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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.

BACKGROUND:: The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making. OBJECTIVE:: This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls. METHODS:: Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men. RESULTS:: In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P = 0.001), right lateral (P = 0.002), and medial (P < 0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (P 0.001). Similar bilateral OFC decreases were observed in male cocaine-dependent subjects at rest. In contrast, cocaine-dependent women showed lower rCBF in the medial, but not lateral, OFC relative to sex-matched healthy controls after placebo infusion (P < 0.01). Male cocaine-dependent subjects also showed decreased rCBF (P < 0.01) in the bilateral anterolateral temporal cortex and anterior cingulate, whereas decreased rCBF was observed in female cocaine-dependent subjects in the bilateral superior frontal gyri. Large and diffuse areas of increased rCBF were observed after placebo infusion in cocaine-dependent men, but not in women, relative to sex-matched healthy controls. CONCLUSIONS:: rCBF appears to be reduced in the bilateral OFC in cocaine-dependent men and in the medial OFC in cocaine-dependent women. Sex differences in the medial and lateral OFC rCBF may be relevant to understanding relapse characteristics differentiating men and women addicted to cocaine. [ABSTRACT FROM AUTHOR]

Background: Cocaine dependence follows a different disease course in men and women, possibly as a consequence of sex-specific neurobiologic responses to chronic cocaine use. We have previously reported that male cocaine-dependent subjects demonstrate a significantly different limbic response to the limbic-stimulus procaine, as measured by regional cerebral blood flow (rCBF), compared with male controls. In this study, we assessed the limbic rCBF response to procaine in female cocaine-addicted subjects (n=10) and female controls (n=10).Methods: Subjects were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Single photon emission computed tomography (SPECT) was used to compare the rCBF response to procaine.Results: Female cocaine-dependent subjects demonstrate a markedly muted, and distinctly different, limbic response to procaine compared with matched healthy controls.Conclusions: The rCBF response to procaine in female cocaine-dependent subjects suggests significant CNS differences compared with non-addicted female controls. Coupled with findings previously observed in male cocaine-dependent subjects, these biologic differences suggest that both male and female subjects experience alterations in limbic responsiveness following the chronic use of cocaine. [ABSTRACT FROM AUTHOR]

Objectives: To explore functional neuroanatomical responses to auditory stimulation before and after implantation. Study Design: A prospective study of three cochlear implant candidates (pure-tone averages of 90 dB HL or greater bilaterally and hearing in noise test [HINT] performances of <40%) in which regional cerebral blood flow (rCBF) was assessed using single photon emission computed tomography (SPECT). Methods: Candidates watched a 15-minute videotaped story under four conditions: audio presented monaurally in the right and left ears (aided), audio presented binaurally (aided), and visual-only presentation of the story. Five minutes into each story, 20 to 25 mCi of technetium 99m (99mTc) hexamethyl-propyleneamine-oxime (HMPAO) (Ceratec; Nycomed Amersham, Princeton, NJ, U.SA) was injected over a 30-second period to ensure that subjects were unaware of tracer administration. Subjects were scanned for 20 minutes using a PRISM 3000 gamma camera (Picker International, Cleveland, OH, U.S.A.). Data were normalized and co-registered, and subtraction images were compiled. Subtraction images contrasted activation patterns generated under the visual-only control condition to the auditory activation states acquired monaurally and binaurally. Results: Right and left ear monaural stimulation in normal hearing subjects resulted in significant bilateral activation of Brodmann areas 41, 42, 21, 22, and 38. Although substantial intersubject response variability was noted, subjects generally failed to bilaterally activate these areas under monaural hearing aid presentations; however, bilateral activation of areas 41 and 22 was noted under binaural presentations. Conclusions: Despite relatively similar hearing losses in each ear, significant differences in preoperative auditory cortex activation were observed between ears. These data suggest that functional brain imaging provides a useful tool for exploring the responsiveness of the auditory cortex in cochlear implant candidates. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is defined by the presence of β-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer's disease. 18 F-flortaucipir (previously known as 18 F-T807; 18 F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer's disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer's disease; non-Alzheimer's disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer's disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer's disease., Competing Interests: S.C.B., L.I., M.J.P., A.S.F., M.L., and E.C.C. are full-time employees of Eli Lilly and Company and own stock in the company. M.D.S. was employed by Eli Lilly and Company at the time this manuscript was being written., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear., Objective: To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum., Design, Setting, and Participants: A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-)., Exposures: Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments., Main Outcomes and Measures: Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset)., Results: Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+., Conclusions and Relevance: In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Background: There is an increasing interest in utilizing tau PET to identify patients early in Alzheimer's disease (AD). In this work, a temporal lobe composite (Eτ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated., Methods: A total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (AD signature ) (Devous et al., J Nucl Med 59:937-43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944-51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs (Eτ+/AD signature +; Eτ+/AD signature -; Eτ-/AD signature -). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+/AD signature - group and B2 NFT scores were created for visual evaluation of uptake., Results: Sixty-four out of 390 analyzable subjects were identified as Eτ+/AD signature -: 84% were Aβ+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+/AD signature - status reflects an early stage of AD, Eτ+/AD signature - subjects deteriorated significantly faster than Eτ-/AD signature - subjects, but significantly slower than Eτ+/AD signature + subjects, on most measures (i.e., change in AD signature SUVr, Eτ ROI cortical thickness, and MMSE). The AD signature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+/AD signature -. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects., Conclusion: The Eτ VOI identified subjects with elevated temporal but not global tau (Eτ+/AD signature -) that were primarily Aβ+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+/AD signature - subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ-/AD signature - subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer's disease., (© 2023. The Author(s).)

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear., Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers., Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ)., Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation., Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations., Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels., Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.

Purpose: A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are tau PET-negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET-positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status., Methods: We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [ 18 F]flortaucipir (n = 1944) or [ 18 F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model., Results: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan., Conclusion: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.

Alzheimer's disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These 'subtypes' were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of 'typical AD' and a revisiting of tau pathological staging.

Importance: Flortaucipir positron emission tomography (PET) scans, rated with a novel, US Food and Drug Administration-approved, clinically applicable visual interpretation method, provide valuable information regarding near-term clinical progression of patients with Alzheimer disease (AD) or mild cognitive impairment (MCI)., Objective: To evaluate the association between flortaucipir PET visual interpretation and patients' near-term clinical progression., Design/setting/participants: Two prospective, open-label, longitudinal studies were conducted from December 2014 to September 2019. Study 1 screened 298 patients and enrolled 160 participants who had a flortaucipir scan at baseline visit. Study 2 selected 205 participants from the AMARANTH trial, which was terminated after futility analysis. Out of the 2218 AMARANTH participants, 424 had a flortaucipir scan around randomization, but 219 did not complete 18-month clinical dementia rating (CDR) assessments and thus were excluded. In both studies, all participants were diagnosed as clinically impaired, and they were longitudinally followed up for approximately 18 months after baseline., Main Outcomes and Measures: Flortaucipir scans were rated as either advanced or nonadvanced AD pattern using a predetermined visual interpretation method. The CDR sum of box (CDR-SB) score was used as primary clinical end point measurement in both studies., Results: Of the 364 study participants who had readable scans, 48% were female (n = 174 of 364), and the mean (SD) age was 71.8 (8.7) years. Two hundred forty participants were rated as having an advanced AD pattern. At 18 months follow-up, 70% of those with an advanced AD pattern (n = 147 of 210) had 1 point or more increase in CDR-SB, an event predefined as clinically meaningful deterioration. In contrast, only 46% of those with a nonadvanced AD pattern scan (n = 48 of 105) experienced the same event (risk ratio [RR], 1.40; 95% CI, 1.11-1.76; P = .005). The adjusted mean CDR-SB changes were 2.28 and 0.98 for advanced and nonadvanced AD pattern groups, respectively (P < .001). Analyses with other clinical end point assessments, as well as analyses with each individual study's data, consistently indicated a higher risk of clinical deterioration associated with an advanced AD scan pattern., Conclusions and Relevance: These results suggest that flortaucipir PET scans, when interpreted with an US Food and Drug Administration-approved, clinically applicable visual interpretation method, may provide valuable information regarding the risk of clinical deterioration over 18 months among patients with AD and MCI., Trial Registration: ClinicalTrials.gov Identifier: NCT02016560 and NCT03901105.

Introduction: Lanabecestat, a beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)-modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported., Methods: AMARANTH and DAYBREAK-ALZ were 104- and 78-week, multicenter, randomized, double-blind, placebo-controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK-ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK-ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aβ neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK-ALZ. Efficacy measures included 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Clinical Dementia Rating-Sum of Boxes, Functional Activities Questionnaire, and Mini-Mental State Examination. These studies stopped early due to futility., Results: Despite previously observed annualized reduction in Aβ neuritic plaque burden, there were no treatment differences in annualized change of aggregated tau neurofibrillary tangle burden (AMARANTH, n = 284; DAYBREAK-ALZ, n = 70), cerebral metabolism (AMARANTH, n = 260; DAYBREAK-ALZ, n = 38) and perfusion (DAYBREAK-ALZ, n = 213). Greater brain volume reduction (AMARANTH, n = 1697 [whole brain]; DAYBREAK-ALZ, n = 650 [whole brain]) occurred on lanabecestat compared to placebo. Higher baseline aggregated tau neurofibrillary tangle burden, lower cerebral metabolism, and lower brain volumes correlated with poorer baseline efficacy scores and greater clinical worsening. Lower baseline cerebral perfusion correlated with poorer baseline efficacy scores. Reduction in cerebral metabolism or whole brain volume correlated with clinical worsening, regardless of treatment assignment., Discussion: Tau pathology and cerebral metabolism assessments showed no evidence of lanabecestat slowing pathophysiologic progression of AD. Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design., Competing Interests: Drs Zimmer, Shcherbinin, Devous, Selzler, Wessels, Downing, Fleisher, Otero Svaldi, and Sims; Ms Bragg; Messrs Landry and Andersen reported being full‐time employees and minor shareholders of Eli Lilly and Company. Drs Shering and Mullen reported being employees of AstraZeneca, which holds the intellectual property for lanabecestat, and being minor shareholders of AstraZeneca. Dr Mullen is a former AstraZeneca employee., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Tau neurofibrillary tangle burden increases with Alzheimer's disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment., Objective: Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains., Methods: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores., Results: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests., Conclusion: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD.

The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ε4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ε4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ε4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ε4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dopaminergic (DA) system function is frequently disrupted after traumatic brain injury (TBI). However, published interventions that target the DA system with the hope of enhancing functional outcomes are inconclusive, partially because of the lack of DA signaling biomarkers that can be used to select patients likely to benefit from DA-directed therapies or to monitor treatment efficacy. The aim of this study was to evaluate the feasibility of using 123 I-iofluopane single-photon emission computerized tomography (SPECT) to assess pre-synaptic DA system dysfunction after severe TBI. Eighteen patients with severe TBI were enrolled in this study. 123 I-iofluopane SPECT imaging was performed at baseline and again 2.5 h after a single dose of methylphenidate (MP) administered enterally. DA transporter (DAT) specific binding ratio (SBR) before and after MP was measured. Functional outcomes included the Disability Rating Scale, JFK Coma Recovery Scale-Revised, Functional Independence Measure, and Functional Assessment Measure. Thirteen of 18 patients completed the study. Average time from injury to SPECT scan was 48 days (standard deviation [SD], 24 days; median, 31). Baseline ioflupane striatal SBR was 1.51 ± 0.46 (median, 1.67). A 43.1% (SD, 16; median, 46.5) displacement of ioflupane from pre-synaptic DAT was observed after MP administration. Baseline SBR positively correlated with functional status at baseline and 4 weeks after completion of the study. Serum MP levels correlated with relative change in SBR ( r s  = 0.60; p  = 0.04). Our findings suggest that 123 I-iofluopane SPECT is a promising tool to determine the severity of pre-synaptic DA terminal disruption and for monitoring pharmacokinetics and pharmacodynamics of therapeutic interventions targeting the DA system.

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.

Background: The objective of this study was to make a quantitative comparison of flortaucipir PET retention with pathological tau and β-amyloid across a range of brain regions at autopsy., Methods: Patients with dementia (two with clinical diagnosis of AD, one undetermined), nearing the end of life, underwent 20-min PET, beginning 80 min after an injection of ~370 mBq flortaucipir [ 18 F]. Neocortical, basal ganglia, and limbic tissue samples were obtained bilaterally from 19 regions at autopsy and subject-specific PET regions of interest corresponding to the 19 sampled target tissue regions in each hemisphere were hand drawn on the PET images. SUVr values were calculated for each region using a cerebellar reference region. Abnormally phosphorylated tau (Ptau) and amyloid-β (Aβ) tissue concentrations were measured for each tissue region with an antibody capture assay (Histelide) using AT8 and H31L21 antibodies respectively., Results: The imaging-to-autopsy interval ranged from 4-29 days. All three subjects had intermediate to high levels of AD neuropathologic change at autopsy. Mean cortical SUVr averaged across all three subjects correlated significantly with the Ptau immunoassay (Pearson r = 0.81; p < 0.0001). When Ptau and Aβ 1-42 were both included in the model, the Ptau correlation with flortaucipir SUVr was preserved but there was no correlation of Aβ 1-42 with flortaucipir. There was also a modest correlation between limbic (hippocampal/entorhinal and amygdala) flortaucipir SUVr and Ptau (Pearson r = 0.52; p < 0.080). There was no significant correlation between SUVr and Ptau in basal ganglia., Conclusions: The results of this pilot study support a quantitative relationship between cortical flortaucipir SUVr values and quantitative measures of Ptau at autopsy. Additional research including more cases is needed to confirm the generalizability of these results. Trial registration, NIH Clinicaltrials.gov NCT # 02516046. Registered August 27, 2015. https://clinicaltrials.gov/ct2/show/NCT02516046?term=02516046&draw=2&rank=1.

[ 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&#95;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.

The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in relationship to age, amyloid-β, and to the development of cognitive impairment due to Alzheimer's disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer's disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-β+ and 90 amyloid-β- subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-β+ but not amyloid-β- subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P < 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P < 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer's disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.)

At autopsy, individuals with Alzheimer's disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed-hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD-and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50-92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo. 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes.

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.)

Alzheimer disease (AD) is characterized by β-amyloid (Aβ) plaques and tau neurofibrillary tangles. There are several PET imaging biomarkers for Aβ including 11 C-PiB and 18 F-florbetapir. Recently, PET tracers for tau neurofibrillary tangles have become available and have shown utility in detection and monitoring of neurofibrillary pathology over time. Flortaucipir F 18 is one such tracer. Initial clinical studies indicated greater tau binding in AD and mild cognitive impairment patients than in controls in a pattern consistent with tau pathology observed at autopsy. However, little is known about the reproducibility of such findings. To our knowledge, this study reports the first data regarding test-retest reproducibility of flortaucipir F 18 PET. Methods: Twenty-one subjects who completed the study (5 healthy controls, 6 mild cognitive impairment, and 10 AD) received 370 MBq of flortaucipir F 18 and were imaged for 20 min beginning 80 min after injection and again at 110 min after injection. Follow-up (retest) imaging occurred between 48 h and 4 wk after initial imaging. Images were spatially normalized to Montreal Neurological Institute template space. SUVRs were calculated using AAL (Automated Anatomical Labeling atlas) volumes of interest (VOIs) for parietal, temporal, occipital, anterior, and posterior hippocampal, parahippocampal, and fusiform regions, as well as a posterior neocortical VOI composed of average values from parietal, temporal, and occipital areas. Further, a VOI derived by discriminant analysis that maximally separated diagnostic groups (multiblock barycentric discriminant analysis [MUBADA]) was used. All VOIs were referenced to a subsection of cerebellar gray matter (cere-crus) as well as a parametrically derived white matter-based reference region (parametric estimate of reference signal intensity [PERSI]). t test, correlation analyses, and intraclass correlation coefficient were used to explore test-retest performance. Results: Test-retest analyses demonstrated low variability in flortaucipir F 18 SUVR. The SD of mean percentage change between test and retest using the PERSI reference region was 2.22% for a large posterior neocortical VOI, 1.84% for MUBADA, 1.46% for frontal, 1.98% for temporal, 2.28% for parietal, and 3.27% for occipital VOIs. Further, significant correlations ( R 2 > 0.85; P < 0.001) were observed for all regions, and intraclass correlation coefficient values (test-retest consistency) were greater than 0.92 for all regions. Conclusion: Significant test-retest reproducibility for flortaucipir F 18 was found across neocortical and mesial temporal lobe structures. These preliminary data suggest that flortaucipir F 18 tau imaging could be used to examine changes in tau burden over time., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

PET imaging of tau pathology in Alzheimer disease may benefit from the use of white matter reference regions. These regions have shown reduced variability compared with conventional cerebellar regions in amyloid imaging. However, they are susceptible to contamination from partial-volume blurring of tracer uptake in the cortex. We present a new technique, PERSI (Parametric Estimation of Reference Signal Intensity), for flortaucipir F 18 count normalization that leverages the advantages of white matter reference regions while mitigating potential partial-volume effects. Methods: Subjects with a clinical diagnosis of Alzheimer disease, mild cognitive impairment, or normal cognition underwent T1-weighted MRI and florbetapir imaging (to determine amyloid [Aβ] status) at screening and flortaucipir F 18 imaging at single or multiple time points. Flortaucipir F 18 images, acquired as 4 × 5 min frames 80 min after a 370-MBq injection, were motion-corrected, averaged, and transformed to Montreal Neurological Institute (MNI) space. The PERSI reference region was calculated for each scan by fitting a bimodal gaussian distribution to the voxel-intensity histogram within an atlas-based white matter region and using the center and width of the lower-intensity peak to identify the voxel intensities to be included. Four conventional reference regions were also evaluated: whole cerebellum, cerebellar gray matter, atlas-based white matter, and subject-specific white matter. SUVr (standardized uptake value ratio) was calculated for a statistically defined neocortical volume of interest. Performance was evaluated with respect to test-retest variability in a phase 2 study of 21 subjects (5-34 d between scans). Baseline variability in controls (SD of SUVr and ΔSUVr) and effect sizes for group differences (Cohen d; Aβ-positive impaired vs. Aβ-negative normal) were evaluated in another phase 2 study with cross-sectional data ( n = 215) and longitudinal data ( n = 142/215; 18 ± 2 mo between scans). Results: PERSI showed superior test-retest reproducibility (1.84%) and group separation ability (cross-sectional Cohen d = 9.45; longitudinal Cohen d = 2.34) compared with other reference regions. Baseline SUVr variability and ΔSUVr were minimal in Aβ control subjects with no specific flortaucipir F 18 uptake (SUVr, 1.0 ± 0.04; ΔSUVr, 0.0 ± 0.02). Conclusion: PERSI reduced variability while enhancing discrimination between diagnostic cohorts. Such improvements could lead to more accurate disease staging and robust measurements of changes in tau burden over time for the evaluation of putative therapies., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology., Methods: Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2., Results: All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage., Discussion: Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust.

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.)

Introduction: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal., Methods: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes., Results: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%., Discussion: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

This study evaluated performance of a commercially available standardized software program for calculation of florbetapir PET standard uptake value ratios (SUVr) in comparison with an established research method. Florbetapir PET images for 183 subjects clinically diagnosed as cognitively normal (CN), mild cognitive impairment (MCI) or probable Alzheimer's disease (AD) (45 AD, 60 MCI, and 78 CN) were evaluated using two software processing algorithms. The research method uses a single florbetapir PET template generated by averaging both amyloid positive and amyloid negative registered brains together. The commercial software simultaneously optimizes the registration between the florbetapir PET images and three templates: amyloid negative, amyloid positive, and an average. Cortical average SUVr values were calculated across six predefined anatomic regions with respect to the whole cerebellum reference region. SUVr values were well correlated between the two methods (r2 = 0.98). The relationship between the methods computed from the regression analysis is: Commercial method SUVr = (0.9757*Research SUVr) + 0.0299. A previously defined cutoff SUVr of 1.1 for distinguishing amyloid positivity by the research method corresponded to 1.1 (95% CI = 1.098, 1.11) for the commercial method. This study suggests that the commercial method is comparable to the published research method of SUVr analysis for florbetapir PET images, thus facilitating the potential use of standardized quantitative approaches to PET amyloid imaging., Competing Interests: None.

Importance: Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults., Objective: To examine whether a continuous, dose-response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults., Design, Setting, and Participants: This cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([18F]-florbetapir) at baseline and cognitive assessments at baseline and a 4-year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline., Main Outcomes and Measures: Linear mixed models assessed the effect of increasing baseline amyloid over time (SUVR × time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein ε4, and the random effect of intercepts were included as covariates., Results: The mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR × time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle-aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein ε4 homozygotes., Conclusions and Relevance: These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization.

Purpose: This study examined the feasibility of using quantitation to augment interpretation of florbetapir PET amyloid imaging., Methods: A total of 80 physician readers were trained on quantitation of florbetapir PET images and the principles for using quantitation to augment a visual read. On day 1, the readers completed a visual read of 96 scans (46 autopsy-verified and 50 from patients seeking a diagnosis). On day 2, 69 of the readers reinterpreted the 96 scans augmenting their interpretation with quantitation (VisQ method) using one of three commercial software packages. A subset of 11 readers reinterpreted all scans on day 2 based on a visual read only (VisVis control). For the autopsy-verified scans, the neuropathologist's modified CERAD plaque score was used as the truth standard for interpretation accuracy. Because an autopsy truth standard was not available for scans from patients seeking a diagnosis, the majority VisQ interpretation of the three readers with the best accuracy in interpreting autopsy-verified scans was used as the reference standard., Results: Day 1 visual read accuracy was high for both the autopsy-verified scans (90%) and the scans from patients seeking a diagnosis (87.3%). Accuracy improved from the visual read to the VisQ read (from 90.1% to 93.1%, p < 0.0001). Importantly, access to quantitative information did not decrease interpretation accuracy of the above-average readers (>90% on day 1). Accuracy in interpreting the autopsy-verified scans also increased from the first to the second visual read (VisVis group). However, agreement with the reference standard (best readers) for scans from patients seeking a diagnosis did not improve with a second visual read, and in this cohort the VisQ group was significantly improved relative to the VisVis group (change 5.4% vs. -1.1%, p < 0.0001)., Conclusion: These results indicate that augmentation of visual interpretation of florbetapir PET amyloid images with quantitative information obtained using commercially available software packages did not reduce the accuracy of readers who were already performing with above average accuracy on the visual read and may improve the accuracy and confidence of some readers in clinically relevant cases.

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., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study., Methods: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months., Results: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit., Conclusion: Knowledge of the amyloid status affects the diagnosis and alters patient management., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD., Objective: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD., Methods: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained., Results: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil., Conclusion: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

Objective: To examine the relationship of β-amyloid (Aβ) deposition to episodic memory in younger (30-49 years), middle-older (50-69 years), and older adults (70-89 years). We hypothesized that subclinical levels of amyloid would be linked to memory in adults across the lifespan in a dose-dependent fashion. Of great interest was whether, within the younger group, a relationship between amyloid level and memory performance could be established., Methods: A total of 147 participants from the Dallas Lifespan Brain Study, aged 30-89, underwent PET imaging with 18 F-florbetapir and cognitive assessment. We assessed the relationship between age group and amyloid and tested whether Aβ differentially affected memory performance across the 3 age groups., Results: We report a significant association of age to amyloid burden for younger and middle-older adults (r = 0.57 and 0.28, respectively), but not for the oldest group, although absolute level of amyloid increased across the age groups. Importantly, the youngest group showed a significant decrease in recall (r = -0.47, p = 0.004) and recognition memory (r = -0.48, p = 0.003) as a function of increases in Aβ burden, whereas this relationship was absent in the middle-older and oldest group (all p > 0.23)., Conclusions: These results indicate that variance in subclinical levels of Aβ in younger adults is meaningful, and suggest that higher SUVRs relative to one's peers at a younger age is not entirely benign., (© 2016 American Academy of Neurology.)

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.

We report kinetic modeling results of dynamic acquisition data from 0 to 100 min after injection with the tau PET tracer 18 F-AV-1451 in 19 subjects., Methods: Subjects were clinically diagnosed as 4 young cognitively normal, 5 old cognitively normal, 5 mild cognitive impairment, and 5 Alzheimer disease (AD). Kinetic modeling was performed using Logan graphical analysis with the cerebellum crus as a reference region. Voxelwise binding potential ([Formula: see text]) and SUV ratio ([Formula: see text]) images were compared., Results: In AD subjects, slower and spatially nonuniform clearance from cortical regions was observed as compared with the controls, which led to focal uptake and elevated retention in the imaging data from 80 to 100 min after injection. BP from the dynamic data from 0 to 100 min correlated strongly (R 2 > 0.86) with corresponding regional [Formula: see text] values. In the putamen, the observed kinetics (positive [Formula: see text] at the tracer delivery stage and plateauing time-SUVR curves for all diagnostic categories) may suggest either additional off-target binding or a second binding site with different kinetics., Conclusion: The kinetics of the 18 F-AV-1451 tracer in cortical areas, as examined in this small group of subjects, differed by diagnostic stage. A delayed 80- to 100-min scan provided a reasonable substitute for a dynamic 0- to 100-min acquisition for cortical regions although other windows (e.g., 75-105 min) may be useful to evaluate., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

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.)

SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)