bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health related quality of life in an at‐risk population during an intervention study and extended follow‐up ‐ the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Lehtisalo Jenni , Ngandu Tiia , Mangialasche Francesca , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta , Tuomilehto Jaakko , Soininen Hilkka , Khalsa Dharma Singh , Kivipelto Miia 
Published: January 2025

AbstractBackgroundThe multidomain lifestyle intervention in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed positive effects on health‐related quality of life (HRQL) during the 2‐year intervention, particularly physical functioning. Our aim was to study how these benefits were maintained over an extended follow‐up.MethodA total of 1259 older adults aged 60‐77 were randomized into multidomain intervention (n = 631) or control groups (n = 628). A validated HRQL scale RAND‐36 with 8 subscales was collected during the original 2‐year intervention (0,1,2 yrs) and during the 11‐year extended follow‐up (7,11 yrs). Emotional well‐being subscale was also available from a mail survey during the COVID19 pandemic (approx. 9 yrs). Changes over time and intervention effect on HRQL were analyzed using mixed‐effects regression.ResultAltogether 1212 (96%) provided HRQL data at baseline, 1069 (85%) after the intervention, and 501 after 11 years (40%). During the follow‐up mean RAND total score decreased from 76.4 to 69.3 All subscales were below baseline after 7 years, and physical functioning subscales started to decline already after 2 years (physical functioning, role limitations due to physical health, and bodily pain). Intervention related improvement in general health perception at the 1st year was maintained up to 11 years (p‐value for difference in change between groups 0.002), but improvement in physical functioning subscales vanished over time. Emotional well‐being started to decline at the 7‐year visit, without group differences. It temporarily improved during the pandemic (p‐value for change from the 7‐year visit 0.001) but declined back at the 11‐year visit.ConclusionOverall HRQL declined over time, as expected with aging. A 2‐year multidomain lifestyle intervention among at‐risk older adults resulted in sustained difference in general health perception, which is an important marker of general health. Lesser decline in physical functioning observed during the intervention was not sustained during the extended follow‐up. In the whole group, emotional well‐being declined later than physical functioning. Temporary improvement during the pandemic could be explained by the timing of the questionnaire (right after lifting restrictions), but it indicates that rapid changes due to external factors have an impact on emotional well‐being of older people.
BACE1 expression in neurodegenerative and neurodevelopmental diseases
Authors: Talib Leda Leme , Cordeiro Augusto Magno Tranquezi , Gattaz Wagner Farid , Forlenza Orestes Vicente 
Published: January 2025

AbstractBackgroundBeta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) was first identified as the rate limiting enzyme of amyloid‐β‐peptide (Aβ) production. The catalytic activity of BACE1 favors the generation of Aβ peptides and overproduction and accumulation of Aβ in the brain triggers downstream neurotoxic events that pertain to the amyloid cascade, leading to the formation of neuritic plaques. Furthermore BACE1 acts in the synapse through processing substrates such as APP‐like proteins, Neuregulin‐1 (Nrg 1), and β2 and β4 subunits of voltage‐gated Na+ channels. Nrg1 is a major physiological substrate of BACE1 during early postnatal development and one of the most important proteins in myelin formation. The cleavage of Nrg1 by BACE1 is essential for synapse development, cell survival and remyelination. However, BACE1 knockout animals have many subtle phenotypic alterations, including deficits in long‐term potentiation, increased seizure susceptibility, and schizophrenic behavior. It is well known that elderly individuals with Down syndrome (SD) develop amyloid plaques similar to those found in Alzheimer's disease (AD).MethodTaking this into account our objective was to confirm the BACE1 role in neurodegenerative diseases (23 AD), in 46 DS and 51 individuals with schizophenia (SCZ) and compare them to 79 healthy controls (HC). The enzyme BACE1 expression were determined by western blotting.ResultThe Kruskal‐wallis analysis show that AD patients present an increase in BACE1 in relation to the other groups (HC, DS and SCZ) (p<0.001). The DSCF pairwise comparasion show that SCZ present a decrease in BACE1 expression compared to HC (p=<0.001). SD present no diference related to HC and SCZ (p=0.515 and p=0.09 respectively) and no differences were observed in BACE1 between DS with cognitive decline and without cognitive decline. As well as no difference between SCZ resistant or not to treatment were noted.ConclusionOur hypothesis is that the amyloidogenesis observed in DS is not derived from the proteolytic action of BACE1 and that possibly the phisiological process of DS is closer to a neurodevelopmental disease as SCZ.
Links between cognition and multivariate brain white matter differences in individuals with family history of Alzheimer's disease
Authors: Tremblay Stefanie A , Spreng R. Nathan , Wearn Alfie , Alasmar Zaki , Pirhadi Amir , Tardif Christine L , Chakravarty M. Mallar , Villeneuve Sylvia , Leppert Ilana R , Carbonell Felix , Medina Yasser Iturria , Steele Christopher J , Gauthier Claudine J ,   The PREVENT‐AD Research Group
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is thought to result from a complex cascade of events involving several pathological processes. Recent studies have reported alterations in white matter (WM) microstructure in the early phase of AD, but WM remains understudied. We used a multivariate approach to capture the complexity and heterogeneity of WM pathologies and its links to cognition and AD risk factors in a more holistic manner.MethodThe MRI data of 134 cognitively unimpaired older adults with a family history of AD from the PREVENT‐AD cohort were analysed. Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (see Figure 1b‐c). We used the Mahalanobis distance (D2) to summarize the MRI metrics into a single score, indicative of the degree a voxel’s microstructure differs relative to a reference. Voxel‐wise D2 was computed for each subject relative to the group average of all other subjects using the MVComp tool and D2 maps were residualized for age (Figure 2). Partial Least Squares (PLS) analyses were then performed to relate WM D2 with cognition (RBANS) and AD risk factors, separately in each sex.ResultIn males, there was only one significant latent variable (LV 1). There were extensive brain WM regions associated with this LV pattern: higher white matter D2, was associated with higher BMI, lower total cholesterol (likely due to lower HDL) and worse cognitive performance in all cognitive domains except attention (Figure 2a‐b).In females, only the first LV was significant. Higher D2 in several WM tracts, including the inferior and superior longitudinal fasciculus, and the parahippocampal cingulum, was associated with lower education, and worse cognitive performance in all cognitive domains except attention and visuospatial construction. Higher WM D2 was also associated with several metabolic risk factors in females including higher SBP, higher BMI, higher glycated hemoglobin (HbA1c) and lower cholesterol (Figure 2c‐d).ConclusionThe different patterns of associations observed suggest there are sex‐specific risk profiles associated with WM microstructure differences in this population of older adults at risk of AD. The WM tracts affected in each sex were also associated with specific cognitive profiles.
Development of a Multidomain Composite Intervention Engagement Score in the U.S. POINTER Trial
Authors: Nouran Mina Ghadimi , Katula Jeffrey A. , Ventrelle Jennifer , Graef Sarah , Garcia Katelyn R , Lovato Laura , Wilmoth Sharon , Woolard Nancy , Leng Xiaoyan , Calandri Ismael Luis , Snyder Heather M , Baker Laura D 
Published: January 2025

AbstractBackgroundMultidomain lifestyle interventions have shown promise to slow cognitive decline and possibly prevent dementia. However, challenges arise in analyzing and interpreting treatment response when participants vary in their adherence to intervention components. The U.S. POINTER trial, a phase 3, multicenter, randomized 2‐year clinical trial, is investigating the impact of lifestyle interventions on cognition in older adults at risk of cognitive decline.MethodsFour composite scores are proposed to assess engagement in the POINTER multidomain intervention.ResultsComposite score one was based on the U.S. POINTER Prescription adherence goals for three intervention domains (physical activity, diet, brain training). For this composite score, values range from 0 to 1.25, where “1” signifies the adherence goal was met, and “1.25” indicates the goal was exceeded (Table 1). The composite score is the sum of values across domains.Composite score two was constructed using Consistent Intervals, maintaining consistent scaling between the measurement of intervention domains and the values. The composite score is the sum of the values across the three domains, each ranging 0 to 1 (Table 1).Composite score three employed a Proportional Approach, measuring engagement in the three intervention domains as a proportion of achieved U.S. POINTER prescription goals. The composite score is the sum of values across domains.Composite score four utilized Exploratory Factor Analysis to identify optimal weighting for each domain’s adherence scores, aiming for a comprehensive assessment of participants' behavior.Missing data are examined in two ways: (a) assume missing data indicates no adherence and assign zero, and (b) multiple imputation to predict missing values before composite calculation. Properties of the four composites are examined using simulated datasets in preparation for later use in U.S. POINTER. Distributions, central tendency, and variability of adherence values for each composite score will be presented.ConclusionFour possible multidomain adherence composite scores are proposed, reflecting intervention engagement in U.S. POINTER. In the future, we will explore sensitivity of each composite score to detect treatment‐related change in cognition. This study will lay the foundation for broader applications in other multidomain trials with quantifiable adherence metrics, such as FINGER and LatAm‐FINGERS.
Late‐onset Alzheimer’s disease and related dementia in Type 2 Diabetes: 20‐year Longitudinal matched cohort study
Authors: Jeong Sohyun , Pascual‐Leone Alvaro , Hsu Yi‐Hsiang 
Published: January 2025

AbstractBackgroundMultiple studies report that patients with diabetes have an increased risk of Alzheimer’s disease and related dementia (ADRD). However, there are limited number of studies with a long‐term follow‐up and accounting for the strong genetic risk factor of APOE genotypes.MethodWe used UK Biobank First occurrences (FO) datasets (Category 1712) in Health‐related outcomes data. Among the 406,049 eligible individuals, 27,125 T2DM cases were 1:1 matched to non‐T2DM by age at first diagnosis, sex, cerebrovascular disease, ischemic heart disease, hypertensive disorders, lipid disorders, obesity, and mood disorders. We applied the Cox proportional hazard model and Fine and Gray competing risk model with mortality as a competing risk. These models were adjusted for years of education, Townsend deprivation score, APOE4 and APOE2 genotypes to assess the ADRD outcomes. Additionally, for subgroup analysis by sex, APOE4 and APOE2 genotypes, we conducted matching within the subgroups and applied the same statistical models to assess ADRD risk in T2DM. We performed additional matching with T2DM polygenic risk score (PRS) and evaluated the non‐genetic T2DM effects toward ADRD risk.ResultThe mean age at diagnosis was around 62 years old and female constituted 61% (Table 1). The ADRD risk was significantly increased in T2DM (HR:1.46, 95% CI: 1.23‐1.73). The Fine and Gray competing risk model presented 1.32 times increased risk in T2DM (95% CI: 1.12‐1.56). In the sex‐stratified analysis, a significantly increased risk was observed in males (HR:1.58, 95% CI:1.28‐1.95) but not in females with T2DM (HR:1.28, 95% CI:0.97‐1.69) (Fig. 1). In APOE stratified analysis, T2DM was not associated with ADRD risk in both APOE4 and APOE2 subgroups. T2DM PRS was negatively correlated with ADRD risk, but in T2DM PRS matched cohort, T2DM significantly increased ADRD (HR:1.52, 95% CI: 1.29‐1.80). Both male (HR: 1.62, 95% CI:1.31‐ 2.00) and female (HR:1.35, 95% CI:1.01‐1.79) subgroups presented elevated risks.ConclusionWe demonstrated a 1.3‐1.5 times increased risk of ADRD in T2DM. This finding was confirmed in PRS matched cohort, suggesting non‐genetic T2DM effects could contribute to ADRD risk.
Can accelerometry identify/monitor neuropsychiatric symptoms correlated with motor activity in persons living with dementia? Results from a diagnostic test accuracy systematic review
Authors: Guseva Elena , Iaboni Andrea , Lanctôt Krista L. , Herrmann Nathan , Ismail Zahinoor , Burhan Amer M. , Gore Genevieve , Seitz Dallas , Kumar Sanjeev , Bruneau Marie‐Andrée , Lim Andrew , Wilchesky Machelle 
Published: January 2025

AbstractBackgroundWearable sensor technology shows promise for neuropsychiatric symptoms (NPS) identification/monitoring in persons living with dementia (PLWD). Accelerometry measures acceleration of body segments and physical activity. This study explores the diagnostic test accuracy (DTA) of accelerometry to identify the following 6 NPS associated with motor activity: aberrant motor behavior (AMB), aggression, agitation, anxiety, apathy, and wandering.MethodsAs part of a larger systematic review, we conducted an extensive literature search in nine health science and engineering databases. Meta‐analysis involved converting correlations to Fisher's Z scores, calculating 95% confidence intervals using the R Studio Metacor package, and assessing fixed effects, DerSimonian and Laird's random effects models, and heterogeneity.ResultsOut of 12,853 identified records, 84 reports were retained for analysis. Eight reports that provided 12 datasets assessed the DTA of accelerometry data for identifying/monitoring apathy (n=4), AMB (n=1), anxiety (n=2) agitation (n=5), aggression (n=2), and wandering (n=2). Studies included one single‐blinded trial, one non‐randomized trial, and ten observational studies. A random‐effect meta‐analysis yielded a pooled correlation across studies of r=0.61 (0.50; 0.70), heterogeneity I2=68%. When the wandering NPS subgroup was eliminated from analysis, heterogeneity fell considerably to I2=36%, with a pooled correlation of r=0.55 (0.47; 0.62).ConclusionsThese findings suggest that accelerometry consistently provides good to moderate DTA for identifying/ monitoring NPS associated with motor behavior in PLWD. Future research should prioritize standardizing the reporting of measurement procedures, signal thresholds, outcome measures, devices, and reference standards.
Retinal and brain imaging modalities for AD detection and monitoring
Authors: Martins Ralph N , Poudel Purna , Taddei Kevin , Eslick Shaun , Frost Shaun , Hone Eugene 
Published: January 2025

AbstractBackgroundAs an extension of the central nervous system (CNS), the retina shares many similarities with the brain and can manifest signs of various neurological diseases, including Alzheimer’s disease (AD). This study investigates the spectral features of the retina to develop a classification model for the differentiation of individuals with elevated brain amyloid levels.MethodParticipants (n=66) with varying brain Aβ levels, as determined by brain imaging, were non‐invasively imaged using a hyperspectral retinal camera at wavelengths of 450 to 905 nm. Multiple image features from the central view and superior view of retinas were selected and analysed to identify their variability among individuals with different brain amyloid loads. A machine learning classification model was trained to differentiate individuals with varying amyloid levels using the spectra of extracted retinal features.ResultThe retinal reflectance spectra between the wavelengths of 405–585 nm exhibited a significant difference between the individuals with raised brain amyloid levels. The performance of the spectral classification model was dependent on retinal region and showed 0.778–0.857 accuracy, 0.718–0.909 sensitivity, 0.778–0.912 specificity, and 0.758–0.878 AUC.ConclusionThis study highlights the spectral variation of retinal features associated with brain amyloid load. It also demonstrates the feasibility of the retinal hyperspectral imaging technique as a potential inexpensive screening method to identify individuals in the preclinical phases of AD and as a complementary or alternative to brain imaging.
Longitudinal Regional Flortaucipir Profiles in Preclinical Alzheimer’s Disease: Evaluation using A4 phase 3 trial with Solanezumab
Authors: Kotari Vikas , Holdridge Karen Chilcott , Yaari Roy , Schultz Aaron P , Johnson Keith A , Aisen Paul S. S. , Sperling Reisa A , Sims John R. , Shcherbinin Sergey 
Published: January 2025

AbstractBackgroundThe A4 Study (NCT02008357) was a multicenter, randomized, double‐blind, placebo‐controlled phase 3 trial, assessing the safety and efficacy of solanezumab in preclinical Alzheimer’s Disease (AD). We previously reported on the baseline regional flortaucipir (FTP) profiles in this study1. Here, we present the longitudinal tau profiles.MethodsFTP scans were acquired at baseline and weeks 84,168, and 240. All FTP scans were analyzed using an established image processing pipeline to evaluate global[2] and regional tau patterns in template space. Global tau level was measured using an AD‐signature weighted volume‐of‐interest (VOI) (tauSUVR)2. Regional tau uptake and accumulation were measured in 3 prespecified composite regions representing tau pathology in preclinical AD, ordered by hypothetical pathologic spreading: 1) “early” (amygdala, entorhinal cortex, parahippocampal gyrus), 2) “middle” (fusiform, inferior, and middle temporal, and inferior parietal gyri), and 3) “late” (lateral occipital, posterior cingulate, superior parietal, and supramarginal gyri). We evaluated associations between baseline amyloid burden, age, sex, APOE ε4 carriage and longitudinal tau change within placebo group.ResultsAt baseline, a lower tau signal was observed generally in regions identified later in pathologic sequences. Longitudinal change was region‐ and visit‐specific. In both treatment groups, the early and middle regions showed the largest change from baseline at Week 84; the middle region showed the largest change at Weeks 168 and 240; the global assessment changes were smaller than the early and middle regions at each time point (Figure 1; Tables 1&2) and a majority of participants remained global “tau negative”3(tauSUVR<1.11 Figure 2) throughout the trial. Higher baseline global amyloid level was most strongly associated with increased tau PET signal in the prespecified middle composite region at all timepoints (Figure 3).ConclusionA multi‐regional composite VOI staging scheme was developed using baseline tau profiles and prespecified for analysis of longitudinal tau PET images. Results confirmed that cognitively unimpaired, amyloid positive participants demonstrate larger tau accumulation in the early and middle than late and neocortical regions. The early composite performed better at detecting tau accumulation initially and middle composite at later timepoints. This multi‐regional staging scheme appears to be useful to characterize tau progression in this preclinical AD cohort.
Preliminary Evidence for the Combined Efficacy of Focused Ultrasound Blood‐Brain Barrier Opening and Delivery of a Novel Anti‐Amyloid Re Complex for Memory Improvement in a 3xTg‐Alzheimer’s Disease Mouse Model
Authors: Noel Rebecca L , Gorman Samantha L , Batts Alec L , Tsakris Deny L , Jimenez Daniella L , Pelecanou Maria , Sagnou Marina L , Konofagou Elisa 
Published: January 2025

AbstractBackgroundFocused Ultrasound‐induced Blood‐Brain Barrier Opening (FUS‐BBBO) has demonstrated preventative and therapeutic efficacy for improving cognitive and pathological decline in Alzheimer’s Disease (AD). Previous work has demonstrated highly specific binding of a novel Re complex (Re‐1) complex to amyloid‐β (Aβ) in vitro, subsequently inhibiting fibril formation and reducing Aβ‐induced cytotoxicity in neuronal cell cultures. The aim of this preliminary study is to evaluate the efficacy of early intervention combining FUS‐BBBO and Re‐1 for anxiety amelioration and memory improvement in a triple transgenic (3xTg)‐AD mouse model.MethodFour‐month‐old, male, triple transgenic (3xTg)‐AD mice, were divided into four groups for the present study: FUS+Re‐1, FUS, Re‐1, and anesthesia sham. This study consists of ten, bi‐weekly treatments spanning five months. Following treatment, the animals underwent five days of behavioral testing for anxiety (Open Field Test, OFT), spatial memory (Active Place Avoidance, APA), and reversal learning (Active Place Avoidance Reversal) to evaluate the progression of their AD‐associated cognitive deficits.ResultHere we report that the combination of FUS‐BBBO and Re‐1 delivery improves anxiety, long‐term spatial memory, and short‐term reversal learning, compared to FUS or Re‐1 alone, and compared to the anesthesia sham group. The amount of time elapsed in the center of the brightly lit OFT arena is inversely related to each animal’s level of anxiety; thus, the FUS+Re‐1 cohort and the FUS cohorts exhibited the lowest levels of anxiety across the four groups (Figure 1A). Next, the number of shocks delivered to each animal over the course of an Active APA learning trial is inversely related to that animal’s spatial memory capacity. Comparison of animal performance in the final trial of the first day of training, with the first trial of the subsequent day demonstrates that the FUS+Re‐1cohort had the best long‐term memory of the four cohorts (Figure 1B). The FUS+Re‐1 group also demonstrated the most consistent reversal learning improvement when comparing the first and third (final) trial on each of the two APA reversal trial days (Figure 1C‐D).ConclusionThis promising preliminary study offers evidence in support of early intervention with amyloid‐targeting Re‐1 and FUS‐BBBO for cognitive improvement in AD.