Catharina Lange

PETPVE12: an SPM toolbox for Partial Volume Effects correction in brain PET – Application to amyloid imaging with AV45-PET

ABSTRACT Positron emission tomography (PET) allows detecting molecular brain changes in vivo. However, the accuracy of PET is limited by partial volume effects (PVE) that affects quantitative analysis and visual interpretation of the images. Although PVE‐correction methods have been shown to effectively increase the correspondence of the measured signal with the true regional tracer uptake, these procedures are still not commonly applied, neither in clinical nor in research settings. Here, we present an implementation of well validated PVE‐correction procedures as a SPM toolbox, PETPVE12, for automated processing. We demonstrate its utility by a comprehensive analysis of the effects of PVE‐correction on amyloid‐sensitive AV45‐PET data from 85 patients with Alzheimers disease (AD) and 179 cognitively normal (CN) elderly. Effects of PVE‐correction on global cortical standard uptake value ratios (SUVR) and the power of diagnostic group separation were assessed for the region‐wise geometric transfer matrix method (PVEc‐GTM), as well as for the 3‐compartmental voxel‐wise “Müller‐Gärtner” method (PVEc‐MG). Both PVE‐correction methods resulted in decreased global cortical SUVRs in the low to middle range of SUVR values, and in increased global cortical SUVRs at the high values. As a consequence, average SUVR of the CN group was reduced, whereas average SUVR of the AD group was increased by PVE‐correction. These effects were also reflected in increased accuracies of group discrimination after PVEc‐GTM (AUC=0.86) and PVEc‐MG (AUC=0.89) compared to standard non‐corrected SUVR (AUC=0.84). Voxel‐wise analyses of PVEc‐MG corrected data also demonstrated improved detection of regionally increased AV45 SUVR values in AD patients. These findings complement the growing evidence for a beneficial effect of PVE‐correction in quantitative analysis of amyloid‐sensitive PET data. The novel PETPVE12 toolbox significantly facilitates the application of PVE‐correction, particularly within SPM‐based processing pipelines. This is expected to foster the use of PVE‐correction in brain PET for more widespread use. The toolbox is freely available at http://www.fil.ion.ucl.ac.uk/spm/ext/#PETPVE12. HIGHLIGHTSPartial volume effects (PVE) introduce significant bias in PET imaging studies.PETPVE12 is a user‐friendly toolbox for PVE correction within SPM software.We evaluate the toolbox on AV45 PET images from AD patients and controls.PVE correction improves diagnostic group separation based on AV45 PET scans.Results underline the benefit of PVEc for quantitative amyloid PET analysis.

CT-based attenuation correction in I-123-ioflupane SPECT.

Purpose Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane. Materials and methods Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator-characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre. Results CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC. Conclusions The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure.

Performance of Hippocampus Volumetry with FSL-FIRST for Prediction of Alzheimer’s Disease Dementia in at Risk Subjects with Amnestic Mild Cognitive Impairment

MRI-based hippocampus volume, a core feasible biomarker of Alzheimers disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-FIRST for prediction of AD dementia (ADD) in subjects with amnestic mild cognitive impairment (aMCI) from phase 1 of the Alzheimers Disease Neuroimaging Initiative. Receiver operating characteristic analysis of FSL-FIRST hippocampal volume (corrected for head size and age) revealed an area under the curve of 0.79, 0.70, and 0.70 for prediction of aMCI-to-ADD conversion within 12, 24, or 36 months, respectively. Thus, FSL-FIRST provides about the same power for prediction of progression to ADD in aMCI as other volumetry methods.

Performance Evaluation of Stationary and Semi-Stationary Acquisition with a Non-Stationary Small Animal Multi-Pinhole SPECT System

PurposeStep-and-shoot mode with many angular steps results in long frame duration limiting the capability of single-photon emission computed tomography (SPECT) for fast dynamic scans. The present study evaluates acquisition with reduced angular sampling for fast imaging in preclinical research with the nanoSPECT/CTplus four-head multi-pinhole system.ProceduresMeasurements with line sources, homogeneity phantoms and a Jaszczak phantom filled with 99mTc or 123I were performed to evaluate the ‘stationary’ and ‘semi-stationary’ acquisition mode (one or two detector positions, respectively) with respect to spatial resolution, quantification, noise properties and image artefacts. An in vivo mouse study was performed with 99mTc-MAG3.ResultsThe fast acquisition modes resulted in only minor degradation of spatial resolution and quantification accuracy. Statistical noise in reconstructed images was significantly reduced compared to conventional SPECT, particularly at low count statistics. Stationary acquisition resulted in streak artefacts and spatial distortion.ConclusionsThe semi-stationary acquisition mode of the nanoSPECT/CTplus allows fast dynamic SPECT with tolerable loss of image quality.

Semiquantitative slab view display for visual evaluation of 123I-FP-CIT SPECT.

ObjectiveDopamine transporter single-photon emission computed tomography (SPECT) with 123I-FP-CIT is used widely in the diagnosis of clinically uncertain parkinsonian syndromes. In terms of the evaluation of FP-CIT SPECT, some practice guidelines state that visual interpretation alone is generally sufficient in clinical patient care, whereas other guidelines consider semiquantitative analysis of striatal dopamine transporter availability mandatory. This discrepancy might be because of a relative lack of widely available display tools for FP-CIT SPECT. In this study, we evaluate a semiquantitative slab view display optimized for visual evaluation of FP-CIT SPECT that might resolve the discrepancy. Patients and methodsThe reconstructed FP-CIT SPECT image was stereotactically normalized and scaled voxel by voxel to the mean uptake in the entire brain without striata. From the resulting distribution volume ratio image, a 12-mm-thick transversal slice (slab) through the striata was displayed with a standard colour table with predefined fixed thresholds on the distribution volume ratio. Visual scoring of the semiquantitative slab view was performed twice by four independent readers in 235 unselected patients. The specific binding ratio in the caudate and putamen was computed by fully automated semiquantitative analysis with predefined standard regions of interest in template space. ResultsIntrarater and inter-rater agreement of binary visual categorization as ‘normal’ or ‘reduced’ was excellent (mean Cohen’s &kgr;=0.88 and 0.83, respectively). The area under the receiver–operator characteristic curve of the specific putamen-binding ratio for differentiation between visually normal and visually reduced (majority read) was 0.96. ConclusionVisual interpretation of FP-CIT SPECT on the basis of the semiquantitative slab view display provides excellent stability within and between readers as well as very high agreement with semiquantitative analysis. This suggests that the slab view display enables reliable visual interpretation of FP-CIT SPECT in clinical routine patient care.

Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients.

BACKGROUND The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease. OBJECTIVE To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients. METHODS Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimers disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. RESULTS Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p≤0.001). Integration of all modalities resulted in 76% accuracy (p≤0.001). CONCLUSION These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process.

Brain perfusion imaging under acetazolamide challenge for detection of impaired cerebrovascular reserve capacity: positive findings with O-15-water PET in patients with negative Tc-99m-HMPAO SPECT

Cerebrovascular reserve capacity (CVRC) is an important parameter for treatment decisions in chronic cerebrovascular diseases. It can be assessed by measuring the acetazolamide-induced change in regional cerebral blood flow using SPECT with 99mTc-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) or PET with 15O-water. Methods: Our database was searched for patients with moyamoya vasculopathy or atherosclerotic cerebrovascular disease who had undergone 15O-water PET after normal 99mTc-HMPAO SPECT results with respect to CVRC. 15O-water PET was analyzed visually and quantitatively. Quantitative analysis was based on parametric CVRC maps generated by voxelwise image subtraction. Results: The search identified 18 patients (43 ± 15 y, 12 moyamoya vasculopathy). PET revealed impaired CVRC in 8 patients (44%). Quantitative analysis confirmed the positive visual findings in 15O-water PET and the negative findings in 99mTc-HMPAO SPECT. Conclusion: 15O-water PET enables detection of impaired CVRC in a considerable fraction of symptomatic patients with stenoocclusion and negative 99mTc-HMPAO SPECT.

Challenges in Screening and Recruitment for a Neuroimaging Study in Cognitively Impaired Geriatric Inpatients

BACKGROUND Neuroimaging-based biomarkers have the potential to improve etiological diagnosis of cognitive impairment in elderly inpatients. However, there is a relative lack of studies on neuroimaging-based biomarkers in hospitalized geriatric patients, as the vast majority of neuroimaging studies in dementia have focused on memory clinic outpatients. An important aspect of study planning is a priori estimation of the rate of screen failures. OBJECTIVE To report on the rate and causes of screen failures in a prospective study on the utility of neuroimaging (PET, MRI) for the etiological diagnosis of newly manifested cognitive impairment in acutely hospitalized geriatric patients. METHODS Ten acute care geriatrics clinics with 802 beds participated in the study. The potential recruitment rate had been estimated to 5 patients/100 beds/week. RESULTS Seventeen months of pre-screening resulted in 322 potential participants. 109 of these patients were enrolled, i.e., the screen failure rate was 66%. 58% of the screen failures were due to refusal of participation by the patient, most often due to lack of interest in clarifying the cause of the cognitive impairment or due to reluctance to engage in additional diagnostic procedures associated with physical stress. 42% of pre-screened patients were excluded because of violation of the eligibility criteria. CONCLUSION Enrollment for neuroimaging studies presents considerable additional challenges in acutely hospitalized geriatric patients compared to outpatient settings. Low rate of approaching potential candidates by attending geriatricians and a high rate of screen failures have to be anticipated in the study design.

Fully Automatic MRI-Based Hippocampus Volumetry Using FSL-FIRST: Intra-Scanner Test-Retest Stability, Inter-Field Strength Variability, and Performance as Enrichment Biomarker for Clinical Trials Using Prodromal Target Populations at Risk for Alzheimer’s Disease

BACKGROUND MRI-based hippocampus volume is a core clinical biomarker for identification of Alzheimers disease (AD). OBJECTIVE To assess robustness of automatic hippocampus volumetry with the freely available FSL-FIRST software with respect to short-term repeat and across field strength imaging. FSL-FIRST hippocampus volume (FIRST-HV) was also evaluated as enrichment biomarker for mild cognitive impairment (MCI) trials. METHODS Robustness of FIRST-HV was assessed in 51 healthy controls (HC), 74 MCI subjects, and 28 patients with AD dementia from ADNI1, each with two pairs of back-to-back scans, one at 1.5T one at 3T. Enrichment performance was tested in a second sample of 287 ADNI MCI subjects. RESULTS FSL-FIRST worked properly in all four scans in 147 out of 153 subjects of the first sample (49 HC, 72 MCI, 26 AD). In these subjects, FIRST-HV did not differ between the first and the second scan within an imaging session, neither at 1.5T nor at 3T (p≥0.302). FIRST-HV was on average 0.78% larger at 3T compared to 1.5T (p = 0.012). The variance of the FIRST-HV difference was larger in the inter-field strength setting than in the intra-scanner settings (p < 0.0005). Computer simulations suggested that the additional variability encountered in the inter-field strength scenario does not cause a relevant degradation of FIRST-HVs prognostic performance in MCI. FIRST-HV based enrichment resulted in considerably increased effect size of the 2-years change of cognitive measures. CONCLUSION The impact of intra-scanner test-retest and inter-field strength variability of FIRST-HV on clinical tasks is negligible. In addition, FIRST-HV is useful for enrichment in clinical MCI trials.

Utility of Follow-up Dopamine Transporter SPECT With 123I-FP-CIT in the Diagnostic Workup of Patients With Clinically Uncertain Parkinsonian Syndrome

Purpose Dopamine transporter SPECT with 123I-FP-CIT is registered for detection (or exclusion) of nigrostriatal degeneration to support the etiologic classification of parkinsonian syndromes. In case of uncertainty in the interpretation of SPECT findings or unexpected clinical course, follow-up SPECT might be useful. However, the utility of follow-up FP-CIT SPECT has not yet been clarified. Methods One hundred forty-one patients (65.1 ± 10.4 years) from 3 sites with follow-up FP-CIT SPECT 22.4 ± 13.7 months after baseline SPECT were included. Retrospective visual interpretation of FP-CIT SPECT scans was performed by 2 experienced readers according to the following 7-point score: “normal,” some minor degree of uncertainty due to “mild asymmetry” or mild to moderate “uniform reduction,” “Parkinson disease (PD) reduction type 1/2/3,” and “atypical reduction.” Results Normal FP-CIT SPECT or PD characteristic reduction was confirmed by follow-up SPECT in all cases (n = 58). Among patients with some minor degree of uncertainty at baseline (n = 65), the majority (72%) did now show abnormalities in follow-up SPECT, but 20% showed clear progression suggesting nigrostriatal degeneration. The latter was very rare at age younger than 60 years. The final categorization as normal or neurodegenerative was not affected by the time delay between baseline and follow-up SPECT. Conclusions Follow-up FP-CIT SPECT cannot be generally recommended in case of completely normal baseline SPECT or PD characteristic reduction. It also cannot be recommended in patients younger than 60 years, even in case of some minor degree of uncertainty in the baseline SPECT. There is no evidence to delay follow-up FP-CIT SPECT longer than 12 months.