Synthesizing images of tau pathology from cross-modal neuroimaging using deep learning.

Given the prevalence of dementia and the development of pathology-specific disease-modifying therapies, high-value biomarker strategies to inform medical decision-making are critical. In vivo tau-PET is an ideal target as a biomarker for Alzheimer's disease diagnosis and treatment outcome measure. However, tau-PET is not currently widely accessible to patients compared to other neuroimaging methods. In this study, we present a convolutional neural network (CNN) model that imputes tau-PET images from more widely available cross-modality imaging inputs. Participants (n = 1192) with brain T1-weighted MRI (T1w), fluorodeoxyglucose (FDG)-PET, amyloid-PET and tau-PET were included. We found that a CNN model can impute tau-PET images with high accuracy, the highest being for the FDG-based model followed by amyloid-PET and T1w. In testing implications of artificial intelligence-imputed tau-PET, only the FDG-based model showed a significant improvement of performance in classifying tau positivity and diagnostic groups compared to the original input data, suggesting that application of the model could enhance the utility of the metabolic images. The interpretability experiment revealed that the FDG- and T1w-based models utilized the non-local input from physically remote regions of interest to estimate the tau-PET, but this was not the case for the Pittsburgh compound B-based model. This implies that the model can learn the distinct biological relationship between FDG-PET, T1w and tau-PET from the relationship between amyloid-PET and tau-PET. Our study suggests that extending neuroimaging's use with artificial intelligence to predict protein specific pathologies has great potential to inform emerging care models.

Mayo normative studies: regression-based normative data for ages 30-91 years with a focus on the Boston Naming Test, Trail Making Test and Category Fluency.

OBJECTIVE: Normative neuropsychological data are essential for interpretation of test performance in the context of demographic factors. The Mayo Normative Studies (MNS) aim to provide updated normative data for neuropsychological measures administered in the Mayo Clinic Study of Aging (MCSA), a population-based study of aging that randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. We examined demographic effects on neuropsychological measures and validated the regression-based norms in comparison to existing normative data developed in a similar sample. METHOD: The MNS includes cognitively unimpaired adults ≥30 years of age (n = 4,428) participating in the MCSA. Multivariable linear regressions were used to determine demographic effects on test performance. Regression-based normative formulas were developed by first converting raw scores to normalized scaled scores and then regressing on age, age2, sex, and education. Total and sex-stratified base rates of low scores (T < 40) were examined in an older adult validation sample and compared with Mayo's Older Americans Normative Studies (MOANS) norms. RESULTS: Independent linear regressions revealed variable patterns of linear and/or quadratic effects of age (r2 = 6-27% variance explained), sex (0-13%), and education (2-10%) across measures. MNS norms improved base rates of low performance in the older adult validation sample overall and in sex-specific patterns relative to MOANS. CONCLUSIONS: Our results demonstrate the need for updated norms that consider complex demographic associations on test performance and that specifically exclude participants with mild cognitive impairment from the normative sample.

Modeling the temporal evolution of plasma p-tau in relation to amyloid beta and tau PET.

INTRODUCTION: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aß) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS: Individual timing of plasma p-tau progression was strongly associated with Aß PET and GFAP progression. In the population, GFAP became abnormal first, then Aß PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION: Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aß than of tau pathology. While Aß deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aß PET was the strongest. HIGHLIGHTS: Plasma p-tau progression was more strongly associated with Aß than tau PET. Progression on plasma p-tau was associated with Aß PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aß PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aß PET.

Mayo Normative Studies: Regression-Based Normative Data for the Auditory Verbal Learning Test for Ages 30-91 Years and the Importance of Adjusting for Sex.

OBJECTIVE: Rey's Auditory Verbal Learning Test (AVLT) is a widely used word list memory test. We update normative data to include adjustment for verbal memory performance differences between men and women and illustrate the effect of this sex adjustment and the importance of excluding participants with mild cognitive impairment (MCI) from normative samples. METHOD: This study advances the Mayo's Older Americans Normative Studies (MOANS) by using a new population-based sample through the Mayo Clinic Study of Aging, which randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. Regression-based normative T-score formulas were derived from 4428 cognitively unimpaired adults aged 30-91 years. Fully adjusted T-scores correct for age, sex, and education. We also derived T-scores that correct for (1) age or (2) age and sex. Test-retest reliability data are provided. RESULTS: From raw score analyses, sex explained a significant amount of variance in performance above and beyond age (8-10%). Applying original age-adjusted MOANS norms to the current sample resulted in significantly fewer-than-expected participants with low delayed recall performance, particularly in women. After application of new T-scores adjusted only for age, even in normative data derived from this sample, these age-adjusted T-scores showed scores <40 T occurred more frequently among men and less frequently among women relative to T-scores that also adjusted for sex. CONCLUSIONS: Our findings highlight the importance of using normative data that adjust for sex with measures of verbal memory and provide new normative data that allow for this adjustment for the AVLT.

Diagnostic accuracy of the Cogstate Brief Battery for prevalent MCI and prodromal AD (MCI A+ T+ ) in a population-based sample.

INTRODUCTION: This study evaluated the diagnostic accuracy of the Cogstate Brief Battery (CBB) for mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) in a population-based sample. METHODS: Participants included adults ages 50+ classified as cognitively unimpaired (CU, n = 2866) or MCI (n = 226), and a subset with amyloid (A) and tau (T) positron emission tomography who were AD biomarker negative (A-T-) or had prodromal AD (A+T+). RESULTS: Diagnostic accuracy of the Learning/Working Memory Composite (Lrn/WM) for discriminating all CU and MCI was moderate (area under the curve [AUC] = 0.75), but improved when discriminating CU A-T- and MCI A+T+ (AUC = 0.93) and when differentiating MCI participants without AD biomarkers from those with prodromal AD (AUC = 0.86). Conventional cut-offs yielded lower than expected sensitivity for both MCI (38%) and prodromal AD (73%). DISCUSSION: Clinical utility of the CBB for detecting MCI in a population-based sample is lower than expected. Caution is needed when using currently available CBB normative data for clinical interpretation.

Predicting Progression to Mild Cognitive Impairment.

Despite much attention to the use of biomarkers for predicting Alzheimer disease, little information is available at the individual level. We used the population-based Mayo Clinic Study of Aging to estimate absolute risk of cognitive impairment by biomarker group. Risk increased with age and any biomarker abnormality. For example, a 75-year-old with abnormal amyloid and cortical thinning biomarkers has about a 20% chance of cognitive impairment by age 80 years, whereas with normal biomarkers the chance is <10%. Persons with only one abnormal biomarker had similar intermediate risks. ANN NEUROL 2019;85:155-160.

Entorhinal cortex tau, amyloid-ß, cortical thickness and memory performance in non-demented subjects.

As more biomarkers for Alzheimer's disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with 11C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, 18F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-ß levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.

Cortical atrophy patterns of incident MCI subtypes in the Mayo Clinic Study of Aging.

INTRODUCTION: We examined differences in cortical thickness in empirically derived mild cognitive impairment (MCI) subtypes in the Mayo Clinic Study of Aging. METHODS: We compared cortical thickness of four incident MCI subtypes (n = 192) to 1257 cognitive unimpaired individuals. RESULTS: The subtle cognitive impairment cluster had atrophy in the entorhinal and parahippocampal cortex. The amnestic, dysnomic, and dysexecutive clusters also demonstrated entorhinal cortex atrophy as well as thinning in temporal, parietal, and frontal isocortex in somewhat different patterns. DISCUSSION: We found patterns of atrophy in each of the incident MCI clusters that corresponded to their patterns of cognitive impairment. The identification of MCI subtypes based on cognitive and structural features may allow for more efficient trial and study designs. Given individuals in the subtle cognitive impairment cluster have less structural changes and cognitive decline and may represent the earliest group, this could be a unique group to target with early interventions.

Tau-positron emission tomography correlates with neuropathology findings.

INTRODUCTION: Comparison of tau (flortaucipir) positron emission tomography (FTP-PET) to autopsy is important to demonstrate the relationship of FTP-PET to neuropathologic findings. METHODS: Autopsies were performed on 26 participants who had antemortem FTP-PET. FTP-PET standardized uptake value ratios (SUVRs) were compared to autopsy diagnoses and Braak tangle stage. Quantitative tau burden was compared to regional FTP-PET signal. RESULTS: Participants with Braak stages of IV or greater had elevated FTP-PET signal. FTP-PET was elevated in participants with Alzheimer's disease. An FTP-PET SUVR cut point of 1.29 was determined to be optimal. Quantitative measurements of hippocampal and temporal lobe tau burden were highly correlated to FTP-PET signal (rho's from 0.61 to 0.70, P ≤ .02). DISCUSSION: Elevated FTP-PET reflects Braak IV or greater neuropathology. Participants with primary age-related tauopathy and hippocampal sclerosis did not show elevated FTP-PET signal. Secondary neuropathologic diagnoses of Alzheimer's disease neuropathologic change can lead to borderline elevated FTP-PET signal.

Neuropsychological subtypes of incident mild cognitive impairment in the Mayo Clinic Study of Aging.

INTRODUCTION: We evaluated whether incident mild cognitive impairment (MCI) subtypes could be empirically derived in the Mayo Clinic Study of Aging. METHODS: We performed cluster analysis on neuropsychological data from 506 participants with incident MCI. RESULTS: The 3-cluster solution resulted in (1) amnestic, (2) dysexecutive, (3) dysnomic subtypes. The 4-cluster solution produced these same three groups and a fourth group with subtle cognitive impairment (SCI). The SCI cluster was a subset of the amnestic cluster and distinct from well-matched cognitively unimpaired participants based on memory and global z-score area under the receiver operating characteristic curve analyses and probability of progression to MCI/dementia. DISCUSSION: We empirically identified three neuropsychological subtypes of MCI that share some features with MCI subtypes identified in the Alzheimer's Disease Neuroimaging Initiative. The fourth subtype with SCI in the Mayo Clinic Study of Aging differed from the fourth cluster-derived normal group in Alzheimer's Disease Neuroimaging Initiative and could represent a group to target with early interventions.

Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease.

INTRODUCTION: Neuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential. METHODS: We compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB-PET), 18F-fluorodeoxyglucose PET (FDG-PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed. RESULTS: PiB-PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG-PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with "none" or "sparse" neuritic plaque scores had elevated PiB-PET signal due to diffuse amyloid plaque. Participants with findings characterized as "suspected non-Alzheimer's pathophysiology" represented 15% of the group. DISCUSSION: PiB-PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG-PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non-Alzheimer's pathophysiology most commonly had primary age-related tauopathy.

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated with Dementia with Lewy Bodies: A Pilot Study.

BACKGROUND/AIMS: Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB. METHODS: We performed a 12-week pilot trial of armodafinil therapy (125-250 mg orally daily) in DLB outpatients with hypersomnia. The patients underwent neurologic examinations, a neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method. RESULTS: Of 20 participants, 17 completed the protocol. The median age was 72 years, most of the participants were men (80%), and most had spouses as caregivers. The Epworth Sleepiness Scale (p < 0.001), Maintenance of Wakefulness Test (p = 0.003), and Clinical Global Impression of Change (p < 0.001) scores improved at week 12. The Neuropsychiatric Inventory total score (p = 0.003), visual hallucinations (p = 0.003), and agitation (p = 0.02) improved at week 4. Caregiver overall quality of life improved at week 12 (p = 0.004). No adverse events occurred. CONCLUSION: These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies for managing hypersomnolence in these patients.

Amyloid-ß deposition and regional grey matter atrophy rates in dementia with Lewy bodies.

Alzheimer's disease pathology frequently coexists with Lewy body disease at autopsy in patients with probable dementia with Lewy bodies. More than half of patients with probable dementia with Lewy bodies have high amyloid-ß deposition as measured with 11C-Pittsburgh compound B binding on positron emission tomography. Biomarkers of amyloid-ß deposition precede neurodegeneration on magnetic resonance imaging during the progression of Alzheimer's disease, but little is known about how amyloid-ß deposition relates to longitudinal progression of atrophy in patients with probable dementia with Lewy bodies. We investigated the associations between baseline 11C-Pittsburgh compound B binding on positron emission tomography and the longitudinal rates of grey matter atrophy in a cohort of clinically diagnosed patients with dementia with Lewy bodies (n = 20), who were consecutively recruited to the Mayo Clinic Alzheimer's Disease Research Centre. All patients underwent 11C-Pittsburgh compound B positron emission tomography and magnetic resonance imaging examinations at baseline. Follow-up magnetic resonance imaging was performed after a mean (standard deviation) interval of 2.5 (1.1) years. Regional grey matter loss was determined on three-dimensional T1-weighted magnetic resonance imaging with the tensor-based morphometry-symmetric normalization technique. Linear regression was performed between baseline 11C-Pittsburgh compound B standard unit value ratio and longitudinal change in regional grey matter volumes from an in-house modified atlas. We identified significant associations between greater baseline 11C-Pittsburgh compound B standard unit value ratio and greater grey matter loss over time in the posterior cingulate gyrus, lateral and medial temporal lobe, and occipital lobe as well as caudate and putamen nuclei, after adjusting for age (P < 0.05). Greater baseline 11C-Pittsburgh compound B standard unit value ratio was also associated with greater ventricular expansion rates (P < 0.01) and greater worsening over time in Clinical Dementia Rating Scale, sum of boxes (P = 0.02). In conclusion, in patients with probable dementia with Lewy bodies, higher amyloid-ß deposition at baseline is predictive of faster neurodegeneration in the cortex and also in the striatum. This distribution is suggestive of possible interactions among amyloid-ß, tau and α-synuclein aggregates, which needs further investigation. Furthermore, higher amyloid-ß deposition at baseline predicts a faster clinical decline over time in patients with probable dementia with Lewy bodies.

Accelerated vs. unaccelerated serial MRI based TBM-SyN measurements for clinical trials in Alzheimer's disease.

OBJECTIVE: Our primary objective was to compare the performance of unaccelerated vs. accelerated structural MRI for measuring disease progression using serial scans in Alzheimer's disease (AD). METHODS: We identified cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD subjects from all available Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with usable pairs of accelerated and unaccelerated scans. There were a total of 696 subjects with baseline and 3 month scans, 628 subjects with baseline and 6 month scans and 464 subjects with baseline and 12 month scans available. We employed the Symmetric Diffeomorphic Image Normalization method (SyN) for normalization of the serial scans to obtain tensor based morphometry (TBM) maps which indicate the structural changes between pairs of scans. We computed a TBM-SyN summary score of annualized structural changes over 31 regions of interest (ROIs) that are characteristically affected in AD. TBM-SyN scores were computed using accelerated and unaccelerated scan pairs and compared in terms of agreement, group-wise discrimination, and sample size estimates for a hypothetical therapeutic trial. RESULTS: We observed a number of systematic differences between TBM-SyN scores computed from accelerated and unaccelerated pairs of scans. TBM-SyN scores computed from accelerated scans tended to have overall higher estimated values than those from unaccelerated scans. However, the performance of accelerated scans was comparable to unaccelerated scans in terms of discrimination between clinical groups and sample sizes required in each clinical group for a therapeutic trial. We also found that the quality of both accelerated vs. unaccelerated scans were similar. CONCLUSIONS: Accelerated scanning protocols reduce scan time considerably. Their group-wise discrimination and sample size estimates were comparable to those obtained with unaccelerated scans. The two protocols did not produce interchangeable TBM-SyN estimates, so it is arguably important to use either accelerated pairs of scans or unaccelerated pairs of scans throughout the study duration.

Patterns of Early Neocortical Amyloid-ß Accumulation: A PET Population-Based Study.

The widespread deposition of amyloid-ß (Aß) plaques in late-stage Alzheimer disease is well defined and confirmed by in vivo PET. However, there are discrepancies between which regions contribute to the earliest topographic Aß deposition within the neocortex. Methods: This study investigated Aß signals in the perithreshold SUV ratio range using Pittsburgh compound B (PiB) PET in a population-based study cross-sectionally and longitudinally. PiB PET scans from 1,088 participants determined the early patterns of PiB loading in the neocortex. Results: Early-stage Aß loading is seen first in the temporal, cingulate, and occipital regions. Regional early deposition patterns are similar in both apolipoprotein ε4 carriers and noncarriers. Clustering analysis shows groups with different patterns of early amyloid deposition. Conclusion: These findings of initial Aß deposition patterns may be of significance for diagnostics and understanding the development of Alzheimer disease phenotypes.

Mayo Normative Studies: Amyloid and Neurodegeneration Negative Normative Data for the Auditory Verbal Learning Test and Sex-Specific Sensitivity to Mild Cognitive Impairment/Dementia.

Background: Conventional normative samples include individuals with undetected Alzheimer's disease neuropathology, lowering test sensitivity for cognitive impairment. Objective: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A-N-) for Rey's Auditory Verbal Learning Test (AVLT). We compared these MNS A-N- norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. Methods: The A-N- sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A-N- norms in two independent samples of CU (n = 261) and mild cognitive impairment (MCI)/dementia participants (n = 392) > 55 years of age. Results: Variability associated with age decreased by almost half in the A-N- norm sample relative to the conventional norm sample. Fully-adjusted MNS A-N- norms showed approximately 7- 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1- 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. Conclusions: A-N- norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A-N- norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches.

Evidence against a temporal association between cerebrovascular disease and Alzheimer's disease imaging biomarkers.

Whether a relationship exists between cerebrovascular disease and Alzheimer's disease has been a source of controversy. Evaluation of the temporal progression of imaging biomarkers of these disease processes may inform mechanistic associations. We investigate the relationship of disease trajectories of cerebrovascular disease (white matter hyperintensity, WMH, and fractional anisotropy, FA) and Alzheimer's disease (amyloid and tau PET) biomarkers in 2406 Mayo Clinic Study of Aging and Mayo Alzheimer's Disease Research Center participants using accelerated failure time models. The model assumes a common pattern of progression for each biomarker that is shifted earlier or later in time for each individual and represented by a per participant age adjustment. An individual's amyloid and tau PET adjustments show very weak temporal association with WMH and FA adjustments (R = -0.07 to 0.07); early/late amyloid or tau timing explains <1% of the variation in WMH and FA adjustment. Earlier onset of amyloid is associated with earlier onset of tau (R = 0.57, R2 = 32%). These findings support a strong mechanistic relationship between amyloid and tau aggregation, but not between WMH or FA and amyloid or tau PET.

Mayo normative studies: A conditional normative model for longitudinal change on the Auditory Verbal Learning Test and preliminary validation in preclinical Alzheimer's disease.

Introduction: The aim of this study was to develop a conditional normative model for Rey's Auditory Verbal Learning Test (AVLT) that accounts for practice effects. Methods: In our normative sample, robust conditional norms were derived from 1001 cognitively unimpaired (CU) adults ages 50 to 89 who completed the AVLT up to eight times. Linear mixed-effects models adjusted for baseline performance, prior test exposures, time, demographics, and interaction terms. In our preliminary validation, mean performance on conditional and typical normative scores across two to four completed follow-up tests in preclinical Alzheimer's disease participants at baseline with positive amyloid and tau positron emission (n = 27 CU amyloid [A]+tau[T]+) was compared to biomarker negative individuals (n = 269 CU A-T-). Results: AVLT performance using typical norms did not differ across A+T+ and A-T- groups. Conditional norms z-scores were lower in the A+T+ relative to the A-T- group for 30-minute recall (P = .033) and sum of trials (P = .030). Discussion: Conditional normative methods that account for practice effects show promise for identifying longitudinal cognitive decline.

The Overlap Index as a Means of Evaluating Early Tau PET Signal Reliability.

In tau PET, a reliable method to detect early tau accumulation in the brain is crucial. Noise, artifacts, and off-target uptake impede detection of subtle true-positive ligand binding. We hypothesize that identifying voxels with stable activity over time can enhance detection of true-positive tau. Methods: In total, 339 participants in the clinical spectrum ranging from clinically unimpaired to Alzheimer disease dementia underwent at least 2 serial tau PET scans with flortaucipir. The overlap index (OI) method was proposed to detect spatially identical, voxelwise SUV ratio (SUVR) elevation when seen sequentially in serial tau PET scans. The association of OI with tau accumulation, clinical diagnosis, and cognitive findings was evaluated. Results: OI showed good dynamic range in the low-SUVR window. Only OI was able to identify subgroups with increasing tau PET signal in low-SUVR meta-region-of-interest (ROI) groups. OI showed improved association with early clinical disease progression and cognitive scores versus meta-ROI SUVR measures. Conclusion: OI was more sensitive to tau signal elevation and longitudinal change than standard ROI measures, suggesting it is a more sensitive method for detecting early, subtle deposition of neurofibrillary tangles.

Long-term associations between amyloid positron emission tomography, sex, apolipoprotein E and incident dementia and mortality among individuals without dementia: hazard ratios and absolute risk.

Dementia and mortality rates rise inexorably with age and consequently interact. However, because of the major logistical difficulties in accounting for both outcomes in a defined population, very little work has examined how risk factors and biomarkers for incident dementia are influenced by competing mortality. The objective of this study was to examine long-term associations between amyloid PET, APOE ɛ4, sex, education and cardiovascular/metabolic conditions, and hazard and absolute risk of dementia and mortality in individuals without dementia at enrolment. Participants were enrolled in the Mayo Clinic Study of Aging, a population-based study of cognitive ageing in Olmsted County, MN, USA. All were without dementia and were age 55-92 years at enrolment and were followed longitudinally. Predictor variables were amyloid PET, APOE ɛ4 status, sex, education, cardiovascular/metabolic conditions and age. The main outcomes were incident dementia and mortality. Multivariable, multi-state models were used to estimate mortality and incident dementia rates and absolute risk of dementia and mortality by predictor variable group. Of the 4984 participants in the study, 4336 (87%) were cognitively unimpaired and 648 (13%) had mild cognitive impairment at enrolment. The median age at enrolment was 75 years; 2463 (49%) were women. The median follow-up time was 9.4 years (7.5 years after PET). High versus normal amyloid (hazard ratio 2.11, 95% confidence interval 1.43-2.79), APOE ɛ4 (women: hazard ratio 2.24, 95% confidence interval 1.80-2.77; men: hazard ratio 1.37, 95% confidence interval 1.09-1.71), older age and two additional cardiovascular/metabolic conditions (hazard ratio 1.37, 95% confidence interval 1.22-1.53) were associated with the increased hazard of dementia (all P < 0.001). Among APOE ɛ4 carriers with elevated amyloid, remaining lifetime risk of dementia at age 65 years was greater in women [74% (95% confidence interval 65-84%) high and 58% (95% confidence interval 52-65%) moderate amyloid], than men [62% (95% confidence interval 52-73%) high and 44% (95% confidence interval 35-53%) moderate amyloid]. Overall, the hazard and absolute risk of dementia varied considerably by predictor group. The absolute risk of dementia associated with predictors characteristic of Alzheimer's disease was greater in women than men while at the same time the combination of APOE ɛ4 non-carrier with normal amyloid was more protective in women than men. This set of findings may be attributed in part to different biological effects and in part to lower mortality rates in women.