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Abstract: [18F]Altanserin, an important PET radioligand for the in vivo imaging of the 5-HT2A receptor, was synthesized from its precursor nitro-altanserin in DMF or DMSO at high temperatures of 150°C in an overall radiochemical yield (EOB) of 23–25% after 75min. A new solid phase work-up procedure involving the acidification of the crude reaction mixture and a C18-SepPak-solid phase separation preceded the final HPLC purification. This led to a significantly reduced synthesis time as a result of a stable and early elution from the HPLC column using improved HPLC conditions (MeOH/THF/NaOAc 0.05N pH 5: 27/18/55, flow: 5mL/min, Symetry Prep 7μm C18 (Waters)). The synthesis was performed semi-automatically in a modified GE TracerLab synthesis module using an in-house-developed program. The synthesized [18F]altanserin was used in our ongoing human and animal PET imaging studies. [Copyright &y& Elsevier]

Background: Radiolabeling is critical in complex chemical reactions involving positron emission tomography (PET) radiotracer production. The process is now automated within a synthesis module to enhance efficiency and reduce radiation exposure. The key to this automation is the use of radiation detectors to monitor radioactivity transfer and ensure the progression of reactions. However, the high cost of these detectors has motivated the need for a more affordable alternative., Purpose: This study aimed to develop a compact and cost-efficient detector using scintillating fibers and silicon photomultipliers (SiPMs) to track radioactivity throughout PET radiotracer production., Methods: Monte Carlo simulations were performed with the Geant4-based M-TAG software for four detector geometries (single fiber, single fiber with bolus, 16-fiber bundle, and spiral) to optimize the detector construction for better detection efficiency. The simulations scored the energy deposited into the scintillating fibers per simulated particle, which was used to estimate the expected voltage pulse height from the SiPM considering the total light collection efficiency. Based on the simulation results, two detector configurations (16-fiber bundle and spiral fiber) were constructed using plastic scintillating fibers, optical fibers, a 6 mm × $\times$ 6 mm SiPM, and commonly available electronic components. The detectors were calibrated using a Fluorine-18 ( 18 F $^{18}{\rm F}$ ) source with typical activity levels used in radiotracer production. Detector performances were subsequently evaluated through linearity tests and measurement uncertainty assessments. Errors up to ± 5 % $\pm 5\%$ were considered acceptable for troubleshooting purposes., Results: The calibration curves showed a linear response with changing activity for both detectors. The calibrated detectors offered real-time activity measurements ranging from 0.10 to 49.41 GBq, with a 3-s refresh rate. In the activity range above 0.145 GBq, the uncertainties were less than 5 % $5\%$ for both the 16-fiber and spiral configurations. The spiral detector recorded a signal with a half-life of 105.88 ± 0.40 $105.88 \pm 0.40$ min, closely aligning with the reference half-life of 18 F $^{18}{\rm F}$ ., Conclusions: Cost-efficient plastic scintillation fiber detectors were developed to facilitate the troubleshooting of automated synthesis of PET radiotracers., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Our objective was to evaluate the in vitro binding properties of [ 18 F]flortaucipir, 6-(fluoro- 18 F)-3-(1 H -pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ 18 F]MK6240), and 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9 H -pyrrolo[2,3-b:4,5c']dipyridine ([ 18 F]PI2620) head-to-head in postmortem human brain tissue. Methods: Autoradiography was used to assess uptake of [ 18 F]flortaucipir, [ 18 F]MK6240, and [ 18 F]PI2620 in control and Alzheimer disease (AD) autopsy-confirmed brain tissues. The study focused on the analysis of the prefrontal cortex, hippocampus, and cerebellum sections in 12 controls and 12 AD cases, as well as whole-brain hemisphere in 1 control and 1 AD sample, for each radiotracer. The binding values of [ 18 F]flortaucipir, [ 18 F]MK6240, and [ 18 F]PI2620 were calculated from regions of interest manually drawn in the prefrontal, hippocampal, and cerebellar cortices. Results: For all 3 radioligands investigated, we observed significant tracer binding differences between control and AD tissues in the whole-brain hemisphere, prefrontal cortex, and hippocampus but not in the cerebellar cortex. [ 18 F]MK6240 and [ 18 F]PI2620 had higher effect sizes to differentiate control and AD cases than did [ 18 F]flortaucipir. Bland-Altman analyses revealed strong correlations between [ 18 F]MK6240, [ 18 F]PI2620, and [ 18 F]flortaucipir, with the highest agreement found for [ 18 F]MK6240 versus [ 18 F]PI2620. Conclusion: The 3 radioligands showed comparable diagnostic properties to assess tau aggregates in vitro. Binding to AD brain tissues was higher for [ 18 F]MK6240 and [ 18 F]PI2620 than for [ 18 F]flortaucipir. Additionally, [ 18 F]MK6240 and [ 18 F]PI2620 had greater selectivity, displaying decreased uptake in control brain tissue compared with [ 18 F]flortaucipir. These results might provide insights on ongoing initiatives to create a universal scale for tau imaging studies., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids., (© 2024. The Author(s).)

Introduction: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers., Methods: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [ 18 F]AZD4694 and tau-PET with [ 18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals., Results: Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau-217 (AUC [CI 95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI 95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI 95%  = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity., Discussion: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice., Highlights: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau 181 , p-tau 217 and p-tau 231 with established immunoassay techniques., Methods: We measured p-tau 181 , p-tau 217 and p-tau 231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau 181 , p-tau 217 and p-tau 231 . P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity., Results: Mass spectrometry and immunoassays of p-tau 217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau 181 and p-tau 231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays., Conclusions: Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification., (© 2023. The Author(s).)

Addictions are thought to be fostered by the emergence of poorly regulated mesocorticolimbic responses to drug-related cues. The development and persistence of these responses might be promoted by altered glutamate transmission, including changes to type 5 metabotropic glutamate receptors (mGluR5s). Unknown, however, is when these changes arise and whether the mGluR5 and mesocorticolimbic alterations are related. To investigate, non-dependent cocaine polydrug users and cocaine-naïve healthy controls underwent a positron emission tomography scan (15 cocaine users and 14 healthy controls) with [ 11 C]ABP688, and a functional magnetic resonance imaging scan (15/group) while watching videos depicting activities with and without cocaine use. For some drug videos, participants were instructed to use a cognitive strategy to lower craving. Both groups exhibited drug cue-induced mesocorticolimbic activations and these were larger in the cocaine polydrug users than healthy controls during the session's second half. During the cognitive regulation trials, the cocaine users' corticostriatal responses were reduced. [ 11 C]ABP688 binding was unaltered in cocaine users, relative to healthy controls, but post hoc analyses found reductions in those with 75 or more lifetime cocaine use sessions. Finally, among cocaine users (n = 12), individual differences in prefrontal [ 11 C]ABP688 binding were associated with midbrain and limbic region activations during the regulation trials. Together, these preliminary findings raise the possibility that (i) recreational polydrug cocaine users show biased brain processes towards cocaine-related cues and (ii) repeated cocaine use can lower cortical mGluR5 levels, diminishing the ability to regulate drug cue responses. These alterations might promote susceptibility to addiction and identify early intervention targets., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears., Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages., Results: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss., Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation., (© 2023. The Author(s).)

JNJ-42491293 is a metabotropic glutamate 2 (mGlu 2 ) positive allosteric modulator (PAM) that was radiolabelled with [ 11 C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu 2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [ 11 C]-JNJ-42491293 could interact with an unidentified, non-mGlu 2 receptor binding site. The brain distribution of [ 11 C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [ 11 C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [ 11 C]-JNJ-42491293 in combination with vehicle or the mGlu 2 PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [ 11 C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [ 11 C]-JNJ-42491293 did not modify the SUVs obtained with [ 11 C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [ 11 C]-JNJ-42491293 interacts selectively, or even at all, with mGlu 2 receptors in the marmoset, in agreement with findings previously reported in macaque and human., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: [18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694., Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups., Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex., Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies., Competing Interests: No conflicts of interest relevant to this article exist., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-β+ individuals with mild cognitive impairment and 29 amyloid-β+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [ 18 F]MK6240 tau and [ 18 F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

6-(fluoro- 18 F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ 18 F]MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [ 18 F]MK6240 in target regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [ 18 F]MK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.25 ± 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [ 18 F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 ± 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-β-negative and tau-negative, 58.50 ± 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-β status, cross-sectionally and over time. [ 18 F]MK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting ∼75% of the region) and in the Braak II region (affecting ∼35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [ 18 F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [ 18 F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Digital microfluidics (DMF) has the signatures of an ideal liquid handling platform - as shown through almost two decades of automated biological and chemical assays. However, in the current state of DMF, we are still limited by the number of parallel biological or chemical assays that can be performed on DMF. Here, we report a new approach that leverages design-of-experiment and numerical methodologies to accelerate experimental optimization on DMF. The integration of the one-factor-at-a-time (OFAT) experimental technique with machine learning algorithms provides a set of recommended optimal conditions without the need to perform a large set of experiments. We applied our approach towards optimizing the radiochemistry synthesis yield given the large number of variables that affect the yield. We believe that this work is the first to combine such techniques which can be readily applied to any other assays that contain many parameters and levels on DMF.

Background and Objectives: To assess the concordance and discordance between the core Alzheimer disease (AD) CSF biomarkers and [ 18 F]fluorodeoxyglucose (FDG)-PET patterns evaluated clinically in memory clinic patients who meet appropriate use criteria for AD biomarker investigations., Methods: We retrospectively assessed participants with atypical and/or early-onset dementia evaluated at a tertiary care memory clinic. All individuals underwent CSF evaluations for Aβ42, phosphorylated tau (P-tau181) and total tau, and brain [ 18 F]FDG-PET. [ 18 F]FDG-PET data were visually interpreted by 2 nuclear medicine experts as being consistent with AD or non-AD. CSF biomarker results were similarly grouped into AD biomarker positive/negative. Contingency tables and Kappa coefficients were used to establish the level of agreement and disagreement between CSF and [ 18 F]FDG-PET results in all individuals., Results: One hundred thirty-six individuals had both [ 18 F]FDG-PET and lumbar puncture performed as part of the early-onset and/or atypical dementia assessments. [ 18 F]FDG-PET showed a pattern suggestive of AD in 43% of patients, while CSF biomarkers showed results consistent with AD in 57% of participants. In patients who met criteria for AD biomarker investigations, we found that [ 18 F]FDG-PET was discordant with CSF AD biomarkers in nearly 20% of cases; 12% of individuals with [ 18 F]FDG-PET scans consistent with AD had AD-negative CSF results; and 7% of individuals with [ 18 F]FDG-PET scans not consistent with AD had AD-positive CSF results, potentially suggesting atypical AD variants or less advanced neurodegeneration. [ 18 F]FDG-PET discriminated patients with an AD-positive CSF profile from patients with an AD-negative profile with a sensitivity and specificity higher than 80% (sensitivity: 81%, 95% CI = 71-88%, SP: 81%, 95% CI = 68-89%). Furthermore, [ 18 F]FDG-PET had a positive predictive value of 87% (95% CI = 78-93%) and a negative predictive value of 72% (95% CI = 60-82%)., Discussion: CSF and [ 18 F]FDG-PET disagreed in nearly 20% of the cases studied in this clinical series. While CSF Aβ42 and P-tau181 biomarkers are specific for AD, the topographical information from [ 18 F]FDG-PET may provide complementary information., (© 2022 American Academy of Neurology.)

Alzheimer's disease (AD) phenotypes might result from differences in selective vulnerability. Evidence from preclinical models suggests that tau pathology has cell-to-cell propagation properties. Therefore, here, we tested the cell-to-cell propagation framework in the amnestic, visuospatial, language, and behavioral/dysexecutive phenotypes of AD. We report that each AD phenotype is associated with a distinct network-specific pattern of tau aggregation, where tau aggregation is concentrated in brain network hubs. In all AD phenotypes, regional tau load could be predicted by connectivity patterns of the human brain. Furthermore, regions with greater connectivity displayed similar rates of longitudinal tau accumulation in an independent cohort. Connectivity-based tau deposition was not restricted to a specific vulnerable network but was rather a general property of brain organization, linking selective vulnerability and transneuronal spreading models of neurodegeneration. Together, this study indicates that intrinsic brain connectivity provides a framework for tau aggregation across diverse phenotypic manifestations of AD.

Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE). Ex-vivo studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while in vivo whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [ 3 H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (B max ) and dissociation constants (K D ) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and K D (multiple linear regression analysis). There was no significant difference in K D between the groups, which suggests that the decreased mGluR5 availability found in vivo with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [ 3 H]ABP688 binding, as previously suggested in mTLE patients studied in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zimmermann, Minuzzi, Aliaga Aliaga, Guiot, Hall, Soucy, Massarweh, El Mestikawy, Rosa-Neto and Kobayashi.)

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1-3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology., (© 2022. The Author(s).)

Gold-standard diagnosis of Alzheimer's disease (AD) relies on histopathological staging systems. Using the topographical information from [ 18 F]MK6240 tau positron-emission tomography (PET), we applied the Braak tau staging system to 324 living individuals. We used PET-based Braak stage to model the trajectories of amyloid-β, phosphorylated tau (pTau) in cerebrospinal fluid (pTau 181 , pTau 217 , pTau 231 and pTau 235 ) and plasma (pTau 181 and pTau 231 ), neurodegeneration and cognitive symptoms. We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau-PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III-IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, whereas Braak stages V-VI were incompatible with normal cognition. In 159 individuals with follow-up tau-PET, progression beyond stage III took place uniquely in the presence of amyloid-β positivity. Our findings support PET-based Braak staging as a framework to model the natural history of AD and monitor AD severity in living humans., (© 2022. The Author(s).)

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [ 11 C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [ 11 C]martinostat using [ 11 C]methyl triflate in ethanol, as opposed to the originally described synthesis using [ 11 C]methyl iodide and DMSO. [ 11 C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [ 11 C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [ 11 C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [ 11 C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing., (© 2022 John Wiley & Sons, Ltd.)

Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT 1 and MT 2 ). The melatonergic system is an emerging therapeutic target for new pharmacological interventions in the treatment of sleep and mood disorders; thus, imaging tools to further investigate its role in the brain are highly sought-after. We aimed to develop selective radiotracers for in vivo imaging of both MT 1 and MT 2 by positron emission tomography (PET). We identified four previously reported MT ligands with picomolar affinities to the target based on different scaffolds which were also amenable for radiolabeling with either carbon-11 or fluorine-18. [ 11 C]UCM765, [ 11 C]UCM1014, [ 18 F]3-fluoroagomelatine ([ 18 F]3FAGM), and [ 18 F]fluoroacetamidoagomelatine ([ 18 F]FAAGM) have been synthesized in high radiochemical purity and evaluated in wild-type rats. All four tracers showed moderate to high brain permeability in rats with maximum standardized uptake values (SUV max of 2.53, 1.75, 3.25, and 4.47, respectively) achieved 1-2 min after tracer administration, followed by a rapid washout from the brain. Several melatonin ligands failed to block the binding of any of the PET tracer candidates, while in some cases, homologous blocking surprisingly resulted in increased brain retention. Two 18 F-labeled agomelatine derivatives were brought forward to PET scans in non-human primates and autoradiography on human brain tissues. No specific binding has been detected in blocking studies. To further investigate pharmacokinetic properties of the putative tracers, microsomal stability, plasma protein binding, log D , and membrane bidirectional permeability assays have been conducted. Based on the results, we conclude that the fast first pass metabolism by the enzymes in liver microsomes is the likely reason of the failure of our PET tracer candidates. Nevertheless, we showed that PET imaging can serve as a valuable tool to investigate the brain permeability of new therapeutic compounds targeting the melatonergic system.

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β 42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer's disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [ 18 F]MK6240 and [ 18 F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [ 18 F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t 186  = -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

The common marmoset has emerged as a popular model in neuroscience research, in part due to its reproductive efficiency, genetic and neuroanatomical similarities to humans and the successful generation of transgenic lines. Stereotaxic procedures in marmosets are guided by 2D stereotaxic atlases, which are constructed with a limited number of animals and fail to account for inter-individual variability in skull and brain size. Here, we developed a frameless imaging-guided stereotaxic system that improves upon traditional approaches by using subject-specific registration of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) data to identify a surgical target, namely the putamen, in two marmosets. The skull surface was laser-scanned to create a point cloud that was registered to the 3D reconstruction of the skull from CT. Reconstruction of the skull, as well as of the brain from MR images, was crucial for surgical planning. Localisation and injection into the putamen was done using a 6-axis robotic arm controlled by a surgical navigation software (Brainsight™). Integration of subject-specific registration and frameless stereotaxic navigation allowed target localisation specific to each animal. Injection of alpha-synuclein fibrils into the putamen triggered progressive neurodegeneration of the nigro-striatal system, a key feature of Parkinson's disease. Four months post-surgery, a PET scan found evidence of nigro-striatal denervation, supporting accurate targeting of the putamen during co-registration and subsequent surgery. Our results suggest that this approach, coupled with frameless stereotaxic neuronavigation, is accurate in localising surgical targets and can be used to assess endpoints for longitudinal studies., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Tracking longitudinal tau tangles accumulation across the Alzheimer's disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-β-negative, 22 cognitively unimpaired elderly amyloid-β-positive, 21 mild cognitive impairment amyloid-β-positive and 17 Alzheimer's disease dementia amyloid-β-positive individuals) with baseline amyloid-β 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90-110 min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer's disease dementia who died after the PET scans. We found that the cognitively unimpaired amyloid-β-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-β-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer's dementia amyloid-β-positive exhibited tau accumulation in Braak regions III-VI but not I-II. Cognitively impaired amyloid-β-positive individuals that were Braak II-IV at baseline displayed a 4.6-7.5% annual increase in tau accumulation in the Braak III-IV regions, whereas those who were cognitively impaired amyloid-β-positive Braak V-VI at baseline showed an 8.3-10.7% annual increase in the Braak regions V-VI. Neuropathological assessments confirmed PET-based Braak stages V-VI in the two brain donors. Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer's disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual's baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer's disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ-). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the AD-vulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials., (© 2020. The Author(s).)

APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer's disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the other major proteinopathy of Alzheimer's disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer's disease subjects: (1) 211 participants who underwent tau-PET with [ 18 F]MK6240 and amyloid-PET with [ 18 F]AZD4694, (2) 264 individuals who underwent tau-PET with [ 18 F]Flortaucipir and amyloid-PET with [ 18 F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [ 18 F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer's disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies., (© 2020. The Author(s).)

[ 11 C]Verubulin (a.k.a.[ 11 C]MCP-6827), [ 11 C]HD-800 and [ 11 C]colchicine have been developed for imaging microtubules (MTs) with positron emission tomography (PET). The objective of this work was to conduct an in vivo comparison of [ 11 C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer's Disease tissue. Our preliminary PET imaging studies of [ 11 C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. In vitro autoradiography with [ 11 C]verubulin showed an unexpected higher uptake in AD patient tissue compared with healthy controls. We also conducted the first comparative in vivo PET imaging study with [ 11 C]verubulin, [ 11 C]HD-800 and [ 11 C]colchicine in a non-human primate. [ 11 C]Verubulin and [ 11 C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lindberg, Mossine, Aliaga, Hopewell, Massarweh, Rosa-Neto, Shao, Bernard-Gauthier, Scott and Vasdev.)

Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([ 11 C]PBR28), amyloid-β (Aβ) ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [ 11 C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Previous positron emission tomography (PET) studies using [ 11 C]ABP688 show reduced metabotropic glutamate receptor type 5 (mGluR5) allosteric binding site availability in the epileptogenic hippocampus of mesial temporal lobe epilepsy (MTLE) patients. However, the link between mGluR5 abnormalities and postsurgical outcomes remains unclear. Here, we test whether reduced PET [ 11 C]ABP688 binding in cornu ammonis (CA) sectors more vulnerable to glutamatergic excitotoxicity relates to surgical outcomes., Methods: We obtained magnetic resonance imaging (MRI) and [ 11 C]ABP688-PET from 31 unilateral MTLE patients and 30 healthy controls. MRI hippocampal subfields were segmented using FreeSurfer. To respect the lower PET special resolution, MRI-derived anatomical subfields were combined into CA1-3, CA4/dentate gyrus, and Subiculum. Partial volume corrected [ 11 C]ABP688 nondisplaceable binding potential (BP ND ) values were averaged across each subfield, and Z-scores were calculated. Subfield [ 11 C]ABP688-BP ND was compared between seizure-free and non-seizure-free patients. In addition, we also assessed subfield volumes and [ 18 F]fluorodeoxyglucose (FDG) uptake in each clinical group., Results: MTLE [ 11 C]ABP688-BP ND was reduced in ipsilateral (epileptogenic) CA1-3 and CA4/dentate-gyrus (p < .001, 95% confidence interval [CI] = .29-.51) compared to controls, with no difference in Subiculum. [ 11 C]ABP688-BP ND and subfield volumes were compared between seizure-free (Engel IA, n = 13) and non-seizure-free patients (Engel IC-III, n = 10). In ipsilateral CA1-3 only, [ 11 C]ABP688-BP ND was lower in seizure-free patients than in non-seizure-free patients (p = .012, 95% CI = 1.46-11.0) independently of volume. A subset analysis of 12 patients with [ 11 C]ABP688-PET+[ 18 F]FDG-PET showed no between-group significant difference in [ 18 F]FDG uptake, whereas CA1-3 [ 11 C]ABP688-BP ND remained significantly lower in the seven of 12 seizure-free patients (p = .03, 95% CI = -3.13 to -.21)., Significance: Reduced mGluR5 allosteric site availability in hippocampal CA1-3, measured in vivo by [ 11 C]ABP688-PET, is associated with postsurgery seizure freedom independent of atrophy or hypometabolism. Information derived from hippocampal CA1-3 [ 11 C]ABP688-PET is a promising imaging biomarker potentially impactful in surgical decisions for MRI-negative/PET-negative MTLE patients., (© 2021 International League Against Epilepsy.)

Objective: To assess the frequency of biologically defined Alzheimer disease (AD) in relation to age, sex, APOE ε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET., Methods: We assessed cognitively unimpaired (CU) elderly (n = 166), patients with amnestic mild cognitive impairment (n = 77), and patients with probable AD dementia (n = 62) who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [ 18 F]AZD4694 and tau-PET with [ 18 F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles was assessed using logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs)., Results: The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically defined AD (positive predictive value 85.2%). A total of 7.88% of CU were positive for both amyloid-PET and tau-PET. Frequency of biologically defined AD increased with age (OR 1.14; p < 0.0001) and frequency of APOE ε4 allele carriers (single ε4: OR 3.82; p < 0.0001; double ε4: OR 17.55, p < 0.0001)., Conclusion: Whereas we observed strong, but not complete, agreement between clinically defined probable AD dementia and biomarker positivity for both β-amyloid and tau, we also observed that biologically defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically defined AD and related entities., Classification of Evidence: This study provides Class I evidence that biologically defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of CU elderly., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Amyloid-β deposition into plaques is a pathologic hallmark of Alzheimer disease appearing years before the onset of symptoms. Although cerebral amyloid-β deposition occurs on a continuum, dichotomization into positive and negative groups has advantages for diagnosis, clinical management, and population enrichment for clinical trials. 18 F-AZD4694 (also known as 18 F-NAV4694) is an amyloid-β imaging ligand with high affinity for amyloid-β plaques. Despite being used in multiple academic centers, no studies have assessed a quantitative cutoff for amyloid-β positivity using 18 F-AZD4694 PET. Methods: We assessed 176 individuals [young adults ( n = 22), cognitively unimpaired elderly ( n = 89), and cognitively impaired ( n = 65)] who underwent amyloid-β PET with 18 F-AZD4694, lumbar puncture, structural MRI, and genotyping for APOEε4 18 F-AZD4694 values were normalized using the cerebellar gray matter as a reference region. We compared 5 methods for deriving a quantitative threshold for 18 F-AZD4694 PET positivity: comparison with young-control SUV ratios (SUVRs), receiver-operating-characteristic (ROC) curves based on clinical classification of cognitively unimpaired elderly versus Alzheimer disease dementia, ROC curves based on visual Aβ-positive/Aβ-negative classification, gaussian mixture modeling, and comparison with cerebrospinal fluid measures of amyloid-β, specifically the Aβ 42 /Aβ 40 ratio. Results: We observed good convergence among the 4 methods: ROC curves based on visual classification (optimal cut point, 1.55 SUVR), ROC curves based on clinical classification (optimal cut point, 1.56 SUVR) gaussian mixture modeling (optimal cut point, 1.55 SUVR), and comparison with cerebrospinal fluid measures of amyloid-β (optimal cut point, 1.51 SUVR). Means and 2 SDs from young controls resulted in a lower threshold (1.33 SUVR) that did not agree with the other methods and labeled most elderly individuals as Aβ-positive. Conclusion: Good convergence was obtained among several methods for determining an optimal cutoff for 18 F-AZD4694 PET positivity. Despite conceptual and analytic idiosyncrasies linked with dichotomization of continuous variables, an 18 F-AZD4694 threshold of 1.55 SUVR had reliable discriminative accuracy. Although clinical use of amyloid PET is currently by visual inspection of scans, quantitative thresholds may be helpful to arbitrate disagreement among raters or in borderline cases., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

In contrast to cardiac sympathetic activity which can be assessed with established PET tracers, there are currently no suitable radioligands to measure cardiac parasympathetic (cholinergic) activity. A radioligand able to measure cardiac cholinergic activity would be an invaluable clinical and research tool since cholinergic dysfunction has been associated with a wide array of pathologies (e.g., chronic heart failure, myocardial infarction, arrythmias). [ 18 F]Fluoroethoxybenzovesamicol (FEOBV) is a cholinergic radiotracer that has been extensively validated in the brain. Whether FEOBV PET can be used to assess cholinergic activity in the heart is not known. Hence, this study aimed to evaluate the properties of FEOBV for cardiac PET imaging and cholinergic activity mapping. PET data were collected for 40 minutes after injection of 230 ± 50 MBq of FEOBV in four healthy participants (1 female; Age: 37 ± 10; BMI: 25 ± 2). Dynamic LV time activity curves were fitted with Logan graphical, 1-tissue compartment, and 2-tissue compartment models, yielding similar distribution volume estimates for each participant. Our initial data show that FEOBV PET has favorable tracer kinetics for quantification of cholinergic activity and is a promising new method for assessing parasympathetic function in the heart.

Objective: To determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms., Methods: We assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity- and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [ 18 F]AZD4694, tau-PET with [ 18 F]MK6240, MRI, and neuropsychological testing., Results: Voxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction., Conclusions: Our results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

To determine the extent of metabotropic glutamate receptor type 5 (mGluR5) network abnormalities associated with focal cortical dysplasia (FCD), we performed graph theoretical analysis of [ 11 C]ABP688 PET binding potentials (BP ND ), which allows for quantification of mGluR5 availability. Undirected graphs were constructed for the entire cortex in 17 FCD patients and 33 healthy controls using inter-regional similarity of [ 11 C]ABP688 BP ND . We assessed group differences in network integration between healthy controls and the ipsilateral and contralateral hemispheres of FCD patients. Compared to healthy controls, FCD patients showed reduced network efficiency and reduced small-world connectivity. The mGluR5 network of FCD patients was also less resilient to targeted removal of high centrality nodes, suggesting a less integrated network organization. In highly efficient hub nodes of FCD patients, we observed a significant negative correlation between local efficiency and duration of epilepsy only in the contralateral hemisphere, suggesting that some nodes may be more vulnerable to persistent epileptic activity. Our study provides the first in vivo evidence for a widespread reduction in cortical mGluR5 network integration in FCD patients. In addition, we find that ongoing epileptic activity may alter chemoarchitectural brain organization resulting in reduced efficiency in distant regions that are essential for network integration., (Copyright © 2020. Published by Elsevier Inc.)

Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Abnormal brain amyloid beta (Aβ) is typically assessed in vivo using global concentrations from cerebrospinal fluid and positron emission tomography (PET). However, it is unknown whether the assessment of the topographical distribution of Aβ pathology can provide additional information to identify, among global Aβ positive individuals, those destined for dementia., Methods: We studied 260 amnestic mild cognitive impairment (MCI) subjects who were Aβ-PET positive with [ 18 F]florbetapir. Using [ 18 F]florbetapir, we assessed the percentage of voxels sowing Aβ abnormality as well as the standardized uptake value ratio (SUVR) values across brain regions. Regressions tested the predictive effect of Aβ on progression to dementia over 2 years., Results: Neither global nor regional [ 18 F]florbetapir SUVR concentrations predicted progression to dementia. In contrast, the spatial extent of Aβ pathology in regions comprising the default mode network was highly associated with the development of dementia over 2 years., Discussion: These results highlight that the regional distribution of Aβ abnormality may provide important complementary information at an individual level regarding the likelihood of Aβ positive MCI to progress to dementia., Competing Interests: All authors report no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy., Methods: We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses., Findings: We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%)., Interpretation: Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease., Funding: Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial., Objective: To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age., Design, Setting, and Participants: This is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [18F]flortaucipir and amyloid-β PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study., Main Outcomes and Measures: A main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio., Results: The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19; P < .001)., Conclusions and Relevance: Our results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.

Introduction: Mild behavioral impairment (MBI) is characterized by the emergence of neuropsychiatric symptoms in elderly persons. Here, we examine the associations between MBI and Alzheimer's disease (AD) biomarkers in asymptomatic elderly individuals., Methods: Ninety-six cognitively normal elderly individuals underwent MRI, [ 18 F]AZD4694 β-amyloid-PET, and [ 18 F]MK6240 tau-PET. MBI was assessed using the MBI Checklist (MBI-C). Pearson's correlations and voxel-based regressions were used to evaluate the relationship between MBI-C score and [ 18 F]AZD4694 retention, [ 18 F]MK6240 retention, and gray matter (GM) volume., Results: Pearson correlations revealed a positive relationship between MBI-C score and global and striatal [ 18 F]AZD4694 standardized uptake value ratios (SUVRs). Voxel-based regression analyses revealed a positive correlation between MBI-C score and [ 18 F]AZD4694 retention. No significant correlations were found between MBI-C score and [ 18 F]MK6240 retention or GM volume., Conclusion: We demonstrate for the first time a link between MBI and early AD pathology in a cognitively intact elderly population, supporting the use of the MBI-C as a metric to enhance clinical trial enrolment., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Purpose: Manual and automatic blood sampling at different time intervals is considered the gold standard to determine the arterial input function (AIF) in dynamic positron emission tomography (PET). However, blood sampling is characterized by poor time resolution and is an invasive procedure. The aim of this study was to characterize the scintillating fibers used to develop a non-invasive positron detector., Methods: The detector consists of a scintillating fiber coupled at each end to transmission fiber-optic cables that are connected to photo multiplier tubes in a dual readout setup. The detector is designed to be wrapped around the wrist of the patient undergoing dynamic PET. The attenuation length and bending losses were measured with excitation from gamma radiation ( 137 Cs) and ultraviolet (UV) light. The response to positron-emitting radio-tracers was evaluated with 18 F and 11 C., Results: The attenuation length for a 3.0 m and 1.5 m long scintillating fiber both coincides with the attenuation length given by the manufacturer when excited with the 137 Cs source, but not with the UV source due to the differences in scintillation mechanisms. The bending losses are smaller than the measurement uncertainty for the 137 Cs source irradiation, and increase when the bending radius decrease for the UV source irradiation. The signal-to-noise ratio for 18 F and 11 C solutions are 1.98 and 22.54 respectively. The measured decay constant of 11 C agrees with its characteristic value., Conclusion: The performed measurements in the dual readout configuration suggest that scintillating fibers may be suitable to determine the AIF non-invasively., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)