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ImportancePlasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes.ObjectiveTo analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease.Design, Setting, and ParticipantsTRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels.InterventionsRandomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction.Main Outcomes and MeasuresChange in plasma biomarker levels after donanemab treatment.ResultsIn TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, –0.04 [95% CI, –0.07 to –0.02]; P = .002 and –0.04 [95% CI, –0.07 to –0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P R = 0.453 [95% CI, 0.306-0.579]; P 217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P R = 0.393 [95% CI, 0.254-0.517]; P Conclusions and RelevanceSignificant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation.Trial RegistrationClinicalTrials.gov Identifier: NCT03367403

Importanceβ-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease.ObjectiveTo perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures.Design, Setting, and ParticipantsThe Study of LY3002813 in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels.InterventionsDonanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance.Main Outcomes and MeasuresChange in amyloid, tau, and clinical decline after donanemab treatment.ResultsThe primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, −0.54; 95% CI, −0.66 to −0.39; P APOE) ε4 carriers (95% CI, 24%-59%; P Conclusions and RelevanceResults of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status.Trial RegistrationClinicalTrials.gov Identifier: NCT03367403

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

1657 Introduction: Cardiac involvement in sarcoidosis is a complex disorder with challenging therapy options and often inadequate long-term clinical measures of treatment response. Cardiac PET imaging offers the unique ability of non-invasively assess the presence of myocardial inflammation by 18F-Fluorodeoxyglucose (18F-FDG), and to monitor the overall perfusion and left ventricular ejection fraction (LVEF) during the same imaging session. We aimed to assess the potential added value of the combined perfusion and metabolic cardiac PET imaging in patients treated for suspected cardiac sarcoidosis for assessing therapy response. Following the appropriate sarcoid diet, twenty-five patients were imaged with 40 mCi of Rubidium-82 (Rb82) at rest, and 10 mCi of 18-FDG PET imaging at baseline, after 6 months to one year, and at least after two years of having started clinical therapies with a combination of prednisone, metrotrexate or adalimumab. The standard 17-segment left ventricle model was used for regional assessment. The overall resting LVEF increased from 45±12% at baseline to 53±6.8% after six months, and to a 51±10% after two years of starting the treatment. The change in LVEF was more pronounced between baseline and six months for those patients where the resting perfusion was normal at baseline or normalized at six months, compared to those where the summed resting score remained positive (9.63±6% and 3.25±8.1, respectively, P

Background A hallmark of Alzheimer’s disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for t...

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.

Background and ObjectivesThis study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline.MethodsTwenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of Aβ42, Aβ42/Aβ40 ratio, tau phosphorylated at position 181 (p-tau181), and total tau (t-tau) were measured. Clinical and cognitive decline were examined with longitudinal CDR and cognitive composite scores (Global and Knight ADRC-Preclinical Alzheimer Cognitive Composite [Knight ADRC-PACC] Score).ResultsParticipants in the progressor and symptomatic AD groups had significantly elevated [11C]PK11195 standard uptake value ratios (SUVRs) in the hippocampus but not in the precuneus region. In the subcohort with CSF biomarkers (16 of the 24), significant negative correlations between CSF Aβ42 or Aβ42/Aβ40 and [11C]PK11195 SUVR were observed in the hippocampus and precuneus. No correlations were observed between [11C]PK11195 SUVR and CSF p-tau181 or t-tau at baseline in those regions. Higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions predicted longitudinal decline on cognitive tests.DiscussionMicroglial activation is increased in individuals with brain amyloidosis and predicts worsening cognition in AD.Classification of EvidenceThis study provides Class II evidence that in patients with AD, higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions was associated with longitudinal decline on cognitive tests.

Using flortaucipir, Pontecorvo et al. reveal an increase in cortical tau over 18 months in Aβ+ but not Aβ- subjects, and an association between baseline tau and the magnitude of changes in tau and cognitive performance. The abundance and distribution of tau may influence both tau spreading and cognitive decline., 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.

Tauopathy is a hallmark pathology of Alzheimer’s disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer’s disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer’s disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer’s disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-β, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer’s disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-β. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-β was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer’s disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer’s disease.

Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer’s disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Methods: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

Alzheimer’s Disease (AD) tau pathology originates in the brainstem and subsequently spreads to the entorhinal cortex, hippocampus and finally to temporal, parietal and prefrontal association cortices in a relatively stereotyped progression. Current evidence attributes this orderly progression to trans-neuronal spread of misfolded tau protein along the projection pathways of affected neurons. The aggregation of tau is being increasingly recognized as a trustworthy biomarker preceding the appearance of Alzheimer’s disease (AD) symptoms. One major goals of disease modifying therapies has been to stop or slow down the tau aggregation process. In order to evaluate drug efficacy, it would be desirable to have an accurate model predictive of a patient’s future tau burden, against which the tau measurements from drug-receiving cohorts could be compared. Here we report the development of such a model, evaluated in a cohort of 88 subjects clinically diagnosed as Mild Cognitively Impaired (MCI = 60) or Alzheimer’s disease (AD = 28) and tracked over a period of 18 months. Our approach combined data-driven and model-based methodologies, with the goal of predicting changes in tau within suitably specified target regions. We show that traditional statistical methods, allied to a network diffusion model for tau propagation in the brain, provide a remarkable prediction of the magnitude of incremental tau deposited in particular cortical areas of the brain over this period (MCI: R2 = 0.65±0.16; AD: R2 = 0.71±0.11) from baseline data. Our work has the potential to greatly strengthen the repertoire of analysis tools used in AD clinical trials, opening the door to future interventional trials with far fewer sample sizes than currently required.

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 [18F]. 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 Aβ1-42 were both included in the model, the Ptau correlation with flortaucipir SUVr was preserved but there was no correlation of Aβ1-42 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

[18F]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 [18F]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 (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM ( r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80–100 min correlated well with NLR-derived DVR ( r2 = 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.

BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

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 (R2 = 0.894) and Avid (R2 = 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 × SUVrAvid − 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.

Alzheimer disease (AD) is characterized by β-amyloid (Aβ) plaques and tau neurofibrillary tangles. There are several PET imaging biomarkers for Aβ including 11C-PiB and 18F-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 (R2 > 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.

Reactive oxygen species (ROS) are believed to play a major role in the proinflammatory, M1-polarized form of neuroinflammation. However, it has been difficult to assess the role of ROS and their role in neuroinflammation in animal models of disease because of the absence of probes capable of measuring their presence with the functional imaging technique positron emission tomography (PET). This study describes the synthesis and in vivo evaluation of [18F]ROStrace, a radiotracer for imaging superoxide in vivo with PET, in an LPS model of neuroinflammation. [18F]ROStrace was found to rapidly cross the blood–brain barrier (BBB) and was trapped in the brain of LPS-treated animals but not the control group. [18F]ox-ROStrace, the oxidized form of [18F]ROStrace, did not cross the BBB. These data suggest that [18F]ROStrace is a suitable radiotracer for imaging superoxide levels in the central nervous system with PET.

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

This study examined the feasibility of using quantitation to augment interpretation of florbetapir PET amyloid imaging.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.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).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.

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.

18F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate 18F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods:18F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue-based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased 18F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R2 > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0-1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110-130 min and approximately 30% at 160-180 min relative to 80-100 min. Distribution volume (130 min) was lower by 30%-35% in the YHV than AHV. Conclusion: Our data suggest that although 18F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80-100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation.

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

[18F]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 [18F]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 (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) (r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM (r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80–100 min correlated well with NLR-derived DVR (r2 = 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.

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

We report kinetic modeling results of dynamic acquisition data from 0 to 100 min after injection with the tau PET tracer 18F-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 ( B P ) and SUV ratio ( S U V R 80 − 100 ) 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 (R2 > 0.86) with corresponding regional S U V R 80 − 100 − 1 values. In the putamen, the observed kinetics (positive S U V R 1 − 5 − 1 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 18F-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.

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.

Background: Published appropriate use criteria (AUC) describe patients for whom amyloid positron emission tomography (PET) might be most useful. This study compared the impact of amyloid PET on diagnosis and management in subjects likely to either meet or not meet AUC. Methods: Physicians provided a provisional diagnosis and management plan for patients presenting with cognitive decline before and after amyloid PET imaging with florbetapir F 18. Participants were classified as AUC-like or not, based on the prescan diagnosis and demographic features. Results: In all, 125 of 229 participants (55%) were classified as AUC-like. Sixty-two percent of the AUC-like subjects had a change in diagnosis after scanning compared with 45% of the non-AUC subjects (p = 0.011). Both groups demonstrated high rates of change in their management plans after scanning (88.0% for AUC-like cases, 85.6% for non-AUC cases). Conclusions: The impact of amyloid imaging on diagnosis and planned management was maintained and, if anything, amplified in AUC-like patients.