Domènec Ros

Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study

BACKGROUND Serial dopamine transporter (DAT) imaging in patients with Parkinsons disease (PD) and other synucleinopathies shows progressive nigrostriatal dopaminergic dysfunction. Because idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can precede the classic symptoms of PD and other synucleinopathies, we postulated that serial DAT imaging in patients with IRBD could be used to detect decline in striatal tracer uptake, indicating progressive nigrostriatal cell degeneration. METHODS In a prospective study, 20 patients with IRBD (mean age 70·55 years [SD 6·02]) underwent serial DAT imaging with (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT at baseline and again after 1·5 years and 3 years; 20 age-matched and sex-matched control participants (69·50 years [6·77]) underwent imaging at baseline and 3 years. The striatum to occipital cortex uptake ratios were calculated for the putamen and caudate nucleus in each hemisphere. In patients, the ratio was judged to be reduced when it was less than two SD of the mean ratio in controls at the same timepoint. Differences in (123)I-FP-CIT uptake between patients and controls in each striatal region and rates of decline were assessed by use of multivariate ANOVA (MANOVA). FINDINGS Compared with controls, patients had significantly reduced mean (123)I-FP-CIT binding in all four striatal regions at baseline and after 3 years. Striatal (123)I-FP-CIT uptake was reduced compared with that in controls in ten patients at baseline and in 13 patients after 3 years. In patients, the mean reduction in (123)I-FP-CIT uptake from baseline to 3 years was 19·36% (95% CI 15·14 to 23·59) in the left putamen, 15·57% (10·87 to 20·28) in the right putamen, 10·81% (6·49 to 15·18) in the left caudate nucleus, and 7·14% (2·74 to 11·56) in the right caudate nucleus. After adjustment for the baseline (123)I-FP-CIT uptake ratios, the decline in (123)I-FP-CIT binding at baseline to 3 years was significantly greater in patients than in controls in the left putamen (9·78% difference between groups, 95% CI 3·22 to 16·32), right putamen (5·43%, 1·99 to 12·86), and left caudate nucleus (8·07%, 1·44 to 14·70), but not in the right caudate nucleus (4·16%, -3·00 to 11·34). At the 3-year assessment, three patients were diagnosed with PD. These patients had the lowest (123)I-FP-CIT uptake at baseline and a mean reduction in (123)I-FP-CIT uptake at 3 years of 32·81% in the left putamen, 30·40% in the right putamen, 26·51% in the left caudate nucleus, and 23·75% in the right caudate nucleus. INTERPRETATION In patients with IRBD, serial (123)I-FP-CIT SPECT shows decline in striatal tracer uptake that reflects progressive nigrostriatal dopaminergic dysfunction. Serial (123)I-FP-CIT SPECT can be used to monitor the progression of nigrostriatal deficits in patients with IRBD, and could be useful in studies of potential disease-modifying compounds in these patients. FUNDING Fondo de Investigaciones Sanitarias of Spain.

Geometrical and Monte Carlo projectors in 3D PET reconstruction

PURPOSE In the present work, the authors compare geometrical and Monte Carlo projectors in detail. The geometrical projectors considered were the conventional geometrical Siddon ray-tracer (S-RT) and the orthogonal distance-based ray-tracer (OD-RT), based on computing the orthogonal distance from the center of image voxel to the line-of-response. A comparison of these geometrical projectors was performed using different point spread function (PSF) models. The Monte Carlo-based method under consideration involves an extensive model of the system response matrix based on Monte Carlo simulations and is computed off-line and stored on disk. METHODS Comparisons were performed using simulated and experimental data of the commercial small animal PET scanner rPET. RESULTS The results demonstrate that the orthogonal distance-based ray-tracer and Siddon ray-tracer using PSF image-space convolutions yield better images in terms of contrast and spatial resolution than those obtained after using the conventional method and the multiray-based S-RT. Furthermore, the Monte Carlo-based method yields slight improvements in terms of contrast and spatial resolution with respect to these geometrical projectors. CONCLUSIONS The orthogonal distance-based ray-tracer and Siddon ray-tracer using PSF image-space convolutions represent satisfactory alternatives to factorizing the system matrix or to the conventional on-the-fly ray-tracing methods for list-mode reconstruction, where an extensive modeling based on Monte Carlo simulations is unfeasible.

Quantification of dopaminergic neurotransmission SPECT studies with 123I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation

Purpose123I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation.MethodsThe SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed.ResultsFor both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV.ConclusionOur findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies.

Fluordeoxyglucose-PET study in first-episode schizophrenic patients during the hallucinatory state, after remission and during linguistic-auditory activation.

ObjectivesWe tested the hypothesis that endogenous auditory verbal hallucinations (AVH) involve activation of auditory/linguistic association cortices that are usually activated by externally presented speech. MethodsNine neuroleptic-naive patients with first-episode schizophrenia (Diagnostic and Statistical Manual for Mental Disorders-IV criteria) with prominent AVH underwent three PET scans using 18F-fluordeoxyglucose (FDG): (i) shortly after presentation, while experiencing prominent and frequent AVH; (ii) after medication-induced remission (R), using a stable dose of risperidone; (iii) also in remission, during bilateral linguistic auditory activation (LAA) induced by spoken text mimicking the content of the hallucinations experienced while the first PET was performed, using headphones. PET scans were acquired using an Advanced-Nxi Scanner (GE Healthcare). Intrasubject realignment, spatial normalization and statistical analysis of PET images were carried out using statistical parametric mapping. Differences between AVH and R and between LAA and R were statistically evaluated using a voxel-wise paired t-test. A voxel level threshold of P<0.01 was used to determine which regions underwent the most significant changes in 18F-FDG uptake. ResultsDuring AVH, patients demonstrated a significant activation of the supplementary motor area, anterior cingulum, medial superior frontal area and cerebelum. Activation was also observed in the left superior frontal area, right superior temporal pole and right orbitofrontal region. During LAA, greater FDG uptake was observed in the right and left superior and middle temporal cortices, left hippocampus and parahippocampal regions. ConclusionOur findings show a different pattern of regional cerebral glucose metabolism between AVH and physiological auditory activation. This feature does not support the hypothesis that AVH in acute schizophrenic patients reflects an abnormal activation of auditory–linguistic pathways. However, it does suggest that cortical regions implicated in the generation of inner speech could be involved.

Iterative reconstruction with correction of the spatially variant fan-beam collimator response in neurotransmission SPET imaging

The dopamine transporter (DAT) has been shown to be a sensitive indicator of nigrostriatal dopamine function. Although visual inspection is often sufficient to assess DAT imaging, quantification could improve the diagnostic accuracy of single-photon emission tomography (SPET) studies of the dopaminergic system. The aim of this study was to assess the accuracy of quantification of the striatal/background uptake ratio when correction for attenuation, scatter and spatially variant fan-beam collimator response is performed in technetium-99m and iodine-123 SPET imaging. A numerical striatal phantom was implemented, and simulated projections of low-energy photons were obtained by using the SimSET Monte Carlo code. High-energy contamination in 123I studies was modelled from experimental measurements with 99mTc and 123I. The ordered subsets expectation maximisation (OSEM) algorithm was employed in reconstruction. Mean improvements of 8% and 16% were obtained in the calculated striatal/background uptake ratio in the putamen and the caudate, respectively, when the spatially variant point spread function was included in the transition matrix. Ideal scatter correction resulted in improvements in the putamen and caudate of 9% for 99mTc agents and 19% for 123I agents. Improvements averaged 31% in the putamen and 43% in the caudate when correction for attenuation, scatter and spatially variant collimator response was included in the reconstruction.

The influence of a relaxation parameter on SPECT iterative reconstruction algorithms

Algebraic reconstruction techniques (ARTs) have been intensively studied in image reconstruction. However, reconstructed images often exhibit a characteristic noise when applied to emission tomography. In this work, we study the influence of the ART relaxation parameter and identify values of that parameter which yield smooth images and good convergence. The study includes both simulated and real single photon emission computed tomographic (SPECT) data. In the simulated studies, scattering, attenuation, noise and detector response were included. Relaxation factors ranging between 0.01 and 0.35 were considered. Total counts in projections were between 2.5 x 10(5) and 10(6) in one slice. The goodness of the reconstructions was assessed by using the correlation coefficient between the pattern and the actual reconstruction (CC), the background coefficient of variation (CV), the contrast (CON) and the signal-to-noise ratio (SNR). The results show that values for the relaxation factor and number of interations close to 0.1 and 8, respectively, yield reconstructed images in which CC, CV, CON and SNR have well balanced values and CC, CV and SNR are very close to the extremal. An increase in either the number of iterations or in the relaxation factor results in a rise of CON but the other three FOMs deteriorate. The results from the real phantom, which are in agreement with those of the simulated studies, validate the simulation method and demonstrate the influence of the relaxation parameter.

APOE -by-sex interactions on brain structure and metabolism in healthy elderly controls

Background The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE-by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC). Methods Cross-sectional study. HC from the Alzheimer’s Disease Neuroimaging Initiative with available CSF (n = 274) and/or 3T-MRI (n = 168) and/or a FDG-PET analyses (n = 328) were selected. CSF amyloid-β1–42 (Aβ1–42), total-tau (t-tau) and phospho-tau (p-tau181p) levels were measured by Luminex assays. We analyzed the APOE-by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses. Results APOE4 carriers had lower CSF Aβ1–42 and higher CSF p-tau181p values than non-carriers, but there was no APOE-by-sex interaction on CSF biomarkers. The APOE-by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers. Conclusions The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE-by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion.

Differential brain glucose metabolic patterns in antipsychotic-naïve first-episode schizophrenia with and without auditory verbal hallucinations.

BACKGROUND Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication. METHODS The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [(18)F]fluoro-deoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences. RESULTS We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error-corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal-parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < -3.3). LIMITATIONS The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings. CONCLUSION Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.

Development of a variable-radius pinhole SPECT system with a portable gamma camera.

OBJECTIVE To develop a small-animal SPECT system using a low cost commercial portable gamma camera equipped with a pinhole collimator, a continuous scintillation crystal and a position-sensitive photomultiplier tube. MATERIAL AND METHODS The gamma camera was attached to a variable radius system, which enabled us to optimize sensitivity and resolution by adjusting the radius of rotation to the size of the object. To investigate the capability of the SPECT system for small animal imaging, the dependence of resolution and calibration parameters on radius was assessed and acquisitions of small phantoms and mice were carried out. RESULTS Resolution values, ranging from 1.0mm for a radius of 21.4mm and 1.4mm for a radius of 37.2mm were obtained, thereby justifying the interest of a variable radius SPECT system. CONCLUSIONS The image quality of phantoms and animals were satisfactory, thus confirming the usefulness of the system for small animal SPECT imaging.

Assessment of SPM in Perfusion Brain SPECT Studies. A Numerical Simulation Study Using Bootstrap Resampling Methods

Statistical parametric mapping (SPM) has become the technique of choice to statistically evaluate positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT) functional brain studies. Nevertheless, only a few methodological studies have been carried out to assess the performance of SPM in SPECT. The aim of this paper was to study the performance of SPM in detecting changes in regional cerebral blood flow (rCBF) in hypo- and hyperperfused areas in brain SPECT studies. The paper seeks to determine the relationship between the group size and the rCBF changes, and the influence of the correction for degradations. The assessment was carried out using simulated brain SPECT studies. Projections were obtained with Monte Carlo techniques, and a fan-beam collimator was considered in the simulation process. Reconstruction was performed by using the ordered subsets expectation maximization (OSEM) algorithm with and without compensation for attenuation, scattering, and spatial variant collimator response. Significance probability maps were obtained with SPM2 by using a one-tailed two-sample f-test. A bootstrap resampling approach was used to determine the sample size for SPM to detect the between-group differences. Our findings show that the correction for degradations results in a diminution of the sample size, which is more significant for small regions and low-activation factors. Differences in sample size were found between hypo- and hyperperfusion. These differences were larger for small regions and low-activation factors, and when no corrections were included in the reconstruction algorithm.