Association between retinal thickness and ß-amyloid brain accumulation in individuals with subjective cognitive decline: Fundació ACE Healthy Brain Initiative.

BACKGROUND: Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-ß (Aß) uptake. AIMS: We investigated the association of retinal thickness quantified by OCT with Aß accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD. METHODS: One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/-) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2. RESULTS: Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 µm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02-1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02-1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: ß = 0.23, p = 0.004; at v2: ß = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months. CONCLUSIONS: Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aß uptake.

Left-hemispheric predominance of nigrostriatal deficit in isolated REM sleep behavior disorder.

OBJECTIVE: Unilateral onset of parkinsonism due to nigrostriatal damage of the contralateral hemisphere is frequent in Parkinson disease (PD). There is evidence for a left-hemispheric bias of motor asymmetry in right-handed patients with PD indicating a hemispheric dominance. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of PD and other synucleinopathies. To test the hypothesis that right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction, we evaluated this aspect using neuroimaging instruments. METHODS: In 167 right-handed patients with IRBD without parkinsonism, we evaluated in each hemisphere the integrity of the striatal dopaminergic terminals by dopamine transporter (DAT)-SPECT and the substantia nigra echogenicity by transcranial sonography. RESULTS: DAT-SPECT showed lower specific binding ratio (SBR) in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. The percentage of patients with lower SBR was greater in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. In those who developed a synucleinopathy in <5 years from DAT-SPECT, there was a lower SBR in the left putamen and left caudate nucleus than in the right putamen and right caudate nucleus. Substantia nigra echogenic size was greater in the left than in the right side in patients with hyperechogenicity and among individuals who phenoconverted in <5 years from transcranial sonography. CONCLUSION: Right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction. In premotor PD, the neurodegenerative process begins asymmetrically, initially impairing the nigrostriatal system of the dominant hemisphere.

Regional patterns of 18F-florbetaben uptake in presenilin 1 mutation carriers.

Individuals with autosomal dominant Alzheimer's disease (ADAD) present amyloid deposits before symptoms onset. We aimed to investigate efficacy and safety of 18F-florbetaben (FBB) for assessing amyloid deposition in ADAD. We acquired FBB positron emission tomography and magnetic resonance imaging of 25 individuals from PSEN1 families (NCT02362880). We studied individual uptake patterns, group differences, and correlation with estimated years to symptoms onset, as well as adverse events. We found that asymptomatic carriers (N = 14) showed increased FBB uptake across the cerebral cortex and in the caudate. FBB accumulation appeared more than 15 years before onset in the precuneus and bankssts, among other regions, overlapping regions showing increased cortical thickness in the same subjects. FBB uptake correlated with estimated years to symptoms onset in several areas, especially the rostral anterior cingulate. Symptomatic carriers (N = 7) had an elevated FBB uptake plateau. No adverse events were reported. Overall, we found progressive FBB uptake in ADAD starting 2 decades before symptoms. The rostral anterior cingulate is a candidate area to track Aß deposition in addition to the precuneus.

Epileptogenic Zone Localization With 18FDG PET Using a New Dynamic Parametric Analysis.

Introduction: [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is part of the regular preoperative work-up in medically refractory epilepsy. As a complement to visual evaluation of PET, statistical parametric maps can help in the detection of the epileptogenic zone (EZ). However, software packages currently available are time-consuming and little intuitive for physicians. We develop a user-friendly software (referred as PET-analysis) for EZ localization in PET studies that allows dynamic real-time statistical parametric analysis. To evaluate its performance, the outcome of PET-analysis was compared with the results obtained by visual assessment and Statistical Parametric Mapping (SPM). Methods: Thirty patients with medically refractory epilepsy who underwent presurgical 18F-FDG PET with good post-operative outcomes were included. The 18F-FDG PET studies were evaluated by visual assessment, with SPM8 and PET-analysis. In SPM, parametric T-maps were thresholded at corrected p < 0.05 and cluster size k = 50 and at uncorrected p < 0.001 and k = 100 (the most used parameters in the literature). Since PET-analysis rapidly processes different threshold combinations, T-maps were thresholded with multiple p-value and different clusters sizes. The presurgical EZ identified by visual assessment, SPM and PET-analysis was compared to the confirmed EZ according to post-surgical follow-up. Results: PET-analysis obtained 66.7% (20/30) of correctly localizing studies, comparable to the 70.0% (21/30) achieved by visual assessment and significantly higher (p < 0.05) than that obtained with the SPM threshold p < 0.001/k = 100, of 36.7% (11/30). Only one study was positive, albeit non-localizing, with the SPM threshold corrected p < 0.05/k = 50. Concordance was substantial for PET-analysis (κ = 0.643) and visual interpretation (κ = 0.622), being fair for SPM (κ = 0.242). Conclusion: Compared to SPM with the fixed standard parameters, PET-analysis may be superior in EZ localization with its easy and rapid processing of different threshold combinations. The results of this initial proof-of-concept study validate the clinical use of PET-analysis as a robust objective complementary tool to visual assessment for EZ localization.

Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers.

BACKGROUND: The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts. METHODS: A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([18F]flutemetamol and [18F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aß42, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded. RESULTS: All Centiloid cut-offs fell within the range of 25-35, except for CSF Aß42 that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aß42 ratios was higher than that of CSF Aß42. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs. CONCLUSIONS: A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels. TRIAL REGISTRATION: ALFA+ Study, NCT02485730 ALFA PET Sub-study, NCT02685969.

PISCOM: a new procedure for epilepsy combining ictal SPECT and interictal PET.

PURPOSE: We present a modified version of the SISCOM procedure that uses interictal PET instead of interictal SPECT for seizure onset zone localization. We called this new nuclear imaging processing technique PISCOM (PET interictal subtracted ictal SPECT coregistered with MRI). METHODS: We retrospectively studied 23 patients (age range 4-61 years) with medically refractory epilepsy who had undergone MRI, ictal SPECT, interictal SPECT and interictal FDG PET and who had been seizure-free for at least 2 years after surgical treatment. FDG PET images were reprocessed (rFDG PET) to assimilate SPECT features for image subtraction. Interictal SPECT and rFDG PET were compared using statistical parametric mapping (SPM). PISCOM and SISCOM images were evaluated visually and using an automated volume of interest-based analysis. The results of the two studies were compared with each other and with the known surgical resection site. RESULTS: SPM showed no significant differences in cortical activity between SPECT and rFDG PET images. PISCOM and SISCOM showed equivalent results in 17 of 23 patients (74%). The seizure onset zone was successfully identified in 19 patients (83%) by PISCOM and in 17 (74%) by SISCOM: in 15 patients (65%) the two techniques showed concordant successful results. The volume of interest-based analysis showed no significant differences between PISCOM and SISCOM in identifying the extension of the seizure onset zone. However, PISCOM showed a lower amount of indeterminate activity due to propagation, background or artefacts. CONCLUSION: Preliminary findings of this initial proof-of-concept study suggest that perfusion and glucose metabolism in the cerebral cortex can be correlated and that PISCOM may be a valid technique for identification of the seizure onset zone. However, further studies are needed to validate these results.

Optimization of the reconstruction parameters in [123I]FP-CIT SPECT.

The aim of this work was to obtain a set of parameters to be applied in [123I]FP-CIT SPECT reconstruction in order to minimize the error between standardized and true values of the specific uptake ratio (SUR) in dopaminergic neurotransmission SPECT studies. To this end, Monte Carlo simulation was used to generate a database of 1380 projection data-sets from 23 subjects, including normal cases and a variety of pathologies. Studies were reconstructed using filtered back projection (FBP) with attenuation correction and ordered subset expectation maximization (OSEM) with correction for different degradations (attenuation, scatter and PSF). Reconstruction parameters to be optimized were the cut-off frequency of a 2D Butterworth pre-filter in FBP, and the number of iterations and the full width at Half maximum of a 3D Gaussian post-filter in OSEM. Reconstructed images were quantified using regions of interest (ROIs) derived from Magnetic Resonance scans and from the Automated Anatomical Labeling map. Results were standardized by applying a simple linear regression line obtained from the entire patient dataset. Our findings show that we can obtain a set of optimal parameters for each reconstruction strategy. The accuracy of the standardized SUR increases when the reconstruction method includes more corrections. The use of generic ROIs instead of subject-specific ROIs adds significant inaccuracies. Thus, after reconstruction with OSEM and correction for all degradations, subject-specific ROIs led to errors between standardized and true SUR values in the range [-0.5, +0.5] in 87% and 92% of the cases for caudate and putamen, respectively. These percentages dropped to 75% and 88% when the generic ROIs were used.

Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder.

OBJECTIVE: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short-term development of clinically defined synucleinopathy. METHODS: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123 I-FP-CIT DAT-SPECT. Results were compared to 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed up during 5.7 ± 2.2 (range, 2.6-9.9) years. RESULTS: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up, 25 (28.7%) subjects developed clinically defined synucleinopathy (Parkinson's disease in 11, dementia with Lewy bodies in 13, and multiple system atrophy in 1) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs 6% at 3 years, 33% vs 18% at 5 years; log rank test, p = 0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease free after 3 years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and likelihood ratio 1.54 to predict synucleinopathy. INTERPRETATION: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after 3 years' follow-up. These observations may be useful to select candidates for disease modification trials in IRBD. Ann Neurol 2017;82:419-428.

Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-ß and Tau in Parkinson's Disease1.

Tau and amyloid-ß (Aß) aggregates have been suggested to play a role in the development of dementia in Parkinson's disease (PD). Positron emission tomography (PET) with [18F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aß and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aß with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18F]FDDNP PET, and CSF Aß-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18F]FDDNP binding in lateral temporal regions and lower levels of CSF Aß levels compared to PDND, with a congruent correlation between the [18F]FDDNP binding and CSF Aß levels. Longitudinally, higher baseline lateral temporal [18F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aß and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time.

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-ß1-42 (Aß1-42), 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 Aß1-42 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.

Improved image quality in pinhole SPECT by accurate modeling of the point spread function in low magnification systems.

PURPOSE: Single photon emission computed tomography (SPECT) has become an important noninvasive imaging technique in small-animal research. Due to the high resolution required in small-animal SPECT systems, the spatially variant system response needs to be included in the reconstruction algorithm. Accurate modeling of the system response should result in a major improvement in the quality of reconstructed images. The aim of this study was to quantitatively assess the impact that an accurate modeling of spatially variant collimator/detector response has on image-quality parameters, using a low magnification SPECT system equipped with a pinhole collimator and a small gamma camera. METHODS: Three methods were used to model the point spread function (PSF). For the first, only the geometrical pinhole aperture was included in the PSF. For the second, the septal penetration through the pinhole collimator was added. In the third method, the measured intrinsic detector response was incorporated. Tomographic spatial resolution was evaluated and contrast, recovery coefficients, contrast-to-noise ratio, and noise were quantified using a custom-built NEMA NU 4-2008 image-quality phantom. RESULTS: A high correlation was found between the experimental data corresponding to intrinsic detector response and the fitted values obtained by means of an asymmetric Gaussian distribution. For all PSF models, resolution improved as the distance from the point source to the center of the field of view increased and when the acquisition radius diminished. An improvement of resolution was observed after a minimum of five iterations when the PSF modeling included more corrections. Contrast, recovery coefficients, and contrast-to-noise ratio were better for the same level of noise in the image when more accurate models were included. Ring-type artifacts were observed when the number of iterations exceeded 12. CONCLUSIONS: Accurate modeling of the PSF improves resolution, contrast, and recovery coefficients in the reconstructed images. To avoid the appearance of ring-type artifacts, the number of iterations should be limited. In low magnification systems, the intrinsic detector PSF plays a major role in improvement of the image-quality parameters.

Dopamine transporter imaging in the aged rat: a [¹²³I]FP-CIT SPECT study.

INTRODUCTION: Rodent models are extensively used to assess the biochemical and physiological changes associated with aging. They play a major role in the development of therapies for age-related pathologies such as Parkinson's disease. To validate the usefulness of these animal models in aging or age-related disease research, the consistency of cerebral aging processes across species must be evaluated. The dopaminergic system seems particularly susceptible to the aging process. One of the results of this susceptibility is a decline in striatal dopamine transporter (DAT) availability. METHODS: We sought to ascertain whether similar age changes could be detected in-vivo in rats, using molecular imaging techniques such as single photon emission computed tomography (SPECT) with [(123)I]FP-CIT. RESULTS: A significant decrease of 17.21% in the striatal specific uptake ratio was observed in the aged rats with respect to the young control group. CONCLUSIONS: Our findings suggest that age-related degeneration in the nigrostriatal track is similar in humans and rats, which supports the use of this animal in models to evaluate the effect of aging on the dopaminergic system. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our findings indicate that age-related degeneration in the nigrostriatal track is similar in humans and rats and that these changes can be monitored in vivo using small animal SPECT with [(123)I]FP-CIT, which could facilitate the translational research in rat models of age related disorders of dopaminergic system.

In vivo evaluation of the dopaminergic neurotransmission system using [123I]FP-CIT SPECT in 6-OHDA lesioned rats.

The 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease (PD) has been used to evaluate the nigrostriatal pathway. The aim of this work was to explore the relationship between the degree of 6-OHDA-induced dopaminergic degeneration and [(123)I]FP-CIT binding using single photon emission computed tomography (SPECT). Fourteen rats received a 6-OHDA injection (4 or 8 µg) into the left medial forebrain bundle. After 3 weeks, magnetic resonance imaging and scans with a small-animal SPECT system were performed. Finally, the nigrostriatal lesion was assessed by immunohistochemical analysis. Immunohistochemical analysis confirmed two levels of dopaminergic degeneration. Lesions induced by 6-OHDA diminished the ipsilateral [(123)I]FP-CIT binding by 61 and 76%, respectively. The decrease in tracer uptake between control and lesioned animals was statistically significant, as was the difference between the two 6-OHDA lesioned groups. Results concluded that [(123)I]FP-CIT SPECT is a useful technique to discriminate the degree of dopaminergic degeneration in a rat model of PD.

Infarct volume prediction using apparent diffusion coefficient maps during middle cerebral artery occlusion and soon after reperfusion in the rat.

Middle cerebral artery occlusion (MCAO) in rodents causes brain infarctions of variable sizes that depend on multiple factors, particularly in models of ischemia/reperfusion. This is a major problem for infarct volume comparisons between different experimental groups since unavoidable variability can induce biases in the results and imposes the use of large number of subjects. MRI can help to minimize these difficulties by ensuring that the severity of ischemia is comparable between groups. Furthermore, several studies showed that infarct volumes can be predicted with MRI data obtained soon after ischemia onset. However, such predictive studies require multiparametric MRI acquisitions that cannot be routinely performed, and data processing using complex algorithms that are often not available. The aim here was to provide a simplified method for infarct volume prediction using apparent diffusion coefficient (ADC) data in a model of transient MCAO in rats. ADC images were obtained before, during MCAO and after 60 min of reperfusion. Probability histograms were generated using ADC data obtained either during MCAO, after reperfusion, or both combined. The results were compared to real infarct volumes, i.e.T2 maps obtained at day 7. Assessment of the performance of the estimations showed better results combining ADC data obtained during occlusion and at reperfusion. Therefore, ADC data alone can provide sufficient information for a reasonable prediction of infarct volume if the MRI information is obtained both during the occlusion and soon after reperfusion. This approach can be used to check whether drug administration after MRI acquisition can change infarct volume prediction.

Including anatomical and functional information in MC simulation of PET and SPECT brain studies. Brain-VISET: a voxel-based iterative method.

Monte Carlo (MC) simulation provides a flexible and robust framework to efficiently evaluate and optimize image processing methods in emission tomography. In this work we present Brain-VISET (Voxel-based Iterative Simulation for Emission Tomography), a method that aims to simulate realistic [ (99m) Tc]-SPECT and [ (18) F]-PET brain databases by including anatomical and functional information. To this end, activity and attenuation maps generated using high-resolution anatomical images from patients were used as input maps in a MC projector to simulate SPECT or PET sinograms. The reconstructed images were compared with the corresponding real SPECT or PET studies in an iterative process where the activity inputs maps were being modified at each iteration. Datasets of 30 refractory epileptic patients were used to assess the new method. Each set consisted of structural images (MRI and CT) and functional studies (SPECT and PET), thereby allowing the inclusion of anatomical and functional variability in the simulation input models. SPECT and PET sinograms were obtained using the SimSET package and were reconstructed with the same protocols as those employed for the clinical studies. The convergence of Brain-VISET was evaluated by studying the behavior throughout iterations of the correlation coefficient, the quotient image histogram and a ROI analysis comparing simulated with real studies. The realism of generated maps was also evaluated. Our findings show that Brain-VISET is able to generate realistic SPECT and PET studies and that four iterations is a suitable number of iterations to guarantee a good agreement between simulated and real studies.

Analytical, experimental, and Monte Carlo system response matrix for pinhole SPECT reconstruction.

PURPOSE: To assess the performance of two approaches to the system response matrix (SRM) calculation in pinhole single photon emission computed tomography (SPECT) reconstruction. METHODS: Evaluation was performed using experimental data from a low magnification pinhole SPECT system that consisted of a rotating flat detector with a monolithic scintillator crystal. The SRM was computed following two approaches, which were based on Monte Carlo simulations (MC-SRM) and analytical techniques in combination with an experimental characterization (AE-SRM). The spatial response of the system, obtained by using the two approaches, was compared with experimental data. The effect of the MC-SRM and AE-SRM approaches on the reconstructed image was assessed in terms of image contrast, signal-to-noise ratio, image quality, and spatial resolution. To this end, acquisitions were carried out using a hot cylinder phantom (consisting of five fillable rods with diameters of 5, 4, 3, 2, and 1 mm and a uniform cylindrical chamber) and a custom-made Derenzo phantom, with center-to-center distances between adjacent rods of 1.5, 2.0, and 3.0 mm. RESULTS: Good agreement was found for the spatial response of the system between measured data and results derived from MC-SRM and AE-SRM. Only minor differences for point sources at distances smaller than the radius of rotation and large incidence angles were found. Assessment of the effect on the reconstructed image showed a similar contrast for both approaches, with values higher than 0.9 for rod diameters greater than 1 mm and higher than 0.8 for rod diameter of 1 mm. The comparison in terms of image quality showed that all rods in the different sections of a custom-made Derenzo phantom could be distinguished. The spatial resolution (FWHM) was 0.7 mm at iteration 100 using both approaches. The SNR was lower for reconstructed images using MC-SRM than for those reconstructed using AE-SRM, indicating that AE-SRM deals better with the projection noise than MC-SRM. CONCLUSIONS: The authors' findings show that both approaches provide good solutions to the problem of calculating the SRM in pinhole SPECT reconstruction. The AE-SRM was faster to create and handle the projection noise better than MC-SRM. Nevertheless, the AE-SRM required a tedious experimental characterization of the intrinsic detector response. Creation of the MC-SRM required longer computation time and handled the projection noise worse than the AE-SRM.Nevertheless, the MC-SRM inherently incorporates extensive modeling of the system and therefore experimental characterization was not required.

Chronic intermittent hypoxia preserves bone density in a mouse model of sleep apnea.

Very recent clinical research has investigated whether obstructive sleep apnea (OSA) may modulate bone homeostasis but the few data available are conflicting. Here we report novel data obtained in a mouse study specifically designed to determine whether chronic intermittent hypoxia realistically mimicking OSA modifies bone mineral density (BMD). Normal male and female mice and orchidectomized mice (N=10 each group) were subjected to a pattern of high-frequency intermittent hypoxia (20s at 5% and 40s at 21%, 60 cycles/h) for 6h/day. Identical groups breathing room air (normoxia) were the controls. After 32 days of intermittent hypoxia/normoxia the trabecular bone mineral density (BMD) in the peripheral femora were measured by micro-CT scanning. When compared with normoxia (two-way ANOVA), intermittent hypoxia did not significantly modify BMD in the three animal groups tested. Data in this study suggest that the type of intermittent hypoxia characterizing OSA, applied as a single challenge, preserves bone homeostasis.

FocusDET, a new toolbox for SISCOM analysis. Evaluation of the registration accuracy using Monte Carlo simulation.

Subtraction of Ictal SPECT Co-registered to MRI (SISCOM) is an imaging technique used to localize the epileptogenic focus in patients with intractable partial epilepsy. The aim of this study was to determine the accuracy of registration algorithms involved in SISCOM analysis using FocusDET, a new user-friendly application. To this end, Monte Carlo simulation was employed to generate realistic SPECT studies. Simulated sinograms were reconstructed by using the Filtered BackProjection (FBP) algorithm and an Ordered Subsets Expectation Maximization (OSEM) reconstruction method that included compensation for all degradations. Registration errors in SPECT-SPECT and SPECT-MRI registration were evaluated by comparing the theoretical and actual transforms. Patient studies with well-localized epilepsy were also included in the registration assessment. Global registration errors including SPECT-SPECT and SPECT-MRI registration errors were less than 1.2 mm on average, exceeding the voxel size (3.32 mm) of SPECT studies in no case. Although images reconstructed using OSEM led to lower registration errors than images reconstructed with FBP, differences after using OSEM or FBP in reconstruction were less than 0.2 mm on average. This indicates that correction for degradations does not play a major role in the SISCOM process, thereby facilitating the application of the methodology in centers where OSEM is not implemented with correction of all degradations. These findings together with those obtained by clinicians from patients via MRI, interictal and ictal SPECT and video-EEG, show that FocusDET is a robust application for performing SISCOM analysis in clinical practice.

Validation of an automatic dose injection system for Ictal SPECT in epilepsy.

UNLABELLED: The purpose of our study was to evaluate the performance and clinical usefulness of an automated injector system (AIS) that administers an automated injection for ictal SPECT after calculating the volume of tracer to be injected over time. METHODS: To test the AIS, repeated injections were performed at different times after tracer preparation. The clinical study consisted of 56 patients with drug-resistant, complex partial seizures. Tracer for ictal SPECT was injected using automated injection in 27 patients and manual injection (MI) in the remaining 29. Injection time (T(I)) was measured in seconds from seizure onset to the end of volume injection. The SISCOM (Subtraction Ictal Spect Co-registered to MRI) procedure was used to locate the epileptogenic seizure focus with SPECT. The definition of seizure focus was made by consensus of the epilepsy unit using conventional diagnostic methods. RESULTS: During the experimental phase, there were no system failures, and the error in injected doses when using automated injection was lower than with MI. During the clinical phase, T(I) using manual injection was 41 s with a range of 14-103 s, compared with an AIS average of 33 s with a range of 19-63 s (P < 0.05). Ictal SPECT and SISCOM successfully localized the seizure focus in 21 of the 27 patients (78%) by AIS and in 19 of the 29 patients (65%) by MI (P = 0.14). Furthermore, nursing staff found the AIS method more convenient than the MI method. CONCLUSION: An AIS can improve the quality of work of the nursing staff in the neurology ward and allow a finer adjustment of the injection dose. Early results using an AIS would indicate a reduction in injection time and improved SPECT accuracy.