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1.  Evaluation of Inhibitory Effect of Recreational Drugs on Dopaminergic Terminal Neuron by PET and Whole-Body Autoradiography 
BioMed Research International  2014;2014:157923.
There is little investigation for the functional roles of peripheral dopamine. [18F]FDOPA has been used in cancer imaging (i.e., neuroendocrine and tumors pancreatic tumors) and neuroimaging (i.e., Parkinson's disease and Huntington's disease). Here, we accessed side effects of recreational drugs such as ketamine, cocaine, and methamphetamine on dopamine neurons in peripheral organs by using positron emission tomography (PET) imaging and quantitative whole-body autoradiography (QWBAR) with [18F]FDOPA. The images were applied for the measurement of specific binding ratios (SBRs) of striatum with the cerebellum as the reference region. Clear striatal [18F]FDOPA-derived radioactivity was observed. Moderate level of radiotracer accumulation was presented in the mucosal layers of the stomach and small intestine. The medulla layers of kidney had higher radioactivity than that of the cortex. Blocking images markedly eliminated the specific binding of [18F]FDOPA in the striatum and in peripheral organs such as stomachs, intestines, and kidney. Ketamine showed the highest inhibitory effect on striatal [18F]FDOPA-derived radioactivity followed by cocaine and methamphetamine. The current results demonstrated a useful crossing-validating tool that enhances the capability of [18F]FDOPA for further investigations of the alteration of dopaminergic neurons in the brain disorder or cancer diseases in peripheral tissues.
PMCID: PMC4022164  PMID: 24877059
2.  Comparative evaluation of 18F-FDOPA, 13N-AMMONIA, 18F-FDG PET/CT and MRI in primary brain tumors - A pilot study 
To determine the diagnostic reliability of 18F-FDOPA, 13N-Ammonia and 18F-FDG PET/CT in primary brain tumors and comparison with magnetic resonance imaging (MRI).
Materials and Methods:
A total of 23 patients, 8 preoperative and 15 postoperative, undergoing evaluation for primary brain tumors were included in this study. Of them, 9/15 were operated for high grade gliomas (7/9 astrocytomas and 2/9 oligodendrogliomas) and 6/15 for low grade gliomas (5/6 astrocytomas and 1/6 oligodendroglioma). After PET study, 2 of 8 preoperative cases were histopathologically proven to be of benign etiology. 3 low grade and 2 high grade postoperative cases were disease free on 6 months follow-up. Tracer uptake was quantified by standardized uptake values (SUVmax) and the SUV max ratio of tumor to normal symmetrical area of contra lateral hemisphere (T/N). 18F-FDOPA uptake was also quantified by SUVmax ratio of tumor to striatum (T/S). Conventional MR studies were done in all patients.
Both high-grade and low-grade tumors were well visualized with 18F-FDOPA PET. Sensitivity of 18F-FDOPA PET was substantially higher (6/6 preoperative, 3/3 low grade postoperative, 7/7 high grade postoperative) than with 18F-FDG (3/6 preoperative, 1/3 low grade postoperative, 3/7 high grade postoperative) and 13N-Ammonia PET (2/6 preoperative, 1/3 low grade postoperative, 1/7 high grade postoperative). FDOPA was equally specific as FDG and Ammonia PET in operated cases but was falsely positive in two preoperative cases. Sensitivity of FDOPA (16/16) was more than MRI (13/16).
18F-FDG uptake correlates with tumor grade. Though 18F-FDOPA PET cannot distinguish between tumor grade, it is more reliable than 18F-FDG and 13N-Ammonia PET for evaluating brain tumors. 18F-FDOPA PET may prove to be superior to MRI in evaluating recurrence and residual tumor tissue. 13N-Ammonia PET did not show any encouraging results.
PMCID: PMC3237222  PMID: 22174511
13N-Ammonia; 18F-FDG; 18F-FDOPA; brain tumors; MRI; PET; sensitivity
3.  Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis 
EJNMMI Research  2013;3:69.
[18 F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [18 F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques.
[18 F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [11C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity.
The different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BPND; r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BPND) but not with the contralateral PET measures. EDVR and BPND in the contralateral striatum were not different from controls and were not correlated with the denervation severity.
The demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [18 F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control.
PMCID: PMC3875899  PMID: 24088510
Dopamine synthesis; FDOPA; Parkinson's disease; PET; Microdialysis; 6-OHDA lesion
4.  Differentiating multiple system atrophy from Parkinson's disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging 
Objectives: The differential diagnosis between typical idiopathic Parkinson's disease (PD) and the striatonigral variant of multiple system atrophy (MSA-P) is often difficult because of the presence of signs and symptoms common to both forms of parkinsonism, particularly at symptom onset. This study investigated striatal and midbrain findings in MSA-P and PD patients in comparison with normal controls with the use of positron emission tomography (PET) and three dimensional magnetic resonance imaging (3D MRI) based volumetry to increase the differential diagnostic accuracy between both disease entities.
Methods: Nine patients with MSA-P, 24 patients with PD, and seven healthy controls were studied by MRI and PET with 6-[18F]-fluoro-L-dopa (FDOPA), [18F]fluoro-deoxyglucose (FDG), and 11-C-Raclopride (RACLO). Striatal and extrastriatal volumes of interest (VOI) were calculated on the basis of the individual MRI data. The PET data were transferred to the VOI datasets and subsequently analysed.
Results: MSA-P differed significantly from PD patients in terms of decreased putaminal volume, glucose metabolism, and postsynaptic D2 receptor density. The striatal FDOPA uptake was equally impaired in both conditions. Neither MRI volumetry nor PET imaging of the midbrain region further contributed to the differential diagnosis between PD and MSA-P.
Conclusions: The extent and spatial distribution of functional and morphological changes in the striatum permit the differentiation of MSA-P from PD. Both, multi-tracer PET and 3D MRI based volumetry, may be considered equivalent in the assessment of different striatal abnormality in both disease entities. In contrast, MRI and PET imaging of the midbrain does not provide a further gain in diagnostic accuracy.
PMCID: PMC1738131  PMID: 12397143
5.  [18F]FDOPA PET as an Endophenotype for Parkinson’s Disease Linkage Studies 
Parkinson Disease (PD) is a late onset disorder with age-dependent penetrance that may confound genetic studies since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at-risk subjects. Positron emission tomography (PET) measurements of 6-[18F]fluorodopa ([18F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [18F]FDOPA PET in 11 members of a large, multi-incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [18F]FDOPA posterior putamen uptake was defined as less than three standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to “PET definite PD”. The remainder had normal PETs. The average maximum LOD score with the pre-PET was 6.14±0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36±1.23. The [18F]FDOPA PET endophenotype permits phenoconversion in multi-incident PD families and may increase LOD score accuracy and power of an informative pedigree.
PMCID: PMC2646004  PMID: 16528749
Parkinson’s disease; Positron Emission Tomography; Linkage; Endophenotype; Amish
6.  Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats 
EJNMMI Research  2011;1:25.
We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements.
Different doses of 6-OHDA (0, 7, 14, and 28 μg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing.
Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations.
Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).
PMCID: PMC3251329  PMID: 22214344
Parkinson's disease; positron emission tomography; [18F]FDOPA; 6-OHDA; dopamine
7.  Comparative study of 18F-DOPA, 13N-Ammonia and F18-FDG PET/CT in primary brain tumors 
To determine the diagnostic reliability of 18F-FDOPA, 13N-Ammonia and F18-FDG PET/CT in primary brain tumors. We evaluated the amino acid and glucose metabolism of brain tumors by using PET with 18F-FDOPA, 13N-Ammonia and F18-FDG PET/CT.
Materials and Methods:
Nine patients undergoing evaluation for brain tumors were studied. Tracer uptake was quantified by the use of standardized uptake values and the ratio of tumor uptake to normal identical area of contra lateral hemisphere (T/N). In addition, PET uptake with 18F-FDOPA was quantified by use of ratio of tumor uptake to striatum uptake (T/S). The results were correlated with the patient's clinical profile.
Both high-grade and low-grade tumors were well visualized with 18F-FDOPA. The sensitivity for identifying tumors was substantially higher with 18F-FDOPA PET than with F18-FDG and 13N-Ammonia PET as determined by simple visual inspection. The sensitivity for identifying recurrence in low grade gliomas is higher with 13N-Ammonia than with F18-FDG.
18F-FDOPA PET is more reliable than F18-FDG and 13N-Ammonia PET for evaluating brain tumors.
PMCID: PMC3543579  PMID: 23326065
13N-Ammonia; F18-FDG; 18F-FDOPA; brain tumors; diagnosis; PET; sensitivity
8.  Using a reference tissue model with spatial constraint to quantify [11C]Pittsburgh compound B PET for early diagnosis of Alzheimer’s disease 
NeuroImage  2007;36(2):298-312.
Reference tissue model (RTM) is a compartmental modeling approach that uses reference tissue time activity curve (TAC) as input for quantification of ligand-receptor dynamic PET without blood sampling. There are limitations in applying the RTM for kinetic analysis of PET studies using [11C]Pittsburgh compound B ([11C]PIB). For region of interest (ROI) based kinetic modeling, the low specific binding of [11C]PIB in a target ROI can result in a high linear relationship between the output and input. This condition may result in amplification of errors in estimates using RTM. For pixel-wise quantification, due to the high noise level of pixel kinetics, the parametric images generated by RTM with conventional linear or nonlinear regression may be too noisy for use in clinical studies.
We applied RTM with parameter coupling and a simultaneous fitting method as a spatial constraint for ROI kinetic analysis. Three RTMs with parameter coupling were derived from a classical compartment model with plasma input: a RTM of 4 parameters (R1, k′2R, k4, BP) (RTM4P); a RTM of 5 parameters (R1, k2R, NS, k6, BP) (RTM5P); and a simplified RTM (SRTM) of 3 parameters (R1, k′2R, BP) (RTM3P). The parameter sets [k′2R, k4], [k2R, NS, k6], and k′2R are coupled among ROIs for RTM4P, RTM5P, and RTM3P, respectively. A linear regression with spatial constraint (LRSC) algorithm was applied to the SRTM for parametric imaging. Logan plots were used to estimate the distribution volume ratio (DVR) (= 1 + BP (binding potential)) in ROI and pixel levels. Ninety-minute [11C]PIB dynamic PET was performed in 28 controls and 6 individuals with mild cognitive impairment (MCI) on a GE Advance scanner. ROIs of cerebellum (reference tissue) and 15 other regions were defined on coregistered MRI’s.
The coefficients of variation of DVR estimates from RTM3P obtained by the simultaneous fitting method were lower by 77 - 89% (in striatum, frontal, occipital, parietal, and cingulate cortex) as compared to that by conventional single ROI TAC fitting method. There were no significant differences in both TAC fitting and DVR estimates between the RTM3P and the RTM4P or RTM5P. The DVR in striatum, lateral temporal, frontal and cingulate cortex for MCI group was 25% to 38% higher compared to the control group (p ≤ 0.05), even in this group of individuals with generally low PIB retention. The DVR images generated by the SRTM with LRSC algorithm had high linear correlations with those from the Logan plot (R2 = 0.99). In conclusion, the RTM3P with simultaneous fitting method is shown to be a robust compartmental modeling approach that may be useful in [11C]PIB PET studies to detect early markers of Alzheimer’s disease where specific ROIs have been hypothesized. In addition, the SRTM with LRSC algorithm may be useful in generating R1 and DVR images for pixel-wise quantification of [11C]PIB dynamic PET.
PMCID: PMC2001263  PMID: 17449282
9.  A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson's disease 
Brain imaging and behavior  2011;5(3):203-211.
Although [18F]fluoro-L-dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.
PMCID: PMC3150388  PMID: 21556744
Fluorodopa; motor control; Parkinson's disease; positron emission tomography; ageing; Tongue/*physiopathology; Facial Muscles/*physiopathology
10.  Dopamine Cell Implantation in Parkinson’s Disease: Long-Term Clinical and 18F-FDOPA PET Outcomes 
We have previously reported the results of a 1-y double-blind, placebo-controlled study of embryonic dopamine cell implantation for Parkinson’s disease. At the end of the blinded phase, we found a significant increase in putamen uptake on 18F-fluorodopa (18F-FDOPA) PET reflecting the viability of the grafts. Nonetheless, clinical improvement was significant only in younger (age ≤ 60 y) transplant recipients, as indicated by a reduction in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores.
We now report long-term clinical and PET outcomes from 33 of the original trial participants who were followed for 2 y after transplantation and 15 of these subjects who were followed for 2 additional years. Longitudinal changes in UPDRS motor ratings and caudate and putamen 18F-FDOPA uptake were assessed with repeated-measures ANOVA. Relationships between these changes over time were evaluated by the analysis of within-subject correlations.
We found that UPDRS motor ratings declined over time after transplantation (P < 0.001). Clinical improvement at 1 y was relatively better for the younger transplant recipients and for men, but these age and sex differences were not evident at longer-term follow-up. Significant increases in putamen 18F-FDOPA uptake were evident at all posttransplantation time points (P < 0.001) and were not influenced by either age or sex. Posttransplantation changes in putamen PET signal and clinical outcome were significantly intercorrelated (P < 0.02) over the course of the study. Image analysis at the voxel level revealed significant bilateral increases in 18F-FDOPA uptake at 1 y (P < 0.001) in the posterior putamen engraftment sites. PET signal in this region increased further at 2 and 4 y after engraftment. Concurrently, this analysis disclosed progressive declines in radiotracer uptake in the nonengrafted caudate and ventrorostral putamen. Clinical improvement after transplantation correlated with the retention of PET signal in this region at the preoperative baseline.
These results suggest that clinical benefit and graft viability are sustained up to 4 y after transplantation. Moreover, the dependence of clinical (but not imaging) outcomes on subject age and sex at 1 y may not persist over the long term. Last, the imaging changes reliably correlate with clinical outcome over the entire posttransplantation time course.
PMCID: PMC2946843  PMID: 20008998
18F-FDOPA; PET; Parkinson’s disease; transplantation; long-term outcome
11.  Rate of 6-[18F]fluoro-L-dopa uptake decline in striatal subregions in Parkinson’s disease 
Using both a volume of interest (VOI) and whole brain voxel-wise approach, we compared rates of decline of 6-L-[18F]-fluorodopa (FDOPA) positron emission tomography (PET) uptake ipsilateral (IL) and contralateral (CL) to the initially symptomatic limbs over 4.5 years in 26 subjects with Parkinson’s disease (PD) and 11 controls. The VOI approach used six subregions: Head/body of caudate nucleus, whole putamen, and posterior putamen. The absolute rate of decline in PD was significantly greater than in controls in all subregions, but did not differ significantly by region. Ratios of uptake between regions did not change during the study with the exception of the IL putamen/caudate ratio. Both male gender and advancing age were associated with lower baseline FDOPA uptake in PD, but no difference in decline rates. In the PD group, decline rates were marginally greater during earlier time segments. Striatal FDOPA uptake was significantly correlated with disease duration and with progression of time during the study, but only moderately correlated with UPDRS scores. We conclude that FDOPA uptake in subregions of the striatum is strongly correlated with disease duration and age, and declines equally from symptom onset in PD. This implies that in idiopathic PD, relative preservation of uptake in the anterior striatum reflects a delay in pathologic involvement of nigrostriatal projections to these regions.
PMCID: PMC3080432  PMID: 21449008
Parkinson’s disease; Fluorodopa positron emission tomography; disease progression; aging; gender
12.  Reduced uptake of [18F]FDOPA PET in asymptomatic welders with occupational manganese exposure 
Neurology  2011;76(15):1296-1301.
Welding exposes workers to manganese (Mn) fumes, but it is unclear if this exposure damages dopaminergic neurons in the basal ganglia and predisposes individuals to develop parkinsonism. PET imaging with 6-[18F]fluoro-l-dopa (FDOPA) is a noninvasive measure of nigrostriatal dopaminergic neuron integrity. The purpose of this study is to determine whether welding exposure is associated with damage to nigrostriatal neurons in asymptomatic workers.
We imaged 20 asymptomatic welders exposed to Mn fumes, 20 subjects with idiopathic Parkinson disease (IPD), and 20 normal controls using FDOPA PET. All subjects were examined by a movement disorders specialist. Basal ganglia volumes of interest were identified for each subject. The specific uptake of FDOPA, Ki, was generated for each region using graphical analysis method.
Repeated measures general linear model (GLM) analysis demonstrated a strong interaction between diagnostic group and region (F4,112 = 15.36, p < 0.001). Caudate Kis were lower in asymptomatic welders (0.0098 + 0.0013 minutes−1) compared to control subjects (0.0111 + 0.0012 minutes−1, p = 0.002). The regional pattern of uptake in welders was most affected in the caudate > anterior putamen > posterior putamen. This uptake pattern was anatomically reversed from the pattern found in subjects with IPD.
Active, asymptomatic welders with Mn exposure demonstrate reduced FDOPA PET uptake indicating dysfunction in the nigrostriatal dopamine system. The caudate Ki reduction in welders may represent an early (asymptomatic) marker of Mn neurotoxicity and appears to be distinct from the pattern of dysfunction found in symptomatic IPD.
PMCID: PMC3090062  PMID: 21471467
13.  In-vivo measurement of LDOPA uptake, dopamine reserve and turnover in the rat brain using [18F]FDOPA PET 
Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson's disease (PD). We demonstrate methodology for such measurements using [18F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a kloss term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [11C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [18F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [18F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [11C]DTBZ binding potential (BPND). The uptake and trapping rate (kref) decreased after lesioning, but relatively less so than [11C]DTBZ BPND. For normal controls, striatal estimates were kref=0.037±0.005 per minute, EDVR=1.07±0.22 and kloss=0.024±0.003 per minute (30 minutes turnover half-time), with repeatability (coefficient of variation) ≤11%. [18F]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD.
PMCID: PMC3597374  PMID: 22929441
dopamine synthesis; FDOPA; 6-OHDA lesion; Parkinson's disease; PET
14.  Functional characterization of non-metastatic paraganglioma and pheochromocytoma by 18F-FDOPA PET: focus on missed lesions 
Clinical endocrinology  2013;79(2):170-177.
Aims and methods
To evaluate the clinical value of 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET in relation to tumour localization and the patient’s genetic status in a large series of pheochromocytoma/paraganglioma (PHEO/PGL) patients and to discuss in detail false-negative results.
A retrospective study of PGL patients who were investigated with 18F-FDOPA PET or PET/CT imaging in two academic endocrine tumour centers was conducted (La Timone University Hospital, Marseilles, France and National Institutes of Health (NIH), Bethesda, MD, USA).
One hundred sixteen patients (39.7% harboring germline mutations in known disease susceptibility genes) were evaluated for a total of 195 PHEO/PGL foci. 18F-FDOPA PET correctly detected 179 lesions (91.8%) in 107 patients (92.2%).
Lesion-based sensitivities for parasympathetic PGLs (head, neck, or anterior/middle thoracic ones), PHEOs, and extra-adrenal sympathetic (abdominal or posterior thoracic) PGLs were 98.2% [96.5% for Timone and 100% for NIH], 93.9% [93.8% and 93.9%], and 70.3% [47.1% and 90%], respectively (P<0.001).
Sympathetic (adrenal and extra-adrenal) SDHx-related PGLs were at a higher risk for negative 18F-FDOPA PET than non-SDHx-related PGLs (14/24 vs 0/62, respectively, p<0.001). By contrast, the risk of negative 18F-FDOPA PET was lower for parasympathetic PGLs regardless of the genetic background (1/90 in SDHx vs 1/19 in non-SDHx tumours, p= 0.32).
18F-FDOPA PET failed to detect 2 head and neck PGLs (HNPGL), likely due to their small size, while most missed sympathetic PGL were larger and may have exhibited a specific 18F-FDOPA-negative imaging phenotype. 18F-FDG PET detected all the missed sympathetic lesions.
18F-FDOPA PET appears to be a very sensitive functional imaging tool for HNPGL regardless of the genetic status of the tumours. Patients with false-negative tumours on 18F-FDOPA PET should be tested for SDHx mutations.
PMCID: PMC3610811  PMID: 23230826
Positron emission tomography; 18F-fluorodihydroxyphenylalanine; paraganglioma; radiopharmaceuticals; genetics
15.  Enzyme inhibition of dopamine metabolism alters 6-[18F]FDOPA uptake in orthotopic pancreatic adenocarcinoma 
EJNMMI Research  2013;3:18.
An unknown location hampers removal of pancreatic tumours. We studied the effects of enzyme inhibitors on the uptake of 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the pancreas, aiming at improved imaging of pancreatic adenocarcinoma.
Mice bearing orthotopic BxPC3 pancreatic adenocarcinoma were injected with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and scanned with positron emission tomography/computed tomography (PET/CT). For [18F]FDOPA studies, tumour-bearing mice and sham-operated controls were pretreated with enzyme inhibitors of aromatic amino acid decarboxylase (AADC), catechol-O-methyl transferase (COMT), monoamine oxidase A (MAO-A) or a combination of COMT and MAO-A. Mice were injected with [18F]FDOPA and scanned with PET/CT. The absolute [18F]FDOPA uptake was determined from selected tissues using a gamma counter. The intratumoural biodistribution of [18F]FDOPA was recorded by autoradiography. The main [18F]FDOPA metabolites present in the pancreata were determined with radio-high-performance liquid chromatography.
[18F]FDG uptake was high in pancreatic tumours, while [18F]FDOPA uptake was highest in the healthy pancreas and significantly lower in tumours. [18F]FDOPA uptake in the pancreas was lowest with vehicle pretreatment and highest with pretreatment with the inhibitor of AADC. When mice received COMT + MAO-A inhibitors, the uptake was high in the healthy pancreas but low in the tumour-bearing pancreas.
Combined use of [18F]FDG and [18F]FDOPA is suitable for imaging pancreatic tumours. Unequal pancreatic uptake after the employed enzyme inhibitors is due to the blockade of metabolism and therefore increased availability of [18F]FDOPA metabolites, in which uptake differs from that of [18F]FDOPA. Pretreatment with COMT + MAO-A inhibitors improved the differentiation of pancreas from the surrounding tissue and healthy pancreas from tumour. Similar advantage was not achieved using AADC enzyme inhibitor, carbidopa.
PMCID: PMC3618317  PMID: 23497589
Pancreas; Adenocarcinoma; [18F]FDOPA; AADC; COMT
16.  Functional Brain Imaging 
Executive Summary
The objective of this analysis is to review a spectrum of functional brain imaging technologies to identify whether there are any imaging modalities that are more effective than others for various brain pathology conditions. This evidence-based analysis reviews magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) for the diagnosis or surgical management of the following conditions: Alzheimer’s disease (AD), brain tumours, epilepsy, multiple sclerosis (MS), and Parkinson’s disease (PD).
Clinical Need: Target Population and Condition
Alzheimer’s disease is a progressive, degenerative, neurologic condition characterized by cognitive impairment and memory loss. The Canadian Study on Health and Aging estimated that there will be 97,000 incident cases (about 60,000 women) of dementia (including AD) in Canada in 2006.
In Ontario, there will be an estimated 950 new cases and 580 deaths due to brain cancer in 2006. Treatments for brain tumours include surgery and radiation therapy. However, one of the limitations of radiation therapy is that it damages tissue though necrosis and scarring. Computed tomography (CT) and magnetic resonance imaging (MRI) may not distinguish between radiation effects and resistant tissue, creating a potential role for functional brain imaging.
Epilepsy is a chronic disorder that provokes repetitive seizures. In Ontario, the rate of epilepsy is estimated to be 5 cases per 1,000 people. Most people with epilepsy are effectively managed with drug therapy; but about 50% do not respond to drug therapy. Surgical resection of the seizure foci may be considered in these patients, and functional brain imaging may play a role in localizing the seizure foci.
Multiple sclerosis is a progressive, inflammatory, demyelinating disease of the central nervous system (CNS). The cause of MS is unknown; however, it is thought to be due to a combination of etiologies, including genetic and environmental components. The prevalence of MS in Canada is 240 cases per 100,000 people.
Parkinson’s disease is the most prevalent movement disorder; it affects an estimated 100,000 Canadians. Currently, the standard for measuring disease progression is through the use of scales, which are subjective measures of disease progression. Functional brain imaging may provide an objective measure of disease progression, differentiation between parkinsonian syndromes, and response to therapy.
The Technology Being Reviewed
Functional Brain Imaging
Functional brain imaging technologies measure blood flow and metabolism. The results of these tests are often used in conjunction with structural imaging (e.g., MRI or CT). Positron emission tomography and MRS identify abnormalities in brain tissues. The former measures abnormalities through uptake of radiotracers in the brain, while the latter measures chemical shifts in metabolite ratios to identify abnormalities. The potential role of functional MRI (fMRI) is to identify the areas of the brain responsible for language, sensory and motor function (sensorimotor cortex), rather than identifying abnormalities in tissues. Magnetoencephalography measures magnetic fields of the electric currents in the brain, identifying aberrant activity. Magnetoencephalography may have the potential to localize seizure foci and to identify the sensorimotor cortex, visual cortex and auditory cortex.
In terms of regulatory status, MEG and PET are licensed by Health Canada. Both MRS and fMRI use a MRI platform; thus, they do not have a separate licence from Health Canada. The radiotracers used in PET scanning are not licensed by Health Canada for general use but can be used through a Clinical Trials Application.
Review Strategy
The literature published up to September 2006 was searched in the following databases: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, and International Network of Agencies for Health Technology Assessment (INAHTA). The database search was supplemented with a search of relevant Web sites and a review of the bibliographies of selected papers.
General inclusion criteria were applied to all conditions. Those criteria included the following:
Full reports of systematic reviews, randomized controlled trials (RCTs), cohort-control studies, prospective cohort studies (PCS’), and retrospective studies.
Sample sizes of at least 20 patients (≥ 10 with condition being reviewed).
English-language studies.
Human studies.
Any age.
Studying at least one of the following: fMRI, PET, MRS, or MEG.
Functional brain imaging modality must be compared with a clearly defined reference standard.
Must report at least one of the following outcomes: sensitivity, specificity, accuracy, positive predictive value (PPV), receiver operating characteristic curve, outcome measuring impact on diagnostic testing, treatment, patient health, or cost.
Summary of Findings
There is evidence to indicate that PET can accurately diagnose AD; however, at this time, there is no evidence to suggest that a diagnosis of AD with PET alters the clinical outcomes of patients.
The addition of MRS or O-(2-18F-Fluoroethyl)-L-Tyrosine (FET)-PET to gadolinium (Gd)-enhanced MRI for distinguishing malignant from benign tumours during primary diagnosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients to distinguish malignant from benign tumours is unclear, because patients with a suspected brain tumour will likely undergo a biopsy despite additional imaging results.
The addition of MRS, FET-PET, or MRI T2 to Gd-enhanced MRI for the differentiation of recurrence from radiation necrosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients with a suspected recurrence is in the monitoring of patients. Based on the evidence available, it is unclear if one of the imaging modalities (MRS, FET-PET, or MRI T2) offers significantly improved specificity over another.
There may be a role for fMRI in the identification of surgical candidates for tumour resection; however, this requires further research.
Based on the studies available, it is unclear if MEG has similar accuracy in localizing seizure foci to intracranial electroencephalogram (ICEEG). More high-quality research is needed to establish whether there is a difference in accuracy between MEG and ICEEG.
The results of the studies comparing PET to noninvasive electroencephalogram (EEG) did not demonstrate that PET was more accurate at localizing seizure foci; however, there may be some specific conditions, such as tuberous sclerosis, where PET may be more accurate than noninvasive EEG.
There may be some clinical utility for MEG or fMRI in presurgical functional mapping; however, this needs further investigation involving comparisons with other modalities. The clinical utility of MRS has yet to be established for patients with epilepsy.
Positron emission tomography has high sensitivity and specificity in the diagnosis of PD and the differential diagnosis of parkinsonian syndromes; however, it is unclear at this time if the addition of PET in the diagnosis of these conditions contributes to the treatment and clinical outcomes of patients.
There is limited clinical utility of functional brain imaging in the management of patients with MS at this time. Diagnosis of MS is established through clinical history, evoked potentials, and MRI. Magnetic resonance imaging can identify the multifocal white lesions and other structural characteristics of MS.
PMCID: PMC3379170  PMID: 23074493
17.  18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab 
Neuro-Oncology  2012;14(8):1079-1089.
The current study examined the use of voxel-wise changes in 18F-FDOPA and 18F-FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression-free survival (PFS) and 6-month overall survival (OS) according to receiver-operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased 18F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P < .05); however, 18F-FLT uptake did not stratify OS. This study suggests that an increase in FDOPA or FLT PET uptake on PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab.
PMCID: PMC3408264  PMID: 22711609
Bevacizumab; 18F-FDOPA; 18F-FLT, glioblastoma; PRMs
18.  Feasibility of PET Template-Based Analysis on F-18 FP-CIT PET in Patients with De Novo Parkinson’s Disease 
The aim of this study was to evaluate the feasibility of FP-CIT PET template-based quantitative analysis on F-18 FP-CIT PET in patients with de novo Parkinson’s disease (PD), compared with MR-based and manual methods. We also assessed the correlation of quantitative parameters of those methods with clinical severity of the disease.
Forty patients with de novo PD underwent both MRI and F-18 FP-CIT PET. Images were spatially normalized to a standardized PET template. Mean counts of 4 ROIs: putamen, caudate, occipital cortex and cerebellum, were obtained using the quantification program, Korean Statistical Probabilistic Anatomical Map (KSPAM). Putamen-to-caudate ratio (PCR), asymmetry index (ASI), specific-to-nonspecific ratios with two different references: to occipital cortex (SOR) and cerebellum (SCR) were compared. Parameters were also calculated from manually drawn ROI method and MR-coregistrated method.
All quantitative parameters showed significant correlations across the three different methods, especially between the PET-based and manual methods. Among them, PET-based SOR and SCR values showed an excellent correlation and concordance with those of manual method. In relationship with clinical severity, only ASI achieved significantly inverse correlations with H&Y stage and UPDRS motor score. There was no significant difference between the quantitative parameters of both occipital cortex and cerebellum in all three methods, which implied that quantitation using PET-based method could be reproducible regardless of the reference region.
Quantitative parameters using FP-CIT PET template-based method correlated well with those using laborious manual method with excellent concordance. Moreover, PET-based quantitation was less influenced by the reference region than MR-based method. It suggests that PET-based method can provide objective and quantitative parameters quickly and easily as a feasible analysis in place of conventional method.
PMCID: PMC4041974  PMID: 24900086
Parkinson’s disease; F-18 FP-CIT PET; Template-based quantitative analysis; Korean statistical probabilistic anatomical map (KSPAM); Dopamine transporter (DAT)
19.  Value of fusion of PET and MRI in the detection of intra-pelvic recurrence of gynecological tumor: comparison with 18F-FDG contrast-enhanced PET/CT and pelvic MRI 
Annals of Nuclear Medicine  2013;28(1):25-32.
To evaluate the diagnostic value of retrospective image fusion from pelvic magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (PET) in detecting intra-pelvic recurrence of gynecological tumor.
Thirty patients with a suspicion of recurrence of gynecological malignancy underwent inline contrast-enhanced PET/computed tomography (CT) and pelvic contrast-enhanced MRI for restaging. Diagnostic performance about the local recurrence, pelvic lymph node and bone metastasis and peritoneal lesion of PET/low-dose non-enhanced CT (PET/ldCT), PET/full-dose contrast-enhanced CT (PET/ceCT), contrast-enhanced MRI, and retrospective image fusion from PET and MRI (fused PET/MRI) were evaluated by two experienced readers. Final diagnoses were obtained by histopathological examinations, radiological imaging and clinical follow-up for at least 6 months. McNemar test was employed for statistical analysis.
Documented positive locally recurrent disease, pelvic lymph node and bone metastases, and peritoneal dissemination were present in 53.3, 26.7, 10.0, and 16.7 %, respectively. Patient-based sensitivity for detecting local recurrence, pelvic lymph node and bone metastasis and peritoneal lesion were 87.5, 87.5, 100 and 80.0 %, respectively, for fused PET/MRI, 87.5, 62.5, 66.7 and 60.0 %, respectively, for contrast-enhanced MRI, 62.5, 87.5, 66.7 and 80.0 %, respectively, for PET/ceCT, and 50.0, 87.5, 66.7 and 60.0 %, respectively, for PET/ldCT. The sensitivity of diagnosing local recurrence by fused PET/MRI was significantly better than that of PET/ldCT (p = 0.041). The patient-based sensitivity, specificity and accuracy for the detection of intra-pelvic recurrence/metastasis were 91.3, 100 and 93.3 % for fused PET/MRI, 82.6, 100 and 86.7 % for contrast-enhanced MRI, 82.6, 100 and 86.7 % for PET/ceCT and 78.3, 85.7 and 80.0 % for PET/ldCT.
Fused PET/MRI combines the individual advantages of MRI and PET, and is a valuable technique for assessment of intra-pelvic recurrence of gynecological cancers.
PMCID: PMC4328133  PMID: 24129541
Fused PET/MRI; PET/CT; MRI; Restaging; Gynecological tumor
20.  Increased Turnover of Dopamine in Caudate Nucleus of Detoxified Alcoholic Patients 
PLoS ONE  2013;8(9):e73903.
A previous study of the DOPA decarboxylase substrate 6-[18F]fluoro-L-DOPA (FDOPA) with positron emission tomography (PET) detected no difference of the net blood-brain transfer rate (Kinapp) between detoxified alcoholic patients and healthy controls. Instead, the study revealed an inverse correlation between Kinapp in left ventral striatum and alcohol craving scores. To resolve the influx and efflux phases of radiolabeled molecules, we independently estimated the unidirectional blood-brain FDOPA clearance rate (K) and the washout rate of [18F]fluorodopamine and its deaminated metabolites (kloss), and we also calculated the total distribution volume of decarboxylated metabolites and unmetabolized FDOPA as a steady-state index of the dopamine storage capacity (Vd) in brain. The craving scores in the 12 alcoholics correlated positively with the rate of loss (kloss) in the left ventral striatum. We conclude that craving is most pronounced in the individuals with relatively rapid dopamine turnover in the left ventral striatum. The blood-brain clearance rate (K), corrected for subsequent loss of radiolabeled molecules from brain, was completely normal throughout the brain of the alcoholics, in whom the volume of distribution (Vd) was found to be significantly lower in the left caudate nucleus. The magnitude of Vd in the left caudate head was reduced by 43% relative to the 16 controls, consistent with a 58% increase of kloss. We interpret the findings as indicating that a trait for rapid dopamine turnover in the ventral striatum subserves craving and reward-dependence, leading to an acquired state of increased dopamine turnover in the dorsal striatum of detoxified alcoholic patients.
PMCID: PMC3770672  PMID: 24040111
21.  The Bioenergetic Status Relates to Dopamine Neuron Loss in Familial PD with PINK1 Mutations 
PLoS ONE  2012;7(12):e51308.
Mutations in the PINK1 gene cause autosomal recessive familial Parkinson’s disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous (31P) and proton (1H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA Ki values correlated positively with MI (r = 0.879, p<0.001) and inversely with β-ATP (r = −0.784, p = 0.008) and GPC concentrations (r = −0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance.
PMCID: PMC3519591  PMID: 23251494
22.  Clinical significance of MRI/18F-FDG PET fusion imaging of the spinal cord in patients with cervical compressive myelopathy 
18F-FDG PET is used to investigate the metabolic activity of neural tissue. MRI is used to visualize morphological changes, but the relationship between intramedullary signal changes and clinical outcome remains controversial. The present study was designed to evaluate the use of 3-D MRI/18F-FDG PET fusion imaging for defining intramedullary signal changes on MRI scans and local glucose metabolic rate measured on 18F-FDG PET scans in relation to clinical outcome and prognosis.
We studied 24 patients undergoing decompressive surgery for cervical compressive myelopathy. All patients underwent 3-D MRI and 18F-FDG PET before surgery. Quantitative analysis of intramedullary signal changes on MRI scans included calculation of the signal intensity ratio (SIR) as the ratio between the increased lesional signal intensity and the signal intensity at the level of the C7/T1 disc. Using an Advantage workstation, the same slices of cervical 3-D MRI and 18F-FDG PET images were fused. On the fused images, the maximal count of the lesion was adopted as the standardized uptake value (SUVmax). In a similar manner to SIR, the SUV ratio (SUVR) was also calculated. Neurological assessment was conducted using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy.
The SIR on T1-weighted (T1-W) images, but not SIR on T2-W images, was significantly correlated with preoperative JOA score and postoperative neurological improvement. Lesion SUVmax was significantly correlated with SIR on T1-W images, but not with SIR on T2-W images, and also with postoperative neurological outcome. The SUVR correlated better than SIR on T1-W images and lesion SUVmax with neurological improvement. Longer symptom duration was correlated negatively with SIR on T1-W images, positively with SIR on T2-W images, and negatively with SUVmax.
Our results suggest that low-intensity signal on T1-W images, but not on T2-W images, is correlated with a poor postoperative neurological outcome. SUVmax of lesions showing increased signal intensity and SUVR measured on fusion MRI/PET scans are more sensitive parameters for predicting clinical outcome than signal intensity on the MRI scan.
PMCID: PMC3458200  PMID: 22854985
Cervical myelopathy; MRI; [18F]-Fluoro-deoxyglucose (FDG) positron emission tomography (PET); Fusion imaging; Spinal cord
23.  Relationship of striatal dopamine synthesis capacity to age and cognition 
Past research has demonstrated that performance on frontal lobe-dependent tasks is associated with dopamine system integrity, and that various dopamine system deficits occur with aging. The positron emission tomography (PET) radiotracer 6-[18F]-fluoro-L-m-tyrosine (FMT) is a substrate of the dopamine-synthesizing enzyme, aromatic amino acid decarboxylase (AADC). Studies using 6-[18F]fluorodopa (FDOPA) (another AADC substrate) to measure how striatal PET signal and age relate have had inconsistent outcomes. The varying results occur in part from tracer processing that renders FDOPA signal subject to aspects of post-release metabolism, which may themselves change with aging. In contrast, FMT remains a purer measure of AADC function. We used partial volume corrected FMT PET scans to measure age-related striatal dopamine synthesis capacity in 21 older (mean 66.9) and 16 younger (mean 22.8) healthy adults. We also investigated how striatal FMT signal related to a cognitive measure of frontal lobe function. Older adults showed significantly greater striatal FMT signal than younger adults. Within the older group, FMT signal in dorsal caudate (DCA) and dorsal putamen (DPUT) was greater with age, suggesting compensation for deficits elsewhere in the dopamine system. In younger adults, FMT signal in DCA was lower with age, likely related to ongoing developmental processes. Younger adults who performed worse on tests of frontal lobe function showed greater FMT signal in right DCA, independent of age effects. Our data suggest that higher striatal FMT signal represents non-optimal dopamine processing. They further support a relationship between striatal dopamine processing and frontal lobe cognitive function.
PMCID: PMC2880923  PMID: 19109513
FMT; PET; normal aging; striatum; cognition; aromatic amino acid decarboxylase; dopa decarboxylase; caudate; putamen; basal ganglia; prefrontal; upregulation
24.  What is the most accurate whole-body imaging modality for assessment of local and distant recurrent disease in colorectal cancer? A meta-analysis 
The objective of this study was to compare the diagnostic performance of positron emission tomography (PET), PET/CT, CT and MRI as whole-body imaging modalities for the detection of local and/or distant recurrent disease in colorectal cancer (CRC) patients who have a (high) suspicion of recurrent disease, based on clinical findings or rise in carcinoembryonic antigen (CEA).
A meta-analysis was undertaken. PubMed and Embase were searched for studies on the accuracy of whole-body imaging for patients with suspected local and/or distant recurrence of their CRC. Additionally, studies had to have included at least 20 patients with CRC and 2 × 2 contingency tables had to be provided or derivable. Articles evaluating only local recurrence or liver metastasis were excluded. Summary receiver-operating characteristic (ROC) curves were constructed from the data on sensitivity and specificity of individual studies and pooled estimates of diagnostic odds ratios (DORs) and areas under the ROC curve (AUCs) were calculated. To test for heterogeneity the Cochran Q test was used.
Fourteen observational studies were included which evaluated PET, PET/CT, CT and/or MRI. Study results were available in 12 studies for PET, in 5 studies for CT, in 5 studies for PET/CT and in 1 study for MRI. AUCs for PET, PET/CT and CT were 0.94 (0.90–0.97), 0.94 (0.87–0.98) and 0.83 (0.72–0.90), respectively. In patient based analyses PET/CT had a higher diagnostic performance than PET with an AUC of 0.95 (0.89–0.97) for PET/CT vs 0.92 (0.86–0.96) for PET.
Both whole-body PET and PET/CT are very accurate for the detection of local and/or distant recurrent disease in CRC patients with a (high) suspicion of recurrent disease. CT has the lowest diagnostic performance. This difference is probably mainly due to the lower accuracy of CT for detection of extrahepatic metastases (including local recurrence). For clinical practice PET/CT might be the modality of choice when evaluating patients with a (high) suspicion of recurrent disease, because of its best performance in patient based analyses and confident prediction of disease status.
PMCID: PMC3126998  PMID: 21468765
Colorectal cancer; Whole-body imaging; Recurrence; Staging
25.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
The objective was to update the 2001 systematic review conducted by the Institute For Clinical Evaluative Sciences (ICES) on the use of positron emission tomography (PET) in assessing myocardial viability. The update consisted of a review and analysis of the research evidence published since the 2001 ICES review to determine the effectiveness and cost-effectiveness of PET in detecting left ventricular (LV) viability and predicting patient outcomes after revascularization in comparison with other noninvasive techniques.
Left Ventricular Viability
Heart failure is a complex syndrome that impairs the contractile ability of the heart to maintain adequate blood circulation, resulting in poor functional capacity and increased risk of morbidity and mortality. It is the leading cause of hospitalization in elderly Canadians. In more than two-thirds of cases, heart failure is secondary to coronary heart disease. It has been shown that dysfunctional myocardium resulting from coronary heart disease (CAD) may recover contractile function (i.e. considered viable). Dysfunctional but viable myocardium may have been stunned by a brief episode of ischemia, followed by restoration of perfusion, and may regain function spontaneously. It is believed that repetitive stunning results in hibernating myocardium that will only regain contractile function upon revascularization.
For people with CAD and severe LV dysfunction (left ventricular ejection fraction [LVEF] <35%) refractory to medical therapy, coronary artery bypass and heart transplantation are the only treatment options. The opportunity for a heart transplant is limited by scarcityof donor hearts. Coronary artery bypass in these patients is associated with high perioperative complications; however, there is evidence that revascularization in the presence of dysfunctional but viable myocardium is associated with survival benefits and lower rates of cardiac events. The assessment of left ventricular (LV) viability is, therefore, critical in deciding whether a patient with coronary artery disease and severe LV dysfunction should undergo revascularization, receive a heart transplant, or remain on medical therapy.
Assessment of Left Ventricular Viability
Techniques for assessing myocardial viability depend on the measurement of a specific characteristic of viable myocytes such as cell membrane integrity, preserved metabolism, mitochondria integrity, and preserved contractile reserve. In Ontario, single photon emission computed tomography (SPECT) using radioactive 201thallium is the most commonly used technique followed by dobutamine echocardiography. Newer techniques include SPECT using technetium tracers, cardiac magnetic resonance imaging, and PET, the subject of this review.
Positron Emission Tomography
PET is a nuclear imaging technique based on the metabolism of radioactive analogs of normal substrates such as glucose and water. The radiopharmaceutical used most frequently in myocardial viability assessment is F18 fluorodeoxyglucose (FDG), a glucose analog. The procedure involves the intravenous administration of FDG under controlled glycemic conditions, and imaging with a PET scanner. The images are reconstructed using computer software and analyzed visually or semi-quantitatively, often in conjunction with perfusion images. Dysfunctional but stunned myocardium is characterized by normal perfusion and normal FDG uptake; hibernating myocardium exhibits reduced perfusion and normal/enhanced FDG uptake (perfusion/metabolism mismatch), whereas scar tissue is characterized by reduction in both perfusion and FDG uptake (perfusion/metabolism match).
Review Strategy
The Medical Advisory Secretariat used a search strategy similar to that used in the 2001 ICES review to identify English language reports of health technology assessments and primary studies in selected databases, published from January 1, 2001 to April 20, 2005. Patients of interest were those with CAD and severe ventricular dysfunction being considered for revascularization that had undergone viability assessment using either PET and/or other noninvasive techniques. The outcomes of interest were diagnostic and predictive accuracy with respect to recovery of regional or global LV function, long-term survival and cardiac events, and quality of life. Other outcomes of interest were impact on treatment decision, adverse events, and cost-effectiveness ratios.
Of 456 citations, 8 systematic reviews/meta-analyses and 37 reports on primary studies met the selection criteria. The reports were categorized using the Medical Advisory Secretariat levels of evidence system, and the quality of the reports was assessed using the criteria of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) developed by the Centre for Dissemination of Research (National Health Service, United Kingdom). Analysis of sensitivity, specificity, predictive values and likelihood ratios were conducted for all data as well as stratified by mean left ventricular ejection fraction (LVEF). There were no randomized controlled trials. The included studies compared PET with one or more other noninvasive viability tests on the same group of patients or examined the long-term outcomes of PET viability assessments. The quality assessment showed that about 50% or more of the studies had selection bias, interpreted tests without blinding, excluded uninterpretable segments in the analysis, or did not have clearly stated selection criteria. Data from the above studies were integrated with data from the 2001 ICES review for analysis and interpretation.
Summary of Findings
The evidence was derived from populations with moderate to severe ischemic LV dysfunction with an overall quality that ranges from moderate to low.
PET appears to be a safe technique for assessing myocardial viability.
CAD patients with moderate to severe ischemic LV dysfunction and residual viable myocardium had significantly lower 2-year mortality rate (3.2%) and higher event-free survival rates (92% at 3 years) when treated with revascularization than those who were not revascularized but were treated medically (16% mortality at 2-years and 48% 3-year event-free survival).
A large meta-analysis and moderate quality studies of diagnostic accuracy consistently showed that compared to other noninvasive diagnostic tests such as thallium SPECT and echocardiography, FDG PET has:
Higher sensitivity (median 90%, range 71%–100%) and better negative likelihood ratio (median 0.16, range 0–0.38; ideal <0.1) for predicting regional myocardial function recovery after revascularization.
Specificity (median 73%, range 33%–91%) that is similar to other radionuclide imaging but lower than that of dobutamine echocardiography
Less useful positive likelihood ratio (median 3.1, range 1.4 –9.2; ideal>10) for predicting segmental function recovery.
Taking positive and negative likelihood ratios together suggests that FDG PET and dobutamine echocardiography may produce small but sometimes important changes in the probability of recovering regional wall motion after revascularization.
Given its higher sensitivity, PET is less likely to produce false positive results in myocardial viability. PET, therefore, has the potential to identify some patients who might benefit from revascularization, but who would not have been identified as suitable candidates for revascularization using thallium SPECT or dobutamine echocardiography.
PET appears to be superior to other nuclear imaging techniques including SPECT with 201thallium or technetium labelled tracers, although recent studies suggest that FDG SPECT may have comparable diagnostic accuracy as FDG PET for predicting regional and global LV function recovery.
No firm conclusion can be reached about the incremental value of PET over other noninvasive techniques for predicting global function improvement or long-term outcomes in the most important target population (patients with severe ischemic LV dysfunction) due to lack of direct comparison.
An Ontario-based economic analysis showed that in people with CAD and severe LV dysfunction and who were found to have no viable myocardium or indeterminate results by thallium SPECT, the use of PET as a follow-up assessment would likely result in lower cost and better 5-year survival compared to the use of thallium SPECT alone. The projected annual budget impact of adding PET under the above scenario was estimated to range from $1.5 million to $2.3 million.
In patients with severe LV dysfunction, that are deemed to have no viable myocardium or indeterminate results in assessments using other noninvasive tests, PET may have a role in further identifying patients who may benefit from revascularization. No firm conclusion can be drawn on the impact of PET viability assessment on long-term clinical outcomes in the most important target population (i.e. patients with severe LV dysfunction).
PMCID: PMC3385418  PMID: 23074467

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