bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Exergaming in Cognitive Functions for People with MCI and dementia. A systematic review and meta‐analysis
Authors: Chan Joyce YC , Chan Aaron TC , Tsoi Kelvin KF 
Published: December 2023

AbstractBackgroundCognitive decline is one of the initial symptoms of older adults with mild cognitive impairment (MCI) and dementia. Physical activity has been found to be able to prevent cognitive decline in older adults with MCI and dementia. Exergaming is a form of technology‐driven physical activity which is suggested for older adults. However, it is still unclear whether exergaming is able to help older adults with MCI and dementia to prevent deterioration of cognitive functions. Therefore, we performed a systematic review and meta‐analysis to examine the effect of exergaming on cognitive functions in older adults with MCI and dementia.MethodA systematic literature search was conducted via OVID databases. Studies recruited older adults with MCI or dementia, and examined the effect of an exergaming intervention and compared with a non‐exergaming group were included. Both randomized controlled trails and quasi‐experimental studies were eligible. The outcomes were global cognition and verbal memory. All outcomes were measured by using standard cognitive assessment tools. The effects were pooled by meta‐analysis.ResultNine studies involving 497 older adults with MCI or dementia were included. The mean age ranged from 67 to 84, and the percentage of male ranged from 27% to 72%. Seven studies were RCT; two studies were with quasi‐experimental design. Older adults who received exergaming showed better global cognition than the control group (SMD = 0.32, 95% CI = 0.1 to 0.54). For memory functions, older adults who received exergaming showed better verbal memory than the control group (SMD = 0.85, 95% CI = 0.63 to 1.67). In subgroup analysis, older adults who received exergaming showed better global cognition than the usual care group (SMD = 0.44, 95% CI = 0.19 to 0.69), and comparable performance with the traditional exercise group.ConclusionExergaming was demonstrated to be a potential psychosocial intervention to prevent cognitive and memory decline in older adults with MCI and dementia. Exergaming can capture behavioral data that may be able to further understand the change in the cognitive abilities of older adults at risk. However, the number of studies was small, further investigation of the effect of exergaming is suggested.
Natural cubic splines for the analysis of Alzheimer’s trials
Authors: Donohue Michael C. , Langford Oliver , Insel Philip S. , van Dyck Christopher H , Petersen Ronald C. , Craft Suzanne , Raman Rema , Sims John R. , Sperling Reisa A. , Aisen Paul S. S 
Published: December 2023

AbstractBackgroundMixed model repeated measures (MMRM) is the most common analysis approach in clinical trials for Alzheimer’s disease. The model treats time as a categorical variable, which can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. Since MMRM entails a mean parameter for each group and visit, the model can be inefficient for longer trials of Preclinical Alzheimer’s. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time.MethodWe use model selection techniques to compare the predictive value of spline models to slope models, MMRM, and models that assume a proportional treatment effect using data from several completed trials. These trials include the ADCS trial of donepezil in MCI, trials of intranasal insulin and a fyn kinase inhibitor in mild Alzheimer’s dementia, and the A4 trial of solanezumab in Preclinical Alzheimer’s. Simulation studies assess the power and Type I error of these models for trials in Preclinical Alzheimer’s, MCI, and mild dementia.ResultThe spline model with ADAS‐Cog version effect attained the best predictive value for the trials in mild dementia. The proportional model was preferred for the trial in MCI, but the proportional effect assumption was violated, and the treatment effect estimate was in the wrong direction. Considering that the spline with two degrees of freedom and version effect provide fits that are similar to MMRM in Figure 1, we concluded that two degrees of freedom appear to be sufficient to capture enough of the general trend to assess the treatment effect. AIC results from the A4 Study will be considered and included after the study is completed in Spring 2023.ConclusionThe spline model is shown to have better predictive value and precision in real datasets and has better power and Type I error control in a variety of simulation scenarios.
Statistical innovations in the API ADAD Colombia trial: a randomized, double‐blind, placebo‐controlled, parallel‐group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab
Authors: Hu Nan , Mackey Howard , Doody Rachelle S. , Lopera Francisco , Tariot Pierre N. , Reiman Eric M. , Thomas Ronald G. , Langbaum Jessica B. , Sink Kaycee M. 
Published: December 2023

AbstractBackgroundA number of extended families in Colombia with early‐onset ADAD have a PSEN1 mutation at codon 280 (E280A), comprise the largest ADAD kindred in the world. Trial participants have been treated with crenezumab (an experimental anti‐amyloid monoclonal antibody) or placebo. Topline results were presented in August, 2022 at AAIC. Although the trial did not demonstrate a statistically significant clinical benefit in either of its co‐primary endpoints, multiple statistical innovations were incorporated into this trial.MethodThe API ADAD Colombia trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 2b study evaluating the efficacy, safety, and tolerability of crenezumab in cognitively unimpaired ADAD PSEN1 E280A mutation carriers in Colombia (NCT01998841). Due to under enrollment and concerns with the sensitivity of the primary endpoint, the protocol was amended mid‐trial to change from 260 weeks of treatment to a common‐close design whereby treatment continued in the double‐blind portion until the last enrolled participant received 260 weeks of treatment. Because of the change in trial design and power considerations, the primary analysis was adapted from a traditional mixed model with repeated measures (MMRM) based analysis to a random coefficient regression model (RCRM) based analysis. To quantitatively examine the adequacy of the RCRM assumptions, a robust variance estimator (Huber 1967; White 1982) was prespecified as a sensitivity analysis to calculate the standard errors and p‐values of the co‐primary endpoints. This study used a type‐I‐error‐controlled statistical procedure to identify and elevate the Free and Cued Selective Reminding Test (FCSRT) cueing index to a co‐primary endpoint. To comprehensively assess the crenezumab effect across primary and secondary endpoints, the prespecified relative reduction point estimates along with the bootstrapped 95% confidence intervals were generated.ResultInnovative statistical methods in this trial will be presented.ConclusionAlthough the API Colombia study did not meet its co‐primary endpoints, statistical learnings from this trial can benefit development of future AD trials. To further maximize the value of this unique trial dataset, participant‐level data will be made publicly available, including clinical, imaging, and biomarker data.Funding: NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. FlorbetapirPET was partly supported by Avid and Lilly.
Alternative Endpoints and Models for AD Prevention Trials
Authors: Wang Guoqiao , Li Yan , Xiong Chengjie , McDade Eric , Bateman Randall J. 
Published: December 2023

AbstractBackgroundThere are several challenges for AD prevention trials. First, the subtle cognitive change in asymptomatic disease stages requires large sample sizes, e.g. 400‐500/arm for two phase 3 confirmatory trials, or 800‐900/arm for a single phase 3 confirmatory trial, using the traditional MMRM. Second, large, international trials may necessitate the use of different tracers for imaging biomarker assessment due to global availability issues, however, statistical models that harmonize tracer differences within clinical trials are still lacking. Third, primary prevention trials using time to event endpoint demands even larger sample sizes, e.g., 1650/arm for TRAILBLAZER‐ALZ 3 with time‐to‐first‐conversion from CDR global 0 to >0 as the outcome. The percentage slowing relative to placebo decline (e.g., lecanemab led to 27% slowing at 18 months) is a popular concept to describe treatment effect. Instead of estimating the absolute difference using MMRM, we proposed to model this percentage treatment effect directly using the percentage or proportional MMRM (pMMRM). pMMRM can harmonize assessments from different tracers by converting the absolute difference into a shared proportional treatment effect across tracers. When using time‐to‐conversion as the primary outcome, instead of using a single event, Cox proportional hazards models for recurrent events can capture the treatment effect after the first event, where a recurrent event is defined as any increment over the previous visit in CDR global.MethodWe first demonstrated that disease modifying treatment effects are essentially proportional retreatment effects. Then, we evaluated the power advantage of pMMRM over MMRM and Cox recurrent events model over single event model through simulations. Finally, we demonstrated how to harmonize data from different tracers using pMMRM.ResultFigure 1 demonstrates that disease modifying treatment effects are like proportional treatment effects, leading to diverged disease progression trajectories and increased absolute differences. Figure 2 shows the power comparison between MMRM and pMMRM. pMMRM led to a power increase up to 30% over MMRM.ConclusionAlternative models such as pMMRM or Cox recurrent event models can yield greater power and pMMRM can harmonize assessment from different tracers, which may help enable global prevention trials in AD with disease modifying drug effects.
Correlation between vestibular dysfunction with worse cognitive outcomes in the elderly
Authors: Ribeiro Marlon Bruno Nunes , Mancini Patricia Cotta , Bicalho Maria Aparecida Camargo 
Published: December 2023

AbstractBackgroundthe vestibular system has neural connections from the vestibular nucleus to limbic and cortical areas, involved in both cognition and spatial orientation. The superior vestibular cortex consists of a network that interacts with other sensory systems, such as visual, sensorimotor, motor and cognition. Studies have found structural changes in the brain of patients with persistent perceptual postural dizziness (PPPD) when compared to controls, particularly in visual, vestibular and limbic areas, including a decrease in gray matter volume and turnover, a decrease in blood flow to the cortex region.Methodcross‐sectional, observational and analytical study. The sample consisted of 50 elderly people, of both sexes, aged between 60 and 86 years. Elderly individuals with vestibular dysfunction confirmed by Vestibular Evoked Myogenic Potential (VEMP) and Video Head Impulse Test (v‐HIT) tests were included. Balance and the impact of dizziness on quality of life were evaluated through tests and vestibular scales. Cognition, functioning and depression were assessed in a quiet room using tests and scales. Univariate analysis was performed using the Spearman test. Variables that presented correlation ≤ 0.2 were selected for multivariate analysis by linear regression. A significance level of 5% was adopted (p< 0.05).Resultthere was a correlation between vestibular dysfunction and imbalance with the results of neuropsychological assessment (p = 0.000), depressive symptoms (p = 0.001) and functionality (p = 0.002).Conclusionin this present study, a correlation was found between vestibular dysfunction and imbalance with the worst clinical and functional indices, worse functionality, depressive symptoms and in visuospatial function skills, executive functions and praxis.
Cardiac Autonomic Function of older adults with mild cognitive impairment during eyes‐closed resting state
Authors: Rosales‐Lagarde Alejandra , Mateos‐Salgado Erik Leonardo , Rodríguez‐Torres Erika E. , de Montis Arango , Domínguez‐Aguilar Ramiro , Santana‐Garduño Hazael , Sánchez‐González Sonia Arely 
Published: December 2023

AbstractBackgroundA different autonomic function would be expected between older adults with mild cognitive impairment (MCI) versus a control group (CTRL), having older adults with MCI a higher rate of risk factors than CTRL subjects. These risk factors consist in diseases (arterial hypertension and diabetes) and traumatic events (cranioencephalic trauma), among others.MethodThe cardiac autonomic function was evaluated through high frequency (HF) (or Respiratory Sinus Arrhythmia, RSA) and low frequency (LF) of heart rate variability. The electroencephalogram (EEG) (19 derivations) and the electrocardiogram (ECG) of 8 subjects: 4 with MCI and 4 CTRL (ages: 66.75 ± 3 and 70.5 ± 6 years; education: 9.5 ± 0.8 and 10.25 ± 4 years, respectively), were registered during eyes‐closed resting condition for 5 minutes. From each group, 3/4 MCI and 2/4 of CTRL subjects had risk factors. After verifying subjects were in the eyes closed resting state by the EEG, free artifact segments of the ECG with a mean duration of 3:18 ± 1 were analyzed.ResultNo statistically significant differences were found between both groups in the values of HF and LF expressed in natural logarithm.ConclusionA larger sample and a more unequal proportion of risk factors must be considered to evaluate the relationship between MCI and autonomic cardiac function.
Synergistic contributions of vascular risk factors and APOE ε4 carriage to cognitive performance in middle‐aged adults enrolled in the Healthy Brain Project
Authors: Rosenich Emily , Norfolk Maya , Buckley Rachel F. , Lim Yen Ying 
Published: December 2023

AbstractBackgroundMidlife vascular risk factors (VRFs) and APOE ε4 carriage are individually associated with poor cognitive performance and increased dementia risk. However, the extent to which VRFs interact with APOE ε4 carriage to influence cognition in midlife remains unclear. This study aimed to investigate interactions between VRFs and APOE status on cognitive performance in cognitively normal (CN) middle‐aged adults.MethodCN adults aged 40‐70 enrolled in the Healthy Brain Project with ≥75% complete baseline data on five VRFs and APOE status were included (N = 1610; 546 ε4 carriers). Cardiovascular risk was operationalized by assessing history of hypertension, hypercholesterolemia, diabetes mellitus, body mass index (BMI) ≥25, and current cigarette smoking. Participants were categorized into low (0) or high vascular risk groups (≥1 VRF) determined via median split. Analyses of covariance (ANCOVAs) investigated interactions between VRF group × APOE status on attention and memory composites (derived from the Cogstate Brief Battery), controlling for age, sex, education, ethnicity, and depressive/anxiety symptoms. Linear regression analyses explored contributions of individual VRFs on memory in ε4 carriers and non‐carriers.ResultA significant VRF group × APOE status interaction was observed for memory (p = .04), but attention was lower in those at high vascular risk, regardless of APOE ε4 status (Table 1, Figure 1A and 1B). For memory, APOE ε4 carriers with high vascular risk demonstrated worse performance compared to ε4 carriers and non‐carriers with low vascular risk (Figure 1A and 1B). Linear regression analyses revealed that BMI ≥25 and hypercholesterolemia were significantly associated with worse memory performance in ε4 carriers only (Table 2).ConclusionIn CN middle‐aged adults, vascular risk significantly modified associations between APOE status and memory performance, such that ε4 carriers with high vascular risk demonstrated the lowest memory performance. More specifically, higher BMI and hypercholesterolemia were significantly associated with lower observed memory performance within this group. Results suggest that middle‐aged ε4 carriers with vascular risk factors may be an important sub‐group to target within lifestyle prevention trials to reduce future risk of cognitive impairment and decline.
Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology
Authors: Yu Jin‐Tai 
Published: December 2023

AbstractBackgroundThe association between hearing impairment and Alzheimer’s disease (AD) and the mechanisms involved remain unclear.MethodsSurvival analyses were performed in 66,577 participants from the UK Biobank to investigate whether hearing impairment is associated with an increased risk of AD. The association of hearing status with cognitive function, brain structure and CSF proteins were explored in cross‐sectional, longitudinal, and mediation analyses across the UK Biobank (n = 165,550), Chinese Alzheimer’s Biomarker and Lifestyle (CABLE, n = 867), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 802).ResultsHearing impairment was associated with an increased risk of AD over 11 years of follow‐up (HR 1.80, 95%CI 1.50‐2.15). Poor hearing status was associated with worse cognitive function in cross‐sectional and longitudinal studies. Moreover, hearing impairment was significantly related to lower volume of the temporal cortex, hippocampus, amygdala, inferior parietal lobe, precuneus and orbitofrontal cortex, to lower integrity of white matter tracts, and to a higher level of CSF tau protein. Mediation analyses showed that brain structure and CSF tau partly mediated the association between hearing impairment and cognitive decline.ConclusionHearing impairment is a risk factor for AD, and is associated with brain structure, tau pathology, and cognitive decline.
Dementia is an auditory brain disorder
Authors: Warren Jason D , Hardy Chris JD , Johnson Jeremy , Jiang Jessica , Bamiou Doris‐Eva 
Published: December 2023

AbstractBackgroundWhile impaired hearing has emerged as a major potentiating factor for dementia, the basis for this relationship has not been defined. Most studies have emphasised the role of peripheral hearing loss. However, we hear with our brains: natural listening places immense computational demands on neural circuitry, and the neural networks pre‐eminently targeted by major dementias are essential for decoding and responding appropriately to the auditory environment. Auditory brain dysfunction is therefore predicted both to contribute importantly to hearing impairment in Alzheimer’s and other dementias and to be integral to the expression of neurodegenerative pathologies. Here I present an overview of evidence that speaks to this hypothesis.MethodsIn a series of linked experiments, we have assessed aspects of auditory cognition – the processes whereby the brain perceives, interprets and acts upon sounds ‐ in patient cohorts with Alzheimer’s disease and major syndromes of frontotemporal dementia, relative to healthy older individuals. We designed novel psychoacoustic tests to assess aspects of auditory scene analysis (the ‘cocktail party effect’ and localisation of sounds in space), comprehension of acoustically degraded speech and the processing of semantic and emotional information in sound in cognitively impaired people. Neuroanatomical mechanisms were assessed using voxel‐based morphometry and functional MRI.ResultsAcross experiments, after taking peripheral hearing function and general cognitive performance into account, patients with Alzheimer’s disease and frontotemporal dementias showed characteristic ‘auditory phenotypes’ or profiles of auditory cognitive impairment. Alzheimer’s disease is associated with impaired auditory scene analysis, linked to atrophy and dysfunction of temporo‐parietal cortical regions in the core ‘default mode network’ targeted by Alzheimer pathology. Frontotemporal dementia syndromes produce distinct impairments of auditory feature analysis, sound recognition and emotional valuation.ConclusionsAuditory brain dysfunction plays a key role in everyday hearing impairment and reflects core pathophysiology in major dementias. These findings raise the exciting prospect that auditory cognitive measures might be used in the early diagnosis of dementia, in guiding novel hearing interventions and as dynamic markers of therapeutic response in the dawning era of disease modification.
A genetic and proteomic approach to understanding neuropsychiatric symptoms in ADRD
Authors: Wingo Thomas S. , Liu Yue , Gerasimov Ekaterina S , Vattathil Selina , Wynne Meghan E , Faundez Victor , Liu Jiaqi , Bennett David A. A , Seyfried Nicholas T , Levey Allan I. , Wingo Aliza P. 
Published: December 2023

AbstractBackgroundThree lines of epidemiologic evidence link several psychiatric disorders to ADRD. First, experiencing schizophrenia or a mood/anxiety disorder in early/mid‐adulthood increases the risk of developing dementia by 6‐folds. Second, approximately 80% of ADRD patients experience neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, agitation, delusions, and hallucinations. Third, these NPS overlap with symptoms of schizophrenia and mood/anxiety disorders. Given these observations, this study focuses on the question of whether these psychiatric disorders and ADRD have shared pathophysiology, which may underlie the manifestation of NPS in ADRDMethodTo investigate whether there is a shared genetic and molecular basis between the psychiatric conditions (major depressive disorder [MDD], bipolar disorder [BD], neuroticism, anxiety, PTSD, schizophrenia, and alcoholism) and ADRD (AD, Lewy body dementia [LBD], ALS, Parkinson’s disease [PD]), we performed three analyses. First, we examined genetic correlations between a psychiatric disorder and an ADRD using GWAS results in each condition and LDSC regression. Second, to identify causal genes and proteins for each of these brain conditions, we integrated each GWAS results with human brain proteomes (n = 722) using multiple independent state‐of‐the‐art integration approaches (PWAS, Mendelian randomization, colocalization analysis). Third, we examined protein‐protein interactions (PPIs) between a psychiatric causal protein and an ADRD causal protein using BIOGRID database.ResultFrom LDSC regression, we found 7 pairs of a psychiatric condition and an ADRD having significant genetic correlations, suggesting a shared genetic diathesis between these psychiatric conditions (MDD, BD, neuroticism, anxiety, PTSD, alcoholism) and ADRD (AD, LBD, ALS). Furthermore, among the causal proteins we identified for each condition, 30% of the ADRD causal proteins (13 of 42) were also causal proteins in the psychiatric conditions, highlighting a shared pathophysiology. Moreover, we found 2.6‐folds more PPIs between a psychiatric causal protein and an ADRD causal protein than by chance (p = 0.003, 120 PPIs).ConclusionTogether, these 3 levels of novel evidence highlight a shared genetic and molecular basis between several psychiatric conditions and ADRD, which may underlie the pathophysiology of NPS in ADRD. The 13 shared causal proteins are promising targets for further validation in NPS in ADRD and towards the goal of developing effective therapeutics for NPS.