Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET.

A major challenge in positron emission tomography (PET) amyloid imaging studies of Alzheimer's disease (AD) is the reliable detection of early amyloid deposition in human brain. Manual region-of-interest (ROI) delineation on structural magnetic resonance (MR) images is generally the reference standard for the extraction of count-rate data from PET images, as compared to automated MR-template(s) methods that utilize spatial normalization and a single set of ROIs. The goal of this work was to assess the inter-rater reliability of manual ROI delineation for PiB PET amyloid retention measures and the impact of CSF dilution correction (CSF) on this reliability for data acquired in elderly control (n=5) and AD (n=5) subjects. The intraclass correlation coefficient (ICC) was used to measure reliability. As a secondary goal, ICC scores were also computed for PiB outcome measures obtained by an automated MR-template ROI method and one manual rater; to assess the level of reliability that could be achieved using different processing methods. Fourteen ROIs were evaluated that included anterior cingulate (ACG), precuneus (PRC) and cerebellum (CER). The PiB outcome measures were the volume of distribution (V(T)), summed tissue uptake (SUV), and corresponding ratios that were computed using CER as reference (DVR and SUVR). Substantial reliability (ICC≥0.932) was obtained across 3 manual raters for V(T) and SUV measures when CSF correction was applied across all outcomes and regions and was similar in the absence of CSF correction. The secondary analysis revealed substantial reliability in primary cortical areas between the automated and manual SUV [ICC≥0.979 (ACG/PRC)] and SUVR [ICC≥0.977/0.952 (ACG/PRC)] outcomes. The current study indicates the following rank order among the various reliability results in primary cortical areas and cerebellum (high to low): 1) V(T) or SUV manual delineation, with or without CSF correction; 2) DVR or SUVR manual delineation, with or without CSF correction; 3) SUV automated delineation, with CSF correction; and 4) SUVR automated delineation, with or without CSF correction. The high inter-rater reliability of PiB outcome measures in primary cortical areas (ACG/PRC) is important as reliable methodology is needed for the detection of low levels of amyloid deposition on a cross-sectional basis and small changes in amyloid deposition on a longitudinal basis.

Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B.

There is increasing evidence for an empiric link between late-life depression and Alzheimer disease (AD). The neuropathology of AD, previously only confirmed at autopsy, may now be detectable in vivo using selective imaging ligands for beta-amyloid. Positron emission tomography (PET) with [11C] 6-OH-BTA-1 [Pittsburgh Compound-B (PiB)] has shown high tracer retention in cortical areas in patients with clinical diagnoses of probable AD and low retention in age-matched controls. We also previously reported variable PiB retention in patients with mild cognitive impairment (MCI). In this study, we used PiB-PET to evaluate whether amyloid is present in elders with treated major depression, many of whom have persistent cognitive impairment. We evaluated 9 subjects with remitted major depression [3M: 6F, mean (SD) age=71.8(5.7) y]. Seven of the 9 depressed subjects also met criteria for the diagnosis of MCI. PiB-PET data from healthy elders [n=8; mean (SD) age=71.5(3.0) y] were used for comparison. PET was acquired with arterial sampling and PiB retention was quantified using magnetic resonance imaging-guided cortical regions and graphical analysis of time-activity data; arterial line failure led to exclusion of 1 depressed subject. The data demonstrated variably elevated PiB retention. PiB retention in the 2 depressed subjects with normal cognitive ability was in the range of nondepressed cognitively normal subjects. PiB retention in 3 of the 6 depressed subjects with MCI fell in the range of subjects with AD. PiB retention in the remaining 3 depressed subjects with cooccurring MCI was variable and generally was intermediate to the other subjects. Our findings are consistent with and supportive of the hypothesis that depression may herald the development of AD in some individuals.

Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B.

We evaluated the region-to-region correlation, laterality and asymmetry of amyloid deposition in subjects with mild cognitive impairment (MCI) or Alzheimer's disease (AD) using the amyloid tracer, Pittsburgh Compound B (PiB). Seventeen subjects, including 7 with MCI (MMSE 26.7+/-2.4) and 10 with AD (MMSE of 24.8+/-2.7) underwent PiB imaging. Measures of laterality (i.e., group-wise predilection for right or left) and asymmetry (i.e., group-wise predilection for unequal PiB retention between the two hemispheres) were calculated for 17 Regions of Interest (ROIs). Regional correlations were calculated along with within-group and between-groups statistical analyses of laterality and asymmetry metrics. The median correlation between PiB retention across all pairs of ROIs was 0.65, with highest correlations found in areas of highest PiB retention (r=0.74). Overall, PiB retention was symmetric bilaterally, but there was PiB laterality in MCI in dorsal frontal cortex [(t(6)=3.05, p=0.02, L>R] and sensory-motor area [t(6)=3.10, p=0.02, L>R] and in AD in the occipital pole (t(9)=-2.63, p=0.03, R>L). The most significant asymmetries in PiB retention were found in sub-cortical white matter (t(6)=3.99, p=0.01) and middle precuneus [(t(6)=3.57, p=0.01] in MCI, and in lateral temporal cortex (t(9)=3.02, p=0.01) and anterior ventral striatum [t(9)=2.37, p=0.04] in AD. No group differences (AD versus MCI) were detected in laterality [F (1, 15)=0.15, p=0.7] or asymmetry [F (1, 15)=0.7, p=0.42].

Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease.

Deposition of amyloid plaques is believed to be a central event in the development of Alzheimer's disease (AD). The present study was undertaken to evaluate statistical methods for the assessment of group differences in retention of an amyloid imaging agent, PIB, throughout the brain and to compare these results to FDG studies of glucose metabolism performed in the same subjects on the same day. PET studies were performed in 10 mild to moderate AD and 11 control subjects. Parametric images of PIB retention (over 90 min post-injection) were generated using the Logan graphical analysis with cerebellar (CER, reference region) data as input. FDG parametric images were created by summing the uptake over 40-60 min post-injection and normalizing that to the CER to give a standardized uptake value ratio. Data were compared using parametric (SPM) and non-parametric (SnPM) statistical methods with familywise error (FWE) and false discovery rate (FDR) corrections. PIB results were consistent with previous regional results as AD subjects showed highly significant retention in frontal, parietal, temporal, and posterior cingulate cortices (FDR-corrected p<1.4e-10). FDG results showed regions of marginally significant decreases in uptake in AD subjects (frontal, parietal, temporal, posterior cingulate cortices: FDR-corrected p<0.1) consistent with previous studies. Relative to FDG, the PIB analyses were of greater statistical significance and larger spatial extent. Additionally, the PIB analyses retained significance after both FWE and FDR corrections. These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment.

Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis.

UNLABELLED: PET studies have been performed using the amyloid binding radiotracer Pittsburgh Compound B (PIB). Previous quantitative analyses using arterial blood showed that the Logan graphical analysis using 90 min of emission data (ART90) provided a reliable measure of PIB retention. This work reports on simplified methods of analysis for human PIB imaging. METHODS: PIB PET scans were conducted in 24 subjects (6 Alzheimer's disease [AD], 10 mild cognitive impairment [MCI], 8 controls) with arterial blood sampling. Retest scans were performed on 8 subjects (3 AD, 1 MCI, 4 controls) within 28 d. Data were analyzed over 60 and 90 min using the Logan analysis and (a) metabolite-corrected input functions based on arterial plasma (ART60, ART90), (b) carotid artery time-activity data with a population average metabolite correction (CAR60, CAR90); and (c) cerebellar reference tissue (CER60, CER90). Data also were analyzed using the simplified reference tissue method (SRTM60, SRTM90) and a single-scan method based on late-scan ratios of standardized uptake values (SUVR60, SUVR90). RESULTS: All methods of analysis examined effectively discerned regional differences between AD and control subjects in amyloid-laden cortical regions, although the performance of the simplified methods varied in terms of bias, test-retest variability, intersubject variability, and effect size. CAR90 best agreed with ART90 distribution volume ratio (DVR) measures across brain regions and subject groups and demonstrated satisfactory test-retest variability (+/-7.1% across regions). CER90 and CER60 showed negative biases relative to ART90 in high-DVR subjects but had the lowest test-retest variability. The single-scan SUV-based methods showed the largest effect sizes for AD and control group differences and performed well in terms of intersubject and test-retest variability. CONCLUSION: Of the simplified methods for PIB analysis examined, CAR90 provided DVR measures that were most comparable to ART90; CER90 was the most reproducible and SUVR90 produced the largest effect size. All simplified methods were effective at distinguishing AD and control differences and may be effectively used in the analysis of PIB. SUVR60 data can be obtained with as little as 20 min of PET emission data collection. The relative strengths and limitations of each method must be considered for each experimental design.

Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B.

A valid quantitative imaging method for the measurement of amyloid deposition in humans could improve Alzheimer's disease (AD) diagnosis and antiamyloid therapy assessment. Our group developed Pittsburgh Compound-B (PIB), an amyloid-binding radiotracer, for positron emission tomography (PET). The current study was aimed to further validate PIB PET through quantitative imaging (arterial input) and inclusion of subjects with mild cognitive impairment (MCI). Pittsburgh Compound-B studies were performed in five AD, five MCI, and five control subjects and five subjects were retested within 20 days. Magnetic resonance images were acquired for partial volume correction and region-of-interest definition (e.g., posterior cingulate: PCG; cerebellum: CER). Data were analyzed using compartmental and graphical approaches. Regional distribution volume (DV) values were normalized to the reference region (CER) to yield DV ratios (DVRs). Good agreement was observed between compartmental and Logan DVR values (e.g., PCG: r=0.89, slope=0.91); the Logan results were less variable. Nonspecific PIB retention was similar across subjects (n=15, Logan CER DV: 3.63+/-0.48). Greater retention was observed in AD cortical areas, relative to controls (P<0.05). The PIB retention in MCI subjects appeared either 'AD-like' or 'control-like'. The mean test/retest variation was approximately 6% in primary areas-of-interest. The Logan analysis was the method-of-choice for the PIB PET data as it proved stable, valid, and promising for future larger studies and voxel-based statistical analyses. This study also showed that it is feasible to perform quantitative PIB PET imaging studies that are needed to validate simpler methods for routine use across the AD disease spectrum.