[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick’s disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer’s disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson’s disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.

IntroductionChronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.ObjectiveTo study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.MethodsWe performed [18F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.ResultsDespite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.ConclusionAV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.

Introduction The objective of the study is to validate attention and memory tasks that elicit event-related potentials (ERPs) for utility as sensitive biomarkers for early dementia. Methods A 3-choice vigilance task designed to evaluate sustained attention and standard image recognition memory task designed to evaluate attention, encoding, and image recognition memory were administered with concurrent electroencephalography acquisition to elicit ERPs in mild cognitive impairment (MCI) and healthy cohorts. ERPs were averaged, and mean or maximum amplitude of components was measured and compared between and within cohorts. Results There was significant suppression of the amplitude of the late positive potential in the MCI cohort compared with the healthy controls during 3-choice vigilance task, predominantly over occipital and right temporal-parietal region, and standard image recognition memory task over all regions. During standard image recognition memory task, diminished performance showed strong correlation with electroencephalography measurements. The old/new effects observed in the healthy controls cohort correlated with performance and were lost in MCI. Discussion ERPs obtained during cognitive tasks may provide a powerful tool for assessing MCI and have strong potential as sensitive and robust biomarkers for tracking disease progression and evaluating response to investigative therapeutics.

No abstract

Introduction: early recognition of stroke signs lead to a better opportunity for acute management, to decrease morbidity and mortality impact. Public awareness campaigns have been developed with English language acronyms for recognition of these signs, but language and cultural differences should be taken into account for these educational strategies. Hypothesis: we assessed the hypothesis that there is a need for a validated tool for Spanish speaking population for early recognition of stroke warning signs. Material and methods: a 12-item electronic and paper-based survey for non-health related professionals evaluated the knowledge of early stroke signs in a Costa Rican sample. Using data from the FAST acronym, we developed a Spanish based acronym focused on the 3 most common symptoms, which was evaluated with medical professionals and non-medical population for clarity of message and informative content through a 10-item survey. Results: 706 non-medical professional subjects answered the evaluation survey (56.7% female, median age 33 years [IQR 24-43 years]), with 76.2% answering that they were not capable of diagnose an acute stroke, and 97.2% considering the necessity of develop an educational campaign for acute stroke signs recognition. CAMALEON acronym (CAra [face], MAno/brazo [hand/arm], LEnguaje [language] and teléfONo [telephone]) was created adapting FAST acronym to Spanish. 25 medical professionals evaluated the medical content of the Spanish acronym (based on an educational video) with a 95% of acceptance of its content to explain medical symptoms; also 91% of 100 non-medical subjects were able to recognize adequately the symptoms after viewing the video material. This academic initiative is endorsed by the World Stroke Academy from the World Stroke Organization. Conclusion: CAMALEON strategy is an adequate acronym for early recognition of acute stroke signs for Spanish speaking countries that should be validated in stroke awareness campaigns.

Background In the COVID‐19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic’s impact on the well‐being and cognition of older adults within and outside of the United States (US). Method 1,747 (646 White, 991 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and 14 Latin American countries completed an online survey regarding well‐being and cognition during the pandemic. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups, and Latinos living in the US and Latin America. Result Mean age was 66·5 (SD = 7·70) years and mean education was 15·4 (SD = 2·76) years. We found no differences in the pandemic’s overall impact across US ethnoracial groups. Compared to Whites, Latinos reported greater economic impact (p < ·001, ηp2 = .031); while Blacks reported experiencing discrimination more often (p < ·001, ηp2 = .050). Blacks and Latinos reported more positive coping (p < ·001, ηp2 = 040). Latin American Latinos reported greater pandemic impact (p < ·001, ηp2 =.013 ), more positive coping (p =·006, ηp2 =.008 ), and less discrimination than US Latinos (p < ·001, ηp2 = .013 ). Conclusion The COVID‐19 pandemic has differentially impacted the well‐being of older ethnically diverse individuals in the US and Latin America. Future studies should examine how mediators like income and coping skills modify the pandemic’s impact.

No abstract