bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marital status associated with excess ADRD mortality among Californians during the COVID‐19 pandemic
Authors: DeVost Michelle A , Chen Yea‐Hung , Charpignon Marie‐Laure , Wells Whitney M , Kiang Mathew V , Mooney Alyssa C , Riley Alicia R , Glymour M. Maria , Chen Ruijia 
Published: December 2023

AbstractBackgroundSocial support shapes the health of older adults with Alzheimer’s disease and related dementias (ADRD), and marital status is linked to ADRD risk and all‐cause mortality. During the Covid‐19 pandemic, older adults with ADRD may have been particularly reliant on key social ties such as spouses. We estimated excess ADRD mortality by marital status among older Californians during the pandemic.MethodUsing California monthly mortality data from January 2016 to February 2020, we built autoregressive integrated moving average time series models to estimate the number of expected deaths with ADRD as a final or contributing cause between March 2020 and December 2022, stratified by marital status and age group. We obtained population estimates from the US Census’ American Community Survey. We calculated cumulative and monthly excess deaths per 100,000 living individuals and relative risk ratios (by dividing the number of observed deaths by the number expected). We simulated models 10,000 times to estimate 95% prediction intervals (PIs) for cumulative measures of excess.ResultAmong older Californians who died with ADRD during the study period, 7% were 65‐74, 26% were 75‐84, and 67% were 85+ (Table 1). Compared to people who were divorced, never married, or widowed, married people experienced the lowest spikes in per capita excess mortality associated with ADRD during the 2020 winter surge, regardless of age group (Figure 1). Among people who were 75 years and older, married people had the fewest estimated cumulative excess deaths per 100,000 population (1385, 95%PI: (1033, 1746)) compared to divorced (3217 (2294, 4155)), never married (2621 (1777, 3471)), and widowed people (2156 (770, 3560) (Table 1), although prediction intervals overlapped.ConclusionBeing married may have protected against excess ADRD mortality during the pandemic among older Californians. The link between marital status and ADRD mortality risk likely reflects several mechanisms: social and emotional support; instrumental support to adhere to safety protocols during contagious outbreaks; caregiving and practical assistance with the activities of daily living; access to a broader social network that may include adult children; and advocacy to ensure appropriate medical care and support.
The relationship of intraindividual variability on mobile cognitive testing with age and frontotemporal dementia disease severity
Authors: Sanderson‐Cimino Mark E. , Clark Annie L , Wise Amy B. , Dhanam Sreya , Taylor Jack C , Paolillo Emily W. , Heuer Hilary W. , Hassenstab Jason J. , Kramer Joel H. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Staffaroni Adam M. ,   ALLFTD Consortium
Published: December 2023

AbstractBackgroundThere has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity.MethodParticipants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses.ResultGreater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p = .02) tasks; a positive but non‐significant association was seen with memory testing (p = .16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (𝛃 = .39, p = .004) than those with CDR®+NACC‐FTLD’s of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (𝛃 = .85, p<.001) and Go/No‐go tasks (𝛃 = .51, p = .007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (𝛃 = .27, p<.001) and Go/no‐go (𝛃 = .23, p<.001) tasks.ConclusionIncreased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted.
Frailty, Brain Aging and Alzheimer’s Disease Brain Signatures: Longitudinal Associations from Middle to Old Age
Authors: Franz Carol E , Buchholz Erik , Reynolds Chandra A. , Hunt Jack F.V. , Schroeder Angelica , Cortes Isaac , Kremen William S. 
Published: December 2023

AbstractBackgroundFrailty—feelings of weakness, fatigue, and lack of physiological resiliency—places older adults at increased risk for Alzheimer’s Disease (AD) and related dementias. A possible mechanism underlying these associations may be the effects of frailty on brain aging prior to old age.MethodA prospective observational study of approximately 502 community‐based men of predominantly European ancestry without dementia at baseline, from the Vietnam Era Twin Study of Aging (VETSA). Frailty index and MRI imaging were collected at three waves at average ages 56, 62, and 68. We created frailty index (FI) scores using 37 items from previously validated cumulative deficit model indices. Imaging measures included brain‐age (BA; Cole et al. 2018), as well as a validated thickness/hippocampal volume AD‐signature (CTS), and a novel gray matter mean diffusivity AD‐signature (MDS), both weighted averages of MRI‐based morphometry or diffusivity in eight AD‐related brain regions. Different longitudinal models were tested using structural equation modeling in Mplus. Models were adjusted for age, race/ethnicity, education, and smoking.ResultFI was highly correlated over time (range rs = 0.69 to 0.77), as were the brain signatures (range rs = 0.52 to 0.85). The best fitting model was the simplex/auto‐regressive model with correlated random intercepts. Figures 1‐3 show significant associations in the covariate‐adjusted models. FI is significantly associated with brain‐age and the cortical thickness/hippocampal volume AD‐signature random intercepts but not the mean diffusivity signature. Associations attenuate when smoking is added to the model. Moreover, when the cortical thickness/hippocampal volume and mean diffusivity AD‐signatures are adjusted for brain‐age then the associations further attenuate and are no longer significant. No cross‐lag associations were significant.ConclusionThe results are striking given the relatively young age of the sample. Across middle age, frailty was associated with worse brain age and a smaller cortical thickness/hippocampal volume AD‐signature. These associations do not appear to be causal, rather biological aging processes running in parallel. Combined with recent evidence showing associations between frailty and AD‐related biomarkers, the results suggest frailty is not just a geriatric disease and support the need for early intervention in biological aging.
The temporal relationship between physical activity, mood, and sleep in older adults via a lead‐lag analysis
Authors: Colina Adrian Noriega , Ai Meishan , Bao Shania Fock Ka , Kramer Arthur F , Geddes Maiya R. 
Published: December 2023

AbstractBackgroundPhysical Activity, sleep, and mood are key modifiable lifestyle behaviours that are individually associated with lower cognitive decline [1]. Prior research suggests there may be a tridirectionally relationship among these three behaviours. The temporal relationship among these behaviours is unknown. Using an Ecological Momentary Assessment (ECA) and a time series analysis we aim to understand the temporal and longitudinal relationship among these factors.MethodWe performed a 10‐day lead‐lag analysis using Moderate‐to‐Vigorous Physical Activity (MVPA) and sleep as measured by a 24‐hour wrist‐worn accelerometer, and a self‐assessed daily mood scale on 30 community dwelling older adults who participated in a behavioural study to enhance physical activity in sedentary individuals (Clinicaltrials.gov identifier: NCT04315363). Participants were included if they did not exercise more than 150 minutes of MVPA per week (International Physical Activity Questionnaire) and were sitting more than 8 hours per day (Marshall Sitting Questionnaire). We examine each variable separately for auto‐correlative relationships for different timepoints of the same variable. The temporal dynamics are calculated from the rank‐order of the lead‐lag coefficients. The relationships between different timepoints of mood, MVPA, and sleep are examined through cross‐correlations.ResultsAutocorrelations showed that mood presented seasonality with baseline mood positively correlated to the subsequent day’s mood (r = +.571, p = .037) and negatively correlated with mood at day 7 (r = ‐.330, p = 0.27) and day 8 (r = ‐.248, p = .013). The temporal dynamics identified mood (B = +.602), preceding MVPA time (B = ‐.001), and sleep time (B = ‐.276) (Figure 1). Furthermore, cross‐correlations demonstrated that mood was positively correlated to MVPA at the same time point (r = ‐.605) and also that previous day mood predicted next day’s MVPA (r = ‐.629). Cross‐correlations confirmed that MVPA (r = ‐.507) and mood (r = ‐.504) predicted next day’s sleep time.ConclusionImproved mood precedes the increase in MVPA and sleep time in sedentary older adults. Understanding temporal dynamics between mood, sleep time, and MVPA, can help develop better interventions targeting increase in physical activity in older adults.
Reference:[1] 2020 Report of the Lancet Commission. https://doi.org/10.1016/S0140‐6736(20)30367‐6.
Occupational complexity with people and late‐life cognitive decline: Does it vary by level of occupational prestige?
Authors: Soh Yenee , Lee Catherine , Peterson Rachel , Whitmer Rachel A. , Glymour M. Maria , Gilsanz Paola 
Published: December 2023

AbstractBackgroundPrior evidence suggests engaging in intellectually challenging activities (e.g., complex work environments) in midlife is associated with favorable late‐life cognition. Substantial evidence exists for the relationship between occupational complexity with people (i.e., occupations with strong social engagement) and favorable cognitive function. Complex occupations often have high prestige, which may provide higher‐quality social interactions, and may be particularly beneficial for cognition. It remains unclear whether cognitive benefits conferred by occupational complexity varies across levels of occupational prestige.MethodThe Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort includes community‐dwelling participants aged 65+ years in Northern California. For self‐reported main lifetime occupation, occupational complexity scores (from the Dictionary of Occupational Titles) for people (range: 0‐8) and Hodge‐Siegel‐Rossi occupational prestige scores (range: 9‐82) were coded. Executive function and verbal episodic memory were assessed 3 times across 4 years with the Spanish and English Neuropsychological Assessment Scales. Linear mixed‐effects models were estimated for associations between occupational complexity with people (in tertiles) and domain‐specific cognitive decline (z‐standardized), stratified by tertiles of occupational prestige (high: 57‐82; medium: 47‐56; low: 14‐46). Models adjusted for baseline age, years since baseline, race/ethnicity, sex, educational attainment, maternal education, practice effects, and interview mode.ResultAmong 1,529 participants (mean age = 76.0 years), 58.9% were female, 24.4% identified as Asian, 26.6% Black, 19.9% Latino, 29.0% White, 49.6% had a college degree or higher, and 21.3% had maternal education >12 years (Table 1). Among those with highest occupational prestige, highest complexity with people was associated with higher baseline executive function (β[95%CI] 0.34 [0.13,0.56] SD units). Among those with medium occupational prestige, no significant associations were found. Among those with lowest occupational prestige, highest complexity with people was associated with higher baseline executive function (0.31[0.07, 0.54]) and verbal episodic memory (0.29[0.03, 0.55]). No associations were found for cognitive decline (Table 2).ConclusionWithin a diverse cohort, we found that higher occupational complexity with people was associated with better baseline cognition among those with highest and lowest occupational prestige, but not for those with middle prestige. Further investigation is needed to disentangle how occupational complexity may differentially impact individuals in different types of occupations.
Acoustic speech metrics that differentiate primary progressive aphasia variants depend on language typology
Authors: Elvira‐García Wendy , Marrero‐Aguiar Victoria , Borras‐Comes Joan , Rubio‐Guerra Sara , Marques‐Kiderle Sonia Karin , Montagut Núria , Faixa Carlota , Auge Laura , Rodriguez Camille Wagner , Grasso Stephanie M , Lleo Alberto , Illán‐Gala Ignacio , Santos‐Santos Miguel A 
Published: December 2023

AbstractBackgroundPrimary Progressive Aphasia (PPA) variants can be distinguished using acoustic speech measures. In particular, the syllabic pairwise‐variability‐index (syll‐PVI), which computes syllable duration differences between unstressed and stressed adjacent syllables, can differentiate between the logopenic (lvPPA) and non‐fluent (nfvPPA) variants in English.MethodWe analysed 5 repetitions of 5 multisyllabic words in a cohort of 37 patients (7 svPPA, 14 lvPPA, 16 nfvPPA) and 15 healthy controls. Data were annotated in Praat (manually revised) and metrics computed in R by means of Generalized Linear Mixed Models. The temporal parameters analysed were speech rate (number of sounds per second), average syllable duration (mean duration of each syllable for each word), and syll‐PVI (the normalized difference in duration between the stressed syllable of a word and the preceding one). Four speech language pathologists with extensive clinical experience with PPA performed blinded independent ratings of apraxia of speech severity in a subset of 31 participants.ResultSyllable duration behaves as expected, the control group had the smallest average syllable duration for the five polysyllabic words, followed by the lvPPA, nfvPPA and svPPA groups. The durations are longer in nfvPPA compared to lvPPA (Cohen’s d = 2.249, p = 0.02). Speech rate shows similar results; the largest difference is found between lvPPA and nfPPA, however it does not reach significance (Cohen’s d = 1.434, p = 0.07). Regarding syll‐PVI, nfvPPA tend to have the value closest to 0 (as expected due to greater presence of apraxia of speech), but the effect size does not reach significance for any word. Mean apraxia of speech severity showed higher correlation with syllable duration (spearman coef = 0.290, p = 0.11) than syll‐PVI (spearman coef = ‐0.073, p = 0.69).ConclusionSyllable duration, and not syll‐PVI, can distinguish lvPPA and nfvPPA in Spanish. This is probably due to a typological difference between English (a prototypical stress‐timed language) and Spanish (a prototypical syllable‐timed language) given that the syllabic‐PVI computes differences between duration of unstressed and stressed syllables and those differences are smaller in syllable‐timed languages. Our results highlight the necessity of considering language particularities in the development of speech and language clinical measures.
Development and implementation of plasma P‐tau immunoassays
Authors: Karikari Thomas K 
Published: December 2023

AbstractBackgroundMultiple advances in plasma biomarkers have been reported in recent times, one of these being the development of plasma p‐tau assays.MethodsIn this invited presentation as part of the Perspectives Session on “Advances in plasma Alzheimer’s disease biomarkers,” I will provide an expert review of the current state of analytical development of plasma p‐tau biomarkers.ResultsSpecifically, I will discuss the biochemical and molecular bases of why specific p‐tau forms are accessible in blood whilst others are not, as well as why these blood p‐tau markers tend to associate predominantly with brain amyloid but not tau pathology. Furthermore, I will highlight new discoveries in the development of biofluid‐based tau markers (both phosphorylated and non‐phosphorylated) that associate with neurofibrillary tangle pathology. Other aspects of my talk will focus on associations of the novel biomarker plasma brain‐derived tau with AD‐signature neurodegeneration. Additionally, I will discuss how newly improved preanalytical handling protocols enable plasma biomarker measurements in remote and resource‐limited settings, towards democratizing access to diagnostics.ConclusionFinally, I will discuss and suggest solutions to challenges around cut‐off generation, inter‐laboratory and inter‐assay measurements.
Modernizing AD clinical trials: why are we designing studies for disease modifying treatments using the symptomatic treatment paradigm?
Authors: Dickson Samuel P. , Mallinckrodt Craig , Wassom Mitchell , Nicodemus‐Johnson Jessie , Knowlton Newman , Hennessey Sean , Hendrix Suzanne B. 
Published: December 2023

AbstractBackgroundUntil the accelerated approvals of aducanumab and lecanemab, the only approved drugs for Alzheimer’s disease (AD) were symptomatic treatments, which showed relatively large improvements but did not alter disease progression. Multiple decades of designing and analyzing trials for symptomatic treatments have optimized the process for acetyl cholinesterase inhibitors and NMDA receptor antagonists, but this paradigm is not optimal for disease‐modifying therapies. As the AD research community continues to transition towards treatments with the potential to alter disease progression, significant course corrections in the design and analysis of clinical trials are required to ensure that treatments with the largest potential for impact do not fail because they’re being evaluated out of context.MethodSeveral design aspects from AD clinical trials are evaluated in the context of disease‐modifying treatments, including the expected effect size, patient population, outcomes, multiplicity adjustments, trial duration, use of biomarkers, and timing of visits. We use publicly available trial results to demonstrate that both the clinical trial process and public interpretation of data will result in costly losses unless significant improvements are accepted and implementedResultIn the context of donepezil’s expected 3‐point change on ADAS‐cog over 6 months, the results for lecanemab (1.5 points over 18 months) seem small, yet lecanemab improvements can be reasonably expected to match donepezil after three years of treatment and continue to increase. Symptomatic treatments were required to demonstrate significant improvement on multiple outcomes, but disease‐modifying treatments should address the underlying disease process. Trials of aducanumab, donanemab, and lecanemab show consistent disease modification of 5 to 6 months less progression over 18 months when outcomes are converted to units of time and combined. This time‐converted composite (which may include biomarkers) can show consistent results earlier in the disease course, allowing prodromal and early AD patients to be studied with greater success.ConclusionThe current message sent by recent approvals is that only sponsors with resources to field clinical trials with thousands of patients have a chance of gaining regulatory approval. By modernizing clinical trials, more sponsors will have a better chance of success, meaning better treatments available to more patients sooner.
Assessment of quantitative susceptibility mapping (QSM) and oxygen extraction fraction (OEF) in the spectrum of Alzheimer’s disease clinical presentations
Authors: Hosseini Seyyed Ali , Servaes Stijn , Therriault Joseph , Tissot Cécile , Rahmouni Nesrine , Macedo Arthur C. , Lussier Firoza Z , Stevenson Jenna , Wang Yi‐Ting , Arias Jaime Fernandez , Aumont Etienne , Socualaya Kely Quispialaya , Nazneen Tahnia , Stevenson Alyssa , Gauthier Serge , Pascoal Tharick A. , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundDifferent methods have been proposed to assess vascular dysfunction in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitively unimpaired (CU) subjects including quantitative susceptibility mapping (QSM), and recently oxygen extraction fraction (OEF). QSM is sensitive to the presence of iron and is a non‐invasive MR approach to measure local tissue susceptibility with high spatial resolution. OEF is a measure of the percentage of oxygen taken from the brain’s blood supply and relates directly to brain oxygen metabolism. Here, we aimed to examine QSM (Figure1) and OEF (Figure1) potential in differentiating AD, MCI, and CU.MethodA cohort of 310 subjects with AD (n = 48), MCI (n = 80), and CU (n = 182) were recruited. All the patients received 3D gradient‐recalled echo sequence MRI. All QSM images were constructed by MEDI+0 and OEF images were constructed by QSM+qBOLD model with CCTV (Temporal clustering, tissue composition, and total variation). Eighty‐two various brain regions of interest (ROI) and 6 Braak ROI were investigated in the current study. ANOVA and Posthoc least significant difference (LSD) tests were implemented for each ROI over AD, MCI, and CU.ResultOver Braak ROI analysis, the ANOVA test showed that the average susceptibility of QSM with Braak 4 ROI is significantly different (p<0.001). LSD test showed that Braak 4 ROI of QSM is significantly different between AD vs. MCI and AD vs. CU (p<0.001). Braak 2 ROI of OEF was significantly different between AD vs. MCI and AD vs. CU (p = 0.21 and p = 0.32, respectively). Over brain ROI, the ANOVA test showed QSM right and left posterior cingulate and right Caudate were significantly different (p<0.001). Besides, these ROIs were significantly different between AD vs. MCI and AD vs. CU, according to the LSD test. Over brain ROI, OEF right Caudate was significantly different (p<0.001) followed by left Caudate and Right transverse temporal with p = 0.002 based on the ANOVA test. However, right and left Caudate were just significantly different between AD vs. CU (p<0.001) based on the LSD test (Table 1 and 2).ConclusionQSM and OEF are affordable non‐invasive MR approaches to assess vascular dysfunction in the spectrum of clinical presentations of AD.