Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy.

OBJECTIVE: Biomarkers are increasingly important to diagnose and test treatments of neurodegenerative diseases such as Parkinson disease (PD). This study compared neuroimaging, neurochemical, and olfactory potential biomarkers to detect central dopamine (DA) deficiency and distinguish PD from multiple system atrophy (MSA). METHODS: In 77 PD, 57 MSA, and 87 control subjects, radioactivity concentrations in the putamen (PUT), caudate (CAU), occipital cortex (OCC), and substantia nigra (SN) were measured 2h after 6-[18F]fluorodopa injection, septal myocardial radioactivity measured 8min after 6-[18F]fluorodopamine injection, CSF and plasma catechols assayed, or olfaction tested (University of Pennsylvania Smell Identification Test (UPSIT)). Receiver operating characteristic curves were constructed, showing test sensitivities at given specificities. RESULTS: PUT:OCC, CAU:OCC, and SN:OCC ratios of 6-[18F]fluorodopa-derived radioactivity were similarly low in PD and MSA (p<0.0001, p<0.0001, p=0.003 compared to controls), as were CSF dihydroxyphenylacetic acid (DOPAC) and DOPA concentrations (p<0.0001, each). PUT:SN and PUT:CAU ratios were lower in PD than in MSA (p=0.004; p=0.005). CSF DOPAC correlated positively with PUT:OCC ratios (r=0.61, p<0.0001). Myocardial 6-[18F]fluorodopamine-derived radioactivity distinguished PD from MSA (83% sensitivity at 80% specificity, 100% sensitivity among patients with neurogenic orthostatic hypotension). Only PD patients were anosmic; only MSA patients had normal olfaction (61% sensitivity at 80% specificity). CONCLUSIONS: PD and MSA feature low PUT:OCC ratios of 6-[18F]fluorodopa-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical approaches but not distinguishing the diseases. PUT:SN and PUT:CAU ratios of 6-[18F]fluorodopa-derived radioactivity, cardiac 6-[18F]fluorodopamine-derived radioactivity, and olfactory testing separate PD from MSA.

Minimum lesion detectability as a measure of PET system performance.

BACKGROUND: A phantom in combination with an imaging protocol was developed to measure the limit of small lesion detection on different PET systems. Seven small spheres with inner diameters ranging from 3.95 up to 15.43 mm were imaged in a Jaszczak ECT Phantom, in air, in a cold background, and with sphere to background contrast ratios of 15:1 down to 1.88:1. The imaging times varied from 1 to 16 min. The imaging protocol was performed on the Gemini TF and Vereos by Philips, the mCT and HRRT by Siemens, and the Discovery 710 by General Electric. For each scanning condition, the images were reconstructed with image voxel sizes of 1 to 4 mm cubic voxels. The reconstruction method used for each system was the one recommended by the manufacture to achieve best small image lesion detection results. A human observer study was performed to determine the smallest observable sphere for each scanning condition. RESULTS: All systems were able to image the smallest sphere of 3.95 mm inner diameter at the 15 to 1 signal to background ratio when imaged for 16 min. For a typical whole body per bed position scan time of 2 to 4 min, the smallest imaged sphere varied between 4.95 and 6.23 mm at the 15:1 contrast ratio and 12.43 and 15.43 mm at a contrast ratio of 1.88:1. In general, all systems were consistent with the Rose criteria when determining lesion detectability. CONCLUSIONS: Besides demonstrating that the current state of the art clinical PET/CT systems have the same lesion detection ability, the study demonstrates how sensitive scan time can be to detecting small lesions which have a relatively small contrast uptake in the range of just 2:1. This should help guide imaging protocols to use longer scan times over regions of the subject in which small lesions are suspect.

Lymph Node Activation by PET/CT Following Vaccination With Licensed Vaccines for Human Papillomaviruses.

BACKGROUND: While PET using F-FDG is most commonly used for imaging malignant tumors, vaccination is known to cause transient inflammation of lymph nodes inducing positive findings on F-FDG PET scans. The pattern, magnitude, and duration of lymph node activation following vaccination have not been clearly defined. Furthermore, the addition of adjuvants to vaccines can further enhance the immune response. The presented study was designed to define lymph node activation following administration of the Food and Drug Administration-licensed human papillomavirus vaccines, Cervarix and Gardasil, which contain similar antigens with different adjuvants. METHODS: Twenty-seven women aged 18 to 25 years were randomized to receive either Cervarix or Gardasil in the clinical trial VRC 900. Fifteen subjects participated in the PET/CT portion of the trial and received scans of lymph node activation at prevaccination and "1 week" (8-14 days) and "1 month" (23-36 days) after the first or third vaccination. RESULTS: PET/CT scans revealed that all vaccine recipients had ipsilateral axillary lymph node activity. Three of 4 Cervarix recipients also showed contralateral lymph node activity 1 month after the first vaccination. For both Cervarix and Gardasil, the SUV activity resolved over time, with activity extended up to day 37 after the first and third vaccinations. CONCLUSIONS: Following intramuscular vaccination, there were no major differences between duration of uptake and intensity of SUV between Cervarix and Gardasil recipients in ipsilateral axillary lymph nodes. Contralateral node activation was detected up to 1 month after the first vaccination in Cervarix recipients only, possibly reflecting differences in vaccine adjuvant formulation.

Using cerebral white matter for estimation of nondisplaceable binding of 5-HT1A receptors in temporal lobe epilepsy.

UNLABELLED: The estimation of nondisplaceable binding from cerebellar white matter, rather than from whole cerebellum, was proposed for the PET tracer carbonyl-(11)C-WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridyl)cyclohexanecarboxamidel]) because of the heterogeneity of total ligand binding in this region. For the 5-hydroxytryptamine receptor 1A (5-HT(1A)) antagonist (18)F-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-2-pyridyl)trans-4-fluorocyclohexanecarboxamide ((18)F-FCWAY), the estimation of nondisplaceable binding from cerebellum (V(ND)) may be additionally biased by spillover of (18)F-fluoride activity from skull. We aimed to assess the effect of using cerebral white matter as reference region on detection of group differences in 5-HT(1A) binding with PET and (18)F-FCWAY. METHODS: In 22 temporal lobe epilepsy patients (TLE) and 10 healthy controls, (18)F-FCWAY distribution volume in cerebral white matter (V(WM)) was computed using an extrapolation method as part of a partial-volume correction (PVC) algorithm. To assess the feasibility of applying this method to clinical studies in which PVC is not performed, V(WM) was also calculated by placing circular, 6-mm-diameter regions of interest (ROIs) in the centrum semiovalis on parametric images. Binding potentials were BP(F) = (V(T) - V(ND))/f(P) and BP(F-WM) = (V(T) - V(WM))/f(P), where V(T) is total distribution volume and f(P) = (18)F-FCWAY plasma free fraction. Statistical analysis was performed using t tests and linear regression. RESULTS: In the whole group, V(WM) was 14% +/- 19% lower than V(ND) (P < 0.05). V(WM)/f(P) was significantly (P < 0.05) lower in patients than in controls. All significant (P < 0.05) reductions of 5-HT(1A) receptor availability in TLE patients detected by BP(F) were also detected using BP(F-WM). Significant (P < 0.05) reductions of 5-HT(1A) specific binding were detected by BP(F-WM), but not BP(F), in ipsilateral inferior temporal cortex, contralateral fusiform gyrus, and contralateral amygdala. However, effect sizes were similar for BP(F-WM) and BP(F). The value of V(WM) calculated with the ROI approach did not significantly (P > 0.05) differ from that calculated with the extrapolation approach (0.67 +/- 0.32 mL/mL and 0.72 +/- 0.34 mL/mL, respectively). CONCLUSION: Cerebral white matter can be used for the quantification of nondisplaceable binding of 5-HT(1A) without loss of statistical power for detection of regional group differences. The ROI approach is a good compromise between computational complexity and sensitivity to spillover of activity, and it appears suitable to studies in which PVC is not performed. For (18)F-FCWAY, this approach has the advantage of avoiding spillover of (18)F-fluoride activity onto the reference region.

Regional rates of cerebral protein synthesis measured with L-[1-11C]leucine and PET in conscious, young adult men: normal values, variability, and reproducibility.

We report regional rates of cerebral protein synthesis (rCPS) measured with the fully quantitative L-[1-(11)C]leucine positron emission tomography (PET) method. The method accounts for the fraction (lambda) of unlabeled amino acids in the precursor pool for protein synthesis derived from arterial plasma; the remainder (1-lambda) comes from tissue proteolysis. We determined rCPS and lambda in 18 regions and whole brain in 10 healthy men (21 to 24 years). Subjects underwent two 90-min dynamic PET studies with arterial blood sampling at least 2 weeks apart. Rates of cerebral protein synthesis varied regionally and ranged from 0.97+/-0.70 to 2.25+/-0.20 nmol/g per min. Values of rCPS were in good agreement between the two PET studies. Mean differences in rCPS between studies ranged from 9% in cortical regions to 15% in white matter. The lambda value was comparatively more uniform across regions, ranging from 0.63+/-0.03 to 0.79+/-0.02. Mean differences in lambda between studies were 2% to 8%. Intersubject variability in rCPS was on average 6% in cortical areas, 9% in subcortical regions, and 12% in white matter; intersubject variability in lambda was 2% to 8%. Our data indicate that in human subjects low variance and highly reproducible measures of rCPS can be made with the L-[1-(11)C]leucine PET method.