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The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to beta-pleated sheet aggregates of the amyloid-beta (Abeta) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Abeta deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Abeta-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Abeta plaque load and peptide levels, [(3)H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Abeta42 or Abeta40, and to vascular Abeta deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Abeta plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular 'ghost' NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [(3)H]PiB binding and insoluble Abeta peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [(3)H]PiB binding, insoluble Abeta peptide levels, 6-CN-PiB- and Abeta plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) Abeta deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Abeta plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Abeta plaque burden. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [ 18 F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [ 3 H]OXD-2115, and in silico models were used to predict brain uptake. [ 18 F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies., (© 2024. The Author(s).)

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either 18 F-flortaucipir or 18 F-MK-6240 PET scans. Methods: 18 F-flortaucipir ( n = 798) and 18 F-MK-6240 ( n = 216) scans were processed and sampled to obtain regional SUV ratios. Subsamples of the cohorts were based on participant diagnosis, age, amyloid-β status (positive or negative), and neurodegeneration status (positive or negative), creating older-adult (age ≥ 55 y) cognitively unimpaired (amyloid-β-negative, neurodegeneration-negative) and cognitively impaired (mild cognitive impairment/Alzheimer disease, amyloid-β-positive, neurodegeneration-positive) groups, and then were further subsampled via matching to reduce significant differences in diagnostic prevalence, age, and Mini-Mental State Examination score. We used the biostatistical estimation of tau threshold hallmarks (BETTH) algorithm to determine sensitivity and specificity in 6 composite regions. Results: Parametric double receiver operating characteristic analysis yielded the greatest joint sensitivity in 5 of the 6 regions, whereas hierarchic clustering, gaussian mixture modeling, and k-means clustering all yielded perfect joint specificity (2.00) in all regions. Conclusion: When 18 F-flortaucipir and 18 F-MK-6240 are used, Alzheimer disease-related tau status is best assessed using 2 thresholds, a sensitivity one based on parametric double receiver operating characteristic analysis and a specificity one based on gaussian mixture modeling, delimiting an uncertainty zone indicating participants who may require further evaluation., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task. We also explored associations of DSST task performance with brain activation, SCD severity, and amyloid-ß (Aß) load., Methods: We analyzed data from 63 cognitively normal older individuals (mean age 73.6 ± 7.2) with varying degree of SCD symptoms. Participants completed a computerized version of DSST in the MR scanner and a Pittsburgh Compound-B (PiB)-PET scan to measure global cerebral Aß load., Results: A voxel-wise analysis revealed that greater SCD severity was associated with lower dorsomedial thalamus activation. While task performance was not associated with brain activation nor Aß load, slower reaction time was associated with greater SCD severity., Discussion: The observed lower dorsomedial thalamus activation may reflect declining familiarity-based working memory and the trans-thalamic executive function pathway in SCD. SCD symptoms may reflect altered neural function and subtle decline of executive function, while Aß load may have an indirect impact on neural function and performance. Self-perceived cognitive decline may serve as a psychological/subjective marker reflecting subtle brain changes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mizuno, Karim, Ly, Lopresti, Cohen, Ali, Mathis, Klunk, Aizenstein and Snitz.)

Reactive gliosis, characterized by reactive astrocytes and activated microglia, contributes greatly to neurodegeneration throughout the course of Alzheimer disease (AD). Reactive astrocytes overexpress monoamine oxidase B (MAO-B). We characterized the clinical performance of 18 F-( S )-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ( 18 F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. Methods: Seventy-seven participants-53 who were elderly and cognitively normal, 7 with mild cognitive impairment, 7 with AD, and 10 who were young and cognitively normal-were recruited for the different aspects of the study. Older participants underwent 3-dimensional magnetization-prepared rapid gradient-echo MRI and amyloid-β, tau, and 18 F-SMBT-1 PET. To ascertain 18 F-SMBT-1 selectivity to MAO-B, 9 participants underwent 2 18 F-SMBT-1 scans, before and after receiving 5 mg of selegiline twice daily for 5 d. To compare selectivity, 18 F-THK5351 studies were also conducted before and after selegiline. Amyloid-β burden was expressed in centiloids. 18 F-SMBT-1 outcomes were expressed as SUV, as well as tissue ratios and binding parameters using the subcortical white matter as a reference region. Results: 18 F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate retention in cortical regions, and the lowest retention in cerebellum and white matter, which tightly follows the known regional brain distribution of MAO-B ( R 2 = 0.84). More than 85% of 18 F-SMBT-1 signal was blocked by selegiline across the brain, and in contrast to 18 F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low nonspecific binding. 18 F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (∼2.6%/y) similar to the in vitro rates of change (∼1.9%/y). Quantitative and semiquantitative measures of 18 F-SMBT-1 binding were strongly associated ( R 2 > 0.94), suggesting that a simplified tissue-ratio approach could be used to generate outcome measures. Conclusion: 18 F-SMBT-1 is a highly selective MAO-B tracer, with low nonspecific binding, high entry into the brain, and reversible kinetics. Moreover, 18 F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting that 18 F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18 F-SMBT-1 will require examination of a much larger series, including participants with mild cognitive impairment and AD., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults., Methods: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later., Results: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05)., Conclusions: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation., Clinical Trial Number: NCT03053908., (Copyright © 2022. Published by Elsevier Inc.)

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, 18 F-flortaucipir and 18 F-MK-6240, in the same subjects. Methods: 18 F-flortaucipir and 18 F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I-VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80-100 min ( 18 F-flortaucipir) or 70-90 min ( 18 F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated ( r 2 > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for 18 F-MK-6240 than for 18 F-flortaucipir. Cerebellar SUVs were similar for 18 F-MK-6240 and 18 F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with 18 F-flortaucipir and most often in the meninges with 18 F-MK-6240. Conclusion: Both 18 F-MK-6240 and 18 F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. 18 F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

The Alzheimer's Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E ( APOE ) genotype. Brain vascular disease burden and brain Aβ burden were measured using white matter lesions (WMLs) and 11 C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aβ standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aβ SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aβ burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aβ burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings.

Background: Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [ 18 F]florbetaben (FBB) and [ 18 F]florbetapir (FBP) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples., Methods: We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer's Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295)., Results: The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [ 18 F]FBB: CL whole cerebellum  = 157.15 × SUVR FBB  - 151.87; threshold=1.08, 18 CL [ 18 F]FBP: CL whole cerebellum  = 188.22 × SUVR FBP  - 189.16; threshold=1.11, 20 CL [ 18 F]FBB: CL composite  = 244.20 × SUVR FBB  - 170.80 [ 18 F]FBP: CL composite  = 300.66 × SUVR FBP  - 208.84 CONCLUSIONS: FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aβ) deposition., Methods: From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using 11 C-Pittsburgh compound-B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers., Results: The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aβ positive, and 51% were equol producers. Equol-producing status (non-producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend P  < .01). Equol-producing status was not associated with Aβ status., Discussion: A randomized-controlled trial of equol targeting WML volume is warranted., Competing Interests: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: The National Institutes of Health (NIH) Toolbox Cognition Battery (NIHTB-CB) was developed to be a common assessment metric across a broad array of research studies. We investigated associations between NIHTB-CB and brain amyloid and tau deposition in cognitively unimpaired older adults., Methods: One hundred eighteen community-based volunteers completed magnetic resonance imaging (MRI), Pittsburgh compound B (PiB)-PET (positron emission tomography) and AV-1451-PET neuroimaging, a neuropsychological evaluation, NIHTB-CB, and the Clinical Dementia Rating (CDR) scale. Demographically adjusted regression models evaluated cognition-biomarker associations; standardized effect sizes allowed comparison of association strength across measures., Results: No NIHTB-CB measures were associated with amyloid deposition. NIHTB-CB measures of fluid cognition, including Pattern Comparison Processing Speed, Dimensional Change Card Sort, and Fluid Cognition Composite, were associated with tau deposition in higher Braak regions. Pattern Comparison Processing Speed was the most robust association with sensitivity analyses., Discussion: NIHTB-CB tasks of processing speed and executive functions may be sensitive to pathologic tau deposition on imaging in normal aging., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

Introduction: Bone marrow-derived multipotent adult progenitor cells (MAPCs) are adult allogeneic adherent stem cells currently investigated clinically for use in acute respiratory distress syndrome (ARDS). To date, there is no agreement on which is the best method for stem cells delivery in ARDS. Here, we compared the efficacy of two different methods of administration and biodistribution of MAPC for the treatment of ARDS in a sheep model., Methods: MAPC were labelled with [ 18 F] fluoro-29-deoxy-D-glucose and delivered by endobronchial (EB) or intravenous route 1 hour after lipopolysaccharide infusion in sheep mechanically ventilated. PET/CT images were acquired to determine the biodistribution and retention of the cells at 1 and 5 hours of administration., Results: The distribution and retention of the MAPC was dependent on the method of cell administration. By EB route, PET images showed that MAPC remained at the site of administration and no changes were observed after 5 hours, whereas with intravenous route, the cells had broad biodistribution to different organs, being the lung the main organ of retention at 1 and 5 hours. MAPC demonstrated an equal effect on arterial oxygenation recovery by either route of administration., Conclusion: The EB or intravenous routes of administration of MAPC are both effective for the treatment of ARDS in an acute sheep model, and the effect of MAPC therapy is not dependent of parenchymal integration or systemic biodistribution., Competing Interests: Competing interests: None declared.

Pulmonary arterial hypertension (PAH) is a life-threatening disease with higher incidence in HIV-infected compared with noninfected patients. SIV-infected NHP develop clinical manifestations of HIV infection, including PAH. To understand the pathogenesis of PAH and determine the relationship between hemodynamic changes and clinical characteristics associated with SIV infection, we performed right heart catheterization and echocardiographic imaging of 21 rhesus macaques before and after SIV infection. Between 6 and 12 mo after infection, 11 of the 21 animals had elevated mean pulmonary arterial pressure (mPAP; greater than 25 mm Hg). RV involvement was evident as increased RV glucose uptake in PAH + macaques on positron emission tomography-coupled CT compared with uninfected animals. RV and pulmonary vascular collagen deposition were elevated in PAH + animals. At 12 mo after infection, 6 of the 21 macaques (28.6%) exhibited continued increase in mPAP (progressive PAH), whereas 5 animals (23.8%) had reduced pressure (transient PAH). SIV infection of rhesus macaques led to 3 distinct outcomes with regard to hemodynamic function. Hemodynamic alterations correlated with specific inflammatory profiles and increased RV and pulmonary arterial fibrosis but not with viral load, sex, or CD4 + T-cell levels. This model of a natural cause of PAH provides insight into disease pathways that are important for the development of novel therapeutic targets.

Introduction: Centiloid standardization was developed to establish a quantitative outcome measure of amyloid burden that could accommodate the integration of different amyloid positron emission tomography radiotracers or different methods of quantifying the same tracer. The goal of this study was to examine the use of Centiloids for establishing amyloid classification cutoffs for differing region-of-interest (ROI) delineation schemes., Methods: Using ROIs from hand-drawn delineation in native space as the gold standard, we compared standard uptake value ratios obtained from the 6 hand-drawn ROIs that determine amyloid-positivity classification with standard uptake value ratio obtained from 3 different automated techniques (FreeSurfer, Statistical Parametric Mapping, and superimposed hand-drawn ROIs in Pittsburgh Compound B template space). We tested between-methods reliability using repeated measures models and intraclass correlation coefficients., Results: We found high reliability between the hand-drawn standard method and other methods for almost all the regions considered. However, small differences in standard uptake value ratio were found to lead to unreliable classifications when the hand-drawn native space-derived cutoffs were used across other ROI delineation methods., Discussion: The use of Centiloid standardization greatly improved the agreement of Pittsburgh Compound B classification across methods and may serve as an alternative method for applying cutoffs across methodologically different outcomes.

Introduction: Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimer's disease (AD)., Methods: Fifty-two nondemented adults with DS underwent two cycles of carbon 11-labeled Pittsburgh compound B ([ 11 C]PiB) and T1 weighted magnetic resonance imaging (MRI) scans 3.0 ± 0.6 years apart. Standard uptake value ratio (SUVR) images (50-70 minutes; cerebellar gray matter [GM]) and GM volumes were analyzed in standardized space (Montreal Neurological Institute space)., Results: 85% of PiB(-) subjects remained PiB(-), whereas 15% converted to PiB(+), predominantly in the striatum. None reverted from PiB(+) to PiB(-). Increases in SUVR were distributed globally, but there were no decreases in GM volume. The PiB positivity groups differed in the percent rate of change in SUVR [PiB(-): 0.5%/year, PiB converters: 4.9%/year, and PiB(+): 3.7%/year], but not in GM volume., Discussion: Despite the characteristic striatum-first pattern, the global rate of amyloid accumulation differs by pre-existing amyloid burden and precedes atrophy or dementia in the DS population, similar to general AD progression.

Unlabelled: The primary goal of this study was to assess the suitability of (11)C-Pittsburgh compound B ((11)C-PiB) blood-brain barrier delivery (K1) and relative delivery (R1) parameters as surrogate indices of cerebral blood flow (CBF), with a secondary goal of directly examining the extent to which simplified uptake measures of (11)C-PiB retention (amyloid-β load) may be influenced by CBF, in a cohort of controls and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD)., Methods: Nineteen participants (6 controls, 5 AD, 8 MCI) underwent MR imaging, (15)O-water PET, and (11)C-PiB PET in a single session. Fourteen regions of interest (including cerebellar reference region) were defined on MR imaging and applied to dynamic coregistered PET to generate time-activity curves. Multiple analysis approaches provided regional (15)O-water and (11)C-PiB measures of delivery and (11)C-PiB retention that included compartmental modeling distribution volume ratio (DVR), arterial- and reference-based Logan DVR, simplified reference tissue modeling 2 (SRTM2) DVR, and standardized uptake value ratios. Spearman correlation was performed among delivery measures (i.e., (15)O-water K1 and (11)C-PiB K1, relative K1 normalized to cerebellum [Rel-K1-Water and Rel-K1-PiB], and (11)C-PiB SRTM2-R1) and between delivery measures and (11)C-PiB retention, using the Bonferroni method for multiple-comparison correction., Results: Primary analysis showed positive correlations (ρ ≈0.2-0.5) between (15)O-water K1 and (11)C-PiB K1 that did not survive Bonferroni adjustment. Significant positive correlations were found between Rel-K1-Water and Rel-K1-PiB and between Rel-K1-Water and (11)C-PiB SRTM2-R1 (ρ ≈0.5-0.8, P < 0.0036) across primary cortical regions. Secondary analysis showed few significant correlations between (11)C-PiB retention and relative (11)C-PiB delivery measures (but not (15)O-water delivery measures) in primary cortical areas that arose only after accounting for cerebrospinal fluid dilution., Conclusion: (11)C-PiB SRTM2-R1 is highly correlated with regional relative CBF, as measured by (15)O-water K1 normalized to cerebellum, and cross-sectional (11)C-PiB retention did not strongly depend on CBF across primary cortical regions. These results provide further support for potential dual-imaging assessments of regional brain status (i.e., amyloid-β load and relative CBF) through dynamic (11)C-PiB imaging., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Basic science investigations have consistently shown that repeated exposure to psychostimulant drugs, such as cocaine, activate the immune response and lead to inflammatory changes in the brain. No previous in vivo studies have confirmed this observation in chronic cocaine-abusing humans. To test this hypothesis, we used positron emission tomography imaging to measure the binding of [(11)C]PBR28 to the 18 kDa translocator protein (TSPO), a marker for microglial activation in a group of 15 recently abstinent cocaine abusers and 17 matched healthy controls. [(11)C]PBR28 volumes of distribution expressed relative to total plasma ligand concentration (VT) were measured in subjects with kinetic analysis using the arterial input function. Subjects were also genotyped for the TSPO alanine147 threonine (Ala147Thr, rs6971) polymorphism that has been shown to influence the in vivo binding of PBR28 to TSPO. Consistent with previous reports, the TSPO Ala147Thr genotype predicted the in vivo binding of [(11)C]PBR28. No significant differences in [(11)C]PBR28 VT were observed in the cortical and subcortical regions in cocaine abusers compared with healthy controls. The results of this in vivo study do not support increased TSPO expression and, by extension, microglial activation in chronic cocaine-abusing humans. Further research with more direct markers of microglial activation is necessary to conclusively rule out neuroinflammation in cocaine dependence., (Copyright © 2014 the authors 0270-6474/14/349945-06$15.00/0.)

The Regional Biocontainment Laboratory (RBL) at the University of Pittsburgh is a state-of-the-art ABSL-3 facility that supports research on highly pathogenic viruses and bacteria. Recent advances in radiologic imaging provide several noninvasive, in vivo imaging modalities that can be used to longitudinally monitor animals following experimental infection or vaccination. The University of Pittsburgh RBL provides digital radiography, bioluminescence imaging, and PET/CT. Operating these platforms in an ABSL-3 poses unique challenges. This review will discuss the development and refinement of these imaging platforms in high containment, emphasizing specific challenges and how they were overcome., (© 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

In a recent human positron emission tomography (PET) study we demonstrated the ability to detect amphetamine-induced dopamine (DA) release in the prefrontal cortex as a reduction in the binding of the DA D(2/3) radioligand [(11)C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [(11)C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate DA concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced DA release and [(11)C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg kg(-1), 0.5 mg kg(-1) and 1.0 mg kg(-1)). Amphetamine led to a significant dose-dependent increase in dialysate (0.3 mg kg(-1): 999±287%; 0.5 mg kg(-1): 1320±432%; 1.0 mg kg(-1): 2355±1026%) as measured with microdialysis and decrease in [(11)C]FLB 457 binding potential (BP(ND), 0.3 mg kg(-1): -6±6%; 0.5 mg kg(-1): -16±4%; 1.0 mg kg(-1): -24±2%) as measured with PET. The relationship between amphetamine-induced peak ΔDA and Δ[(11)C]FLB 457 BP(ND) in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate DA release is correlated with the magnitude of the reduction in [(11)C]FLB 457 BP(ND) in the frontal cortex. The use of the [(11)C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical DA release in neuropsychiatric disorders such as schizophrenia and addiction.

Trials to test new drugs currently in development against tuberculosis in humans are impractical. All animal models to prioritize new regimens are imperfect, but nonhuman primates (NHPs) infected with Mycobacterium tuberculosis develop active tuberculosis (TB) disease with a full spectrum of lesion types seen in humans. Serial 2-deoxy-2-[ 18 F]-fluoro-d-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy with individual agents or the four-drug combination therapy most widely used globally. The size and metabolic activity of lung granulomas varied among animals and even within a single animal during development of disease. Individual granulomas within untreated animals had highly local and independent outcomes, some progressing in size and FDG uptake, while others waned, illustrating the highly dynamic nature of active TB. At necropsy, even untreated animals were found to have a proportion of sterile lesions consistent with the dynamics of this infection. A more marked reduction in overall metabolic activity in the lungs (decreased FDG uptake) was associated with effective treatment. A reduction in the size of individual lesions correlated with a lower bacterial burden at necropsy. Isoniazid treatment was associated with a transient increase in metabolic activity in individual lesions, whereas a net reduction occurred in most lesions from rifampin-treated animals. Quadruple-drug therapy resulted in the highest decrease in FDG uptake. The findings of PET-CT imaging may provide an important early correlate of the efficacy of novel combinations of new drugs that can be directly translated to human clinical trials., (Copyright © 2013, American Society for Microbiology. All Rights Reserved.)

Noninvasive imaging methodologies are needed to assess treatment responses to novel molecular targeting approaches for the treatment of squamous cell carcinoma of the head and neck (SCCHN). Computer tomography and magnetic resonance imaging do not effectively distinguish tumors from fibrotic tissue commonly associated with SCCHN tumors. Positron emission tomography (PET) offers functional non-invasive imaging of tumors. We determined the uptake of the PET tracers 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-[(18)F]Fluoro-3'-deoxythymidine ([(18)F]FLT) in several SCCHN xenograft models. In addition, we evaluated the utility of [(18)F]FLT microPET imaging in monitoring treatment response to an EGFR antisense approach targeted therapy that has shown safety and efficacy in a phase I trial. Two of the 3 SCCHN xenograft models tested demonstrated no appreciable uptake or retention of [(18)F]FDG, but consistent accumulation of [(18)F]FLT. The third tumor xenograft SCCHN model (Cal33) demonstrated variable uptake of both tracers. SCCHN xenografts (1483) treated with EGFR antisense gene therapy decreased tumor volumes in 4/6 mice. Reduced uptake of [(18)F]FLT was observed in tumors that responded to epidermal growth factor antisense (EGFRAS) gene therapy compared to non-responding tumors or tumors treated with control sense plasmid DNA. These findings indicate that [(18)F]FLT PET imaging may be useful in monitoring SCCHN response to molecular targeted therapies, while [(18)F]FDG uptake in SCCHN xenografts may not be reflective of the level of metabolic activity characteristic of human SCCHN tumors.

A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.

This longitudinal, case-control pilot study examined amygdala growth in rhesus macaque infants receiving the complete US childhood vaccine schedule (1994-1999). Longitudinal structural and functional neuroimaging was undertaken to examine central effects of the vaccine regimen on the developing brain. Vaccine-exposed and saline-injected control infants underwent MRI and PET imaging at approximately 4 and 6 months of age, representing two specific timeframes within the vaccination schedule. Volumetric analyses showed that exposed animals did not undergo the maturational changes over time in amygdala volume that was observed in unexposed animals. After controlling for left amygdala volume, the binding of the opioid antagonist [(11)C]diprenorphine (DPN) in exposed animals remained relatively constant over time, compared with unexposed animals, in which a significant decrease in [(11)C]DPN binding occurred. These results suggest that maturational changes in amygdala volume and the binding capacity of [(11)C]DPN in the amygdala was significantly altered in infant macaques receiving the vaccine schedule. The macaque infant is a relevant animal model in which to investigate specific environmental exposures and structural/functional neuroimaging during neurodevelopment.

Unlabelled: We measured the whole-body distribution of intravenously injected (11)C-N-propylnorapomorphine ((11)C-NPA), a dopamine agonist PET tracer, in human subjects and determined the resulting absorbed radiation doses., Methods: Six subjects (3 women, 3 men) were injected with (11)C-NPA (nominal dose, 370 MBq). A total of 9 consecutive whole-body PET scans were obtained for each subject. In addition, time-activity curves for 12 organs were determined, and residence times were computed for each subject. Dosimetry was determined for the various body organs and the whole body., Results: The average NPA whole-body radiation dose was 3.17 x 10(-3) mSv per MBq of injected (11)C-NPA. The organ receiving the highest dose was the gallbladder wall, with an average of 2.81 x 10(-2) mSv.MBq(-1)., Conclusion: On the basis of averaged dosimetry results, an administration of less than 1,780 MBq (<48 mCi) of (11)C-NPA yields an organ dose of under 50 mSv (5 rem) to all organs.

Human immunodeficiency virus encephalitis is characterized by infiltration of the brain with infected and activated macrophages; however, it is not known why disease occurs after variable lengths of infection in 25% of immunosuppressed acquired immune deficiency syndrome patients. We determined in vivo correlates (in peripheral blood and the central nervous system) for the development and progression of lentiviral encephalitis by longitudinally following infected and activated macrophages in the brain using positron emission tomography (PET). Using human postmortem brain tissues from both lentivirus-infected encephalitic patients and cell culture systems, we showed that the PET ligand [(3)H](R)-PK11195 bound specifically to virus-infected and activated macrophages. We longitudinally imaged infected and activated brain macrophages in a cohort of macaques infected with simian immunodeficiency virus using [(11)C](R)-PK11195. [(11)C](R)-PK11195 retention in vivo in the brain correlated with viral burden in the brain and cerebrospinal fluid, and with regions of both presynaptic and postsynaptic damage. Finally, longitudinal changes in [(11)C](R)-PK11195 retention in the brain in vivo correlated with changes in circulating monocytes as well as in both natural killer and memory CD4(+) T cells in the periphery. Our results suggest that development and progression of simian immunodeficiency virus encephalitis in vivo correlates with changes in specific cell subtypes in the periphery. A combination of PET imaging and the assessment of these peripheral immune parameters may facilitate longitudinal assessment of lentiviral encephalitis in living patients as well as evaluation of therapeutic efficacies.

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.

The pathology associated with late-stage dementia in human immunodeficiency virus (HIV) infection has been studied extensively. Neuropathological examination has demonstrated abundant activation and infection of macrophages/microglia termed HIV encephalitis. For obvious reasons, less is known regarding the neuropathology of minor cognitive impairment seen in earlier stages of HIV infection. The authors examined the utility of the peripheral benzodiazepine receptor ligand PK11195 in positron emission tomography (PET) imaging to assess microglial/macrophage activation in the brains of HIV-infected subjects with minor neurocognitive impairment in a cross-sectional study of 12 HIV infected individuals and 5 age-matched noninfected controls. Subjects were given a battery of neuropsychological tests in addition to assessing CD4 T-cell count and peripheral viremia followed by contrast enhanced magnetic resonance imaging (MRI) and PET with [15O]H2O followed by [11C](R)-PK11195. Two of the six neurocognitively impaired HIV-infected subjects demonstrated plasma viral breakthrough, whereas only one of six nonimpaired individuals demonstrated plasma viral load near the limits of detection. MRI demonstrated no abnormal enhancement and although atrophy was more prominent in impaired subjects, it was also present though to a lesser extent in nonimpaired subjects. None of the 12 HIV-infected subjects demonstrated increased retention of [11C](R)-PK11195 in the brain parenchyma compared to the 5 controls. These results suggest that either [11C](R)-PK11195 PET assessment is insensitive to the degree of macrophage activation in HIV-associated minor neurocognitive impairment or macrophage activation is not the pathological substrate of this neurological condition.

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.

During the development of in vivo amyloid imaging agents, an effort was made to use micro-positron emission tomography (PET) imaging in the presenilin-1 (PS1)/amyloid precursor protein (APP) transgenic mouse model of CNS amyloid deposition to screen new compounds and further study Pittsburgh Compound-B (PIB), a PET tracer that has been shown to be retained well in amyloid-containing areas of Alzheimer's disease (AD) brain. Unexpectedly, we saw no significant retention of PIB in this model even at 12 months of age when amyloid deposition in the PS1/APP mouse typically exceeds that seen in AD. This study describes a series of ex vivo and postmortem in vitro studies designed to explain this low retention. Ex vivo brain pharmacokinetic studies confirmed the low in vivo PIB retention observed in micro-PET experiments. In vitro binding studies showed that PS1/APP brain tissue contained less than one high-affinity (K(d) = 1-2 nm) PIB binding site per 1000 molecules of amyloid-beta (Abeta), whereas AD brain contained >500 PIB binding sites per 1000 molecules of Abeta. Synthetic Abeta closely resembled PS1/APP brain in having less than one high-affinity PIB binding site per 1000 molecules of Abeta, although the characteristics of the few high-affinity PIB binding sites found on synthetic Abeta were very similar to those found in AD brain. We hypothesize that differences in the time course of deposition or tissue factors present during deposition lead to differences in secondary structure between Abeta deposited in AD brain and either synthetic Abeta or Abeta deposited in PS1/APP brain.

Objectives: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy., Methods: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy., Results: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05)., Conclusions: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

HIV infection in humans and simian immunodeficiency virus (SIV) infection in macaques result in encephalitis in approximately one-quarter of infected individuals and is characterized by infiltration of the brain with infected and activated macrophages. 1-(2-chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (PK11195) is a ligand specific for the peripheral benzodiazepine receptor abundant on macrophages and is expressed in low levels in the noninfected brain. We hypothesized that positron-emission tomography (PET) with the carbon-11-labeled, R-enantiomer form of PK11195 ([(11)C](R)-PK11195) could image brain macrophages and hence the development of encephalitis in vivo. [(11)C](R)-PK11195 binding was assessed in the brain using PET in 11 SIV infected macaques, six of which showed increased binding in vivo. Postmortem examination of the brain in these six macaques demonstrated encephalitis, while macaques that did not show an increase in [(11)C](R)-PK11195 binding did not develop SIV encephalitis. Brain tissue from SIV encephalitic macaques also showed increased [(3)H](R)-PK11195 binding compared with binding in nonencephalitic macaques. Increased PK11195 binding in vivo and in postmortem brain tissue correlated with abundance of macrophages but not astrocytes. Our results suggest that PET [(11)C](R)-PK11195 imaging can detect the presence of macrophages in SIV encephalitis in vivo and may be useful to predict the development of HIV encephalitis and in studies of the pathogenesis and treatment of HIV dementia.