Artificial Intelligence Assistive Software Tool for Automated Detection and Quantification of Amyloid-Related Imaging Abnormalities.

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-ß-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software. Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA. Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023. Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification. Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types. Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-ß-directed monoclonal antibody therapies.

Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P =  0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Aß) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aß removal therapy have a pattern of more severe neurodegenerative process.

Privacy-preserving analysis of time-to-event data under nested case-control sampling.

Analyses of distributed data networks of rare diseases are constrained by legitimate privacy and ethical concerns. Analytical centers (e.g. research institutions) are thus confronted with the challenging task of obtaining data from recruiting sites that are often unable or unwilling to share personal records of participants. For time-to-event data, recently popularized disclosure techniques with privacy guarantees (e.g., Differentially Private Generative Adversarial Networks) are generally computationally expensive or inaccessible to applied researchers. To perform the widely used Cox proportional hazards regression, we propose an easy-to-implement privacy-preserving data analysis technique by pooling (i.e. aggregating) individual records of covariates at recruiting sites under the nested case-control sampling framework before sharing the pooled nested case-control subcohort. We show that the pooled hazard ratio estimators, under the pooled nested case-control subsamples from the contributing sites, are maximum likelihood estimators and provide consistent estimates of the individual level full cohort HRs. Furthermore, a sampling technique for generating pseudo-event times for individual subjects that constitute the pooled nested case-control subsamples is proposed. Our method is demonstrated using extensive simulations and analysis of the National Lung Screening Trial data. The utility of our proposed approach is compared to the gold standard (full cohort) and synthetic data generated using classification and regression trees. The proposed pooling technique performs to near-optimal levels comparable to full cohort analysis or synthetic data; the efficiency improves in rare event settings when more controls are matched on during nested case-control subcohort sampling.

Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET.

Introduction: [18F]AZD4694 is an amyloid beta (Aß) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aß 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, Aß positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aß 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 Aß levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies.

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography.

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-ß plaques and tau neurofibrillary tangles. Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral ß-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). Design, Setting, and Participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. Main Outcomes and Measures: Associations between p-tau biomarkers with amyloid PET and tau PET. Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts. Conclusions and Relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-ß accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease.

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.

A three-range approach enhances the prognostic utility of CSF biomarkers in Alzheimer's disease.

Introduction: Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well-described clinical strengths and methodological limitations. Although neuroimaging studies have explored alternative biomarker interpretation strategies, a formally defined three-range approach and its prognostic impact remains under-explored for cerebrospinal fluid (CSF) biomarkers . Methods: With two-graph receiver-operating characteristics based on different reference schemes, we derived three-range cut-points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid-beta (Aß) positron emission tomography (PET) accumulation in non-demented individuals (Alzheimer's Disease Neuroimaging Initiative [ADNI]; n = 1246). In all analyses, we compared herein-derived three-range CSF cut-points to previously described binary ones. Results: In our main longitudinal analyses, we highlight CSF p-tau181/Aß1-42 three-range cut-points derived based on the cognitively normal Aß-PET negative versus dementia Aß-PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate-range CSF status have similar rates of Aß deposition to those in the clearly abnormal group. Discussion: The proposed approach can refine clinico-biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker-related cognitive decline in comparison to binary cut-points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications.

Feasibility, Acceptability, and Clinical Significance of a Dyadic, Web-Based, Psychosocial and Physical Activity Self-Management Program (TEMPO) Tailored to the Needs of Men with Prostate Cancer and Their Caregivers: A Multi-Center Randomized Pilot Trial.

BACKGROUND: Prostate cancer is the most common cancer diagnosis among men. Family caregivers (often female spouses) play a key role in ensuring patients' needs are met, frequently assuming their role with no formal training, which can contribute to a high burden. The purpose of this study was to pilot TEMPO-the first dyadic, Tailored, wEb-based, psychosocial and physical activity self-Management PrOgram for men with prostate cancer and their caregivers. METHODS: 49 men with prostate cancer and their caregivers were randomized to TEMPO or usual care. Baseline and follow-up questionnaires were completed to assess feasibility, acceptability, and clinical significance. A priori benchmarks for these outcomes were set. Thirteen exit interviews were conducted to further explore acceptability. RESULTS: Feasibility benchmarks were met with the exception for recruitment with on average 6.1 dyads recruited/month (benchmark: 8 dyads/month). Benchmarks of acceptability focused on attrition (<25%) and system usability, which were met. Using the strict criteria for adherence of 100% of the module viewed and participants spending at least 15 min on the module, 45% of participants were adherent. The clinical significance on anxiety and quality of life was supported for caregivers, and mostly supported for the men with prostate cancer. CONCLUSION: This pilot trial was successful, with minor modifications needed prior to a large trial.

Biomarker modeling of Alzheimer's disease using PET-based Braak staging.

Gold-standard diagnosis of Alzheimer's disease (AD) relies on histopathological staging systems. Using the topographical information from [18F]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-ß, phosphorylated tau (pTau) in cerebrospinal fluid (pTau181, pTau217, pTau231 and pTau235) and plasma (pTau181 and pTau231), 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-ß 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.

Model-Based ROC Curve: Examining the Effect of Case Mix and Model Calibration on the ROC Plot.

BACKGROUND: The performance of risk prediction models is often characterized in terms of discrimination and calibration. The receiver-operating characteristic (ROC) curve is widely used for evaluating model discrimination. However, when comparing ROC curves across different samples, the effect of case mix makes the interpretation of discrepancies difficult. Further, compared with model discrimination, evaluating model calibration has not received the same level of attention. Current methods for examining model calibration require specification of smoothing or grouping factors. METHODS: We introduce the "model-based" ROC curve (mROC) to assess model calibration and the effect of case mix during external validation. The mROC curve is the ROC curve that should be observed if the prediction model is calibrated in the external population. We show that calibration-in-the-large and the equivalence of mROC and ROC curves are together sufficient conditions for the model to be calibrated. Based on this, we propose a novel statistical test for calibration that, unlike current methods, does not require any subjective specification of smoothing or grouping factors. RESULTS: Through a stylized example, we demonstrate how mROC separates the effect of case mix and model miscalibration when externally validating a risk prediction model. We present the results of simulation studies that confirm the properties of the new calibration test. A case study on predicting the risk of acute exacerbations of chronic obstructive pulmonary disease puts the developments in a practical context. R code for the implementation of this method is provided. CONCLUSION: mROC can easily be constructed and used to interpret the effect of case mix and calibration on the ROC plot. Given the popularity of ROC curves among applied investigators, this framework can further promote assessment of model calibration. HIGHLIGHTS: Compared with examining model discrimination, examining model calibration has not received the same level of attention among investigators who develop or examine risk prediction models.This article introduces the model-based ROC (mROC) curve as the basis for graphical and statistical examination of model calibration on the ROC plot.This article introduces a formal statistical test based on mROC for examining model calibration that does not require arbitrary smoothing or grouping factors.Investigators who develop or validate risk prediction models can now also use the popular ROC plot for examining model calibration, as a critical but often neglected component in predictive analytics.

Amyloid-dependent and amyloid-independent effects of Tau in individuals without dementia.

OBJECTIVE: To investigate the relationship between the topography of amyloid-ß plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. METHODS: We evaluated 154 individuals who were assessed with amyloid-ß PET with [18 F]AZD4694, tau-PET with [18 F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid-ß PET with [18 F]Florbetapir, tau-PET with [18 F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel-wise linear regressions between amyloid-PET, tau-PET, and their interaction with cognitive function, correcting for age, sex, and years of education. RESULTS: In both cohorts, we observed that tau-PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR-SoB) scores independently of local amyloid-PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau-PET and clinical function were dependent on local amyloid-PET (FWE corrected at p < 0.001). INTERPRETATION: In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid-ß, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid-ß and tau pathologies such as the posterior cingulate and medial frontal cortices, tau's relationship with cognitive dysfunction was dependent on local amyloid-ß concentrations. Our results provide evidence that amyloid-ß in Alzheimer's disease influences cognition by potentiating the deleterious effects of tau pathology.

Impact of a personalised, digital, HIV self-testing app-based program on linkages and new infections in the township populations of South Africa.

INTRODUCTION: Implementation data for digital unsupervised HIV self-testing (HIVST) are sparse. We evaluated the impact of an app-based, personalised, oral HIVST program offered by healthcare workers in Western Cape, South Africa. METHODS: In a quasirandomised study (n=3095), we recruited consenting adults with undiagnosed HIV infection from township clinics. To the HIVST arm participants (n=1535), we offered a choice of an offsite (home, office or kiosk based), unsupervised digital HIVST program (n=962), or an onsite, clinic-based, supervised digital HIVST program (n=573) with 24/7 linkages services.With propensity score analyses, we compared outcomes (ie, linkages, new HIV infections and test referrals) with conventional HIV testing (ConvHT) arm participants (n=1560), recruited randomly from geographically separated clinics. RESULTS: In both arms, participants were young (HIVST vs ConvHT) (mean age: 28.2 years vs 29.2 years), female (65.0% vs 76.0%) and had monthly income <3000 rand (80.8% vs 75%).Participants chose unsupervised HIVST (62.7%) versus supervised HIVST and reported multiple sex partners (10.88% vs 8.7%), exposure to sex workers (1.4% vs 0.2%) and fewer comorbidities (0.9% vs 1.9%). Almost all HIVST participants were linked (unsupervised HIVST (99.7%), supervised HIVST (99.8%) vs ConvHT (98.5%)) (adj RR 1.012; 95% CI 1.005 to 1.018) with new HIV infections: overall HIVST (9%); supervised HIVST (10.9%) and unsupervised HIVST (7.6%) versus ConvHT (6.79%) (adj RR 1.305; 95% CI 1.023 to 1.665); test referrals: 16.7% HIVST versus 3.1% ConvHT (adj RR 5.435; 95% CI 4.024 to 7.340). CONCLUSIONS: Our flexible, personalised, app-based HIVST program, offered by healthcare workers, successfully linked almost all HIV self-testers, detected new infections and increased referrals to self-test. Data are relevant for digital HIVST initiatives worldwide.

Association of plasma P-tau181 with memory decline in non-demented adults.

Alzheimer's disease is the leading cause of dementia worldwide and is characterized by a long preclinical phase in which amyloid-ß and tau accumulate in the absence of cognitive decline. In vivo biomarkers for Alzheimer's disease are expensive, invasive and inaccessible, yet are critical for accurate disease diagnosis and patient management. Recent ultrasensitive methods to measure plasma phosphorylated tau 181 (p-tau181) display strong correlations with tau positron emission tomography, p-tau181 in CSF, and tau pathology at autopsy. The clinical utility of plasma-based p-tau181 biomarkers is unclear. In a longitudinal multicentre observational study, we assessed 1113 non-demented individuals (509 cognitively unimpaired elderly and 604 individuals with mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative who underwent neuropsychological assessments and were evaluated for plasma p-tau181. The primary outcome was a memory composite z-score. Mixed-effect models assessed rates of memory decline in relation to baseline plasma p-tau181, and whether plasma p-tau181 significantly predicted memory decline beyond widely available clinical and genetic data (age, sex, years of education, cardiovascular and metabolic conditions, and APOEε4 status). Participants were followed for a median of 4.1 years. Baseline plasma p-tau181 was associated with lower baseline memory (ß estimate: -0.49, standard error: 0.06, t-value: -7.97), as well as faster rates of memory decline (ß estimate: -0.11, standard error: 0.01, t-value: -7.37). Moreover, the inclusion of plasma p-tau181 resulted in improved prediction of memory decline beyond clinical and genetic data (marginal R 2 of 16.7-23%, χ2 = 100.81, P < 0.00001). Elevated baseline plasma p-tau181 was associated with higher rates of clinical progression to mild cognitive impairment (hazard ratio = 1.82, 95% confidence interval: 1.2-2.8) and from mild cognitive impairment to dementia (hazard ratio = 2.06, 95% confidence interval: 1.55-2.74). Our results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer's disease biomarker.

Plasma pTau181 predicts cortical brain atrophy in aging and Alzheimer's disease.

BACKGROUND: To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer's disease. METHODS: Observational data was obtained from the Alzheimer's Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry. RESULTS: We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months. CONCLUSIONS: Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer's disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.

A study protocol for a multicenter randomized pilot trial of a dyadic, tailored, web-based, psychosocial, and physical activity self-management program (TEMPO) for men with prostate cancer and their caregivers.

BACKGROUND: Prostate cancer predisposes patients and caregivers to a wide range of complex physical and psychosocial challenges, and interventions must incorporate a wide range of self-management strategies to help patients and their caregivers effectively cope with cancer challenges. To palliate this need, our team recently developed and evaluated the initial acceptability of a dyadic, Tailored, wEb-based, psychosocial, and physical activity self-Management PrOgram (TEMPO). TEMPO is a 10-week, interactive, web-based intervention consisting of five modules designed to help dyads manage their physical and psychosocial needs. It aims to teach dyads new self-management strategies and encourages them to increase their physical activity (PA) levels, mainly through walking and strength-based exercises. Initial acceptability evaluation of TEMPO revealed high user satisfaction, in addition to having a number of potential benefits for participants. After integrating suggested changes to TEMPO, the proposed pilot study aims to further test the acceptability and feasibility of TEMPO. METHODS: This study is a multicenter, stratified, parallel, two-group, pilot randomized control trial (RCT), where patient-caregiver dyads are randomized (stratified by anxiety level) to receive (a) TEMPO or (b) usual care. Participants (n goal = 40) are recruited across Canada at participating cancer centers and through self-referral (e.g., online recruitment). Patient inclusion criteria are (a) having received prostate cancer treatment within the past 2 years or scheduled to receive treatment, (b) identified a primary caregiver willing to participate in the study, and (c) has access to the Internet. Eligible caregivers are those identified by the patient as his primary source of support. Dyads complete a baseline questionnaire (T1) and another one 3 months later (T2) assessing various aspects of physical and emotional functioning (e.g., the Medical Outcomes Study (MOS) 12-item Short Form Health Survey (SF-12), the Hospital Anxiety and Depression Scale (HADS), and the Perceived Stress Scale (PSS)), self-management behaviors (e.g., the Health Education Impact Questionnaire (heiQ)), physical activity (the International Physical Activity Questionnaires (IPAQ) and the Multidimensional Self-efficacy for Exercise Scale (MSES)), and dyadic coping (the Dyadic Coping Inventory (DCI)). Dyads that used TEMPO are also asked to participate in a semi-structured exit interview exploring their overall experience with the program. DISCUSSION: This feasibility analysis will begin to develop the knowledge base on TEMPO's value for men with prostate cancer and their caregivers to inform a larger trial. TRIAL REGISTRATION: NCT04304196.

Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment.

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 [18F]AZD4694 and tau-PET with [18F]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 ß-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.

APOEε4 potentiates the relationship between amyloid-ß and tau pathologies.

APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer's disease and is associated with cerebral amyloid-ß. 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-ß. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer's disease subjects: (1) 211 participants who underwent tau-PET with [18F]MK6240 and amyloid-PET with [18F]AZD4694, (2) 264 individuals who underwent tau-PET with [18F]Flortaucipir and amyloid-PET with [18F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [18F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-ß on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-ß, 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-ß was related to increased tau load, while the interaction between amyloid-ß 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-ß and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.

Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative.

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-ß (Aß) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aß and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aß PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aß PET scans show little increase but plasma p-tau181 is increased if CSF Aß has already changed prior to Aß PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aß- and Aß+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.