Search

Background: We have previously established the reliability and cross-sectional validity of the SIST-M (Structured Interview and Scoring Tool-Massachusetts Alzheimer's Disease Research Center), a shortened version of an instrument shown to predict progression to Alzheimer disease (AD), even among persons with very mild cognitive impairment (vMCI).Objective: To test the predictive validity of the SIST-M.Methods: Participants were 342 community-dwelling, nondemented older adults in a longitudinal study. Baseline Clinical Dementia Rating (CDR) ratings were determined by either (1) clinician interviews or (2) a previously developed computer algorithm based on 60 questions (of a possible 131) extracted from clinician interviews. We developed age+sex+education-adjusted Cox proportional hazards models using CDR-sum-of-boxes (CDR-SB) as the predictor, where CDR-SB was determined by either a clinician interview or an algorithm; models were run for the full sample (n = 342) and among those jointly classified as vMCI using clinician-based and algorithm-based CDR ratings (n = 156). We directly compared predictive accuracy using time-dependent receiver operating characteristic (ROC) curves.Results: AD hazard ratios (HRs) were similar for clinician-based and algorithm-based CDR-SB: for a 1-point increment in CDR-SB, the respective HRs [95% confidence interval (CI)] were 3.1 (2.5, 3.9) and 2.8 (2.2, 3.5); among those with vMCI, the respective HRs (95% CI) were 2.2 (1.6, 3.2) and 2.1 (1.5, 3.0). Similarly high predictive accuracy was achieved: the concordance probability (weighted average of the area-under-the-ROC curves) over follow-up was 0.78 versus 0.76 using clinician-based versus algorithm-based CDR-SB.Conclusion: CDR scores based on items from this shortened interview had high predictive ability for AD-comparable to that using a lengthy clinical interview. [ABSTRACT FROM AUTHOR]

Latent class models provide a useful framework for clustering observations based on several features. Application of latent class methodology to correlated, high-dimensional ordinal data poses many challenges. Unconstrained analyses may not result in an estimable model. Thus, information contained in ordinal variables may not be fully exploited by researchers. We develop a penalized latent class model to facilitate analysis of high-dimensional ordinal data. By stabilizing maximum likelihood estimation, we are able to fit an ordinal latent class model that would otherwise not be identifiable without application of strict constraints. We illustrate our methodology in a study of schwannoma, a peripheral nerve sheath tumor, that included 3 clinical subtypes and 23 ordinal histological measures. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Biological and clinical heterogeneity is a major challenge in research for developing new treatments for Alzheimer's disease (AD). AD may be defined by its amyloid beta and tau pathologies, but we recognize that mixed pathologies are common, and that diverse genetics, central nervous system (CNS) and systemic pathophysiological processes, and environmental/experiential factors contribute to AD's diverse clinical and neuropathological features. All these factors are rational targets for therapeutic development; indeed, there are hundreds of candidate pharmacological, dietary, neurostimulation, and lifestyle interventions that show benefits in homogeneous laboratory models. Conventional clinical trial designs accommodate heterogeneity poorly, and this may be one reason that progress in translating candidate interventions has been so difficult. We review the challenges of AD's heterogeneity for the clinical trials enterprise. We then discuss how advances in repeatable biomarkers and digital phenotyping enable novel "single-case" and adaptive trial designs to accelerate therapeutics development, moving us closer to personalized research and medicine for AD. HIGHLIGHTS: Alzheimer's disease is diverse in its clinical features, course, risks, and biology. Typical randomized controlled trials are exclusive and necessarily large to attain arm comparability with broad outcomes. Repeated blood biomarkers and digital tracking can improve outcome measure precision and sensitivity. This enables the use of novel "single-case" and adaptive trial designs for inclusivity, rigor, and efficiency., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6-22 and HR: 3.6, 95% CI: 1.1-12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2-6), trouble swallowing (HR 2.5, 95% CI: 1.4-4.5) and changes in speech (HR:2.4, 95% CI:1.1-4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1-5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2-38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6-46), preserved olfaction (HR: 8.7, 95% CI: 1.7-45), anhidrosis (HR: 1.8, 95% CI: 1-3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1-2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting., Methods: We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022., Results: A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small., Discussion: Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention., Highlights: We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Alzheimer's Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent., Methods: To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available ( N  = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus., Results: SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD., Discussion: The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Flaherty, Sui, Masurkar, Betensky, Rusinek and Lazar.)

Background: Hidradenitis suppurativa (HS) is a debilitating cutaneous disease characterized by severe painful inflammatory nodules/abscesses. At present, data regarding the epidemiology and pathophysiology of this disease are limited., Objective: To define the prevalence and comorbidity associations of HS., Methods: This was a cross-sectional study of EPIC TM Cosmos © examining over 180 million US patients. Prevalences were calculated by demographic and odds ratios (OR) and identified comorbidity correlations., Results: All examined metabolism-related, psychological, and autoimmune/autoinflammatory (AI) diseases correlated with HS. The strongest associations were with pyoderma gangrenosum [OR 26.56; confidence interval (CI): 24.98-28.23], Down syndrome (OR 11.31; CI 10.93-11.70), and polycystic ovarian syndrome (OR 11.24; CI 11.09-11.38). Novel AI associations were found between HS and lupus (OR 6.60; CI 6.26-6.94) and multiple sclerosis (MS; OR 2.38; CI 2.29-2.48). Cutaneous malignancies were largely not associated in the unsegmented cohort; however, among Black patients, novel associations with melanoma (OR 2.39; CI 1.86-3.08) and basal cell carcinoma (OR 2.69; CI 2.15-3.36) were identified., Limitations: International Classification of Diseases (ICD)-based disease identification relies on coding fidelity and diagnostic accuracy., Conclusion: This is the first study to identify correlations between HS with melanoma and basal cell carcinoma (BCC) among Black patients as well as MS and lupus in all patients with HS., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objectives: Chronic systemic inflammation has been hypothesized to be a mechanistic factor leading to post-acute cognitive dysfunction after COVID-19. However, little data exist evaluating longitudinal inflammatory markers., Methods: We conducted a secondary analysis of data collected from the CONTAIN randomized trial of convalescent plasma in patients hospitalized for COVID-19, including patients who completed an 18-month assessment of cognitive symptoms and PROMIS Global Health questionnaires. Patients with pre-COVID-19 dementia/cognitive abnormalities were excluded. Trajectories of serum cytokine panels, D-dimer, fibrinogen, C-reactive peptide (CRP), ferritin, lactate dehydrogenase (LDH), and absolute neutrophil counts (ANCs) were evaluated over 18 months using repeated measures and Friedman nonparametric tests. The relationships between the area under the curve (AUC) for each inflammatory marker and 18-month cognitive and global health outcomes were assessed., Results: A total of 279 patients (N = 140 received plasma, N = 139 received placebo) were included. At 18 months, 76/279 (27%) reported cognitive abnormalities and 78/279 (28%) reported fair or poor overall health. PROMIS Global Mental and Physical Health T-scores were 0.5 standard deviations below normal in 24% and 51% of patients, respectively. Inflammatory marker levels declined significantly from hospitalization to 18 months for all markers (IL-2, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, INFγ, TNFα, D-dimer, fibrinogen, ferritin, LDH, CRP, neutrophils; all p < 0.05), with the exception of IL-1β, which remained stable over time. There were no significant associations between the AUC for any inflammatory marker and 18-month cognitive symptoms, any neurologic symptom, or PROMIS Global Physical or Mental health T-scores. Receipt of convalescent plasma was not associated with any outcome measure., Discussion: At 18 months posthospitalization for COVID-19, cognitive abnormalities were reported in 27% of patients, and below average PROMIS Global Mental and Physical Health scores occurred in 24% and 51%, respectively. However, there were no associations with measured inflammatory markers, which decreased over time.

Objective: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments., Methods: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60-91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ- using positron emission tomography with 11C Pittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years., Results: At the cross-section, there were no statistically significant differences in performance between Aβ+/- participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ- participants (Cohen d = 0.49, 95% confidence interval = 0.10-0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001)., Interpretation: Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507-517., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Competing Interests: Conflicts of interest Dr Lo Sicco is a current investigator for Pfizer. She is a consultant for Pfizer and Aquis. Dr Garshick reports consultant fees from Horizon Therapeutics, Abbvie, BMS and Kiniksa. Drs Karagounis, Betensky, Klein, Karim, Liu, and Carli Needle, Ambika Nohria, Jessica Gjonaj, and Jinal Shah have no conflicts of interest.

Objective: Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning over repeated evaluations on participants' own devices. This provides the opportunity to derive individual multiday learning curve scores over short intervals. Here, we report feasibility, reliability, and validity, of a 7-day cognitive battery from the Boston Remote Assessment for Neurocognitive Health (Multiday BRANCH), an unsupervised web-based assessment., Method: Multiday BRANCH was administered remotely to 181 cognitively unimpaired older adults using their own electronic devices. For 7 consecutive days, participants completed three tests with associative memory components (Face-Name, Groceries-Prices, Digit Signs), using the same stimuli, to capture multiday learning curves for each test. We assessed the feasibility of capturing learning curves across the 7 days. Additionally, we examined the reliability and associations of learning curves with demographics, and traditional cognitive and subjective report measures., Results: Multiday BRANCH was feasible with 96% of participants completing all study assessments; there were no differences dependent on type of device used ( t = 0.71, p = .48) or time of day completed ( t = -0.08, p = .94). Psychometric properties of the learning curves were sound including good test-retest reliability of individuals' curves (intraclass correlation = 0.94). Learning curves were positively correlated with in-person cognitive tests and subjective report of cognitive complaints., Conclusions: Multiday BRANCH is a feasible, reliable, and valid cognitive measure that may be useful for identifying subtle changes in learning and memory processes in older adults. In the future, we will determine whether Multiday BRANCH is predictive of the presence of preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Importance: The spring 2020 surge of COVID-19 unprecedentedly strained ventilator supply in New York City, with many hospitals nearly exhausting available ventilators and subsequently seriously considering enacting crisis standards of care and implementing New York State Ventilator Allocation Guidelines (NYVAG). However, there is little evidence as to how NYVAG would perform if implemented., Objectives: To evaluate the performance and potential improvement of NYVAG during a surge of patients with respect to the length of rationing, overall mortality, and worsening health disparities., Design, Setting, and Participants: This cohort study included intubated patients in a single health system in New York City from March through July 2020. A total of 20 000 simulations were conducted of ventilator triage (10 000 following NYVAG and 10 000 following a proposed improved NYVAG) during a crisis period, defined as the point at which the prepandemic ventilator supply was 95% utilized., Exposures: The NYVAG protocol for triage ventilators., Main Outcomes and Measures: Comparison of observed survival rates with simulations of scenarios requiring NYVAG ventilator rationing., Results: The total cohort included 1671 patients; of these, 674 intubated patients (mean [SD] age, 63.7 [13.8] years; 465 male [69.9%]) were included in the crisis period, with 571 (84.7%) testing positive for COVID-19. Simulated ventilator rationing occurred for 163.9 patients over 15.0 days, 44.4% (95% CI, 38.3%-50.0%) of whom would have survived if provided a ventilator while only 34.8% (95% CI, 28.5%-40.0%) of those newly intubated patients receiving a reallocated ventilator survived. While triage categorization at the time of intubation exhibited partial prognostic differentiation, 94.8% of all ventilator rationing occurred after a time trial. Within this subset, 43.1% were intubated for 7 or more days with a favorable SOFA score that had not improved. An estimated 60.6% of these patients would have survived if sustained on a ventilator. Revising triage subcategorization, proposed improved NYVAG, would have improved this alarming ventilator allocation inefficiency (25.3% [95% CI, 22.1%-28.4%] of those selected for ventilator rationing would have survived if provided a ventilator). NYVAG ventilator rationing did not exacerbate existing health disparities., Conclusions and Relevance: In this cohort study of intubated patients experiencing simulated ventilator rationing during the apex of the New York City COVID-19 2020 surge, NYVAG diverted ventilators from patients with a higher chance of survival to those with a lower chance of survival. Future efforts should be focused on triage subcategorization, which improved this triage inefficiency, and ventilator rationing after a time trial, when most ventilator rationing occurred.

Background: Little is known about the long-term cognitive impact of internet usage among older adults. This research characterized the association between various measures of internet usage and dementia., Methods: We followed dementia-free adults aged 50-64.9 for a maximum of 17.1 (median = 7.9) years using the Health and Retirement Study. The association between time-to-dementia and baseline internet usage was examined using cause-specific Cox models, adjusting for delayed entry and covariates. We also examined the interaction between internet usage and education, race-ethnicity, sex, and generation. Furthermore, we examined whether the risk of dementia varies by the cumulative period of regular internet usage to see if starting or continuing usage in old age modulates subsequent risk. Finally, we examined the association between the risk of dementia and daily hours of usage. Analyses were conducted from September 2021 to November 2022., Results: In 18,154 adults, regular internet usage was associated with approximately half the risk of dementia compared to non-regular usage, CHR (cause-specific hazard ratio) = 0.57, 95% CI = 0.46-0.71. The association was maintained after adjustments for self-selection into baseline usage (CHR = 0.54, 95% CI = 0.41-0.72) and signs of cognitive decline at the baseline (CHR = 0.62, 95% CI = 0.46-0.85). The difference in risk between regular and non-regular users did not vary by educational attainment, race-ethnicity, sex, and generation. In addition, additional periods of regular usage were associated with significantly reduced dementia risk, CHR = 0.80, 95% CI = 0.68-0.95. However, estimates for daily hours of usage suggested a U-shaped relationship with dementia incidence. The lowest risk was observed among adults with 0.1-2 h of usage, though estimates were non-significant due to small sample sizes., Conclusions: Regular internet users experienced approximately half the risk of dementia than non-regular users. Being a regular internet user for longer periods in late adulthood was associated with delayed cognitive impairment, although further evidence is needed on potential adverse effects of excessive usage., (© 2023 The American Geriatrics Society.)

In observational cohort studies with complex sampling schemes, truncation arises when the time to event of interest is observed only when it falls below or exceeds another random time, that is, the truncation time. In more complex settings, observation may require a particular ordering of event times; we refer to this as sequential truncation. Estimators of the event time distribution have been developed for simple left-truncated or right-truncated data. However, these estimators may be inconsistent under sequential truncation. We propose nonparametric and semiparametric maximum likelihood estimators for the distribution of the event time of interest in the presence of sequential truncation, under two truncation models. We show the equivalence of an inverse probability weighted estimator and a product limit estimator under one of these models. We study the large sample properties of the proposed estimators and derive their asymptotic variance estimators. We evaluate the proposed methods through simulation studies and apply the methods to an Alzheimer's disease study. We have developed an R package, seqTrun, for implementation of our method., (© 2022 The International Biometric Society.)

There is currently no targeted therapy to treat NF1-mutant melanomas. In this study, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1 wild-type melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using The Cancer Genome Atlas data and immunohistochemistry. Digital spatial profiling with multiplex immunohistochemistry and immunofluorescence were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% of cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 than NF1 wild-type (P = 0.008), which was independently validated both in The Cancer Genome Atlas dataset (P = 0.01, P = 0.03) and with immunohistochemistry (P = 0.013, P = 0.036), respectively. Digital spatial profiling analysis showed upregulation of LY6E within the tumor cells (false discovery rate < 0.01, log2 fold change > 1), confirmed with multiplex immunofluorescence showing colocalization of LY6E in melanoma cells. The combination of MAPK/extracellular signal‒regulated kinase kinase and CDC20 coinhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-mutant cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Truncation occurs in cohort studies with complex sampling schemes. When truncation is ignored or incorrectly assumed to be independent of the event time in the observable region, bias can result. We derive completely nonparametric bounds for the survivor function under truncation and censoring; these extend prior nonparametric bounds derived in the absence of truncation. We also define a hazard ratio function that links the unobservable region in which event time is less than truncation time, to the observable region in which event time is greater than truncation time, under dependent truncation. When this function can be bounded, and the probability of truncation is known approximately, it yields narrower bounds than the purely nonparametric bounds. Importantly, our approach targets the true marginal survivor function over its entire support, and is not restricted to the observable region, unlike alternative estimators. We evaluate the methods in simulations and in clinical applications.

Background and Objectives: We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies., Methods: We analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling., Results: Carrying the APOE ε4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOE ε3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOE ε4 carriers declined faster than APOE ε3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOE ε4 vs APOE ε3/ε3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOE ε4 vs APOE ε3/ε3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOE ε4 vs APOE ε3/ε3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOE ε4 vs APOE ε3/ε3). Compared with slow decliners, fast decliners were more likely to carry the APOE ε4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy., Discussion: In a large national sample selected to represent the normal aging-early AD continuum, the APOE ε4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain., (© 2022. The Author(s).)

There is often delayed entry into observational studies, which results in left truncation. In the estimation of the distribution of time-to-event from left-truncated data, standard survival analysis methods require quasi-independence between the truncation time and event time. Incorrectly assuming quasi-independence may lead to biased estimation. We address the problem of estimation of the survival distribution when dependence between the event time and its left truncation time is induced by shared covariates. We introduce propensity scores for truncated data and propose two inverse probability weighting methods that adjust for both truncation and dependence, if all of the shared covariates are measured. The proposed methods additionally allow for right censoring. We evaluate the proposed methods in simulations, conduct sensitivity analyses, and provide guidelines for use in practice. We illustrate our approach in application to data from a central nervous system lymphoma study. The proposed methods are implemented in the R package, depLT., (© 2021 The International Biometric Society.)

Background: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults., Methods: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later., Results: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05)., Conclusions: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation., Clinical Trial Number: NCT03053908., (Copyright © 2022. Published by Elsevier Inc.)

The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer's disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship., (© 2022. Springer Nature B.V.)

Background Acute myocardial infarctions are increasingly common among young adults. We investigated sex and racial differences in the evaluation of chest pain (CP) among young adults presenting to the emergency department. Methods and Results Emergency department visits for adults aged 18 to 55 years presenting with CP were identified in the National Hospital Ambulatory Medical Care Survey 2014 to 2018, which uses stratified sampling to produce national estimates. We evaluated associations between sex, race, and CP management before and after multivariable adjustment. We identified 4152 records representing 29 730 145 visits for CP among young adults. Women were less likely than men to be triaged as emergent (19.1% versus 23.3%, respectively, P <0.001), to undergo electrocardiography (74.2% versus 78.8%, respectively, P =0.024), or to be admitted to the hospital or observation unit (12.4% versus 17.9%, respectively, P <0.001), but ordering of cardiac biomarkers was similar. After multivariable adjustment, men were seen more quickly (hazard ratio [HR], 1.15 [95% CI, 1.05-1.26]) and were more likely to be admitted (adjusted odds ratio, 1.40 [95% CI, 1.08-1.81]; P =0.011). People of color waited longer for physician evaluation (HR, 0.82 [95% CI, 0.73-0.93]; P <0.001) than White adults after multivariable adjustment, but there were no racial differences in hospital admission, triage level, electrocardiography, or cardiac biomarker testing. Acute myocardial infarction was diagnosed in 1.4% of adults in the emergency department and 6.5% of admitted adults. Conclusions Women and people of color with CP waited longer to be seen by physicians, independent of clinical features. Women were independently less likely to be admitted when presenting with CP. These differences could impact downstream treatment and outcomes.

Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.

Introduction: Neurological complications among hospitalized COVID-19 patients may be associated with elevated neurodegenerative biomarkers., Methods: Among hospitalized COVID-19 patients without a history of dementia (N = 251), we compared serum total tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and amyloid beta (Aβ40,42) between patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions. COVID-19 patient biomarker levels were also compared to non-COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161)., Results: Admission t-tau, p-tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in non-COVID controls with MCI or AD., Discussion: Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Truncated survival data arise when the event time is observed only if it falls within a subject specific region. The conventional risk-set adjusted Kaplan-Meier estimator or Cox model can be used for estimation of the event time distribution or regression coefficient. However, the validity of these approaches relies on the assumption of quasi-independence between truncation and event times. One model that can be used for the estimation of the survival function under dependent truncation is a structural transformation model that relates a latent, quasi-independent truncation time to the observed dependent truncation time and the event time. The transformation model approach is appealing for its simple interpretation, computational simplicity and flexibility. In this paper, we extend the transformation model approach to the regression setting. We propose three methods based on this model, in addition to a piecewise transformation model that adds greater flexibility. We investigate the performance of the proposed models through simulation studies and apply them to a study on cognitive decline in Alzheimer's disease from the National Alzheimer's Coordinating Center. We have developed an R package, tranSurv, for implementation of our method.

Objective: Active neutrophils are important contributors to Alzheimer's disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia. Methods: We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk. Results: The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline. Conclusion: Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramos-Cejudo, Johnson, Beiser, Seshadri, Salinas, Berger, Fillmore, Do, Zheng, Kovbasyuk, Ardekani, Bubu, Parekh, Convit, Betensky, Wisniewski and Osorio.)

Clinical studies with time to event endpoints typically report the median follow-up (i.e., censoring) time for the subjects in the trial, alongside the median time to event. The reason for this is to provide information about the opportunity for subjects in the study to experience the event of interest (Betensky, 2015 [1]). The median follow-up time is often calculated from the Kaplan-Meier estimate for time to censoring. In most clinical studies, the censoring time is a composite measure, defined as the minimum of time to drop-out from the study and time to administrative end of study. The time to drop-out component may or may not be observed; it is observed only if drop-out occurs before the event and the end of the study. However, the time to end of study is observed for each subject, as it is the time from entry to the study to the calendar date that is administratively set as the end of the study. It is known even for subjects who have the event prior to the end of the study. This decomposition of the censoring time into a time that is itself potentially censored and a time that is fully observed raises the interesting question of whether estimation of the censoring distribution could be improved through a decoupling of these times. We demonstrate in simulations that consideration of censoring in this way yields reduced variability under some circumstances and should be used in practice. We illustrate these concepts through application to a meningioma study., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier Inc.)

Early in the COVID-19 pandemic, anti-malarial agent hydroxychloroquine (HCQ) was touted as a potentially effective COVID-19 treatment due to its purported antiinflammatory and antiviral effects.

Background: Seizures are rare during repetitive transcranial magnetic stimulation (rTMS) treatment, but estimating risk is difficult because of study heterogeneity and sampling limitations. Moreover, there are few studies comparing rates between device manufacturers., Objective: The objective of this study was to calculate rTMS seizure rates across various FDA-cleared devices in naturalistic clinical settings., Methods: In July and August 2018, approximately 500 members of the Clinical TMS Society (CTMSS) were electronically surveyed about seizures in their practices. Seizures were distinguished from non-seizures by a remote semi-structured interview with a Board-certified neurologist and Co-Chair of the CTMSS Standards Committee. Exact Poisson calculations were used to estimate seizure rates and confidence intervals across the four most widely used manufacturers., Results: The survey was completed by 134 members, with 9 responses excluded because of data inconsistencies. In total, 18 seizures were reported in 586,656 sessions and 25,526 patients across all device manufacturers. The overall seizure rate was 0.31 (95% CI: 0.18, 0.48) per 10,000 sessions, and 0.71 (95% CI: 0.42, 1.11) per 1000 patients. The Brainsway H-coil seizure rate of 5.56 per 1000 patients (95% CI: 2.77,9.95) was significantly higher (p < 0.001) than the three most widely used figure- 8 coil devices' combined seizure rate of 0.14 per 1000 patients (95% CI: 0.01, 0.51)., Conclusion: The absolute risk of a seizure with rTMS is low, but generic Brainsway H-coil treatment appears to be associated with a higher relative risk than generic figure- 8 coil treatment. Well-designed prospective studies are warranted to further investigate this risk., Competing Interests: Declaration of competing interest JT: I have no conflicts of interest. Part of my time was supported by the Sidney R. Baer, Jr. Foundation. NN: I have no conflicts of interest. AS: I have no conflicts of interest. Part of my time during the era of data collection was supported by the Brain and Behavior Research Foundation's Young Investigator Award as well as the Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. AP: I have no conflicts of interest. DF: I serve on the Scientific Advisory Board for Brainsway. RB: I have no conflicts of interest. DP: I have no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that the APOE genotype is a significant driver of heterogeneity in Alzheimer disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation., Methods: We applied novel reverse-time longitudinal models to analyze the trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores-2 common outcome measures in AD clinical trials-in 1,102 autopsy-proven AD cases (moderate/frequent neuritic plaques and Braak tangle stage III or greater) from the National Alzheimer's Coordinating Center Neuropathology database resembling participants with mild to moderate AD in therapeutic clinical trials., Results: APOE ε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOE ε3/ε3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than APOE ε2 carriers (1.65 points per year), whereas APOE ε2 vs APOE ε3/ε3 difference was not statistically significant. APOE ε4 carriers had ≈1.1 times faster MMSE decline than APOE ε3/ε3 carriers (-3.45 vs -3.03 points per year) and ≈1.4 times faster decline than APOE ε2 carriers (-2.43 points per year), whereas APOE ε2 carriers had ≈1.2 times slower decline than APOE ε3/ε3 carriers (-2.43 vs -3.03 points per year). These findings remained largely unchanged after controlling for the effect of AD neuropathologic changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies., Conclusion: Compared to the APOE ε3 / ε3 reference genotype, the APOE ε2 and ε4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Extensions of the Kaplan-Meier estimator have been developed to illustrate the relationship between a time-varying covariate of interest and survival. In particular, Snapinn et al and Xu et al developed estimators to display survival for patients who always have a certain value of a time-varying covariate. These estimators properly handle time-varying covariates, but their clinical interpretation is limited. It is of greater clinical interest to display survival for patients whose covariates lie along certain defined paths. In this article, we propose extensions of Snapinn et al and Xu et al's estimators, providing crude and covariate-adjusted estimates of the survival function for patients defined by covariate paths. We also derive analytical variance estimators. We demonstrate the utility of these estimators with medical examples and a simulation study., (© 2021 John Wiley & Sons, Ltd.)

Importance: To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms., Objective: To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020., Design, Setting, and Participants: A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C., Main Outcomes and Measures: Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C. The characterization of mucocutaneous features was verified by 2 board-certified pediatric dermatologists., Results: Twenty-five children (11 girls [44%]; median age, 3 years [range, 0.7-17 years]) were identified who met definitional criteria for MIS-C; an additional 10 children (5 girls [50%]; median age, 1.7 years [range, 0.2-15 years]) were included as probable MIS-C cases (patients met all criteria with the exception of laboratory test evidence of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection or known exposure). The results of polymerase chain reaction tests for SARS-CoV-2 were positive for 10 patients (29%), and the results of SARS-CoV-2 immunoglobulin G tests were positive for 19 patients (54%). Of the 35 patients, 29 (83%) exhibited mucocutaneous changes, with conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), periorbital erythema and edema (n = 7), strawberry tongue (n = 8), and malar erythema (n = 6) being the most common findings. Recognition of mucocutaneous findings occurred a mean of 2.7 days (range, 1-7 days) after the onset of fever. The duration of mucocutaneous findings varied from hours to days (median duration, 5 days [range, 0-11 days]). Neither the presence nor absence of mucocutaneous findings was significantly associated with overall disease severity., Conclusions and Relevance: In this case series of hospitalized children with suspected MIS-C during the COVID-19 pandemic, a wide spectrum of mucocutaneous findings was identified. Despite their protean and transient nature, these mucocutaneous features serve as important clues in the recognition of MIS-C.

Introduction: As clinical trials move toward earlier intervention, we sought to redefine the β-amyloid (Aβ)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aβ accumulation and cognitive decline in 3 independent samples of clinically normal individuals., Methods: Sequential Aβ cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aβ-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356)., Results: Within samples, cutoffs derived from future Aβ-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5)., Discussion: These optimized thresholds can help to inform future research and clinical trials targeting early Aβ. Threshold convergence raises the possibility of contemporaneous early changes in Aβ and cognition., Classification of Evidence: This study provides Class II evidence that among clinically normal individuals a specific Aβ-PET threshold is predictive of cognitive decline., (© 2020 American Academy of Neurology.)

The receiver operating characteristic (ROC) curve displays sensitivity versus 1-specificity over a set of thresholds. The area under the ROC curve (AUC) is a global scalar summary of this curve. In the context of time-dependent ROC methods, we are interested in global scalar measures that summarize sequences of time-dependent AUCs over time. The concordance probability is a candidate for such purposes. The concordance probability can provide a global assessment of the discrimination ability of a test for an event that occurs at random times and may be right censored. If the test adequately differentiates between subjects who survive longer times and those who survive shorter times, this will assist clinical decisions. In this context the concordance probability may support assessment of precision medicine tools based on prognostic biomarkers models for overall survival. Definitions of time-dependent sensitivity and specificity are reviewed. Some connections between such definitions and concordance measures are also reviewed and we establish new connections via new measures of global concordance. We explore the relationship between such measures and their corresponding time-dependent AUC. To illustrate these concepts, an application in the context of Alzheimer's disease is presented.

Background: The conventional clinical trial design in Alzheimer's disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an "average" patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level ("N-of-1") regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design., Methods: Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments., Discussion: This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research., Trial Registration: ClinicalTrials.gov, NCT03811847 . Registered on 21 January 2019.