Reina W. Kloet

Microglia Activation in Recent-Onset Schizophrenia: A Quantitative (R)-[11C]PK11195 Positron Emission Tomography Study

BACKGROUND Schizophrenia is a brain disease involving progressive loss of gray matter of unknown cause. Most likely, this loss reflects neuronal damage, which should, in turn, be accompanied by microglia activation. Microglia activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography (PET). The purpose of this study was to investigate whether microglia activation occurs in patients with recent-onset schizophrenia. METHODS Ten patients with recent-onset schizophrenia and 10 age-matched healthy control subjects were included. A fully quantitative (R)-[(11)C]PK11195 PET scan was performed on all subjects, including arterial sampling to generate a metabolite-corrected input curve. RESULTS Compared with control subjects, binding potential of (R)-[(11)C]PK11195 in total gray matter was increased in patients with schizophrenia. There were no differences in other PET parameters. CONCLUSIONS Activated microglia are present in schizophrenia patients within the first 5 years of disease onset. This suggests that, in this period, neuronal injury is present and that neuronal damage may be involved in the loss of gray matter associated with this disease. Microglia may form a novel target for neuroprotective therapies in schizophrenia.

Performance evaluation of the ECAT HRRT : an LSO-LYSO double layer high resolution, high sensitivity scanner

The ECAT high resolution research tomograph (HRRT) is a dedicated brain and small animal PET scanner, with design features that enable high image spatial resolution combined with high sensitivity. The HRRT is the first commercially available scanner that utilizes a double layer of LSO/LYSO crystals to achieve photon detection with depth-of-interaction information. In this study, the performance of the commercial LSO/LYSO HRRT was characterized, using the NEMA protocol as a guideline. Besides measurement of spatial resolution, energy resolution, sensitivity, scatter fraction, count rate performance, correction for attenuation and scatter, hot spot recovery and image quality, a clinical evaluation was performed by means of a HR+/HRRT human brain comparison study. Point source resolution varied across the field of view from approximately 2.3 to 3.2 mm (FWHM) in the transaxial direction and from 2.5 to 3.4 mm in the axial direction. Absolute line-source sensitivity ranged from 2.5 to 3.3% and the NEMA-2001 scatter fraction equalled 45%. Maximum NECR was 45 kcps and 148 kcps according to the NEMA-2001 and 1994 protocols, respectively. Attenuation and scatter correction led to a volume uniformity of 6.3% and a system uniformity of 3.1%. Reconstructed values deviated up to 15 and 8% in regions with high and low densities, respectively, which can possibly be assigned to inaccuracies in scatter estimation. Hot spot recovery ranged from 60 to 94% for spheres with diameters of 1 to 2.2 cm. A high quantitative agreement was met between HR+ and HRRT clinical data. In conclusion, the ECAT HRRT has excellent resolution and sensitivity properties, which is a crucial advantage in many research studies.

Microglial activation in healthy aging.

Healthy brain aging is characterized by neuronal loss and decline of cognitive function. Neuronal loss is closely associated with microglial activation and postmortem studies have indeed suggested that activated microglia may be present in the aging brain. Microglial activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography. The purpose of this study was to measure specific binding of (R)-[(11)C]PK11195 in healthy subjects over a wide age range. Thirty-five healthy subjects (age range 19-79 years) were included. In all subjects 60-minute dynamic (R)-[(11)C]PK11195 scans were acquired. Specific binding of (R)-[(11)C]PK11195 was calculated using receptor parametric mapping in combination with supervised cluster analysis to extract the reference tissue input function. Increased binding of (R)-[(11)C]PK11195 with aging was found in frontal lobe, anterior and posterior cingulate cortex, medial inferior temporal lobe, insula, hippocampus, entorhinal cortex, thalamus, parietal and occipital lobes, and cerebellum. This indicates that activated microglia appear in several cortical and subcortical areas during healthy aging, suggesting widespread neuronal loss.

Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement

Alzheimers disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimers disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimers disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound-B binding and decreased [(18)F]fluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal [(11)C]Pittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized β: 0.55), attention (standardized β: 0.39) and executive functioning (standardized β: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized β: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimers disease are not restricted to topographical differentiation in downstream processes but may originate from distinctive distributions of early upstream events. As such, increased amyloid burden, together with metabolic dysfunction, in the parietal lobe of younger patients with Alzheimers disease may contribute to the distinct cognitive profile in these patients.

Macrophage positron emission tomography imaging as a biomarker for preclinical rheumatoid arthritis: Findings of a prospective pilot study

OBJECTIVE To conduct a prospective pilot study to determine whether macrophage targeting by 11C-(R)-PK11195 positron emission tomography (PET) can visualize subclinical synovitis in arthralgia patients who have anti-citrullinated protein antibodies (ACPAs). METHODS Twenty-nine arthralgia patients who were positive for ACPAs but did not have clinical arthritis were studied. High (spatial)-resolution 11C-(R)-PK11195 PET scans of the hands and wrists were performed. For all metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient), tracer uptake was scored semiquantitatively (0-3 scale) by 2 observers who were blinded with regard to the clinical data. Patients were followed up prospectively for 24 months to investigate the development of clinical arthritis. RESULTS Overall agreement and kappa values for the readings of the 2 observers were, respectively, 97% and 0.91 (95% confidence interval [95% CI] 0.74-1) at the patient level and 99% and 0.81 (95% CI 0.65-0.96) at the joint level. In 4 patients, at least 1 and as many as 5 PET-positive joints (score≥1) were found at baseline. Within 2 years of followup, 9 patients had developed clinical arthritis. This included all 4 patients with positive findings on the 11C-(R)-PK11195 scan, who developed clinical arthritis in the hand/wrist region, as identified on PET scans. Of the 5 remaining arthritis patients with negative findings on PET scans, 2 developed arthritis in the hand joints and 3 developed arthritis at locations outside the field of view of the PET scanner. CONCLUSION Subclinical arthritis in ACPA-positive arthralgia patients could be visualized by 11C-(R)-PK11195 PET scanning and was associated with development of arthritis within 2 years of followup. This indicates that 11C-(R)-PK11195 PET may be useful in determining arthritis activity in the preclinical phase of RA.

HRRT Versus HR+ Human Brain PET Studies: An Interscanner Test–Retest Study

The high-resolution research tomograph (HRRT) is a dedicated human brain PET scanner. The purpose of this study was to compare the quantitative accuracy of the HRRT with that of the clinical HR+ PET scanner and to assess effects of differences in spatial resolution between both scanners (∼2.7 mm and ∼7.0 mm for HRRT and HR+, respectively). Methods: Paired 11C-flumazenil scans of 7 healthy volunteers were assessed. For each volunteer, dynamic scans (including arterial sampling) were acquired on both scanners on the same day, thereby minimizing intersubject variability. Volume of distribution was generated using Logan plot analysis with plasma input. In addition, other plasma input, reference tissue (with pons as the reference tissue input), and parametric methods were included in the interscanner comparison. Results: Logan volume-of-distribution analysis of HRRT data showed higher values than that of HR+ data (slope with the intercept fixed at the origin of 1.14 ± 0.10 to 1.19 ± 0.10, depending on the HRRT reconstruction method used). Smoothing HRRT reconstructions with a 6-mm full width at half maximum gaussian kernel reduced this slope toward the line of identity (1.04 ± 0.11 to 1.07 ± 0.11), retaining good correlation between HR+ and HRRT data (r, ∼0.98). Similar trends were observed for other plasma input, reference tissue, and parametric methods. However, after reference matching the reference tissue models showed lower HRRT kinetic parameter values than HR+ values (slope with fixed intercept, 0.90 ± 0.10 to 0.94 ± 0.13). Conclusion: Higher values of pharmacokinetic parameter values, obtained from HRRT versus HR+ PET studies, indicate improved HRRT PET quantification primarily due to a reduction in partial-volume effects.

Evaluation of reference regions for (R)-[11C]PK11195 studies in Alzheimer's disease and Mild Cognitive impairment

Inflammation in Alzheimers disease (AD) may be assessed using (R)-[11C]PK11195 and positron emission tomography. Data can be analyzed using the simplified reference tissue model, provided a suitable reference region is available. This study evaluates various reference regions for analyzing (R)-[11C]PK11195 scans in patients with mild cognitive impairment (MCI) and probable AD. Healthy subjects (n = 10, 30 ± 10 years and n = 10, 70 ± 6 years) and patients with MCI (n = 10, 74 ± 6 years) and probable AD (n = 9, 71 ± 6 years) were included. Subjects underwent a dynamic three-dimensional (R)-[11C]PK11195 scan including arterial sampling. Gray matter, white matter, total cerebellum and cerebrum, and cluster analysis were evaluated as reference regions. Both plasma input binding potentials of these reference regions (BPPLASMA) and corresponding reference region input binding potentials of a target region (BPSRTM) were evaluated. Simulations were performed to assess cluster analysis performance at 5% to 15% coefficient of variation noise levels. Reasonable correlations for BPPLASMA (R2 = 0.52 to 0.94) and BPSRTM (R2 = 0.59 to 0.76) were observed between results using anatomic regions and cluster analysis. For cerebellum white matter, cerebrum white matter, and total cerebrum a considerable number of unrealistic BPSRTM values were observed. Cluster analysis did not extract a valid reference region in 10% of the scans. Simulations showed that potentially cluster analysis suffers from negative bias in BPPLASMA. Most anatomic regions outperformed cluster analysis in terms of absence of both scan rejection and bias. Total cerebellum is the optimal reference region in this patient category.

Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury

Our objective was to measure (R)-11C-PK11195 binding as an indirect marker of neuronal damage after traumatic brain injury (TBI). Methods: Dynamic (R)-11C-PK11195 PET scans were acquired for 8 patients 6 mo after TBI and for 7 age-matched healthy controls. (R)-11C-PK11195 binding was assessed using the simplified reference tissue model. Because of widespread traumatic changes in TBI, an anatomic reference region could not be defined. Therefore, supervised cluster analysis was used to generate an appropriate reference tissue input. Results: Increased whole-brain binding of (R)-11C-PK11195 was observed in TBI patients. Regional analysis indicated that increased (R)-11C-PK11195 binding was widespread over the brain. Conclusion: Six months after TBI, there was a prolonged and widespread increase in (R)-11C-PK11195 binding, which is indicative of diffuse neuronal damage.

Measuring response to therapy using FDG PET: semi-quantitative and full kinetic analysis

PurposeImaging with positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) plays an increasingly important role for response assessment in oncology. Several methods for quantifying FDG PET results exist. The goal of this study was to analyse and compare various semi-quantitative measures for response assessment with full kinetic analysis, specifically in assessment of novel therapies.MethodsBaseline and response dynamic FDG studies from two different longitudinal studies (study A: seven subjects with lung cancer and study B: six subjects with gastrointestinal cancer) with targeted therapies were reviewed. Quantification of tumour uptake included full kinetic methods, i.e. nonlinear regression (NLR) and Patlak analyses, and simplified measures such as the simplified kinetic method (SKM) and standardized uptake value (SUV). An image-derived input function was used for NLR and Patlak analysis.ResultsThere were 18 and 9 lesions defined for two response monitoring studies (A and B). In all cases there was excellent correlation between Patlak- and NLR-derived response (R2 > 0.96). Percentage changes seen with SUV were significantly different from those seen with Patlak for both studies (p < 0.05). After correcting SUV for plasma glucose, SUV and Patlak responses became similar for study A, but large differences remained for study B. Further analysis revealed that differences in responses amongst methods in study B were primarily due to changes in the arterial input functions.ConclusionUse of simplified methods for assessment of drug efficacy or treatment response may provide different results than those seen with full kinetic analysis.

Day-to-Day Test–Retest Variability of CBF, CMRO2, and OEF Measurements Using Dynamic 15O PET Studies

PurposeWe assessed test–retest variability of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) measurements derived from dynamic 15O positron emission tomography (PET) scans.ProceduresIn seven healthy volunteers, complete test–retest 15O PET studies were obtained; test–retest variability and left-to-right ratios of CBF, CBV, OEF, and CMRO2 in arterial flow territories were calculated.ResultsWhole-brain test–retest coefficients of variation for CBF, CBV, CMRO2, and OEF were 8.8%, 13.8%, 5.3%, and 9.3%, respectively. Test–retest variability of CBV left-to-right ratios was <7.4% across all territories. Corresponding values for CBF, CMRO2, and OEF were better, i.e., <4.5%, <4.0%, and <1.4%, respectively.ConclusionsThe test–retest variability of CMRO2 measurements derived from dynamic 15O PET scans is comparable to within-session test–retest variability derived from steady-state 15O PET scans. Excellent regional test–retest variability was observed for CBF, CMRO2, and OEF. Variability of absolute CBF and OEF measurements is probably affected by physiological day-to-day variability of CBF.