Volume Of Interest Analysis Research Articles

Alteration of the regional cerebral glucose metabolism in healthy subjects by glucose loading.

High plasma glucose (PG) levels can reduce fluorine-18-labeled fluorodeoxyglucose ((18) F-FDG) uptake, especially in the Alzheimer's disease (AD)-related regions. This fact is supported by studies showing that the resting-state activity in diabetes can be altered in the default mode network (DMN)-related regions, which considerably overlap with the AD-related regions. In order to expand the current knowledge, we aimed to investigate the relationship between increasing PG levels and the regional cerebral metabolic rates for glucose (CMRglc ) as a direct index of brain activity. We performed dynamic (18) F-FDG positron emission tomography with arterial blood sampling once each in the fasting and glucose-loading conditions on 12 young, healthy volunteers without cognitive impairment or insulin resistance. The absolute CMRglc values were calculated for the volume-of-interest (VOI) analysis, and normalized CMRglc maps were generated for the voxelwise analysis. The normalized measurement is known to have smaller intersubject variability than the absolute measurement, and may, thus, lead to greater statistical power. In VOI analysis, no regional difference in the CMRglc was found between the two conditions. In exploratory voxelwise analysis, however, significant clusters were identified in the precuneus, posterior cingulate, lateral parietotemporal, and medial prefrontal regions where the CMRglc decreased upon glucose loading (P < 0.05, corrected). These regions include the representative components of both the DMN and AD pathology. Taken together with the previous knowledge on the relationships between the DMN, AD, and diabetes, it may be inferred that glucose loading induces hypometabolism in the AD-related and DMN-related regions. Hum Brain Mapp 37:2823-2832, 2016. © 2016 Wiley Periodicals, Inc.

Imaging characteristic of dual-phase (18)F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer's disease and mild cognitive impairment.

We investigated dual-phase (18)F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs). A total of 82 subjects (24AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase (18)F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6min after tracer injection (perfusion (18)F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60min after tracer injection (amyloid (18)F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and (18)F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses. HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P < 0.0001). (18)F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and (18)F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when (18)F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced MCI. Our results indicate that brain perfusion deficits and beta-amyloid deposition in AD follow different trajectories that can be successfully traced using dual-phase (18)F-AV-45 PET imaging.

Volume of Interest Analysis of Spatially Normalized PRESTO Imaging to Differentiate between Parkinson Disease and Atypical Parkinsonian Syndrome.

Purpose:Various magnetic resonance imaging (MRI) techniques including T2*-weighted imaging, susceptibility-weighted imaging, and MR relaxometry had been performed to evaluate different patterns of brain iron depositions in Parkinsonian syndrome. The aim of the present study was to evaluate the diagnostic value of a volume of interest (VOI) analysis on the principles of echo shifting with a train of observations (PRESTO) imaging using the statistical parametric mapping (SPM) 8 and the WFU PickAtlas program for the diagnosis of Parkinsonian syndrome.Methods:Fifty subjects, including 13 with the Parkinsonian variant of multiple system atrophy (MSA-P), 12 with progressive supranuclear palsy (PSP), 12 with Parkinson’s disease (PD) and 13 controls were evaluated in this study. After the spatial normalization of PRESTO images on SPM8, the WFU PickAtlas program was performed to create target VOIs in the putamen, red nucleus, substantia nigra, subthalamic nucleus, and dentate nucleus. The signal intensity ratio (SIR) was calculated by normalizing the signal of each VOI to that of the cerebrospinal fluid space. These SIRs were used as determinants in receiver operating characteristic (ROC) analyses.Results:SIR of the putamen was significantly lower in MSA-P than in PSP (P = 0.0051) and controls (P = 0.0004). In contrast, SIR of the red nucleus was significantly lower in PSP than in MSA-P (P = 0.0003), PD (P = 0.0029), and controls (P = 0.0011). In ROC analyses, SIR of the putamen exhibited the highest areas under the curves (AUCs) of 0.83 (vs. PSP) and 0.91 (vs. controls) in the diagnosis of MSA-P. On the other hand, SIR of the red nucleus exhibited the highest AUCs of 0.87 (vs. MSA-P), 0.90 (vs. PD), and 0.89 (vs. controls) in the diagnosis of PSP.Conclusions:The VOI analysis based on spatially normalized PRESTO images may be useful for depicting hypointensity, indicative of abnormal iron depositions, of the putamen and red nucleus in the diagnosis of MSA-P and PSP.

Direct comparison of visual and quantitative bone marrow FDG-PET/CT findings with bone marrow biopsy results in diffuse large B-cell lymphoma: does bone marrow FDG-PET/CT live up to its promise?

Detection of bone marrow involvement using 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) has been proposed as a non-invasive alternative to standard blind bone marrow biopsy (BMB) of the posterior iliac crest in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, studies that directly compare FDG-PET/CT results with histopathology are currently lacking. To directly compare both visual and quantitative bone marrow FDG-PET/CT to BMB at the right posterior iliac crest in patients with newly diagnosed DLBCL. A total of 40 patients with newly diagnosed DLBCL, who had undergone FDG-PET/CT before BMB of the right posterior iliac crest, were retrospectively included. FDG-PET/CT images were visually assessed for bone marrow involvement in the right posterior iliac crest. 3D partial volume corrected mean standardized uptake value (cSUVmean), maximum standardized uptake value (SUVmax), and peak standardized uptake value (SUVpeak) were measured in the right posterior iliac crest, using volume of interest analysis. BMB of the right posterior iliac crest was used as reference standard for bone marrow involvement. Sensitivity and specificity of visual FDG-PET/CT analysis for the detection of bone marrow involvement in the right posterior iliac crest were 14.3% (95% confidence interval [CI], 0.5-53.4%) and 100% (95% CI, 87.6-100%), respectively. cSUVmean, SUVmax, and SUVpeak of BMB-negative patients (1.4 ± 0.49, 2.2 ± 0.69, and 1.7 ± 0.59, respectively) considerably overlapped with those of BMB-positive patients (1.8 ± 0.53, 2.7 ± 0.71, and 2.2 ± 0.61, respectively). In a local, head-to-head comparison with BMB, the diagnostic value of both visual and quantitative FDG-PET/CT for the detection of bone marrow involvement is low in patients with newly diagnosed DLBCL.

Biodistribution and radiation dosimetry of (82)Rb at rest and during peak pharmacological stress in patients referred for myocardial perfusion imaging.

(82)Rb is an ultra-short-lived positron emitter used for myocardial blood flow quantification with PET imaging. The aim of this study was to quantify the biodistribution and radiation dosimetry in patients with coronary disease and in healthy normal volunteers. A total of 30 subjects, 26 patients with known or suspected coronary artery disease (CAD) and four healthy volunteers were injected with (82)Rb chloride at 10 MBq/kg followed by a 10-min dynamic PET scan. Chest scans at rest were acquired in all subjects, as well as one additional biodistribution scan of the head, neck, abdomen, pelvis or thighs. Chest scans under stress were acquired in 25 of the CAD patients. (82)Rb time-integrated activity coefficients were determined in 22 source organs using volume of interest analysis, including corrections for partial-volume losses. The mean time-integrated activity coefficients were used to calculate the whole-body effective dose using tissue weighting factors from the International Commission on Radiological Protection (ICRP) Publications 60 and 103. A total of 283 organ time-integrated activity coefficients were calculated, with a minimum of four values per source organ. The rest and stress mean effective dose was 0.8 mSv/GBq, according to the most recent ICRP definition. Using 10 MBq/kg for 3D PET imaging, the effective dose to a gender-averaged reference person (60 kg female and 73 kg male) is 1.1 mSv for a complete rest and stress perfusion study. For 2D PET using a typical injected activity of 1.1 to 2.2 GBq each for rest and stress, the effective dose for a complete study is 1.8 to 3.5 mSv. The current effective dose estimate in CAD patients is four times lower than the values reported previously by the ICRP, and about 35% lower than previous in vivo studies in young healthy subjects.

The usefulness of bone SPECT/CT imaging with volume of interest analysis in early axial spondyloarthritis.

BackgroundThe role of conventional bone scintigraphy in diagnosing early axial spondyloarthritis (SpA) is yet controversial. Single positron emission computed tomography (SPECT) plus CT is an imaging modality that adds better anatomical information to scintigraphy of the sacroiliac (SI) joint. Our aim was to investigate the usefulness of bone SPECT/CT with volume of interest (VOI) analysis in early axial SpA patients.MethodsTwenty patients (male: female ratio = 12:8; age range = 17–65 years) presenting with inflammatory back pain meeting the Amor criteria of early axial SpA were recruited from a single center in South Korea. Bone scintigraphy was performed 180 min after intravenous injection of 1110 MBq of Tc-99 m-HDP, followed by bone SPECT/CT. The ratio between the entire SI joint and sacrum (SIS ratio) was measured by both bone SPECT/CT and bone scintigraphy. Data from 13 controls were also evaluated. Receiver operating characteristic (ROC) curve was plotted for further analysis, and the correlation between the SIS ratio and SI joint grade by plain radiography was assessed.ResultsThe SIS ratio of early axial SpA patients vs. control subjects was significantly increased in bone SPECT/CT (p < 0.001). However, no significant difference was detected in bone scintigraphy. ROC curve analysis showed a significant difference in the area under curve (AUC) of bone SPECT/CT vs. bone scintigraphy (0.862 vs. 0.523, respectively; p < 0.001). With a cut-off SIS ratio of 1.50, ROC curve analysis showed a sensitivity of 80.0% and specificity of 84.6% in bone SPECT/CT. The SIS ratio measured in SPECT/CT, but not that measured in bone scintigraphy, was significantly increased with a higher grade of SI joint changes in plain radiography (p = 0.014).ConclusionBone SPECT/CT is more useful than conventional bone scintigraphy in identifying sacroiliitis in early axial SpA patients, even with mild SI joint changes in plain radiography. By combining CT, we can accurately delineate the sacrum and SI joint uptake with our VOI method.

Relationship between Alzheimer disease-like pattern of 18F-FDG and fasting plasma glucose levels in cognitively normal volunteers.

Increased plasma glucose (PG) levels can alter the cerebral distribution pattern of (18)F-FDG uptake and reduce (18)F-FDG uptake, especially in the precuneus. The (18)F-FDG distribution pattern in cognitively normal subjects is described as an Alzheimer disease (AD)-like pattern. The aim of this study was to determine the fasting PG levels that can reduce (18)F-FDG uptake in the precuneus. Fifty-one cognitively normal volunteers (mean age ± SD, 69.7 ± 5.9 y) underwent (18)F-FDG PET scanning and were divided into 2 groups according to the level of fasting PG at the time of PET scanning: control (n = 31, 80 mg/dL ≤ fasting PG < 100 mg/dL) and impaired fasting glucose (IFG) (n = 20, 100 mg/dL ≤ fasting PG < 110 mg/dL). (18)F-FDG uptake was compared between the 2 groups using voxelwise analyses with a global normalization method and volume-of-interest (VOI)-based analyses. VOIs were placed on the precuneus, posterior cingulate, and visual cortex, and the ratio of the uptake value on the precuneus VOI to that on the visual cortex VOI (PreCne/VC ratios) and to that on the posterior cingulate VOI (PreCne/PostCin ratios) was calculated. Whole-brain voxelwise analyses showed that (18)F-FDG uptake in the precuneus was significantly lower in the IFG group (P < 0.05, familywise error rate-corrected) than in the control group. VOI analyses showed significantly lower PreCne/VC ratios (P = 0.002) and PreCne/PostCin ratios (P = 0.004) in the IFG group than in the control group. The present study confirmed that increased fasting PG levels decrease (18)F-FDG uptake, especially in the precuneus, as in the AD-like pattern. Furthermore, the study provided initial evidence that the AD-like pattern can appear even in an individual with a mildly higher level of fasting PG (100-110 mg/dL).

Poster #S221 SUICIDALITY IN SCHIZOPHRENIA SPECTRUM DISORDERS: RELATION TO HALLUCINATIONS AND PERSECUTORY DELUSIONS

We recently found marked deficits in sleep spindles, non-rapid eye movement (NREM) sleep oscillations that are generated within the thalamus and then amplified and sustained in the cortex, in patients with schizophrenia compared to both healthy and psychiatric controls. Here, we investigated the thalamic and cortical contributions to these sleep spindle deficits.Anatomical volume of interest analysis (i.e., thalamic volumes) and electroencephalogram (EEG) source modeling (i.e., spindle-related cortical currents) were performed in patients with schizophrenia and healthy comparison subjects.Schizophrenia patients had reduced mediodorsal (MD) thalamic volumes, especially on the left side, compared to healthy controls, whereas whole thalami and lateral geniculate nuclei did not differ between groups. Furthermore, left MD volumes were strongly correlated with the number of scalp-recorded spindles in an anterior frontal region, and cortical currents underlying these anterior frontal spindles were localized in the prefrontal cortex, in Brodmann area (BA) 10. Finally, prefrontal currents at the peak of spindle activity were significantly reduced in schizophrenia patients and correlated with their performance in an abstraction/working memory task.Altogether, these findings point to deficits in a specific thalamo-cortical circuitry in schizophrenia, which is associated with some cognitive deficits commonly reported in those patients.

The power of neuroimaging biomarkers for screening frontotemporal dementia

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disease that can result from either frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD) pathology. It is critical to establish statistically powerful biomarkers that can achieve substantial cost-savings and increase the feasibility of clinical trials. We assessed three broad categories of neuroimaging methods to screen underlying FTLD and AD pathology in a clinical FTD series: global measures (e.g., ventricular volume), anatomical volumes of interest (VOIs) (e.g., hippocampus) using a standard atlas, and data-driven VOIs using Eigenanatomy. We evaluated clinical FTD patients (N = 93) with cerebrospinal fluid, gray matter (GM) magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI) to assess whether they had underlying FTLD or AD pathology. Linear regression was performed to identify the optimal VOIs for each method in a training dataset and then we evaluated classification sensitivity and specificity in an independent test cohort. Power was evaluated by calculating minimum sample sizes required in the test classification analyses for each model. The data-driven VOI analysis using a multimodal combination of GM MRI and DTI achieved the greatest classification accuracy (89% sensitive and 89% specific) and required a lower minimum sample size (N = 26) relative to anatomical VOI and global measures. We conclude that a data-driven VOI approach using Eigenanatomy provides more accurate classification, benefits from increased statistical power in unseen datasets, and therefore provides a robust method for screening underlying pathology in FTD patients for entry into clinical trials.

The feasibility of white matter volume reduction analysis using SPM8 plus DARTEL for the diagnosis of patients with clinically diagnosed corticobasal syndrome and Richardson's syndrome.

PurposeDiagnosing corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is often difficult due to the wide variety of symptoms and overlaps in the similar clinical courses and neurological findings. The purpose of this study was to evaluate the utility of white matter (WM) atrophy for the diagnosis of patients with clinically diagnosed CBD (corticobasal syndrome, CBS) and PSP (Richardson’s syndrome, RS).MethodsWe randomly divided the 3D T1-weighted MR images of 18 CBS patients, 33 RS patients, and 32 age-matched controls into two groups. We obtained segmented WM images in the first group using Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) based on statistical parametric mapping (SPM) 8 plus diffeomorphic anatomical registration through exponentiated Lie algebra. A target volume of interest (VOI) for disease-specific atrophy was subsequently determined in this group using SPM8 group analyses of WM atrophy between patients groups and controls. We then evaluated the utility of these VOIs for diagnosing CBS and RS patients in the second group. Z score values in these VOIs were used as the determinant in receiver operating characteristic (ROC) analyses.ResultsSpecific target VOIs were determined in the bilateral frontal subcortical WM for CBS and in the midbrain tegmentum for RS. In ROC analyses, the target VOIs of CBS and RS compared to those of controls exhibited an area under curve (AUC) of 0.99 and 0.84, respectively, which indicated an adequate diagnostic power. The VOI of CBS revealed a higher AUC than that of RS for differentiating between CBS and RS (AUC, 0.75 vs 0.53).ConclusionsBilateral frontal WM volume reduction demonstrated a higher power for differentiating CBS from RS. This VOI analysis is useful for clinically diagnosing CBS and RS.

MR-based hypoxia measures in human glioma

Hypoxia plays a central role in tumor stem cell genesis and is related to a more malignant tumor phenotype, therapy resistance (e.g. in anti-angiogenic therapies) and radio-insensitivity. Reliable hypoxia imaging would provide crucial metabolic information in the diagnostic work-up of brain tumors. In this study, we applied a novel BOLD-based MRI method for the measurement of relative oxygen extraction fraction (rOEF) in glioma patients and investigated potential benefits and drawbacks. Forty-five glioma patients were examined preoperatively in a pilot study on a 3T MR scanner. rOEF was calculated from quantitative transverse relaxation rates (T2, T2*) and cerebral blood volume (CBV) using a quantitative BOLD approach. rOEF maps were assessed visually and by means of a volume of interest (VOI) analysis. In six cases, MRI-targeted biopsy samples were analyzed using HIF-1α-immunohistochemistry. rOEF maps could be obtained with a diagnostic quality. Focal spots with high rOEF values were observed in the majority of high-grade tumors but in none of the low-grade tumors. VOI analysis revealed potentially hypoxic tumor regions with high rOEF in contrast-enhancing tumor regions as well as in the non-enhancing infiltration zone. Systematic bias was found as a result of non-BOLD susceptibility effects (T2*) and contrast agent leakage affecting CBV. Histological samples demonstrated reasonable correspondence between MRI characteristics and HIF-1α-staining. The presented method of rOEF imaging is a promising tool for the metabolic characterization of human glioma. For the interpretation of rOEF maps, confounding factors must be considered, with a special focus on CBV measurements in the presence of contrast agent leakage. Further validation involving a bigger cohort and extended immuno-histochemical correlation is required.

Evaluation of strategies towards harmonization of FDG PET/CT studies in multicentre trials: comparison of scanner validation phantoms and data analysis procedures

PET quantification based on standardized uptake values (SUV) is hampered by several factors, in particular by variability in PET acquisition settings and data analysis methods. Quantitative PET/CT studies acquired during a multicentre trial require harmonization of imaging procedures to maximize study power. The aims of this study were to determine which phantoms are most suitable for detecting differences in image quality and quantification, and which methods for defining volumes of interest (VOI) are least sensitive to these differences. The most common accreditation phantoms used in oncology FDG PET/CT trials were scanned on the same scanner. These phantoms were those used by the Society of Nuclear Medicine Clinical Trials Network (SNM-CTN), the European Association of Nuclear Medicine/National Electrical Manufacturers Association (EANM/NEMA) and the American College of Radiology (ACR). In addition, tumour SUVs were derived from ten oncology whole-body examinations performed on the same PET/CT system. Both phantom and clinical data were reconstructed using different numbers of iterations, subsets and time-of-flight kernel widths. Subsequently, different VOI methods (VOI(A50%), VOI(max), VOI(3Dpeak), VOI(2Dpeak)) were applied to assess the impact of changes in image reconstruction settings on SUV and recovery coefficients (RC). All phantoms demonstrated sensitivity for detecting changes in SUV and RC measures in response to changes in image reconstruction settings and VOI analysis methods. The SNM-CTN and EANM/NEMA phantoms showed almost equal sensitivity in detecting RC differences with changes in image characteristics. Phantom and clinical data demonstrated that the VOI analysis methods VOI(A50%) and VOI(max) gave SUV and RC values with large variability in relation to image characteristics, whereas VOI(3Dpeak) and VOI(2Dpeak) were less sensitive to these differences. All three phantoms may be used to harmonize parameters for data acquisition, processing and analysis. However, the SNM-CTN and EANM/NEMA phantoms are the most sensitive to parameter changes and are suitable for harmonizing SUV quantification based on 3D VOIs, such as VOI(A50%) and VOI(3Dpeak), and VOImax. Variability in SUV quantification after harmonization could be further minimized using VOI(3Dpeak) analysis, which was least sensitive to residual variability in image quality and quantification.

Construction and Evaluation of Quantitative Small-Animal PET Probabilistic Atlases for [18F]FDG and [18F]FECT Functional Mapping of the Mouse Brain

Automated voxel-based or pre-defined volume-of-interest (VOI) analysis of small-animal PET data in mice is necessary for optimal information usage as the number of available resolution elements is limited. We have mapped metabolic ([18F]FDG) and dopamine transporter ([18F]FECT) small-animal PET data onto a 3D Magnetic Resonance Microscopy (MRM) mouse brain template and aligned them in space to the Paxinos co-ordinate system. In this way, ligand-specific templates for sensitive analysis and accurate anatomical localization were created. Next, using a pre-defined VOI approach, test-retest and intersubject variability of various quantification methods were evaluated. Also, the feasibility of mouse brain statistical parametric mapping (SPM) was explored for [18F]FDG and [18F]FECT imaging of 6-hydroxydopamine-lesioned (6-OHDA) mice.MethodsTwenty-three adult C57BL6 mice were scanned with [18F]FDG and [18F]FECT. Registrations and affine spatial normalizations were performed using SPM8. [18F]FDG data were quantified using (1) an image-derived-input function obtained from the liver (cMRglc), using (2) standardized uptake values (SUVglc) corrected for blood glucose levels and by (3) normalizing counts to the whole-brain uptake. Parametric [18F]FECT binding images were constructed by reference to the cerebellum. Registration accuracy was determined using random simulated misalignments and vectorial mismatch determination.ResultsRegistration accuracy was between 0.21–1.11 mm. Regional intersubject variabilities of cMRglc ranged from 15.4% to 19.2%, while test-retest values were between 5.0% and 13.0%. For [18F]FECT uptake in the caudate-putamen, these values were 13.0% and 10.3%, respectively. Regional values of cMRglc positively correlated to SUVglc measured within the 45–60 min time frame (spearman r = 0.71). Next, SPM analysis of 6-OHDA-lesioned mice showed hypometabolism in the bilateral caudate-putamen and cerebellum, and an unilateral striatal decrease in DAT availability.ConclusionMRM-based small-animal PET templates facilitate accurate assessment and spatial localization of mouse brain function using VOI or voxel-based analysis. Regional intersubject- and test-retest variations indicate that for these targets accuracy comparable to humans can be achieved.

AB0544 The usefulness of bone spect-ct imaging with volume of interest analysis in early axial spondyloarthritis

BackgroundImaging is an important tool in diagnosing axial spondylo-arthritis (SpA). In contrast to magnetic resonance imaging, conventional bone scintigraphy has not been so helpful for early detection of axial SpA....

Abstract 1062: Imaging DNA damage response (DDR) during oncogenesis.

Abstract Introduction: DNA damage repair (DDR) signalling is upregulated during tumorigenesis and acts as a p53-mediated block on proliferation. Expression of the DNA double strand break (DSB) repair protein, γH2AX, is induced by the activated kinases pATM or pATR during oncogenesis. Previously, we showed that γH2AX presents an abundant epitope for non-invasive in vivo imaging of DSBs. We used 111In-labelled anti-γH2AX antibodies, conjugated to the cell penetrating peptide, TAT, to non-invasively image DDR during oncogenesis in a genetically engineered mouse model of HER2/neu-overexpression driven breast cancer. Methods: Balb/neuT mice, genetically modified to express mutated rat neuT under MMTV promotor control, form multiple palpable carcinomas in mammary fat pads when animals are 130 days old. SPECT images were acquired weekly from balb/neuT mice (age 40-140 days; n=23) 24 h after i.v. injection of 111In-labelled anti-γH2AX-Tat or the non-selective agent, 111In-rIgG-Tat using a small animal SPECT/CT scanner. 111In uptake in fat pads was determined using volume of interest analysis. 111In uptake of &amp;gt;5%ID/g was deemed positive. Anatomical and histological changes were assessed at different ages using DCE-MRI imaging and immunohistochemistry. Results: Balb/neuT mice that were 80 days old developed multiple hyperplastic and dysplastic lesions in mammary fat pads. γH2AX foci were observed in these regions in balb/neuT mice that were 80-100 days old (10-15 foci/cell), but were less numerous in overt tumor tissue in 130-day-old mice (4-5 foci/cell). γH2AX foci were not observed in normal tissues in older mice (0 foci/cell), in mammary fat pads in younger mice (0 foci/cell), or in wild type mice (0 foci/cell). Serial SPECT imaging revealed a 7-fold increase in 111In-anti-γH2AX-Tat accumulation in mammary fat pads in mice 80-110 days old (up to 8.5 %ID/g), compared to non-specific control (P=0.0007), but not in younger or older mice (P&amp;gt;0.05). Repeated SPECT imaging itself did not influence tumor occurrence (P&amp;gt;0.05). The median time to detection of positive tissue was 96 days, much sooner than detection of lesions &amp;gt;150 μm by DCE-MRI (117 days), or palpation (130 days) (P&amp;lt;0.0001). Conclusion: Using a γH2AX-targeted radiopharmaceutical, we were able to image the DNA damage response during neuT-mediated oncogenesis in balb/neuT mice. DDR imaging identified neoplastic tissue significantly earlier than anatomical imaging. These results suggest that γH2AX imaging has potential as a screening tool for cancer-prone individuals. Citation Format: Bart Cornelissen, Sarah Able, Veerle Kersemans, Katherine A. Vallis. Imaging DNA damage response (DDR) during oncogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1062. doi:10.1158/1538-7445.AM2013-1062

Interpretable whole-brain prediction analysis with GraphNet

Multivariate machine learning methods are increasingly used to analyze neuroimaging data, often replacing more traditional "mass univariate" techniques that fit data one voxel at a time. In the functional magnetic resonance imaging (fMRI) literature, this has led to broad application of "off-the-shelf" classification and regression methods. These generic approaches allow investigators to use ready-made algorithms to accurately decode perceptual, cognitive, or behavioral states from distributed patterns of neural activity. However, when applied to correlated whole-brain fMRI data these methods suffer from coefficient instability, are sensitive to outliers, and yield dense solutions that are hard to interpret without arbitrary thresholding. Here, we develop variants of the Graph-constrained Elastic-Net (GraphNet), a fast, whole-brain regression and classification method developed for spatially and temporally correlated data that automatically yields interpretable coefficient maps (Grosenick et al., 2009b). GraphNet methods yield sparse but structured solutions by combining structured graph constraints (based on knowledge about coefficient smoothness or connectivity) with a global sparsity-inducing prior that automatically selects important variables. Because GraphNet methods can efficiently fit regression or classification models to whole-brain, multiple time-point data sets and enhance classification accuracy relative to volume-of-interest (VOI) approaches, they eliminate the need for inherently biased VOI analyses and allow whole-brain fitting without the multiple comparison problems that plague mass univariate and roaming VOI ("searchlight") methods. As fMRI data are unlikely to be normally distributed, we (1) extend GraphNet to include robust loss functions that confer insensitivity to outliers, (2) equip them with "adaptive" penalties that asymptotically guarantee correct variable selection, and (3) develop a novel sparse structured Support Vector GraphNet classifier (SVGN). When applied to previously published data (Knutson et al., 2007), these efficient whole-brain methods significantly improved classification accuracy over previously reported VOI-based analyses on the same data (Grosenick et al., 2008; Knutson et al., 2007) while discovering task-related regions not documented in the original VOI approach. Critically, GraphNet estimates fit to the Knutson et al. (2007) data generalize well to out-of-sample data collected more than three years later on the same task but with different subjects and stimuli (Karmarkar et al., submitted for publication). By enabling robust and efficient selection of important voxels from whole-brain data taken over multiple time points (>100,000 "features"), these methods enable data-driven selection of brain areas that accurately predict single-trial behavior within and across individuals.

Decreased carbon-11-flumazenil binding in early Alzheimer’s disease

Neuronal loss in Alzheimer's disease, a better correlate of cognitive impairment than amyloid deposition, is currently gauged by the degree of regional atrophy. However, functional markers, such as GABA(A) receptor density, a marker of neuronal integrity, could be more sensitive. In post-mortem hippocampus, GABA(A) messenger RNA expression is reduced even in mild cognitive impairment. We measured whole-brain GABA(A) binding potential in vivo using [(11)C]-flumazenil positron emission tomography and compared GABA(A) binding with metabolic and volumetric measurements. For this purpose, we studied 12 subjects, six patients with early Alzheimer's disease and six healthy controls, with [(11)C]-flumazenil and [(18)F]-fluorodeoxyglucose positron emission tomography, as well as with high-resolution magnetic resonance imaging. Data were evaluated with both voxel-based parametric methods and volume of interest methods. We found that in early Alzheimer's disease, with voxel-based analysis, [(11)C]-flumazenil binding was decreased in infero-medial temporal cortex, retrosplenial cortex and posterior perisylvian regions. Inter-group differences reached corrected significance when using an arterial input function. Metabolism measured with positron emission tomography and volumetric measurements obtained with magnetic resonance imaging showed changes in regions affected in early Alzheimer's disease, but, unlike with [(11)C]-flumazenil binding and probably due to sample size, the voxel-based findings failed to reach corrected significance in any region of the brain. With volume of interest analysis, hippocampi and posterior cingulate gyrus showed decreased [(11)C]-flumazenil binding. In addition, [(11)C]-flumazenil hippocampal binding correlated with memory performance. Remarkably, [(11)C]-flumazenil binding was decreased precisely in the regions showing the greatest degree of neuronal loss in post-mortem studies of early Alzheimer's disease. From these data, we conclude that [(11)C]-flumazenil binding could be a useful marker of neuronal loss in early Alzheimer's disease.

Altered extrafocal iomazenil activity in mesial temporal lobe epilepsy

To investigate involvement of extrafocal regions in mesial temporal lobe epilepsy (MTLE), we retrospectively explored abnormalities in distribution of iomazenil (IMZ) activity by identifying interhemispheric asymmetry on IMZ-SPECT images of patients with MTLE. Fourteen MTLE patients in whom a good surgical outcome was achieved were included in the study. Voxel-based (VB) analysis and volume-of-interest (VOI) analysis with predefined VOIs were applied to compare IMZ binding between the hemispheres ipsilateral and contralateral to the epileptic focus. VB analysis showed significant decreases in iomazenil binding not only in the ipsilateral anterior temporal lobe including the mesial temporal structures but also in the ipsilateral extratemporal region including the insula, putamen, and medial occipital lobe. VOI analysis showed similar significant decreases in the ipsilateral parahippocampal gyrus, amygdala, putamen, lateral temporal lobe, and lateral occipital lobe. Results of the SPECT analyses suggest that decreased or dysfunctional IMZ activity extends from the mesial temporal lobe to the ipsilateral extrafocal region in patients with MTLE.

Determination of Language Dominance: Wada Test and fMRI Compared Using a Novel Sentence Task

This study aimed to develop a new linguistic based functional magnetic resonance imaging (fMRI)-sentence decision task that reliably detects hemispheric language dominance. FMRI was performed in 13 healthy right-handed controls and 20 patients at 1.5 T prior to neurosurgery. The main components of language were assessed with different paradigms (rhyme, synonym, and sentence). In controls, activations were quantified by a volume of interest analysis. Four neuroimagers tested a visual rating score in the patients group. Interrater agreement and concordance between fMRI and Wada test were calculated. In healthy controls, the frontal language area was activated by the sentence and synonym task in 100% and in 73% by the rhyme task. The temporal language area was activated in 100% by the sentence-, in 64% by the synonym, and in 55% by the rhyme task. In the patients group, interrater agreement was .90 for activations in the inferior frontal and .97 in the superior temporal gyrus. Correlation between the WADA test and fMRI was .86 for the sentence, and .89 for the synonym task. The sentence task provides robust activations in putative essential language areas and can be used for visual analysis of predefined areas to facilitate interpretation of clinical fMRI.

Serotonin transporter binding in the hypothalamus correlates negatively with tonic heat pain ratings in healthy subjects: A [11C]DASB PET study

There is a large body of evidence that the serotonergic system plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) with the serotonin transporter (SERT) tracer [11C]DASB to study the relationship between SERT binding in the brain and responses to noxious heat stimulation in a group of 21 young healthy volunteers. Responses to noxious heat stimuli were assessed in a separate psychophysical experiment and included measurements of pain threshold, pain tolerance, and responses to phasic noxious heat stimuli and to a long lasting (7-minute) tonic noxious heat stimulus. PET data were analyzed using both volume-of-interest (VOI) and voxel-based approaches. VOI analysis revealed a significant negative correlation between tonic pain ratings and SERT binding in the hypothalamus (r=−0.59; p=0.008), a finding confirmed by the parametric analysis. The parametric analysis also revealed a negative correlation between tonic pain ratings and SERT binding in the right anterior insula. Measures of regional SERT binding did not correlate with pain threshold or with responses to short phasic suprathreshold phasic heat stimuli. Finally, the VOI analysis revealed a positive correlation between pain tolerance and SERT binding in the hypothalamus (r=0.53; p=0.02) although this was not seen in the parametric analysis. These data extend our earlier observation that cortical 5-HT receptors co-determine responses to tonic but not to phasic pain. The negative correlation between SERT binding in the hypothalamus and insula with tonic pain ratings suggests a possible serotonergic control of the role of these areas in the modulation or in the affective appreciation of pain.