a promising agent for the investigation of dopamine D2 receptors in clinical conditions.

    Title Assessment of Regional Cerebral Perfusion by 99tcm-hmpao Spect in Chronic Fatigue Syndrome.
    Date March 1993
    Journal Nuclear Medicine Communications
    Excerpt

    Chronic fatigue syndrome (CFS) is a severely disabling illness of uncertain aetiology. It is characterized by a chronic, sustained or fluctuating sense of debilitating fatigue without any other known underlying medical conditions. It is also associated with both somatic and neuropsychological symptoms. Both physical and laboratory findings are usually unremarkable. Regional cerebral blood flow (rCBF) was assessed in 60 clinically defined CFS patients and 14 normal control (NC) subjects using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) single photon emission computed tomography (SPECT). Compared with the NC group, the CFS group showed significantly lower cortical/cerebellar rCBF ratios, throughout multiple brain regions (P < 0.05). Forty-eight CFS subjects (80%) showed at least one or more rCBF ratios significantly less than normal values. The major cerebral regions involved were frontal (38 cases, 63%), temporal (21 cases, 35%), parietal (32 cases, 53%) and occipital lobes (23 cases, 38%). The rCBF ratios of basal ganglia (24 cases, 40%) were also reduced. 99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects. The findings may not be diagnostic of CFS but 99Tcm-HMPAO SPECT may play an important role in clarifying the pathoaetiology of CFS. Further studies are warranted.

    Title Neuroanatomical Localization for Clinical Spect Perfusion Brain Imaging: a Practical Proportional Grid Method.
    Date January 1993
    Journal Nuclear Medicine Communications
    Excerpt

    For the purpose of facilitating anatomical localization in interpretation of 99Tcm-hexamethylpropyleneamine oxime (HMPAO) brain single photon emission tomographic (SPECT) scans, a stereotaxic proportional grid system was applied in the form of an interactive computer program. This method takes advantage of a rotating gamma camera system which permits planar scout imaging for the determination of anatomical reference lines, and standardization of tomographic slices for brain size. Using measurements made on a lateral planar HMPAO image, proportional grids were constructed onto standardized transaxial images. This method was implemented for 33 clinical HMPAO SPECT studies. It required less than 15 min of an operator's time. This simple and practical neuroanatomical localization technique can be instrumental as an aid to the interpretation of routine clinical HMPAO SPECT images.

    Title Violent Visual Hallucinations and Aggression in Frontal Lobe Dysfunction: Clinical Manifestations of Deep Orbitofrontal Foci.
    Date August 1992
    Journal The Journal of Neuropsychiatry and Clinical Neurosciences
    Excerpt

    Three patients from different racial, social, and economic backgrounds were studied because of sudden intrusive thoughts: visions or intrusions of threatening scenes--violent, aggressive, and sometimes horrifying--that lasted from seconds to minutes. Apart from the association with intense anxiety, fear, and aggression, there was no association with oculomotor, motor, sensory, or autonomic dysfunction or altered conscious state. Patients had abnormal intermittent discharges that arose from frontal areas and probably did not spread further. Carbamazepine was useful in two cases. The authors suggest that violent, brief hallucinations with no other epileptic sign may be manifestations of frontal lobe seizures.

    Title 'reverse Crescent Pattern' on Spect Brain Perfusion Scan in Chronic Subdural Hematoma.
    Date August 1992
    Journal Clinical Nuclear Medicine
    Excerpt

    A SPECT brain perfusion scan was performed on a patient who had symptoms of dementia. The SPECT scan showed marked crescentic medial displacement of the left cerebral hemisphere ("reverse crescent pattern"), and mildly decreased cortical perfusion in the affected hemisphere. Crossed cerebellar diaschisis was not present. On x-ray CT, the underlying abnormality was found to be a unilateral chronic subdural hematoma causing a significant mass effect. A reverse crescent pattern without crossed cerebellar diaschisis on SPECT brain perfusion scan in patients with dementia may suggest the diagnosis of chronic subdural hematoma.

    Title Rabbit Syndrome, Antidepressant Use, and Cerebral Perfusion Spect Scan Findings.
    Date March 1992
    Journal Journal of Psychiatry & Neuroscience : Jpn
    Excerpt

    The rabbit syndrome is an extrapyramidal side effect associated with chronic neuroleptic therapy. Its occurrence in a patient being treated with imipramine is described, representing the first reported case of this syndrome in conjunction with antidepressants. Repeated cerebral perfusion SPECT scans revealed decreased basal ganglia perfusion while the movement disorder was present, and a return to normal perfusion when the rabbit syndrome resolved.

    Title Technetium-99m-hmpao Spect in the Evaluation of Patients with a Remote History of Traumatic Brain Injury: a Comparison with X-ray Computed Tomography.
    Date February 1992
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    The functional imaging modality has potential for demonstrating parenchymal abnormalities not detectable by traditional morphological imaging. Fifty-three patients with a remote history of traumatic brain injury (TBI) were studied with SPECT using 99mTc-hexamethylpropyleneamineoxime (HMPAO) and x-ray computed tomography (CT). Overall, 42 patients (80%) showed regional cerebral blood flow (rCBF) deficits by HMPAO SPECT, whereas 29 patients (55%) showed morphological abnormalities by CT. Out of 20 patients with minor head injury, 12 patients (60%) showed rCBF deficits and 5 patients (25%) showed CT abnormalities. Of 33 patients with major head injury, 30 patients (90%) showed rCBF deficits and 24 patients (72%) showed CT abnormalities. Thus, HMPAO SPECT was more sensitive than CT in detecting abnormalities in patients with a history of TBI, particularly in the minor head injury group. In the major head injury group, three patients showed localized cortical atrophy by CT and normal rCBF by HMPAO SPECT. In the evaluation of TBI patients, HMPAO SPECT is a useful technique to demonstrate regional brain dysfunction in the presence of morphological integrity as assessed by CT.

    Title The Scintigraphic Evaluation of Huntington's Disease and Other Movement Disorders Using Single Photon Emission Computed Tomography Perfusion Brain Scans.
    Date March 1991
    Journal Seminars in Nuclear Medicine
    Excerpt

    The increasing availability of single-photon emission computed tomography (SPECT) perfusion brain scans has led to the investigation of a variety of neuropsychiatric conditions including the movement disorders such as Huntington's and Parkinson's disease. In general, observers have noted that Huntington patients have bilaterally decreased uptake of technetium 99m HM-PAO and iodine 123 IMP in the basal ganglia regions involving the heads of the caudate nucleic and adjacent structure, which reflects decreased neuronal function. These functional changes precede the morphological changes due to caudate nucleus atrophy that are observed on computed tomography and magnetic resonance imaging. Cortical changes occur in severely diseased Huntington's patients but are more nonspecific. Prediction of individuals at risk for Huntington's disease using SPECT scans should be done with caution and in association with other clinical data. In contrast, in Parkinson's disease mild diffusely decreased perfusion is commonly noted throughout the cerebral structures, except for the cerebellum. In Parkinson's disease, there is less agreement among observers as to whether the basal ganglia are abnormal. Some observers report that there are no specific basal ganglia perfusion defects in excess of those changes seen elsewhere in the brain. Others report diminished basal ganglia uptake associated with L-dopa therapy in some Parkinson's patients, and in patients with hemi-parkinsonism there have been perfusion deficits reported in the contralateral basal ganglia. In some Parkinson patients, bilateral Alzheimer's-like posterior temporoparietal cortical perfusion defects have been observed in association with progressive dementia. Basal ganglia and cortical perfusion changes also have been reported in a few patients with a variety of other less common movement disorders.

    Title The Cluster Diathesis.
    Date February 1991
    Journal Headache
    Excerpt

    We present further evidence for a sympathetic defect of vasomotor control of the anterior cerebral artery (ACA) on the side of the headache during cluster periods. In 119 cluster headache patients, utilizing transcranial Doppler, we measured CO2 reactivity of the major intracranial vessels, in and out of cluster. Reactivity was significantly lower during the cluster period, but only in the ACA on the side of the headache. Nineteen patients followed sequentially for a full cycle (ie/both in and out of a cluster period) showed the same changes. In 3 out of 6 patients in an active cluster period, we describe a lesion on Gallium single-photon emission computerized tomography (SPECT) in the region of the cavernous sinus which fades as the patient moves out of cluster. It is felt that this lesion may represent the cavernous sinus plexus lesion postulated as the central lesion in cluster. Changes in the sympathetic outflow at this point could explain the changes we have described in ACA CO2 reactivity during cluster.

    Title Increased Iofetamine I 123 Brain Uptake in Metastatic Melanoma.
    Date November 1988
    Journal Archives of Neurology
    Excerpt

    Four of five patients with brain metastases from melanoma had increased lofetamine I 123 uptake in the region of the tumor deposits. A comparison group of five patients with melanoma with no clinical or radiologic evidence of brain involvement and 46 of 47 patients without malignant melanoma but with known brain tumors of other histologic types had normal or decreased iofetamine I 123 brain uptake in the region of the tumor. An exception was one patient whose metastatic small cell lung cancer to the brain showed focally increased uptake. These findings suggest that certain brain tumors such as melanoma are capable of selectively binding iofetamine I 123 because of specific chemical properties of the radiopharmaceutical. Increased uptake of iofetamine I 123 in brain lesions in a patient at risk for metastatic melanoma may be a useful aid to differential diagnosis.

    Title Decreased Iodine-123 Imp Caudate Nucleus Uptake in Patients with Huntington's Disease.
    Date October 1988
    Journal Clinical Nuclear Medicine
    Excerpt

    To determine whether I-123 isopropyl iodoamphetamine (IMP) uptake is reduced in the basal ganglia of patients with Huntington's disease compared with that in aged-matched normal and abnormal control subjects, a caudate ratio was defined that compared the average separation (in pixel units) between the midline and the left and right caudate heads to the width of the brain as measured on transaxial cross-sections of I-123 IMP SPECT brain images. For six patients with Huntington's disease, the average caudate ratio was 29.0% (SD +/- 2.7%), significantly higher than that for 12 normal volunteer subjects (average caudate ratio, 19.1% +/- 3.5%; p less than 0.001) and 13 patients with a variety of other neurologic disorders (average caudate ratio, 19.3 +/- 2.2%; p less than 0.001).

    Title Novel Hypoglycemic Dihydropyridones Serendipitously Discovered from O- Versus C-alkylation in the Synthesis of Vmat2 Antagonists.
    Date
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    Vesicular monoamine transporter type 2 (VMAT2) is a newly emerging target for both diagnostic and therapeutic applications in diabetes mellitus. In pursuit of novel VMAT2 antagonists, we identified a potent hypoglycemic agent with a novel dihydropyridone scaffold. Several analogs were designed and synthesized. A preliminary structure activity relationship (SAR) showed that the dihydropyridone scaffold is required for the activity.

    Title Imaging Inflammation in a Patient with Epilepsy Due to Focal Cortical Dysplasia.
    Date
    Journal Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging
    Excerpt

    BACKGROUND AND PURPOSE: Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS: A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS: PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient's seizure focus as identified by ictal and interictal 18F-fluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS: PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci. J Neuroimaging 2011;XX:1-3.

    Title The Relationship Between Normal Cerebral Perfusion Patterns and White Matter Lesion Distribution in 1,249 Patients with Multiple Sclerosis.
    Date
    Journal Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging
    Excerpt

    BACKGROUND AND PURPOSE: The pathological differences underlying the clinical disease phases in multiple sclerosis (MS) are poorly characterized. We sought to explore the relationship between the distribution of white matter (WM) lesions in relapsing-remitting (RR) and secondary progressive (SP) MS and the normal regional variability of cerebral perfusion. METHODS: WM lesions were identified and quantified on a single magnetic resonance imaging scan from 1,249 patients with MS. The spatial distribution of lesions was compared between early RR, late RR, and SP MS in the context of normal cerebral perfusion patterns provided by a single-photon emission-computed tomography atlas of healthy individuals. RESULTS: Patients with SP MS had more distinct and larger lesions than patients with RR MS. Across all subjects, lesions were present in regions of relatively lower normal perfusion than normal appearing WM. Further, lesions in SP MS were more common in areas of lower perfusion as compared to the lesion distribution in early and late RR MS. CONCLUSION: Chronic plaques were more prevalent in WM regions with lower relative perfusion. Lesions in more highly perfused regions were more commonly observed in early RR MS and therefore, may be more likely to successfully remyelinate and resolve. J Neuroimaging 2012;22:129-136.

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