11C-PiB Uptake Research Articles

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease.

Objective:Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer’s disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer’s disease.Methods:We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer’s disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping.Results:We found that the probable Alzheimer’s disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration.Conclusions:Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Independent Prognostic Utility of 11C-Pittsburgh Compound B PET in Patients with Light-Chain Cardiac Amyloidosis.

11C-Pittsburgh compound B (PiB) PET/CT visualizes the amount of myocardial amyloid deposit and can be used to prognosticate patients with amyloid light-chain (AL) cardiac amyloidosis (CA). However, whether 11C-PiB PET/CT has any independent additional prognostic value beyond the commonly used biomarkers remains unknown. Methods: This prospective study was on a cohort of 58 consecutive patients with AL CA who underwent 11C-PiB PET/CT. The patients were stratified into 2 groups on the basis of a visual assessment of whether there was myocardial 11C-PiB uptake on PET/CT. The primary endpoint was 1-y overall mortality. The independent prognostic utility of 11C-PiB PET/CT was analyzed using net reclassification improvement and integrated discrimination improvement. Results: Among the 58 patients enrolled, 35 were positive for myocardial 11C-PiB uptake on PET/CT. Patients with myocardial 11C-PiB PET uptake had a worse 1-y overall survival rate than those without (81.8% vs. 45.5%, P = 0.003 by log-rank test). In the multivariate analysis, positivity for myocardial 11C-PiB uptake on PET/CT was an independent predictor of 1-y mortality (adjusted hazard ratio, 3.382; 95% CI, 1.011-11.316; P = 0.048). In analysis of 3 subgroups of patients-those with a troponin I level of at least 0.1 ng/mL, those with an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of at least 1,800 pg/mL, and those with a difference of at least 180 mg/L between free light chains (the 3 commonly used biomarkers and their thresholds for staging in AL amyloidosis)-Kaplan-Meier curves showed for all 3 subgroups that patients positive for myocardial 11C-PiB uptake on PET/CT had a worse prognosis than those who were negative. Additionally, when the results of 11C-PiB PET/CT were added to these 3 biomarkers, the performance of 1-y mortality prediction significantly improved by net reclassification improvement (troponin I, 0.861; NT-proBNP, 0.914; difference between free light chains, 0.987) and by integrated discrimination improvement (0.200, 0.156, and 0.108, respectively). Conclusion:11C-PiB PET/CT is a strong independent predictor of 1-y overall mortality and provides incremental prognostic benefits beyond the 3 commonly used biomarkers of AL amyloidosis staging. Considering the recent development of numerous amyloid-targeting molecular imaging agents, further investigations are warranted on whether PET/CT should be included in risk stratification for patients with AL CA.

Myelin imaging measures as predictors of cognitive impairment in MS patients: A hybrid PET-MRI study

BackgroundCognitive impairment is one of the concerns of Multiple Sclerosis (MS) and has been related to myelin loss. Different neuroimaging methods have been used to quantify myelin and relate it to cognitive dysfunctions, among them Magnetization Transfer Ratio (MTR), Diffusion Tensor Imaging (DTI), and, more recently, Positron Emission Tomography (PET) with 11C-PIB. ObjectiveTo investigate different myelin imaging modalities as predictors of cognitive dysfunction. MethodsFifty-one MS patients and 24 healthy controls underwent clinical and neuropsychological assessment and MTR, DTI (Axial Diffusion-AD and Fractional Anisotropy-FA maps), and 11C-PIB PET images in a PET/MR hybrid system. ResultsMTR and DTI(FA) differed in patients with or without cognitive impairment. There was an association of DTI(FA) and DTI(AD) with cognition and psychomotor speed for progressive MS, and of 11C-PIB uptake and MTR for relapsing-remitting MS. MTR in the Thalamus (β= -0.51, p = 0.021) and Corpus Callosum (β= -0.24, p = 0.033) were predictive of cognitive impairment. DTI-FA in the Caudate (β= -26.93, p = 0.006) presented abnormal predictive result. ConclusionLower myelin content by 11C-PIB uptake was associated with worse cognitive status. MTR was predictive of cognitive impairment in MS.

Noninvasive Detection of Cardiac Amyloid With 11C-Pittsburgh Compound B PET/CT and 99mTc-PYP Scintigraphy.

We report the imaging findings of 2 cases of cardiac amyloidosis, one light chain (AL) type and another transthyretin (ATTR) type. The images showed 11C-Pittsburgh compound B (11C-PIB) uptake in the heart with AL amyloidosis, whereas the ATTR amyloidosis showed 11C-PIB-negative and 99mTc-PYP-positive uptake in the heart. It demonstrated that using 99mTc-PYP scintigraphy and 11C-PIB PET/CT might be able to differentiate these 2 major types of cardiac amyloidosis noninvasively.

11C-UCB-J synaptic PET and multimodal imaging in dementia with Lewy bodies

ObjectiveDementia with Lewy bodies (DLB) is a common cause of dementia, but atrophy is mild compared to Alzheimer’s disease. We propose that DLB is associated instead with severe synaptic loss, and we test this hypothesis in vivo using positron emission tomography (PET) imaging of 11C-UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein ubiquitously expressed in synapses.MethodsWe performed 11C-UCB-J PET in two DLB patients (an amyloid-negative male and an amyloid-positive female in their 70s) and 10 similarly aged healthy controls. The DLB subjects also underwent PET imaging of amyloid (11C-PiB) and tau (18F-AV-1451). 11C-UCB-J binding was quantified using non-displaceable binding potential (BPND) determined from dynamic imaging. Changes in 11C-UCB-J binding were correlated with MRI regional brain volume, 11C-PiB uptake and 18F-AV-1451 binding.ResultsCompared to controls, both patients had decreased 11C-UCB-J binding, especially in parietal and occipital regions (FDR-corrected p < 0.05). There were no significant correlations across regions between 11C-UCB-J binding and grey matter, tau (18F-AV1451) or amyloid (11C-PiB) in either patient.ConclusionsQuantitative imaging of in vivo synaptic density in DLB is a promising approach to understanding the mechanisms of DLB, over and above changes in grey matter volume and concurrent amyloid/tau deposition.

Prognostication of cardiac amyloidosis by pittsburgh b compound positron emission tomography

Abstract Introduction Regardless of the underlying pathogenesis of amyloid production, cardiac involvement is the leading cause of morbidity and mortality in systemic amyloidosis. In the cardiac variant, there is an extracellular deposition of amyloid substance throughout the heart. The infiltrative process results in ventricular wall thickening with concentric hypertrophy and low cardiac output. The PiB compound has been promising for the detection of amyloid deposits in the brain but it remains unknown whether this noninvasive evaluation can predict the prognosis of patients with cardiac amyloidosis. Purpose This study sought to investigate the efficacy of 11C-Pittsburgh B (PiB) positron emission tomography for prognostication of cardiac amyloidosis by noninvasively imaging the myocardial amyloid deposition. Methods A total of 33 consecutive patients were enrolled in this prospective pilot study with suspected cardiac amyloidosis. The amyloid deposit was assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial 11C-PiB uptake on PET. Results It was found that the degree of myocardial 11C-PiB PET uptake was significantly greater in the patients of cardiac amyloidosis compared with control group subjects and was parallel with the degree of amyloid deposit on histology (p&amp;lt;0.001). When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial 11C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p=0.013). The clinical outcome was significantly predicted by the degree of myocardial PiB PET uptake on multivariate Cox regression analysis (adjusted hazard ratio: 1.191; 95% confidence interval: 1.062 to 1.340; p=0.005). Conclusion Our study concludes that the noninvasive evaluation of myocardial amyloid load by 11C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in cardiac amyloidosis patients. 11-C Pittsburgh B PET imaging Funding Acknowledgement Type of funding source: Other. Main funding source(s): Self funding

Non-invasive detection and differentiation of cardiac amyloidosis using 99mTc-pyrophosphate scintigraphy and 11C-Pittsburgh compound B PET imaging

Purpose To investigate the utility of the combined use of 11C-Pittsburgh compound B (11C-PiB) positron emission tomography (PET) imaging and 99mTc-pyrophosphate (99mTc-PYP) scintigraphy for detection and differentiation of three major types of cardiac amyloidosis, i.e. immunoglobulin light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt) amyloidosis. Methods Whole-body 11C-PiB PET and 99mTc-PYP scintigraphy were performed in 17 patients with AL amyloidosis, 22 patients with ATTRv, and eight patients with ATTRwt amyloidosis. The correlations between organ involvement and the uptake of 11C-PiB and 99mTc-PYP were analyzed in each patient. Results Cardiac amyloidosis was detectable by 99mTc-PYP scintigraphy or 11C-PiB PET in all systemic amyloidosis patients with cardiac involvement. 99mTc-PYP scintigraphy and 11C-PiB PET showed an interesting complementary relation. Strict combination of positive 11C-PiB and negative 99mTc-PYP uptake (PiB pattern) was observed in all AL amyloidosis patients with cardiac involvement. In contrast, strict combination of positive 99mTc-PYP and negative 11C-PiB uptake (PYP pattern) was observed in all ATTRwt amyloidosis patients with cardiac involvement. ATTRv amyloidosis patients with cardiac involvement were divided into two groups: PiB pattern or PYP pattern. All of the early-onset V30M (p.V50M) ATTRv patients showed the PiB pattern, whereas all of the late-onset V30M and non-V30M ATTRv patients showed the PYP pattern. Conclusions All three major types of cardiac amyloidosis can be detected and differentiated non-invasively by combined use of the two amyloid imaging methods and TTR gene testing.

Quantification of 11C-PIB kinetics in cardiac amyloidosis

BackgroundThe purpose of this work was to determine the optimal tracer kinetic model of 11C-PIB and to validate the use of the simplified methods retention index (RI) and standardized uptake value (SUV) for quantification of cardiac 11C-PIB uptake in amyloidosis. Methods and resultsSingle-tissue, reversible and irreversible two-tissue models were fitted to data from seven cardiac amyloidosis patients who underwent 11C-PIB PET scans and arterial blood sampling for measurement of blood radioactivity and metabolites. The irreversible two-tissue model (2Tirr) best described cardiac 11C-PIB uptake. RI and SUV showed high correlation with the rate of irreversible binding (Ki) from the 2Tirr model (r2 =0.95 and r2 =0.94). Retrospective data from 10 amyloidosis patients and 5 healthy controls were analyzed using RI, SUV, as well as compartment modelling with a population-average metabolite correction. All measures were higher in amyloidosis patients than in healthy controls (p=.001), but with an overlap between groups for Ki. ConclusionAn irreversible two-tissue model best describes the 11C-PIB uptake in cardiac amyloidosis. RI and SUV correlate well with Ki from the 2Tirr model. RI and SUV discriminate better between amyloidosis patients and controls than Ki based on population-average metabolite correction.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer\u2019s disease: a longitudinal PET study

BackgroundThe aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.MethodsForty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.ResultsThose MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.ConclusionsOur baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Significance of 11C-PIB PET/CT in cardiac amyloidosis compared with 99mTc-aprotinin scintigraphy: A pilot study

BackgroundThis study was to investigate the significance of 11C-Pittsburgh B (PIB) PET/CT in patients with suspected cardiac amyloidosis compared with 99mTc-aprotinin scintigraphy. MethodsThirteen consecutive patients with suspected cardiac amyloidosis were considered for enrolment in this prospective pilot study. Participants were scheduled to undergo a series of 11C-PIB PET/CT and 99mTc-aprotinin within a 2-month period. Finally, we evaluated nine cases who underwent both imaging modalities, and compared imaging results with clinical and pathological results and prognosis. ResultsSix of the 9 patients who underwent both imaging modalities were diagnosed with amyloidosis, of whom 3 patients were diagnosed with cardiac amyloidosis from endomyocardial biopsy. These 3 patients with positive 11C-PIB uptake at the left ventricle wall showed worsening of cardiac function progressing in the short term or death caused by acute exacerbation of chronic heart failure. Six of 8 patients with positive uptake on 99mTc-aprotinin presented with amyloid deposition in the left ventricle wall, but symptoms remained stable if results of 11C-PIB were not positive. ConclusionIn a small sample of subjects, the present study showed that 11C-PIB accumulation in myocardium indicated cardiac amyloidosis with poor prognosis. Uptake of 11C-PIB may be related to progressive amyloid deposition to the heart and can predict patient prognosis.

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis

BackgroundIt remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis. ObjectivesThe purpose of this study was to demonstrate that 11C-Pittsburgh B compound positron emission tomography (11C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition. MethodsThis study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial 11C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure. ResultsThe degree of myocardial 11C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R2 = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial 11C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005). ConclusionsThese proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by 11C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

Topography of 11C-Pittsburgh compound B uptake in Alzheimer's disease: a voxel-based investigation of cortical and white matter regions.

Objective:To compare results of positron emission tomography (PET) with carbon-11-labeled Pittsburgh compound B (11C-PIB) obtained with cerebellar or global brain uptake for voxel intensity normalization, describe the cortical sites with highest tracer uptake in subjects with mild Alzheimer’s disease (AD), and explore possible group differences in 11C-PIB binding to white matter.Methods: 11C-PIB PET scans were acquired from subjects with AD (n=17) and healthy elderly controls (n=19). Voxel-based analysis was performed with statistical parametric mapping (SPM).Results:Cerebellar normalization showed higher 11C-PIB uptake in the AD group relative to controls throughout the cerebral cortex, involving the lateral temporal, orbitofrontal, and superior parietal cortices. With global uptake normalization, greatest cortical binding was detected in the orbitofrontal cortex; decreased 11C-PIB uptake in white matter was found in the posterior hippocampal region, corpus callosum, pons, and internal capsule.Conclusion:The present case-control voxelwise 11C-PIB PET comparison highlighted the regional distribution of amyloid deposition in the cerebral cortex of mildly demented AD patients. Tracer uptake was highest in the orbitofrontal cortex. Decreased 11C-PIB uptake in white-matter regions in this patient population may be a marker of white-matter damage in AD.

White Matter Reference Region in PET Studies of 11C-Pittsburgh Compound B Uptake: Effects of Age and Amyloid-β Deposition.

Amyloid-β (Aβ) deposition as seen on PET using an Aβ-binding agent is a critical diagnostic biomarker for Alzheimer disease (AD). Some reports suggest using white matter (WM) as a reference region for quantification of serial Aβ PET studies; however, nonspecific WM retention in Aβ PET in people with dementia or cognitively unimpaired (CU) has been widely reported and is poorly understood. Methods: To investigate the suitability of WM as a reference region and the factors affecting WM 11C-Pittsburgh compound B (11C-PiB) uptake variability, we conducted a retrospective study on 2 large datasets: a longitudinal study of participants (n = 577) who were CU, had mild cognitive impairment, or had dementia likely due to AD; and a cross-sectional study of single-scan PET imaging in CU subjects (n = 1,349). In the longitudinal study, annual changes in WM 11C-PiB uptake were assessed, and in the cross-sectional study, WM 11C-PiB uptake was assessed relative to subject age. Results: Overall, we found that WM 11C-PiB uptake showed age-related increases, which varied with the WM regions selected. Further, variable annual WM 11C-PiB uptake changes were seen with different gray matter (GM) 11C-PiB baseline uptake levels. Conclusion: WM binding increases with age and varies with GM 11C-PiB. These correlations should be considered when using WM for normalization in 11C-PiB PET studies. The cerebellar crus1+crus2 showed no increase with age and cerebellar GM+WM showed minimal increase, supporting their use as reference regions for cross-sectional studies comparing wide age spans. In longitudinal studies, the increase in WM uptake may be minimal in the short-term and thus using WM as a reference region in these studies seems reasonable. However, as participants age, the findings may be affected by changes in WM uptake. Changes in WM 11C-PiB uptake may relate to disease progression, warranting examination of the causes of WM 11C-PiB uptake.

Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease.

Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.

Visualization of multiple organ amyloid involvement in systemic amyloidosis using 11C-PiB PET imaging.

To investigate the utility of Pittsburgh compound B (PiB) positron emission tomography (PET) imaging for evaluating whole-body amyloid involvement in patients with systemic amyloidosis. Whole-body 11C-PiB PET was performed in seven patients with systemic immunoglobulin light-chain (AL) amyloidosis, seven patients with hereditary transthyretin (ATTRm) amyloidosis, one asymptomatic TTR mutation carrier and three healthy controls. The correlations between clinical organ involvement, radiological 11C-PiB uptake and histopathological findings were analysed for each organ. Organ involvement on 11C-PiB PET imaging showed good correlations with the clinical findings for the heart and stomach. Abnormal tracer uptake was also observed in the spleen, lachrymal gland, submandibular gland, sublingual gland, lymph node, brain, scalp, extraocular muscles, nasal mucosa, pharynx, tongue and nuchal muscles, most of which were asymptomatic. Physiological tracer uptake was universally observed in the urinary tract (kidney, renal pelvis, ureter and bladder) and enterohepatic circulatory system (liver, gallbladder, bile duct and small intestine) in all participants. Most of the patients and one healthy control subject showed asymptomatic tracer uptake in the lung and parotid gland. The peripheral nervous system did not show any tracer uptake even in patients with apparent peripheral neuropathy. Histological amyloid deposition was confirmed in biopsied myocardium and gastric mucosa where abnormal 11C-PiB retention was observed. 11C-PiB PET imaging can be used clinically in the systemic evaluation of amyloid distribution in patients with AL and ATTRm amyloidosis. Quantitative analysis of 11C-PiB PET images may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response.

TAU PATHOLOGY AND GRAY MATTER ATROPHY CONTRIBUTE TO COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE

Neuropathological and in vivo studies have revealed a close relationship between tau pathology and cognitive impairment across the Alzheimer's disease (AD) spectrum. However, tau pathology is also intimately associated with neurodegeneration. We therefore assessed in a heterogeneous sample of AD patients whether the relationship between tau pathology, as measured with 18F-AV1451-PET imaging, and cognition remained significant after controlling for local gray matter atrophy and amyloid pathology. We also performed causal mediation analyses to further examine the potential intermediary role of gray matter atrophy. Forty Aβ-PET+ patients with heterogeneous AD phenotypes (Table 1) underwent 3T MRI, 11C-PiB-PET and 18F-AV1451-PET, and episodic and semantic memory, language, executive and visuo-spatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 SUVR and each cognitive domain and Biological Parametric Mapping (BPM) was used to further control for local gray matter volumes, PIB-DVR, or both. Partial correlations and mediation analyses (mediation R package) were performed in brain regions showing an association between cognition and both 18F-AV-1451 SUVR and gray matter volume. The average direct effect (ADE) and average causal mediation effect (ACME), reflecting direct and indirect effects 18F-AV-1451 on cognition, were computed using the mediation R package (non-parametric bootstrapping, 5000 simulations). Decreased cognitive performance in each domain was related to increased 18F-AV-1451 SUVR in specific brain regions conforming to established brain-behavior relationships (Figure 1). This pattern of regional associations remained essentially unchanged – although less spatially extended – when gray matter volume or 11C-PiB uptake maps were added as covariates (Figure 2). Mediation analyses revealed both direct and gray matter-mediated effects of 18F-AV-1451 uptake on cognitive performance (Figure 3). Tau pathology is related in a region-specific manner to cognitive impairment in AD. These regional relationships are weakly related to amyloid burden, but are in part mediated by gray matter volumes. These results suggest that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted, to neuronal loss. Voxel-wise results and scatter plots of the independent regressions between 18F-AV-1451 SUVR and each cognitive domain score. (SPM, p<0.001 - k>500 mm3). Voxel-wise results of the multiple regressions between 18F-AV-1451 SUVR and each cognitive domain score controlling for local grey matter volume and/or local 11C-PiB DVR. (Biological Parametric Mapping, p<0.001 - k>500 mm3) Partial correlations and mediation analyses in the brain areas where both 18F-AV-1451 SUVR and gray matter volume were related to cognitive domain scores.

Accurate analysis and visualization of cardiac 11C-PIB uptake in amyloidosis with semiautomatic software

Background11C-PIB PET is a promising non-invasive diagnostic tool for cardiac amyloidosis. Semiautomatic analysis of PET data is now available but it is not known how accurate these methods are for amyloid imaging. The aim of this study was to evaluate the feasibility of one semiautomatic software tool for analysis and visualization of 11C-PIB left ventricular retention index (RI) in cardiac amyloidosis. Methods and resultsPatients with systemic amyloidosis and cardiac involvement (n = 10) and healthy controls (n = 5) were investigated with dynamic 11C-PIB PET. Two observers analyzed the PET studies with semiautomatic software to calculate the left ventricular RI of 11C-PIB and to create parametric images. The mean RI at 15-25 min from the semiautomatic analysis was compared with RI based on manual analysis and showed comparable values (0.056 vs 0.054 min−1 for amyloidosis patients and 0.024 vs 0.025 min−1 in healthy controls; P = .78) and the correlation was excellent (r = 0.98). Inter-reader reproducibility also was excellent (intraclass correlation coefficient, ICC > 0.98). Parametric polarmaps and histograms made visual separation of amyloidosis patients and healthy controls fast and simple. ConclusionAccurate semiautomatic analysis of cardiac 11C-PIB RI in amyloidosis patients is feasible. Parametric polarmaps and histograms make visual interpretation fast and simple.

Sphenoid Wing Meningioma Behavior on 11C-PiB and 18F-FDG PET

Two patients with mild cognitive impairment underwent C-PiB and F-FDG brain PET. Both patients had previously gone through a contrast-enhanced MRI scan that revealed extra-axial tumors next to the sphenoid wing, suggestive of meningiomas. C-PiB PET images showed a highly increased uptake by the extra-axial masses. These 2 cases represent 1.2% of our C-PiB population (n = 163). No meningioma was found with negative C-PiB uptake. The F-FDG concentration was not increased within the lesions. C-PiB could be used as a meningioma marker.

11C-Pittsburgh B PET Imaging in Cardiac Amyloidosis

ObjectivesThis study sought to investigate the efficacy of 11C-Pittsburgh B (PiB) positron emission tomography (PET)/computed tomography (CT) in the diagnosis of cardiac amyloidosis. BackgroundThe PiB compound has been promising for detection of amyloid deposits in the brain. MethodsA total of 22 consecutive patients were enrolled in this prospective pilot study of monoclonal gammopathy patients with suspected cardiac amyloidosis. The study consisted of a series of 11C-PiB PET/CT, echocardiography, cardiac magnetic resonance, and endomyocardial biopsy within a 1-month period. In addition, 10 normal subjects were recruited to determine the most optimal cut-off value for a positive 11C-PiB PET/CT scan. ResultsAmong the 22 patients, 15 patients were diagnosed as cardiac amyloidosis by endomyocardial biopsy and 5 patients had undergone chemotherapy previously before the 11C-PiB PET/CT. There were no differences in echocardiographic parameters between patients with versus without cardiac amyloidosis, except for a marginal difference in the left ventricular end-diastolic dimension (median 41.0 mm [range 33.0 to 49.0 mm] vs. 50.0 mm [range 38.0 to 55.0 mm], p = 0.066). 11C-PiB PET/CT was positive in 13 of 15 biopsy-proven cardiac amyloidosis patients, whereas none of the patients without cardiac amyloidosis demonstrated positive 11C-PiB PET/CT scan results. The maximal myocardium-to-blood cavity ratio was significantly different between patients with versus without cardiac amyloidosis (median 3.9 [range 1.7 to 19.9] vs. 1.0 [range 0.8 to 1.2], p < 0.001). In association with the significant difference of 11C-PiB uptake in the myocardium between the chemotherapy naïve versus the previous chemotherapy group (median 10.4 [range 1.7 to 19.9] vs. 2.3 [range 1.7 to 3.8], p = 0.014), all except 1 patient among the 5 previously treated patients had responded to chemotherapy by serum free light chain assay results at the time of 11C-PiB PET/CT scan. Conclusions11C-PiB PET/CT may be valuable for the diagnosis of cardiac amyloidosis noninvasively. Whether 11C-PiB PET/CT may be a good surrogate marker of active light chain deposition in the myocardium warrants further investigation in a larger number of patients.

Cortical 11C-PIB Uptake is Associated with Age, APOE Genotype, and Gender in “Healthy Aging”

Our aim was to elucidate factors that contribute to amyloid-β (Aβ) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors. We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11C-PIB, in 64 cognitively healthy subjects (54-89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM). The effects of age (p < 0.001), APOE ε4 carrier status (p = 0.003), and gender (p = 0.001) on composite cortical 11C-PIB uptake were all significant. The effect of educational level was non-significant (p = 0.37). No significant interactions were found between any of the factors. Cortical 11C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49 ± 0.34 versus 1.29 ± 0.26) and males had higher uptake than females (1.49 ± 0.39 versus 1.29 ± 0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11C-PIB uptake in the frontal cortex. Age and APOE ε4 genotype were associated with higher 11C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11C-PIB uptake than women. Possible gender differences in Aβ accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted.