bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategy Use on Digital Cognitive Assessment Differs Between Individuals with and without Elevated Phosphorylated Tau 217 in Cognitively Normal Older Adults: Results from the BioFINDER‐Brown Study
Authors: De Vito Alyssa N. , Joyce Hannah E , Lawrence Molly , Thompson Louisa I. , Caffery Phillip , Bernstein John P.K. , Salloway Steve 
Published: January 2025

AbstractBackgroundNew immunotherapies for Alzheimer’s Disease (AD) have shown promise in slowing disease progression and are most effective in the early stages of the disease. New, low‐cost methodologies are needed to detect early AD pathological change. Digital cognitive tools may represent a cost effective, efficient, and sensitive method to detect early AD‐related pathological change. The present analysis utilizes data from the BioFINDER‐Brown study to investigate whether individuals with and without elevated plasma phosphorylated tau‐ 217 (p‐tau217) demonstrate differential performance on digital cognitive assessments of spatial working memory (SWM) and paired associates learning (PAL).Method90 cognitively normal (CN; M
MMSE = 29.00) older adults (M
age = 63.36, 72.2% female, 95.6% white, 5.6% Latinx) completed a blood draw to evaluate plasma p‐tau217 and two brief tablet‐based digital cognitive assessments: SWM and PAL. as part of screening for the BioFINDER‐Brown study. Approximately 42% of the sample (n = 38) had elevated plasma p‐tau217. Independent samples t‐tests were used to determine whether performance on these measures differed between individuals with and without elevated p‐tau217. Lower scores on both measures are indicative of better performance.ResultThe total number of errors on the SWM was not found to differ between individuals with and without elevated plasma p‐tau217 (t(89) = ‐1.33, p = 0.093). However, differences in strategy use were found on the SWM task (t(89) = ‐2.11, p = 0.019); Individuals with elevated p‐tau217 had a less efficient strategy and required more trials to complete the task (M = 8.79 trials) than non‐elevated individuals (M = 7.65 trials). Group differences between those with and without elevated p‐tau217 on the PAL task approached significance (t(89) = 1.08, p = .075), with worse performance in those with elevated p‐tau217.ConclusionThe preliminary findings suggest that group differences may exist for process scores (i.e., strategy use) but not overall performance on digital cognitive assessments between individuals with and without elevated plasma p‐tau217. Future research should evaluate 1) which digital assessments are most sensitive to AD‐related pathological change and 2) whether digital cognitive assessments can be used in conjunction with novel, affordable plasma biomarkers to improve early detection of AD.
Identifying diverse agitation profiles in dementia: Insights from longitudinal in‐home monitoring data
Authors: Bafaloukou Marirena , Schalkamp Ann‐Kathrin , Sandor Cynthia , Nilforooshan Ramin , Barnaghi Payam ,   CR&T Group
Published: January 2025

AbstractBackgroundAgitation, affecting 30% of people living with dementia (PLwD), presents with heterogeneity, diverse triggers, and variable responses to interventions. Subtype identification particularly in real‐world settings, thus, holds promise for more tailored care.MethodWe used longitudinal, in‐home monitoring data from 61 PLwD from the Minder study. 235 agitation episodes were reported, each describing the presence of agitation during an 8‐day window. Using sensor data, we derived 67 behavioural features related to activity, sleep, and physiology, normalised per PLwD to accommodate individual differences. Principal component analysis identified 14 components via Horn’s parallel analysis. We compared k‐means, Birch, Gaussian Mixture, and k‐Medoids clustering. Number of clusters was determined by Silhouette and Calinski Harabasz Score (chi). Two‐sided Welch’s t‐tests with Bonferroni correction (p<0.05) were used for feature comparison between subtypes. A logistic regression model was trained to predict subtypes based on 47 ambient parameters, with performance compared to a baseline model only incorporating age and sex.ResultK‐means clustering achieved the highest scores with 2 identified subtypes (chi = 34.75, silhouette = 0.21) (Figure 1). 24 (63.16%) of the investigated sleep features were significantly different between the subtypes. No activity or physiological feature was significantly different. The first subtype (71 agitation episodes) was defined by more nocturnal awakenings (p−value = 2.60×10−5, t = 5.48), increased time spent out of bed (p−value = 5.85×10−11
, t = 8.34) and greater variability in bedtimes (p−value = 7.76×10−6
, t = 5.72). The second subtype (164 episodes) exhibited longer sleep durations (p‐value = 1.58×10−3, t = 4.44) and a higher ratio of deep sleep (p−value = 2.41×10−3, t = 4.28) (Figure 2). Ambient features could predict agitation subtype (F1‐score = 70.98%) better than baseline (p−value = 2.71×10−4
, t = 4.51) with lounge morning illuminance contributing most. Agitation subtypes were not stable within participants with 21 (34.43%) appearing in both clusters. The subtypes did not show differences in demographics.ConclusionOur analysis revealed two distinct behavioural agitation patterns, one associated with poor and one with good sleep, that can be predicted with ambient features. Tailoring agitation care to accommodate these subtypes could render treatment strategies more targeted and effective.
Examining domain‐specific cognitive associations with p‐tau217 in a cognitively normal sample: results from the BioFINDER‐Brown Study
Authors: Joyce Hannah E , De Vito Alyssa N. , Caffery Phillip , Salloway Steve , Thompson Louisa I. 
Published: January 2025

AbstractBackgroundEmerging research on plasma Alzheimer’s disease (AD) biomarkers represents a new path towards earlier detection of AD pathology and potentially earlier intervention in cognitively normal individuals. Existing cognitive screening tools lack the sensitivity to distinguish between cognitively normal individuals with and without AD pathology. The present analysis investigated associations between performance on TabCAT digital assessment subtests and levels of plasma phosphorylated tau 217 (p‐tau217) in a cognitively healthy sample.MethodsParticipants were cognitively normal (tMoCA ≥ 16, MMSE ≥ 26) adults (ages 50‐80) screening for the Biofinder‐Brown Study (n = 172, 68.6% female, meanage = 64.3, meaneducation = 17.2). Participants underwent a blood draw for p‐tau217 analysis. A p‐tau level of .17pg/ml was considered elevated. The first 58 individuals screened completed the full TabCAT Brain Health Assessment battery consisting of four subtests: Favorites (episodic memory), Match (processing speed), Line Orientation (visuospatial ability), and Animal Fluency (semantic fluency). Our screening protocol was then abbreviated, and the remaining 114 participants completed only the Favorites subtest. We used Spearman correlations to test associations between p‐tau levels and cognitive performance and independent samples t‐tests to examine differences in cognitive performance by p‐tau status (Elevated vs. Not).ResultsAge‐, sex‐, and education‐adjusted TabCAT scores were not significantly associated with plasma p‐tau 217, except for animal fluency, which was negatively associated with p‐tau level (p = .029). TabCAT BHA Composite and MMSE also showed no associations with p‐tau level. None of the cognitive scores were able to distinguish between individuals with elevated and non‐ elevated plasma p‐tau. Individuals with higher education had significantly lower p‐tau (p = .05). There was no significant relationship between age and p‐tau level.ConclusionsSemantic fluency (animals subtest) performance was significantly correlated with p‐tau217, such that higher fluency scores were associated with lower p‐tau levels. Performances in other cognitive domains, including episodic memory, showed no significant associations. These results suggest that semantic fluency may be more sensitive to elevated p‐tau217 compared other cognitive abilities in cognitively healthy samples. However, the restricted range of cognitive performance in this highly educated sample may have reduced our ability to detect subtle associations between cognition and p‐tau217 levels.
Comparative in‐vitro assessment of RV and KI loaded nanostructured lipid carriers (NLCs) individually and in combination on Neuro‐2a cell lines
Authors: Khan Saif Ahmad , Qamar Zufika , Singh Pirthi Pal , Pervez Suhel , Baboota Sanjula , Ali Javed 
Published: January 2025

AbstractBackgroundButyrylcholinesterase enzyme inhibitor (RV), and kinase inhibitor (KI), as combination therapy is considered more effective treatment approach for Alzheimer’s disease (AD). Hence, this combination has been chosen as a treatment strategy. So, this study emphasises the effectiveness of RV and KI in individuals and in combination on the viability of cell lines.MethodThe cytotoxicity of each drug namely RV and KI were screened on Neuro‐2a cell using MTT assay. The treatments of cells were done with different concentrations of individual drug ranging from 0.97 to 500 µg/ml. Afterwards, IC50 of RV and KI was established, and ratio of both drugs was optimized using combination index (CI), assessing their impact on cell line viability. So, optimised combination ratio (1:1) of RV and KI were loaded in the NLC which was formulated using modified emulsio‐sonication method and optimized using Central Composite Design. Simultaneously, individual drug was also loaded in the NLC using same method. Later the viability of cell line towards different formulations was studied and compared at different concentrations.ResultsOn performing cell line studies, it was observed that there was dose‐dependent %cell viability of drug‐loaded formulation, individually and in combination. At concentration of 1.95 µg/ml, RV‐NLC and KI‐NLC showed there was significant increase (p<0.05) i.e., 25 to 30% in the viability of the cells when compared to RV suspension and KI suspension. On other hand, (RV‐KI)‐NLC showed the highest %cell viability at 500 µg/ml in comparison to the other NLC formulations.ConclusionRV‐NLC, KI‐NLC and RV‐KI NLC exhibited improved delivery of RV and KI into Neuro‐2a cell lines, resulting in higher viability efficacy in comparison to the suspensions of the drugs. However, (RV‐KI)‐loaded NLCs demonstrated even greater viability of the cell lines than the individual drug‐loaded NLCs. Therefore, dual drug‐loaded NLCs can be used as promising drug delivery system for achieving excellent therapeutic efficacy in the treatment of AD.
Exploring the Relationship Between Aβ and α‐Synuclein Pathologies: Longitudinal CSF Analysis and Cognitive Decline in the ADNI
Authors: Tosun Duygu , Hausle Zachary , Zobel‐Thropp Pamela , Shaw Leslie M. , Concha Luis , Singleton Andrew , Weiner Michael W. , Blauwendraat Cornelis 
Published: January 2025

AbstractBackgroundAD and Lewy body (LB) disease are characterised by the pathological deposition of Aβ and α‐synuclein, respectively, and represent two of the most common forms of neurodegenerative diseases. Co‐pathologies are commonly identified at autopsy, suggesting crosstalk between Aβ and α‐synuclein during disease progression. CSF α‐synuclein seed amplification assay (SAA) has proven to be a sensitive and specific tool for detecting α‐synuclein seeds as evidence of LB‐pathology. We recently applied SAA cross‐sectionally to the ADNI cohort on the most recent CSF draw (Phase‐1) and looked at LB pathology prevalence (SAA positivity, SAA+) and its association with AD biomarkers and cognition. Here, we expand the ADNI CSF SAA analysis by incorporating longitudinal time‐points (Phase‐2), specifically focusing on SAA+ participants from Phase‐1. We examined the longitudinal dynamics of Aβ, α‐synuclein seeds, and p‐tau181, along with global and domain‐specific cognitive measures in stable SAA+, stable SAA‐, and those who converted to SAA+ from SAA‐.MethodIn longitudinal Phase‐2 study, 407 CSF samples from 222 participants across ADNI‐1‐3 phases were tested with SAA. Cox regression models were performed to assess factors increasing risk for biomarker positivity progression, separately for SAA, CSF Aβ42, and CSF p‐tau181. Additionally, factors contributing to clinical diagnosis progression (CU‐to‐MCI or MCI‐to‐Dementia) were assessed. Changes in cognitive decline rates accompanying SAA conversion were assessed.ResultAmong Phase‐2 participants, 34 individuals progressed from SAA− to SAA+ by their final CSF time‐point (“SAA Converters”; Figure‐1). Conversion to SAA+ was associated with APOE ε4 homozygosity, Aβ pathology (Figure‐2), and greater rates of cognitive decline after time of SAA conversion (Figure‐3). SAA status did not impact progression of either Aβ or tau phenotypes, or progression in clinical diagnosis (Figure‐2).ConclusionThe findings of this longitudinal study demonstrated a significant association between Aβ pathology and onset of α‐synuclein pathology, as measured by SAA. Moreover, presence of SAA‐positivity was linked to accelerated cognitive decline, although greater risk for clinical diagnosis progression was associated with positivity in Aβ42 and p‐tau181 but not SAA‐positivity. These results highlight the interplay between Aβ and α‐synuclein and their impact on disease progression, emphasizing the importance of further investigation into their underlying mechanisms.
Target Engagement and Therapeutic Effects of AR1001, a Phosphodiesterase‐5 Inhibitor, in Alzheimer’s Disease Models
Authors: Xi Tianyang , Kim Fred , Kim Ju Won , Jung Jun‐Sub , Jeon Eunhae , Jo Hyunji , Nam Ju‐Suk , Song Dong‐Keun , Choung Jai Jun 
Published: January 2025

AbstractBackgroundAR1001 is a specific inhibitor of phosphodiesterase‐5 (PDE5), which degrades cyclic guanosine monophosphate (cGMP). cGMP/cAMP response element‐binding protein (CREB)/brain‐derived neurotrophic factor (BDNF) signaling, which is critical for learning and memory processes, is disturbed in Alzheimer’s disease (AD). AR1001 at the oral dose of 30 mg QD is currently in a global Phase 3 clinical trial in early AD patients (NCT05531526). In this study we sought to determine if AR1001showed target engagement and therapeutic effects in mice at the equivalent dose to that being tested in humans.MethodAn AR1001 oral dose of 6 mg/kg QD in mice is equivalent to an oral dose of 30 mg QD in humans. For the target engagement study, AR1001 was orally administered at 3, 6, and 9 mg/kg QD to overnight‐fasted normal ICR mice for 1 week. Hippocampal levels of cGMP and BDNF 15 min after the last dose were measured by ELISA. To assess the therapeutic effects of AR1001, mice transgenic for familiar AD (3xfAD) were administered 3, 6, and 9 mg/kg QD for 3 weeks, followed by cognitive evaluation using passive avoidance and Morris water maze tests.ResultIn the target engagement study, AR1001 significantly increased hippocampal cGMP and BDNF at doses of 6 and 9 mg/kg QD. In the therapeutic effects study, all 3 doses of AR1001 significantly increased latency in the passive avoidance test compared to untreated controls, and recovered performance to levels of non‐transgenic comparator mice. In the Morris water maze test, AR1001 at 6 and 9 mg/kg significantly increased time spent in the target quadrant compared to untreated controls, and restored performance to levels of non‐transgenic mice.ConclusionWe demonstrate target engagement of AR1001, a PDE5 inhibitor, by showing an increase in cGMP and BNDF levels in the hippocampus following daily treatment. AR1001 had pronounced effects in recovery of cognitive functions in a transgenic mouse model of AD at a dose equivalent to that being tested in the Phase 3 trial in early AD patients.
The Association between Brain Amyloid‐Beta Deposition and Postoperative Cognitive Dysfunction After Pelvic Organ Prolapse Surgery: A Pilot Study
Authors: Ackenbom Mary F , Royse Sarah K. , Davis Esa M. , Orris Steven R. , Vargas Laura G. , Butters Meryl A 
Published: January 2025

AbstractBackgroundResearch on the role of preclinical AD pathology (brain Aβ deposition) and postoperative cognitive dysfunction is limited. We aimed to explore the association between brain Aβ deposition measured via Pittsburgh Compound B (PiB) PET imaging and POCD. We hypothesized that brain Aβ deposition would be associated with POCD in older women at 2 weeks and 3 months after surgery.MethodThis is a prospective cohort study of women aged ≥60 years who underwent urogynecologic surgery. Exclusion criteria included cognitive impairment diagnosis, abnormal cognition screen (Modified Mini‐mental State Exam (3MS) score < 84), and history of stroke. Baseline clinical and sociodemographic data were ascertained by interview and chart review. Brain Aβ deposition (global PiB standardized uptake value ratio (SUVR)) was measured through PiB‐PET using a combined MR/PET scanner. Eight neuropsychological tests, assessing memory, executive function, attention, and language were administered preoperatively, 2 weeks post‐surgery and 3 months post‐surgery. POCD was defined as ≥1 standard deviation (SD) decline on ≥2 neuropsychological tests or ≥ 2 SD decline on ≥1 tests. The association between Aβ PiB SUVR and cognitive performance was tested with Spearman correlation coefficient. Linear regression models, adjusted for clinically relevant variables, were generated.ResultThere were 20 patients enrolled with mean±SD age of 71.3±5.4 years, 14.7±2.23 years of education, baseline 3MS score of 97.3±2.63, and 1.12±0.20 global PiB SUVR. There was 45% (n = 9) POCD incidence at 2 weeks postoperatively and at 24% (n = 4/17) POCD prevalence at 3 months postoperatively. Table 1 summarizes demographics and cognitive performance at each time point. There were no significant correlations between PiB and cognitive domain at each time point although there appears to be a trend towards association of Aβ deposition on Spearman correlations (Table 2; Figure 1). On exploratory linear mixed models, there were no significant associations between Aβ deposition and cognitive performance by domain, nor with POCD.ConclusionIn this cohort of older women, 45% had POCD 2 weeks post‐surgery and 24% had POCD 3 months post‐surgery. Brain Aβ deposition was not associated with cognitive performance nor POCD. Studies with larger cohorts are needed to fully investigate this potential predisposing risk factor.
Greater neighborhood deprivation is related to shorter survival in behavioral‐variant frontotemporal degeneration
Authors: Boyle Rory , Dehghani Nadia , Stites Shana D. , Nelson Brian , Irwin David J , McMillan Corey T , Massimo Lauren 
Published: January 2025

AbstractBackgroundEmerging evidence relates neighborhood deprivation to cognitive decline and neurodegeneration but this is understudied in frontotemporal degeneration (FTD). We assessed the association of neighborhood deprivation with survival in 147 individuals with behavioral‐variant FTD (bvFTD).MethodNeighborhood deprivation was measured using the Area Deprivation Index (ADI), a national percentile ranking of deprivation based on income, education, employment, and housing quality. ADI was split into tertiles: lowest deprivation (ADI:1‐19), intermediate deprivation (ADI:20‐40), and highest deprivation (ADI:41‐93). In a Cox regression, we examined the association between ADI (reference group = lowest deprivation) and survival time (time from symptom onset to death), adjusting for age at symptom onset, sex (reference group = women), and education years. Individuals alive at study close were censored at their last clinic visit.ResultOlder age at symptom onset was associated with shorter survival (hazard ratio [HR] = 1.03[95%CI = 1.01–1.06], p = 0.005). Male sex was associated with longer survival (HR = 0.63[95%CI = 0.42–0.96], p = 0.03). Highest deprivation (HR = 1.84[95%CI = 1.09‐3.1], median survival years = 7[women]‐9[men], p = 0.017), but not intermediate deprivation (HR = 1.58[95%CI = 0.95‐2.63], median survival years = 7[women]‐10[men], p = 0.081), was associated with shorter survival time compared to the lowest deprivation group (median survival years = 10[women]‐12[men]). Similar results were observed in a sex‐stratified model.ConclusionOur results suggest that increased neighborhood deprivation contributes to shorter survival in bvFTD. Further research is needed to replicate this finding and uncover the underlying mechanisms.
Primary results from SPRINT MIND 2020
Authors: Williamson Jeff D. 
Published: January 2025

AbstractBackgroundThe Systolic Blood Pressure Intervention (SPRINT) randomized clinical trial evaluated the effect of intensive blood pressure (BP) control, defined by targeting systolic BP < 120 mm Hg, versus the standard target of < 140 mm Hg. Participants were recruited from 102 sites in the United States and Puerto Rico, aged 50 years or older with hypertension but without diabetes or history of stroke. SPRINT stopped early, after a median treatment of only 3.34 years of intervention, due to benefit on its primary outcome (a composite of cardiovascular events) and all‐cause mortality. SPRINT‐MIND, a sub‐study of SPRINT that evaluated cognitive outcomes, found intensive BP control reduced risk of mild cognitive impairment (MCI) by 19% and reduced the risk of developing either MCI or probable dementia (PD) by 15%. There was also a statistically non‐significant reduction of 17% in PD alone. We investigated the long‐term impact of intensive BP control on MCI and PD by conducting extended cognitive assessment for SPRINT‐MIND, adding follow‐up for cognitive outcomes through December 31, 2023.MethodsThe extended follow‐up was designed to administer a cognitive assessment battery by phone to 7221 participants in the main trial that were not withdrawn or had been adjudicated as having probable dementia and consented to future research. Participants were contacted by phone were asked to provide verbal informed consent. Phone calls began on December 2nd 2019.ResultsThere were 9361 participants originally randomized (mean age, 67.9 years; 3332 women [35.6%]) and of these, 7221 (77%) were free of dementia, and consented to long‐term follow‐up cognitive assessment. During this extended total median follow‐up of 6.9 years, adjudicated PD occurred in a total of 541 participants and MCI occurred in a total of 810 participants.ConclusionThe results from SPRINT MIND 2020 will demonstrate the long‐term benefit of intensive systolic blood pressure control on cognitive function.