Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model.

INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aß) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aß, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aß, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [11 C]PBR28 and Machine Learning Analysis.

BACKGROUND: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. OBJECTIVE: In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. METHODS: We analyzed [11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. RESULTS: We observed a conspicuous pattern of elevated regional [11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. CONCLUSIONS: We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Intact global cognitive and olfactory ability predicts lack of transition to dementia.

INTRODUCTION: Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia. METHODS: In an urban community, 1037 older adults without dementia completed the 40-item University of Pennsylvania Smell Identification Test, which includes the 12-item Brief Smell Identification Test (B-SIT). Data from 749 participants followed up for 4 years were analyzed. RESULTS: In covariate-adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B-SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B-SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow-up with no transitions in the 70-75 and 81-83 years age group quartiles. DISCUSSION: Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation.

Non-invasive estimation of [11C]PBR28 binding potential.

[11C]PBR28 is a PET radioligand used to estimate densities of the 18 kDa translocator protein (TSPO) in vivo. Since there is no suitable reference region, arterial blood samples are required for full quantification. Here, we evaluate a methodology for full quantification of [11C]PBR28 PET data that does not require either a reference region or blood samples. Simultaneous estimation (SIME) uses time-activity curves from several brain regions to estimate binding potential (BPND), a theoretically more sensitive outcome measure than total distribution volume. SIME can be employed with either a measured arterial input function (AIF) or a template input function (tIF) that has similar shape as the AIF, but with arbitrary amplitude. We evaluated the ability of SIME to detect group differences in TSPO densities using PET and arterial plasma data from 21 Alzheimer's disease (AD) patients and 15 controls that underwent [11C]PBR28 imaging. Regional BPND obtained with tIFs were compared to those obtained using measured AIFs. Standard kinetic modeling was also employed for comparison. The sensitivity of each method to detect group differences in TSPO densities were assessed by comparing estimated effect sizes between AD patients and controls. For this purpose, BPND estimated for one region with high pathological burden (inferior temporal cortex), and for one region with low pathological burden (cerebellum) was used. BPND estimates obtained with SIME and tIFs were close to identical to those obtained with AIF (3.0 ± 21% difference, r2 = 0.78). In this dataset, the effect sizes between AD patients and controls for both SIME with AIF and SIME with tIF were similar (30.3%, p = 0.001 and 31.0%, p = 0.004, respectively) and were each greater than the effect size observed using the two-tissue compartment model (16.1%, p = 0.12). None of the tested methods showed difference in TSPO binding in cerebellum. These results demonstrate that BPND can be estimated for [11C]PBR28 using SIME, and may be useful in clinical studies. In addition, arterial sampling may not be necessary if tIFs can be reliably estimated.

(18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier.

Efflux transporters at the blood-brain barrier can decrease the entry of drugs and increase the removal of those molecules able to bypass the transporter. We previously hypothesized that (18)F-FCWAY, a radioligand for the serotonin 5-HT1A receptor, is a weak substrate for permeability glycoprotein (P-gp) based on its very early peak and rapid washout from human brain. To determine whether (18)F-FCWAY is a substrate for P-gp, breast cancer resistance protein (BCRP), and multidrug resistance protein (MRP1) - the three most prevalent efflux transporters at the blood-brain barrier - we performed three sets of experiments. In vitro, we conducted fluorescence-activated cell sorting (FACS) flow cytometry studies in cells over-expressing P-gp, BCRP, and MRP1 treated with inhibitors specific to each transporter and with FCWAY. Ex vivo, we measured (18)F-FCWAY concentration in plasma and brain homogenate of transporter knockout mice using γ-counter and radio-HPLC. In vivo, we conducted positron emission tomography (PET) studies to assess changes in humans who received (18)F-FCWAY during an infusion of tariquidar (2-4mg/kg iv), a potent and selective P-gp inhibitor. In vitro studies showed that FCWAY allowed fluorescent substrates to get into the cell by competitive inhibition of all three transporters at the cell membrane. Ex vivo measurements in knockout mice indicate that (18)F-FCWAY is a substrate only for P-gp and not BCRP. In vivo, tariquidar increased (18)F-FCWAY brain uptake in seven of eight subjects by 60-100% compared to each person's baseline. Tariquidar did not increase brain uptake via some peripheral mechanism, given that it did not significantly alter concentrations in plasma of the parent radioligand (18)F-FCWAY or its brain-penetrant radiometabolite (18)F-FC. These results show that (18)F-FCWAY is a weak substrate for efflux transport at the blood-brain barrier; some radioligand can enter brain, but its removal is hastened by P-gp. Although (18)F-FCWAY is not ideal for measuring 5-HT1A receptors, it demonstrates that weak substrate radioligands can be useful for measuring both increased and decreased function of efflux transporters, which is not possible with currently available radioligands such as (11)C-loperamide and (11)C-verapamil that are avid substrates for transporters.

In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease.

Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.

Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET.

The radiotracer [(11)C]N-desmethyl-loperamide (dLop) images the in vivo function of P-glycoprotein (P-gp), a transporter that blocks the entry of drugs that are substrates into brain. When P-gp is inhibited, [(11)C]dLop, a potent opiate agonist, enters and becomes trapped in the brain. This trapping is beneficial from an imaging perspective, because it amplifies the PET signal, essentially by accumulating radioactivity over time. As we previously demonstrated that this trapping was not caused by binding to opiate receptors, we examined whether [(11)C]dLop, a weak base, is ionically trapped in acidic lysosomes. To test this hypothesis, we measured [(3)H]dLop accumulation in human cells by using lysosomotropics. Because the in vivo trapping of dLop was seen after P-gp inhibition, we also measured [(3)H]dLop uptake in P-gp-expressing cells treated with the P-gp inhibitor tariquidar. All lysosomotropics decreased [(3)H]dLop accumulation by at least 50%. In P-gp-expressing cells, tariquidar (and another P-gp inhibitor) surprisingly decreased [(3)H]dLop uptake. Consequently, we measured [(11)C]dLop uptake before and after tariquidar preadministration in lysosome-rich organs of P-gp KO mice and humans. After tariquidar pretreatment in both species, radioactivity uptake in these organs decreased by 35% to 40%. Our results indicate that dLop is trapped in lysosomes and that tariquidar competes with dLop for lysosomal accumulation in vitro and in vivo. Although tariquidar and dLop compete for lysosomal trapping in the periphery, such competition does not occur in brain because tariquidar has negligible entry into brain. In summary, tariquidar and [(11)C]dLop can be used in combination to selectively measure the function of P-gp at the blood-brain barrier.

Psychotic symptoms are associated with elevated tau PET signal in the amygdala independent of Alzheimer's disease clinical severity and amyloid burden.

Background: Psychosis in Alzheimer's disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau PET burden across older individuals with and without psychotic symptoms. Methods: [18F]AV1451 tau PET binding was compared between 26 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 26 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed on a region-of-interest and voxel level, corrected for amyloid PET burden. Results: Tau was greater in individuals with psychotic symptoms in the amygdala in region-of-interest analyses, and in amygdala, thalamus, putamen, right hippocampus, right entorhinal cortex, and right frontal cortex in voxel-based analyses. When considering different onset and type of psychotic symptoms, tau binding was greatest in those with concurrent delusions. Conclusion: Elevated tau in limbic regions may be relevant for psychotic symptoms in aging and AD.

Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET.

Background: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

The neurobiology of Alzheimer disease defined by neuroimaging.

PURPOSE OF REVIEW: In 2011, a new set of new guidelines for the research diagnosis of three stages of Alzheimer disease was promulgated by the US National Institute of Aging and the Alzheimer Association. For the first time, they include the diagnosis of presymptomatic Alzheimer disease, recognizing that the disease process begins years before cognitive impairment develops. Awareness of this fact has largely been driven by neuroimaging, and particularly by imaging amyloid ß (abeta) deposition in the brain, a procedure approved by the US Food and Drug Administration for clinical use in April 2012. RECENT FINDINGS: In Alzheimer disease, abeta deposition antecedes, probably by decades, the onset of cognitive impairment. In brain regions with greatest abeta deposition, synaptic dysfunction can be imaged beginning at preclinical stages. In regions that are not identical with the ones with greatest abeta deposition but heavily connected with them, regional atrophy and loss of white-matter anisotropy can be detected later in the course of the disease, near the time when mild cognitive impairment supervenes. Together with neuropsychological testing, imaging can improve the prediction of worsening to Alzheimer disease among patients with mild cognitive impairment. SUMMARY: These findings have huge implications for research on therapeutic approaches to Alzheimer disease. For instance, while so far only patients with the clinical diagnosis have been treated with immunotherapy targeting abeta removal, a consensus is building that to be effective, this therapy should be given in the preclinical stages of the disease, which are assessed most advantageously by means of neuroimaging.

Medical Symptom Validity Test (MSVT) profiles in individuals being evaluated for Alzheimer's disease.

Objective:Our purpose was to determine whether Medical Symptom Validity Test (MSVT) profiles could differentiate performance invalidity from true impairment in patients with varying levels of memory impairment and functional ability being evaluated for Alzheimer's disease (AD). Method: Seventy-three older adults (13 healthy controls, 25 mild cognitive impairment [MCI], 16 mild AD, 19 moderate AD) were evaluated with a neuropsychological battery including the MSVT and activities of daily living (ADL) measures. Using MSVT classification guidelines, examinees' MSVT profiles were categorized as: 1) valid, 2) invalid, 3) weak memory, or 4) genuine memory impairment (GMIP). Results: Eighty-four percent of moderate AD examinees produced a GMIP. Among MCI and mild AD examinees, who had only modestly affected ADLs, a substantial proportion manifested a GMIP (40% and 62.5%, respectively). An invalid profile was uncommon across patient groups (12.5% in mild AD, 5.3% in moderate AD, and 0% in MCI). Conclusions: The MSVT functions reasonably well in a dementia sample to determine if an examinee has an invalid profile, although for mild AD examinees, the false positive rate is slightly above the recommended 10% cut-off. However, even individuals with MCI, mild AD and relative preservation of ADLs may manifest a GMIP, demonstrating that such profile is found across patients with lower and higher degrees of functional impairment. Given this finding, the usefulness of the GMIP in differentiating performance invalidity from true impairment in patients being evaluated for AD appears limited.

Joint-label fusion brain atlases for dementia research in Down syndrome.

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community. Highlight: Down syndrome (DS) joint-label-fusion atlases provide accurate positron emission tomography (PET) amyloid measurements.A disorder-specific DS atlas is better than a neurotypical atlas for PET quantification.It is not necessary to use a disease-state-specific atlas for quantification in aged DS.Dorsal striatum results vary, possibly due to this region and dementia progression.

Cognitive impairment and World Trade Centre-related exposures.

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story 'Twin Towers'. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these 'WTC-affected' individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals.

Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction.

BACKGROUND: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. OBJECTIVE: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. METHODS: Cognitively healthy older adults (n = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test). RESULTS: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (ß= -0.22, p = 0.040, CI = -0.45, -0.01), associative memory (ß= -0.26, p = 0.018, CI = -0.45, -0.06), and list learning (ß= -0.31, p = 0.002, CI = -0.51, -0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (ß= -0.25, p = 0.012, CI = -0.44, -0.06; ß= -0.29, p = 0.003, CI = -0.47, -0.10) and list learning only (ß= -0.25, p = 0.014, CI = -0.45, -0.05; ß= -0.28, p = 0.004, CI = -0.48, -0.09). CONCLUSION: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

Neuroinflammation in World Trade Center responders at midlife: A pilot study using [18F]-FEPPA PET imaging.

BACKGROUND: Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation. OBJECTIVES: Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration. METHODS: Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [18F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [18F]-FEPPA total distribution volumes as the outcomes. RESULT: Responders were 56.0 â€‹± â€‹4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [18F]-FEPPA binding predominantly in the hippocampus (d â€‹= â€‹0.72, P â€‹= â€‹0.001) and frontal cortex (d â€‹= â€‹0.64, P â€‹= â€‹0.004). Longer exposure duration to WTC sites was associated with higher [18F]-FEPPA binding in the parietal cortex. CONCLUSION: Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders.

Deep learning improves utility of tau PET in the study of Alzheimer's disease.

INTRODUCTION: Positron emission tomography (PET) imaging targeting neurofibrillary tau tangles is increasingly used in the study of Alzheimer's disease (AD), but its utility may be limited by conventional quantitative or qualitative evaluation techniques in earlier disease states. Convolutional neural networks (CNNs) are effective in learning spatial patterns for image classification. METHODS: 18F-MK6240 (n = 320) and AV-1451 (n = 446) PET images were pooled from multiple studies. We performed iterations with differing permutations of radioligands, heuristics, and architectures. Performance was compared to a standard region of interest (ROI)-based approach on prediction of memory impairment. We visualized attention of the network to illustrate decision making. RESULTS: Overall, models had high accuracy (> 80%) with good average sensitivity and specificity (75% and 82%, respectively), and had comparable or higher accuracy to the ROI standard. Visualizations of model attention highlight known characteristics of tau radioligand binding. DISCUSSION: CNNs could improve tau PET's role in early disease and extend the utility of tau PET across generations of radioligands.

Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid ß (Aß) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 PET. Aß was measured as global SUVR with 18F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aß SUVR compared to men. Continuous Aß SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aß SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aß.

Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease.

BACKGROUND: Olfactory impairment is evident in Alzheimer's disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. OBJECTIVE: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. METHODS: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-ß (Aß42). RESULTS: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01). CONCLUSION: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.NCT Registration Numbers: NCT03373604; NCT02831283.