bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 2a proof‐of‐concept double‐blind, randomized, placebo‐controlled trial of nicotinamide in early Alzheimer’s disease
Authors: Grill Joshua D. , Tam Steven , Thai Gaby , Pierce Aimee , Green Kim N , Gillen Daniel L , Teng Edmond , Kremen Sarah , Beigi Maryam , Rissman Robert A , Leger Gabriel , Zhang Jing , Jin Shelia , Messer Karen , Feldman Howard H. 
Published: December 2023

AbstractBackgroundNicotinamide is a co‐enzyme involved in cellular oxidation‐reduction reactions that can act as an inhibitor of the class III histone deacetylases (HDACs), or sirtuins. HDAC inhibition may have myriad therapeutic pathways, including reducing phosphorylation of tau.MethodWe performed a randomized, placebo‐controlled, Phase 2a proof‐of‐concept trial to evaluate the safety and tolerability of nicotinamide, and its effects on change in cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 231 (p‐tau231) and other Alzheimer’s disease (AD) biomarkers and clinical measures in participants with early AD (Mild Cognitive Impairment or mild dementia) as confirmed by CSF biomarkers. We tested whether 1500 mg BID nicotinamide was superior to placebo in reducing CSF p‐tau231 (primary outcome), with secondary outcomes of p‐tau181, total tau, amyloid beta 40 (Ab40), Ab42, ADAS‐cog13, ADCS‐ADL‐MCI, and CDR‐SB.ResultArms were well balanced for demographic and clinical characteristics (Table 1). Of 47 participants enrolled, one dropped out prior to treatment initiation and six dropped before completion, 2 in the nicotinamide and 4 in the placebo arm. Nicotinamide was well‐tolerated; adverse events were largely balanced by study arm, with few attributed to treatment. There was no statistically significant benefit of nicotinamide on the primary outcome of change in CSF p‐tau231 (ANCOVA; estimated mean difference in change between arms = 2.06, std. error = 4.03; p = 0.61), although the observed mean decline in CSF p‐tau231 was greater in the nicotinamide arm (‐4.7±14.5) than in the placebo arm (‐2.3±10.6; Table 2). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p‐tau181, Ab40, Ab42, and total tau) in similar models (all p‐values>0.05), although observed mean changes in CSF p‐tau181 (0.4±29.8 vs 10.4±41.8) and total tau (8.4±228.6 vs 60.5±237.5) favored nicotinamide compared to placebo. Nicotinamide was associated with significantly less change on CDR‐SB (MMRM; estimate = ‐1.42, std. error = 0.65; p = 0.03), but not on cognitive (ADAS‐cog; estimate = ‐1.93, std. error = 1.93; p = 0.32) or functional (ADCS‐ADL‐MCI; estimate = ‐3.10, std. error = 1.86; p = 0.10) assessments. No adjustments for multiple comparisons were performed.ConclusionThese results may suggest that nicotinamide warrants further study as a treatment for early AD.
#FTDQuickQuestions: An FTD Disorders Registry (FTDDR) Monthly Engagement Survey to Gather Real‐time Insights to Inform Research
Authors: Harlass Sherry , Vincent Lakecia , Reddy Sweatha , Reinecker Robert , Dacks Penny A. , Wheaton Dianna K.H. 
Published: December 2023

AbstractBackgroundFrontotemporal degeneration is a group of rare brain diseases that cause progressive changes to behavior, personality, language, and movement with onset typically before age 60. There are no treatments or cures. FTDDR is an international, web‐based registry (participants n>5,700) that facilitates clinical trial enrollment by collecting disease insights, summarizing data, and mobilizing potential research volunteers. FTDDR uses various data collection and engagement tools to interact with participants and the community at large. Quick Questions was concepted as a mechanism to gather real‐time, cross‐sectional, anonymous data from a broad response‐base not limited by Registry participation.Method#FTDQuickQuestions campaign incorporates social, email, and web to reach members and visitors to collect their data, strengthen existing relationships, connect with people who could benefit from Registry services, and inform research. Each month a pre‐approved question was posted to Facebook and Twitter, linking to a webform with polling options and collected for 2 weeks. Respondent’s location is indexed through IP address. Additionally, the question was emailed to FTDDR participants with brief highlights of the previous survey and a link to view results for it and prior surveys. Full summaries were posted as weblogs.ResultThe survey was launched in June 2022 with the question: Have you tried to get genetic testing for FTD over the last 3 years? Questions have related to FTD research participation, age of diagnosis, age first symptom appeared, where diagnosed person lived. At least one other demographic question is asked to characterize the respondent, including gender or relationship to FTD‐diagnosed person. Number of respondents for the first 7 questions ranged between 555‐857; monthly average 735. Except the initial survey, >75% of responses were received within 24 hours of email. Responses reflect 41 countries; including all 50 U.S. states and the District of Columbia; and 10 Canadian provinces/territories. Majority are women (62%); a third men (35%); 3% declined providing gender.ConclusionFTDDR’s #FTDQuickQuestions is a successful monthly engagement mechanism that enables quick, timely responses to questions about this disease and the people affected by it. While related questions cannot be compared nor connected, this valuable information serves as a cross‐sectional snapshot to inform FTD research.
Application of a digital ambulatory protocol to assess the associations of level and consistency of sleep with daily cognitive performance and cognitive variability
Authors: Derby Carol A. , Gao Qi , Katz Mindy J. , Ji Linying , Buxton Orfeu M. , Wang Cuiling 
Published: December 2023

AbstractBackgroundMost prior work regarding sleep and cognition in older adults has not examined the relation of sleep health to daily cognitive performance measured in real world settings. Fewer studies have examined the extent to which both level and consistency of sleep are related to variability in daily cognitive performance. We applied daily ambulatory assessment methods to examine whether associations of objective and daily subjective measures of sleep quality and duration were related to mean and day‐to‐day variability in cognitive performance.MethodAdults (N = 261) age ≥ 70 years (mean 77.2 ± 4.7) in the Einstein Aging Study sleep project wore an actigraphy watch and completed smart‐phone cognitive assessments over two weeks. All participants were free of dementia (47% Non‐Hispanic White, 40% Non‐Hispanic Black, 13% Other race/ethnicity; mean years education 15 ± 3.6; 67% female). Brief (4‐5 minute) cognitive tests were completed 6 times/day to assess processing speed (Symbol Match Test‐SMT), Visual short term memory binding (Color Shape Test‐CST) and spatial working memory (Grid Memory Test‐GMT). Wake after sleep onset (WASO), night sleep duration (hours), and daytime napping (minutes) were estimated. All measures were summarized as mean over the 2‐weeks and day‐to‐day variability (SD). Linear regression was used to examine associations of mean and variability of sleep with mean and variability (SD) of cognitive performance, adjusting for age, sex, race, and education.ResultBoth mean and SD of sleep were associated with mean cognitive performance: Higher mean and greater SD WASO were associated with worse mean SMT and CST (all p <0.04). Greater SD duration was associated with worse mean GMT (p = 0.003) and greater SD napping was associated with worse SMT (p = 0.04). Sleep was also associated with daily variability in cognition. Greater mean napping was associated with greater SD GMT (p = 0.009), while SD WASO, SD duration and SD napping were each associated with greater variability in GMT (all p <0.01).ConclusionBoth level and consistency of optimal sleep health are related to both average levels of cognitive functioning and day‐to‐day variability in cognitive function. Consistency of sleep health may be particularly important for minimizing variability in spatial working memory.
The association of late‐life volunteering with cognitive function and cognitive decline in the KHANDLE and STAR cohorts
Authors: Lor Yi , Chanti‐Ketterl Marianne , Hokett Emily , Fletcher Evan , Zlatar Zvinka , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M. Maria , Barnes Lisa L. , Whitmer Rachel A. 
Published: December 2023

AbstractBackgroundPrior studies have shown that volunteering in late life is associated with better physical health, social activity, and cognition, but the bulk of evidence is limited to non‐Latino White or Asian populations. The purpose of this analysis was to determine whether volunteering is associated with differences in domain‐specific cognition or cognitive change in a diverse cohort.MethodKaiser Healthy Aging and Diverse Life Experiences Study (KHANDLE) and Study of Healthy Aging in African Americans (STAR) are harmonized cohort studies of long‐term Kaiser Permanente members ages + and 50+ respectively, consisting of 48% Black, 20% White, 17% Asian, and 14% Latinx individuals. Participants self‐reported performing volunteer work for the 12 months prior to baseline for religious, educational, health‐related, or charity organizations. Executive function (EF) and verbal episodic memory (VEM) were measured across three waves using the Spanish and English Neuropsychological Assessment Scales (SENAS) and scores were z‐standardized to the baseline. Linear mixed‐models with random intercepts and slopes evaluated the association of volunteering with baseline cognition and cognitive change over 3 visits (mean follow‐up = 1.2 years) with years since baseline as the timescale and adjusting for baseline age, sex, education, income, practice effects, and interview mode (phone vs in‐person)ResultOf the 2476 participants with average baseline age of 73.7 (SD = 8.2) years, 1167 (42.3%) had volunteered in the 12 months prior to baseline (Table 1). Those who volunteered had on average higher baseline EF (β = 0.184; CI = 0.110, 0.257) and VEM (β = 0.114; CI = 0.040, 0.189) compared to those who did not report volunteering (Table 2, Model 2). There were no statistically significant associations of volunteering and EF or VEM decline, though the direction of the associations suggested that those who volunteered had slower cognitive decline than those who did not volunteer.ConclusionIn this diverse cohort, volunteering was associated with significantly higher baseline cognition, and suggested to be associated with less cognitive change over an average of 1.2 years, though not statistically significant. With additional follow up, we will examine whether volunteering is protective against cognitive impairment, and how physical and mental health may mediate this relationship.
Detection of mild cognitive impairment using digital assessments of cognition
Authors: Wang Cuiling , Gao Qi , Hall Charles B , Cerino Eric S. , Sliwinski Martin J. , Lipton Richard B. , Katz Mindy J. , Derby Carol A. , Garza Angel Garcia De La 
Published: December 2023

AbstractBackgroundConventional cognitive assessment typically provides a single measure of performance at a single point in time in a laboratory setting. Smartphone‐based ecological momentary assessments (EMA) facilitate short‐term intensive assessment of cognitive performance in people’s natural environments. Though heterogeneous variance in digital cognitive assessments has been observed between older adults with mild cognitive impairment (MCI) and cognitively unimpaired (CU), the independent contribution of intra‐individual variability in performance to detection of MCI is poorly characterized in diverse populations of older adults. We examine the ability of digital cognitive assessments of processing speed in discriminating MCI from CU in older adults from a racially/ethnically diverse community sample.MethodEinstein Aging Study (EAS), smartphone‐based digital assessments of cognition, included the response time‐based symbol match test of processing speed. This was assessed 6 times per day over two weeks and was repeated annually. MCI was defined based on in‐house neuropsychological evaluations using Jak‐Bondi criteria. Statistical methods for modeling MCI using digital cognitive assessments include pattern‐mixture discriminant analysis based on heterogeneous linear mixed effects model for digital cognitive measures given MCI, joint modeling using shared random effects with random location scale for digital cognitive measures, and quadratic logistic regression models. All methods take into account the unbalanced adherence rate among individuals and control for covariates including age, sex, years of education, and race/ethnicity. Stratified analyses by race/ethnicity among non‐Hispanic (NH) Whites and Blacks were performed.ResultAmong 311 systematically recruited community‐dwelling non‐demented older adults from the EAS (Mean age = 77.5 years, SD = 4.8; 67.5% Female; 45.3% non‐Hispanic (NH) White, 40.8% NH‐Black), 97 (31.2%) individuals had MCI. Adherence to the EMA protocol was slightly better in individuals who were CU compared to those with MCI. Results from the quadratic logistic model (the easiest to apply) showed evidence of contribution from the quadratic terms that reflect heterogeneous intra‐individual variability in all samples and particularly among NH‐Blacks (p = 0.008).ConclusionWe observe evidence that intra‐individual variability in processing speed improves the ability to discriminate cognitive impairment, particularly among NH‐Black older adults. Leveraging digital technology and performance variability across frequent assessments in the smartphone‐based EMA offers novel opportunities to identify cognitive impairment.
In‐vivo Braak Stage Distribution of Screened and Randomized Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease
Authors: Saad Ziad S. , Cohen Julie S , Fedgchin Maggie M , Quiceno Mary Ellen , Henley David , Kolb Hartmuth C. 
Published: December 2023

AbstractBackgroundTau PET is the gold standard for in‐vivo quantification of tau neurofibrillary tangles (NFT) which, along with amyloid plaques and neurodegeneration, constitute the pathological hallmarks of Alzheimer’s Disease (AD). The ongoing Auτonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia who are tau PET positive. The Janssen plasma p217+tau assay is being used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date, we report on the in‐vivo PET‐based Braak stage distribution and compare the outcomes to published, histology‐based Braak staging.MethodNFT levels were quantified using 18F‐MK‐6240 SUVR in Braak Regions Of Interest (ROI)[1] using cerebellar gray as the reference region. In‐vivo Braak staging (Braakiv) was implemented following the approach by Biel et al.[2], with 18F‐flortaucipir to 18F‐MK‐6240 SUVR threshold conversion from Gogola et al.[3]. Participants with atypical[2] stages were reassigned to the Braak stage corresponding to the highest Braak ROI with average SUVR > 1.4. The screening results reported herein are from the first 355 participants with available biomarker screening data.ResultOf 355 screened participants, 90% were assigned to typical Braakiv stages. Of the 10% atypical stages, 94% were lacking elevated uptake in Braak 2 ROI. When using the coerced stage assignment, the average Braakiv stage was 3.7 across all screened participants and 3.6 in randomized participants (Figure 1). For the 221 randomized participants, 59% were Braakiv stage 4 or less, and 40% were Braakiv stage 3 or less.ConclusionIn early Alzheimer’s disease participants who were screened with tau PET in the ongoing Auτonomy trial, the average Braakiv stage was consistent with the average histology‐based Braak stage in MCI patients of 3.57 [4]. These results further support the use of tau PET‐based in‐vivo staging[5] as a proxy for histology‐based Braak staging.[1] Schöll et al. Neuron 2016.[2] Biel, D., et al. Alz Res Therapy 2021.[3] Gogola A. et al. J Nucl Med. 2022. [4] Markesbery WR. J Alzheimers Dis. 2010.[5] Therriault, J. et al. Nat Aging 2022
Dementia in multimorbidity: scoping review and priorities for research and care
Authors: Stirland Lucy E 
Published: December 2023

AbstractBackgroundMost people with clinical dementia have at least two other conditions. This co‐occurrence of multiple conditions, known as multimorbidity, is associated with worse quality of life, increased mortality and greater healthcare costs. However, there is limited research on the bidirectional interaction of physical multimorbidity and all‐cause dementia.We aimed to review and summarize key themes in this area, especially in the context of recent pharmacological advances.MethodWe searched PubMed and Google Scholar, updating the search strategy of a 2014 review of comorbidity and dementia. We added new key words reflecting recent trends in Alzheimer’s disease research, including: “amyloid”, “biomarker” and “disease‐modifying”. We searched the resulting papers’ references and citations and generated a narrative review of the literature grouped by research methodology.ResultSeveral key themes emerged from the published literature. Epidemiological studies confirmed that most people with dementia have multimorbidity. They additionally identified multimorbidity as a risk factor for dementia or cognitive impairment and found it to be associated with dementia progression and worse quality of life.Studies on the association between multimorbidity and biomarkers of neurodegeneration were either negative or found an inverse relationship. People with multimorbidity were found to be significantly under‐represented in clinical trials, especially those of dementia drugs.Qualitative research on healthcare delivery highlighted the importance of family carers and communication between providers, and a review of care coordination interventions identified important factors that optimize transitions of care.There was also recognition of the need to address racial and ethnic disparities in people with multimorbidity and dementia. Several papers called for a comprehensive understanding of dementia in relation to the whole person and society.ConclusionHaving multiple conditions alongside dementia poses challenges for patients, caregivers and clinicians. Multimorbidity is an important consideration for those designing representative clinical trials, and it may be more difficult to treat dementia in people with several comorbid conditions.This work highlights the need for specific research into the relative contributions of multimorbidity and other person‐centered characteristics on clinically meaningful outcomes. In the context of new and costly therapies, this will inform equitable allocation of research and healthcare resources.
Plasma Alzheimer’s Disease Biomarkers and Brain Amyloid in a Multi‐Ethnic Aging Cohort
Authors: Asken Breton M. , Wang Wei‐en , McFarland Karen , Arias Franchesca , Fiala Jacob , Mayrand Robin P. , Sawada Luana Okino , Freytes Christian , Adeyosoye Michael , DeKosky Steven T , Velez‐Uribe Idaly , Rosselli Monica , Curiel Rosie E , Loewenstein David A. , Marsiske Michael , Armstrong Melissa J , Smith Glenn E. , Adjouadi Malek , Vaillancourt David , Duara Ranjan 
Published: December 2023

AbstractBackgroundDementia diagnoses are more common among Hispanic (HW) than non‐Hispanic white (NHW) older adults. Alzheimer’s disease (AD) is the most common neuropathological finding in patients with dementia. Plasma AD biomarkers have accelerated efforts towards increasing access to timely diagnosis, but existing data often come from cohorts lacking ethnic diversity. Clinical translation of plasma AD biomarkers requires continued evaluation in study cohorts that reflect the growing ethnic diversity of the population.MethodWe studied 379 older adults (age 71.9±7.8 years old, 60.2% female) from the 1Florida Alzheimer’s Disease Research Center who underwent blood draw and analysis for P‐tau181 (Quanterix). Of these, 240 completed Aβ‐PET (converted to Centiloids). Over half (57%) self‐identified as HW (32% Cuba, 18% South American, 7% other). Analyses included 1) comparing plasma biomarker concentrations between clinically normal (CN), amnestic MCI (amnMCI), amnestic dementia (amnDEM), and nonamnestic MCI/dementia (ANCOVA controlling for age), 2) evaluating P‐tau181 correlations with Aβ burden (Spearman’s rho), and 3) determining discriminability (AUC) of Aβ‐PET[+] from Aβ‐PET[‐]. Interactions between independent variables and ethnicity were evaluated to inform whether observed relationships differed between HW and non‐Hispanic white (NHW). Lastly, using a cutoff derived from the PET sub‐cohort, we investigated rates of P‐tau181‐defined “AD positivity” (plasmaAD[+]) between HW and NHW diagnosed with amnMCI. Additional data for plasma GFAP and NfL will also be presented.ResultsPlasma P‐tau181 was higher in amnMCI (p = .004, d = 0.53) and amnDEM (p<.001, d = 0.97) than CN. Higher P‐tau181 related to greater Aβ burden (ρ = .59 [.50‐.67], p<.001) and had good discriminability between Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86 [0.81‐0.91], Youden’s Index = 2.39 pg/mL). There were no significant interactions with ethnicity. Applying the P‐tau181 cutoff (2.39 pg/mL) to all amnMCI participants, HW diagnosed with amnMCI had lower odds of being plasmaAD[+] than NHW (36.5% vs. 58.5%; OR = 0.41 [0.21‐0.78], p = .006).ConclusionPlasma P‐tau181 may aid etiological diagnosis of cognitively impaired older adults from Hispanic and non‐Hispanic ethnic origins. Hispanic ethnicity alone does not significantly influence the interpretation of how plasma P‐tau181 relates to Aβ‐PET, but may be linked to greater likelihood of non‐AD causes of memory loss. Blood‐based biomarkers could help reduce barriers to clinical diagnosis and research participation that disproportionately impact underrepresented groups.