Search

Importance: Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD)., Objective: To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy., Design, Setting, and Participants: This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy., Main Outcomes and Measures: [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater., Results: A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event., Conclusions and Relevance: This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

[ 18 F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer's disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [ 18 F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BP ND ) and volume of distribution (V T ) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_V B ). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BP ND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r 2  = 0.92; slope = 0.99) derived V T correlated well with NLR-derived V T . RPM ( r 2  = 0.95; slope = 0.98) derived BP ND correlated well with NLR-derived DVR. Although SUVr 80-100 min correlated well with NLR-derived DVR ( r 2  = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied., Methods: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group., Results: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease., Conclusions: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.)., (Copyright © 2019 Massachusetts Medical Society.)

Introduction: Klunk et al. recently proposed a means of standardizing quantitation of amyloid burden from positron emission tomography scans to a common Centiloid scale, and we have applied that method to florbetapir., Methods: Florbetapir and Pittsburgh compound B scans were acquired for 46 mixed clinical presentation subjects within 18 ± 20 days. Florbetapir and Pittsburgh compound B cortical standardized uptake value ratio (SUVr) values were well correlated for both standard Centiloid (R 2  = 0.894) and Avid (R 2  = 0.901) volume of interests (VOIs). The methods of Klunk et al. were applied to establish a conversion first from florbetapir SUVr values obtained using standard Centiloid VOIs to Centiloids and then from Avid VOIs (Joshi et al.) to Centiloids., Results: The equation for conversion of florbetapir SUVr from Avid VOIs to the Centiloid scale was as follows: Florbetapir Centiloids = 183 × SUVr Avid - 177. The threshold that discriminated neuropathologically verified none or sparse versus moderate to frequent plaques in autopsy-confirmed data is 24.1 Centiloids., Discussion: These findings may allow improved tracer-independent amyloid quantitation., (Copyright © 2018. Published by Elsevier Inc.)

Objective: 18 F-flortaucipir (formerly 18 F-AV1451 or 18 F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18 F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26)., Methods: Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β ( 11 C-PiB or 18 F-florbetapir) and tau ( 18 F-flortaucipir). 18 F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18 F-flortaucipir., Results: Clinical PSP patients showed bilaterally elevated 18 F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with 18 F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo 18 F-flortaucipir and postmortem tau neuropathology., Interpretation: 18 F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634., (© 2017 American Neurological Association.)

Background: Neuroimaging studies have yielded significant advances in the understanding of neural processes relevant to the development and persistence of addiction. However, these advances have not explored extensively for diagnostic accuracy in human subjects. The aim of this study was to develop a statistical approach, using a machine learning framework, to correctly classify brain images of cocaine-dependent participants and healthy controls. In this study, a framework suitable for educing potential brain regions that differed between the two groups was developed and implemented. Single Photon Emission Computerized Tomography (SPECT) images obtained during rest or a saline infusion in three cohorts of 2-4 week abstinent cocaine-dependent participants (n = 93) and healthy controls (n = 69) were used to develop a classification model. An information theoretic-based feature selection algorithm was first conducted to reduce the number of voxels. A density-based clustering algorithm was then used to form spatially connected voxel clouds in three-dimensional space. A statistical classifier, Support Vectors Machine (SVM), was then used for participant classification. Statistically insignificant voxels of spatially connected brain regions were removed iteratively and classification accuracy was reported through the iterations., Results: The voxel-based analysis identified 1,500 spatially connected voxels in 30 distinct clusters after a grid search in SVM parameters. Participants were successfully classified with 0.88 and 0.89 F-measure accuracies in 10-fold cross validation (10xCV) and leave-one-out (LOO) approaches, respectively. Sensitivity and specificity were 0.90 and 0.89 for LOO; 0.83 and 0.83 for 10xCV. Many of the 30 selected clusters are highly relevant to the addictive process, including regions relevant to cognitive control, default mode network related self-referential thought, behavioral inhibition, and contextual memories. Relative hyperactivity and hypoactivity of regional cerebral blood flow in brain regions in cocaine-dependent participants are presented with corresponding level of significance., Conclusions: The SVM-based approach successfully classified cocaine-dependent and healthy control participants using voxels selected with information theoretic-based and statistical methods from participants' SPECT data. The regions found in this study align with brain regions reported in the literature. These findings support the future use of brain imaging and SVM-based classifier in the diagnosis of substance use disorders and furthering an understanding of their underlying pathology.

Compulsive tanning despite awareness of ultraviolet radiation (UVR) carcinogenicity may represent an "addictive" behavior. Many addictive disorders are associated with alterations in dopamine (D2/D3) receptor binding and dopamine reactivity in the brain's reward pathway. To determine if compulsive tanners exhibited neurobiologic responses similar to other addictive disorders, this study assessed basal striatal D2/D3 binding and UVR-induced striatal dopamine efflux in ten addicted and ten infrequent tanners. In a double-blind crossover trial, UVR or sham UVR was administered in separate sessions during brain imaging with single photon emission computerized tomography (SPECT). Basal D2/D3 receptor density and UVR-induced dopamine efflux in the caudate were assessed using (123)I-iodobenzamide ((123)I-IBZM) binding potential non-displaceable (BPnd). Basal BPnd did not significantly differ between addicted and infrequent tanners. Whereas neither UVR nor sham UVR induced significant changes in bilateral caudate BPnd in either group, post-hoc analyses revealed left caudate BPnd significantly decreased (reflecting increased dopamine efflux) in the addicted tanners - but not the infrequent tanners - during the UVR session only. Bilateral ∆BPnd correlated with tanning severity only in the addicted tanners. These preliminary findings are consistent with a stronger neural rewarding response to UVR in addicted tanners, supporting a cutaneous-neural connection driving excessive sunbed use., Competing Interests: disclosure None declared., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Technical factors play a critical role in the production of best-quality amyloid PET images for interpretation. This article provides specific instructions and general technical information about PET brain scanning of β-amyloid neuritic plaques. The focus of tracer-specific information will be on (18)F-florbetapir (indications, contraindications, dosing, administration, uptake time, scanning time, acquisition, processing, biodistribution, radiation dose, adverse events, and display). General scanning information relevant to all amyloid-imaging agents will be also be presented (e.g., mechanism of uptake, safe handling, positioning, prevention of patient motion, processing, and artifacts)., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Limited functional imaging evidence suggests that increased beta-amyloid deposition is associated with alterations in brain function, even in healthy older adults. However, the majority of these findings report on resting-state activity or functional connectivity in adults over age 60. Much less is known about the impact of beta-amyloid on neural activations during cognitive task performance, or the impact of amyloid in young and middle-aged adults. The current study measured beta-amyloid burden from PET imaging using (18)Florbetapir, in a large continuous age sample of highly-screened, healthy adults (N=137; aged 30-89 years). The same participants also underwent fMRI scanning, performing a memory encoding task. Using both beta-amyloid burden and age as continuous predictors of encoding activity, we report a dose-response relationship of beta-amyloid load to neural function, beyond the effects of age. Specifically, individuals with greater amyloid burden evidence less neural activation in bilateral dorsolateral prefrontal cortex, a region important for memory encoding, as well as reduced neural modulation in areas associated with default network activity: bilateral superior/medial frontal and lateral temporal cortex. Importantly, this reduction of both activation and suppression as a function of amyloid load was found across the lifespan, even in young- and middle-aged individuals. Moreover, this frontal and temporal amyloid-reduced activation/suppression was associated with poorer processing speed, verbal fluency, and fluid reasoning in a subgroup of individuals with elevated amyloid, suggesting that it is detrimental, rather than compensatory in nature., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Pseudo-continuous arterial spin labeling (PCASL) MRI is a relatively new arterial spin labeling technique and has the potential to extend the cerebral blood flow (CBF) measurement to all tissue types, including white matter. However, the arterial transit time (δ(a)) for white matter is not well established and a limited number of reports using multi-delay methods have yielded inconsistent findings. In this study, we used a different approach and measured white matter δ(a) (mean ± standard deviation, 1541 ± 173  ms) by determining the arrival times of exogenous contrast agent in a bolus tracking experiment. The data also confirmed δ(a) of gray matter to be 912 ± 209  ms. In the second part of this study, we used these parameters in PCASL kinetic models and compared relative CBF (rCBF, with respect to the whole brain) maps with those measured using a single photon emission computed tomography (SPECT) technique. It was found that the use of tissue-specific δ(a) in the PCASL model was helpful in improving the correspondence between the two modalities. On a regional level, the gray/white matter CBF ratios were 2.47 ± 0.39 and 2.44 ± 0.18 for PCASL and SPECT, respectively. On a single-voxel level, the variance between the modalities was still considerable, with an average rCBF difference of 0.27., (Copyright © 2011 John Wiley & Sons, Ltd.)

Traumatic axonal injury (TAI) is a common mechanism of traumatic brain injury not readily identified using conventional neuroimaging modalities. Novel imaging modalities such as diffusion tensor imaging (DTI) can detect microstructural compromise in white matter (WM) in various clinical populations including TAI. DTI-derived data can be analyzed using global methods (i.e., WM histogram or voxel-based approaches) or a regional approach (i.e., tractography). While each of these methods produce qualitatively comparable results, it is not clear which is most useful in clinical research and ultimately in clinical practice. This study compared three methods of analyzing DTI-derived data with regard to detection of WM injury and their association with clinical outcomes. Thirty patients with TAI and 19 demographically similar normal controls were scanned using a 3 Tesla magnet. Patients were scanned approximately eight months postinjury, and underwent an outcomes assessment at that time. Histogram analysis of fractional anisotropy (FA) and mean diffusivity showed global WM integrity differences between patients and controls. Voxel-based and tractography analyses showed significant decreases in FA within centroaxial structures involved in TAI. All three techniques were associated with functional and cognitive outcomes. DTI measures of microstructural integrity appear robust, as the three analysis techniques studied showed adequate utility for detecting WM injury.

Recent studies suggest that some of cocaine's central nervous system (CNS) effects may be mediated through its sodium channel inhibiting local anesthetic properties. Local anesthetics that lack cocaine's strong affinity for the dopamine transporter (DAT) also produce sensory and mood effects, further suggesting a role for this neural pathway. Due to an absence of affinity at the DAT, the local anesthetic lidocaine may offer the potential to assess sodium channel activity in vivo in humans. To assess the utility of lidocaine as a CNS probe, we determined regional cerebral blood flow (rCBF) with single photon emission computed tomography (SPECT) following the intravenous administration of lidocaine (0.5 mg/kg) and compared this response to procaine (0.5 mg/kg and 1.0 mg/kg), a local anesthetic with partial affinity for the DAT, and saline. Infusions were administered in nine healthy female controls over a 10-day period with at least 2 days between each scan. Increased rCBF was observed following lidocaine, relative to saline, in the insula, caudate, thalamus, and posterior cingulate. Decreased rCBF was detected in a different region of the posterior cingulate. In general, increases in rCBF were more marked following lidocaine relative to procaine. Mood and sensory changes following lidocaine were limited and significantly less than those induced by either dose of procaine. There were no significant changes in blood pressure or heart rate following either medication. These findings suggest that lidocaine can be safely used to assess sodium channel function in persons with addictive and other psychiatric disorders.

Background: Diffuse axonal injury is a common consequence of traumatic brain injury that frequently involves the parasagittal white matter, corpus callosum, and brainstem., Objective: To examine the potential of diffusion tensor tractography in detecting diffuse axonal injury at the acute stage of injury and predicting long-term functional outcome., Design: Tract-derived fiber variables were analyzed to distinguish patients from control subjects and to determine their relationship to outcome., Setting: Inpatient traumatic brain injury unit., Patients: From 2005 to 2006, magnetic resonance images were acquired in 12 patients approximately 7 days after injury and in 12 age- and sex-matched controls., Main Outcome Measures: Six fiber variables of the corpus callosum, fornix, and peduncular projections were obtained. Glasgow Outcome Scale-Extended scores were assessed approximately 9 months after injury in 11 of the 12 patients., Results: At least 1 fiber variable of each region showed diffuse axonal injury-associated alterations. At least 1 fiber variable of the anterior body and splenium of the corpus callosum correlated significantly with the Glasgow Outcome Scale-Extended scores. The predicted outcome scores correlated significantly with actual scores in a mixed-effects model., Conclusion: Diffusion tensor tractography-based quantitative analysis at the acute stage of injury has the potential to serve as a valuable biomarker of diffuse axonal injury and predict long-term outcome.

In this study we examined the role of functional brain imaging of regional cerebral bloodflow (rCBF) with the use of single photon emission computed tomography (SPECT) for the objective measurement of brain performance in adult cochlear implant (CI) users during speech perception. The subjects consisted of nine normal-hearing and eight CI individuals who watched a 15-min videotape under two conditions: (1) a visual-only presentation; and (2) a left-monaural audio and visual presentation. Cortical activations were observed bilaterally in Brodmann areas 41, 42, 21, 22 and 38 for normal-hearing control subjects. Bilateral activations were also observed in CI individuals who demonstrated high performance on open-set speech recognition tasks; however, activations were smaller in both amplitude and extent than those observed for normal-hearing individuals. CI individuals with minimal open-set recognition demonstrated only unilateral activation of auditory cortex in the hemisphere contralateral to the ear of implantation. These data support SPECT as a tool for objectively documenting cortical activations in adult CI users.

This review considers the role of functional brain imaging techniques in the dementias. The substantial assistance that especially single-photon emission tomography and positron emission tomography can play in the initial diagnosis of dementia and in the differential diagnosis of the specific dementing disorder is discussed. These techniques alone essentially match the sensitivity and specificity of clinical diagnoses in distinguishing Alzheimer's dementia (AD) from age-matched controls, from frontal lobe dementia and vascular dementia, and even from Lewy body dementia. Newer analytic techniques such as voxel-based correlational analyses and discriminant function analyses enhance the power of such differential diagnoses. Functional brain imaging techniques can also significantly assist in patient screening for clinical trials. The correlation of the observed deficits with specific patterns of cognitive abnormalities permits enhanced patient management and treatment planning and improved longitudinal assessment of outcome. It is also noteworthy that the classic abnormalities of temporoparietal and posterior cingulate hypoperfusion or hypometabolism appear to be present prior to symptom onset. These abnormalities predict progression to AD in the presence of the earliest of symptoms, and are present even in cognitively normal but at-risk subjects, with a severity proportional to the risk status. Even greater predictive ability for progression to AD is obtained by combining measures of perfusion or metabolism with risk factors, tau protein levels, hippocampal N-Acetyl aspartate concentrations, or hippocampal volume measures.

The intravenous administration of procaine shows relatively specific activation of limbic structures. Several investigators have utilized this property of procaine to probe limbic system dysfunction in neuropsychiatric disorders. The dose of procaine utilized in human studies varies significantly, however, and the optimal dose of procaine as a limbic probe has not been demonstrated. In two 10-individual groups of healthy female volunteers, we assessed the regional cerebral blood flow (rCBF) response, by single-photon emission computed tomography (SPECT), to saline and 1.38 mg/kg procaine (Group I), and saline, 0.5 mg/kg and 1.0 mg/kg procaine (Group II). Compared to saline, 0.5 mg/kg procaine produced minimal rCBF changes, 1.0 mg/kg procaine induced both limbic and non-limbic activation, and 1.38 mg/kg procaine showed relatively specific rCBF limbic activation. Subjective responses increased in a dose-response manner. We conclude that a dose of 1.38 mg/kg procaine provides a more limited and specific activation of limbic structures than 1.00 mg/kg procaine and thus may be more useful as a specific probe of limbic function.

Objective18 F-flortaucipir (formerly 18 F-AV1451 or 18 F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18 F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).MethodsParticipants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (11 C-PiB or 18 F-florbetapir) and tau (18 F-flortaucipir). 18 F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18 F-flortaucipir.ResultsClinical PSP patients showed bilaterally elevated 18 F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p

Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤ 45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale.

Objective: 18 F-flortaucipir (formerly 18 F-AV1451 or 18 F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18 F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).Methods: Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (11 C-PiB or 18 F-florbetapir) and tau (18 F-flortaucipir). 18 F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18 F-flortaucipir.Results: Clinical PSP patients showed bilaterally elevated 18 F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with 18 F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo 18 F-flortaucipir and postmortem tau neuropathology.Interpretation: 18 F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634. [ABSTRACT FROM AUTHOR]

The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as 18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-β in relationship to age, and to the development of cognitive impairment due to Alzheimer's disease. In this study, flortaucipir tau and florbetapir amyloid positron emission tomography were obtained for 217 subjects including 16 young and 58 older cognitively normal subjects, 95 subjects with mild cognitive impairment (Mini-Mental State Examination 24-30) and 48 subjects with clinically-defined possible or probable Alzheimer's disease (Mini-Mental State Examination >10). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Aβ+) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer's disease > mild cognitive impairment > older cognitively normal) and was significantly elevated for Aβ+ mild cognitive impairment and Alzheimer's disease subjects relative to the respective Aβ- subjects. In contrast, florbetapir Aβ- older cognitively normal subjects showed an increase in flortaucipir standard uptake value ratios in mesial temporal lobe regions (amygdala, hippocampus/choroid plexus region of interest) compared to younger cognitively normal subjects, but no increased standard uptake value ratios in neocortical regions. Analysis of covariance with planned contrasts showed no differences in regional or composite posterior neocortical flortaucipir standard uptake value ratio as a function of diagnostic group among Aβ- older cognitively normal or clinically diagnosed Alzheimer's disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Aβ+ subjects was reminiscent of the cross-sectional distribution of tau reported in post-mortem pathology studies, in that the most commonly affected regions were the inferior and lateral temporal lobes, the same regions where the first signs of increased retention appeared in Aβ+ cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Aβ+ subjects. Although high neocortical flortaucipir retention was consistently associated with an Aβ+ florbetapir positron emission tomography scan, not all Aβ+ subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Aβ+ group, increasing levels of flortaucipir tau binding were associated with increased cognitive impairment, as assessed by Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. These results suggest development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation. Further, the results are consistent with the hypothesis that cortical tau is associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

Background Stress-response biological systems are altered in alcohol-dependent individuals and are reported to predict future relapse. This study was designed to assess neural disruptions in alcohol-dependent participants when exposed to a conditioned stimulus ( CS) warning of the impending onset of a universal, nonpersonalized stressor. Methods Fifteen alcohol-dependent men abstinent for 3 to 5 weeks and 15 age- and race-similar healthy controls were studied. Anticipatory anxiety was induced by a CS paired with an uncertain, physically painful unconditioned stressor. Neural response was assessed using functional magnetic resonance imaging. Results Both groups experienced significant, similar levels of anticipatory anxiety in response to the high-threat relative to the low-threat CS. Whereas control participants markedly increased the blood oxygen level-dependent (BOLD) amplitude in cortical-limbic-striatal regions during the high-threat, relative to low-threat, stimulus, alcohol-dependent participants decreased BOLD amplitude in the pregenual anterior cingulate cortex (pg ACC), medial prefrontal cortex ( mPFC), medial orbitofrontal cortex, posterior cingulate cortex ( PCC), bilateral parietal/occipital cortex, and right hippocampus. Alcohol-dependent participants significantly deactivated pg ACC/ mPFC and PCC clusters, relative to controls, during the high- versus low-threat stimulus. This difference was due to a decrease in % BOLD amplitude during the high-threat stimulus in the alcohol-dependent, but not the control, participants. Conclusions Alcohol-dependent men show cortical-limbic-striatal deactivation during anticipatory anxiety, particularly in regions associated with emotional regulation. These findings suggest a lack of engagement of affective regulatory mechanisms during high-stress situations in alcohol-dependent men. [ABSTRACT FROM AUTHOR]

ABSTRACT The orbitofrontal cortex (OFC) is crucial for the inhibition of extraneous stimuli, evaluation of aversive information and emotional regulation-all behaviors impaired in cocaine addiction. Previous studies suggest that cocaine-addicted subjects have decreased basal activity in the OFC. In this study, we examined regional cerebral blood flow (rCBF) during a saline infusion in two independent populations of abstinent cocaine- (and mostly nicotine-) addicted ( n = 33 and 26) and healthy control ( n = 35 and 20) men and women. Isolated rCBF decreases ( P < 0.001) were observed in the left caudolateral OFC, as well as left superior temporal cortex, in cocaine-addicted subjects relative to controls in both cohorts and bilaterally in the combined cohort. An anatomically defined region of the caudolateral OFC showed similar findings and were evident in both male and female addicted subjects. The reliability of these findings across two cohorts reveals a functional disruption in the lateral OFC, a brain region implicated in the evaluation of behavior-terminating stimuli. This may contribute to an addicted individual's persistent drug use despite negative consequences. [ABSTRACT FROM AUTHOR]

Summary: The measurement of regional cerebral blood flow (rCBF) by single-photon emission computed tomography (SPECT) is a powerful clinical and research tool. There are several clinical applications now documented, a substantial number under active investigation, and a larger number yet to be studied. Standards regarding patient imaging environment and image presentation are becoming established. This article reviews key aspects of SPECT functional brain imaging in clinical practice, with a particular emphasis on therapeutics, including 1) the quality of the tomographic device, 2) the radiopharmaceutical employed, 3) environmental conditions at the time of radiotracer administration, 4) characteristics of the subject, 5) the format used for image presentation, and 6) the essential components of image processing necessary to the achievement of high-quality SPECT brain images. Next, a brief description of relevant radiation safety issues is provided. Finally, applications in molecular imaging, especially in small animal imaging for research as well as drug discovery and development are discussed. The gamut of SPECT studies from currently routine clinical applications to molecular imaging offers a wonderful frontier for opportunities to employ functional brain imaging in neurotherapeutics. [Copyright &y& Elsevier]