bluuebunny/crossref_metadata_2025 huggingface dataset:
Usability of a Self‐Administered Cognitive Assessment in Patients with Progressive Supranuclear Palsy and Correlation with Traditional Neuropsychological Tests: A Mayo Test Drive Pilot Study
Authors: Boots Elizabeth A. , Broeren Megan J. , Ali Farwa , Clark Heather M. , Stierwalt Julie A.G. , Botha Hugo , Stephens Yehkyoung C. , Josephs Keith A. , Whitwell Jennifer L. , Machulda Mary M. , Stricker Nikki H.
Published: January 2025

Background

Self‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).

Method

Eleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.

Result

Ten of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).

Conclusion

In a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.
Humanoid Robots perform cognitive assessments: to address healthcare worker shortages
Authors: Khan Arshia A
Published: January 2025

Background

The rising demand for alternative dementia assessments, fueled by healthcare workforce shortages and the growing population of individuals affected with dementia, necessitates innovative approaches to address accessibility, logistics, and diverse populations. The utilization of robots in cognitive assessments emerges as a promising solution, promising efficiency and engagement, while navigating the complex landscape of dementia care challenges.

Method

Existing cognitive assessment tools were examined to develop a humanoid robot to deliver cognitive assessment. This robot‐assisted cognitive assessment development involved integrating artificial intelligence with robotic technology to create a comprehensive tool. Initially, the design phase included defining the cognitive domains to be assessed and tailoring the assessment tasks to suit robot‐human interaction. The robot’s programming incorporated adaptive features to respond to individual variations in cognitive abilities. Sensory modules, such as cameras and microphones, in the robot were integrated for real‐time data collection, enabling the robot to observe and interact with the individual. Iterative testing and refinement were performed to ensure the accuracy and reliability of the robot‐assisted cognitive assessment tool. Throughout the development process emphasis was on creating a robust and user‐friendly system that aligns with the nuanced nature of cognitive assessments for individuals affected by dementia.

Result

Robot‐assisted cognitive assessments were tested in a nursing home setting, showing promising results and providing valuable insights into residents' cognitive functioning.

Conclusion

The robot assisted assessments, integrated with AI, offer a comprehensive understanding of memory, attention, and other cognitive domains. The individual variability in cognitive abilities among residents is highlighted, enabling personalized care plans tailored to specific needs. The positive engagement and usability reported by residents suggest a potential avenue for integrating this technology into routine care practices. The real‐time data collection capabilities of the robot contribute to a more dynamic and accurate assessment of cognitive health. Caregivers benefit from the objective cognitive performance data, allowing for timely interventions and adjustments in care plans. The iterative feedback loop from residents and caregivers facilitates continuous improvement in the robot‐assisted cognitive assessment tool, making it a valuable and beneficial asset in enhancing the quality of care provided in nursing homes.
Digital Cognitive Screening in Primary Care: Feasibility, Acceptability, and Usability of the MyCog Measurement System
Authors: Young Stephanie Ruth , Dworak Elizabeth , Byrne Greg Joseph , Yoshino‐Benavente Julia , Jones Callie Madison , Curtis Laura M , Wolf Michael S , Nowinski Cindy J.
Published: January 2025

Background

Annual cognitive screening in older adults is essential for early detection of cognitive impairment, yet less than half of cases are detected in primary care. We introduce two innovative app‐based screeners that help overcome barriers to routine cognitive screening. MyCog is a tablet app that is self‐administered in person during the rooming process for a primary care visit (Figure 1). MyCog Mobile is a smartphone app that is self‐administered remotely prior to a primary care visit (Figure 2), which can save clinicians even more time during an in‐person visit. We present evidence from two studies: 1) an evaluation of the adoption and usability of MyCog in primary care; and 2) a pilot study of the reliability and usability of MyCog Mobile.

Method

In Study 1, the implementation of MyCog in 10 primary care clinics was assessed as part of a pragmatic trial evaluating cognitive screening for adults aged 65+ during Annual Wellness Visits (AWVs). Using EHR data, we assessed adoption via the portion of patients who completed MyCog. In Study 2, 51 adults 65+ self‐administered MyCog Mobile remotely on their own smartphones twice about two weeks apart and rated its usability on the Simplified System Usability Scale (S‐SUS). We examined the reliability, correlations with education, and usability ratings.

Result

In Study 1, of the 3921 eligible patients, 1263 completed MyCog (32.2%), with individual clinic compliance ranging from 11% to 68% of patients. Feedback revealed several addressable clinician and patient barriers, including patient frustration on memory tests, unclear test progress, and need for a Spanish version, and minor design flaws. In Study 2, all participants successfully completed each measure, and reliability metrics were broadly acceptable (Table 1). The MyPictures and education correlation was lower than expected. Ratings on the S‐SUS indicated good usability of MyCog Mobile (M = 73.78, SD = 20.11).

Conclusion

MyCog demonstrated good adoption by primary care clinics in a pragmatic trial, which may be improved through design and implementation changes. Some limitations of MyCog may be addressed with MyCog Mobile, which demonstrated preliminary feasibility evidence. Practice implications and next steps are discussed.
A passive electronic medical record‐based cognitive risk calculator predicts neuropsychological performance in older adults
Authors: Saxena Saket A , Hogue Olivia , Rothberg Michael B , Misra‐Hebert Anita D , Milinovich Alexander P , Pfoh Elizabeth R , Busch Robyn M , Krishnan Kamini , Fox Robert J , Kattan Michael W , Floden Darlene
Published: January 2025

Background

Stratifying risk of cognitive decline for an individual patient can be difficult in primary care settings where advanced biomarkers are usually not available. Passive risk calculators that capitalize on existing information contained in the electronic medical record (EMR) hold promise, but most are developed using EMR documentation of cognitive decline which is highly unreliable. This prospective study used objective cognitive testing to build a multivariable cognitive risk model based on EMR records.

Methods

338 primary care patients aged 60 and older who had at least two visits over the previous 5 years completed brief neuropsychological testing to establish current cognitive function and consented to access to their medical records. Records from the preceding 5 years were mined for health status indicators (e.g., BMI, pulse, blood pressure), diagnoses, medications, demographic, and socioeconomic information and entered into a multivariable logistic regression model using Harrell’s step‐down selection. To account for changes in variable values from visit to visit, binary variables (e.g. medications, diagnoses, smoking status) were classified as absent or ever‐present during patient follow‐up, while first, last, and “worst” values were retained for continuous variables (e.g. blood pressure, pulse). Bootstrap resampling was used for internal validation. Model was adjusted for optimism and fit evaluated using calibration curves.

Results

The sample was 59% female and 80% white, with a mean age of 72.5 (SD 7.0) and 15.5 years of education (SD 2.6)). Eighty patients (24%) were cognitively impaired. The model that best identified impairment included age, most recent pulse, race, presence of mood disorder diagnosis, family history of neurological diagnosis, NSAID use, and most recent systolic blood pressure. After adjusting for optimism, the discrimination index was 0.71, indicating good discrimination. Results from the model were transformed to yield patient‐specific probability scores used to trigger risk flag in the patient’s medical record.

Conclusions

An EMR‐based risk calculator successfully discriminated between patients with and without cognitive impairment. Strategies for implementing the cognitive risk flag into clinical practice are discussed.
Validation Study of A Three‐Minute Game‐Based Cognitive Screening Tool For Detecting Cognitive Impairments In Chinese Older Adults
Authors: Wu Jingnan , Li Yatian , Zhou Zhixing , Xia Huanhuan , Chen Nan , Guo Qihao
Published: January 2025

Background

Game‐based Cognitive Assessment – 3‐Minute Version (G3) is a WeChat mini‐program developed for the early screening of cognitive impairments in Chinese older adults. It consists of three game‐like digital cognitive tests, namely “Number Ordering”, “Species Sorting”, and “Gold Finding”. This study aims to assess the sensitivity, specificity, and diagnostic accuracy of G3 in detecting mild cognitive impairment (MCI) and early‐stage dementia in Chinese older adults.

Method

Between February and December 2023, a total of 475 older adults (aged 50 to 89 years) with subjective cognitive complains were recruited. Participants underwent G3 assessment, neuropsychological assessments, neuroimaging, and blood tests. Among them, 230 individuals were diagnosed with cognitive impairments, including MCI and early‐stage dementia, while the remaining 245 older adults exhibited healthy cognition. We compared the G3 performance between the two groups. And the receiver operating characteristic (ROC) curve of G3 were evaluated with sensitivity and specificity calculated.

Result

The average G3 scores (mean ± standard deviation) in the healthy cognition group (63.2±13.04) were significantly higher than impaired cognition group (41.3±12.50, p<0.001). In both groups, the mean G3 scores tended to decline with increasing age. Meanwhile, the decline was more significant in the impaired cognition group compared to the healthy cognition group (Figure 1). G3 demonstrated high diagnostic accuracy in detecting individuals with MCI or early‐stage dementia, with an area under the ROC curve (AUC) of 0.887 (95% confidence interval [CI] = 0.859‐0.916, Figure 2). The optimal cut‐off score for G3 was determined to be 59.5, with a sensitivity of 0.913 and specificity of 0.624.

Conclusion

G3 WeChat mini‐program is a precise and user‐friendly screening tool that exhibits high sensitivity and diagnostic accuracy in detecting early‐stage cognitive impairment among community‐dwelling seniors. Further multicenter research is needed to verify the diagnostic value of G3 for different stages and types of cognitive impairments.
Machine Learning‐Driven Speech Biomarker Analysis: A Novel Approach for Detecting Cognitive Decline in Older Adults
Authors: Li Yatian , Chen Quan , Wu Jingnan , Chen Nan , Zhou Zhixing , Xia Huanhuan , Huang Lin , Guo Qihao
Published: January 2025

Background

Speech impairment appears at early stages of Alzheimer’s disease. A mobile voice recognition‐based cognitive assessment tool, Shanghai Cognitive Screening (SCS), was developed for detecting mild cognitive impairment (MCI) and dementia in the community. The objective of this study is to investigate speech biomarkers associated with cognitive impairments based on SCS, and to evaluate the diagnostic accuracy of speech feature‐based machine learning (ML) models for detecting MCI.

Method

A total of 301 older adults were recruited to perform SCS assessments, with 135 of them were diagnosed with cognitive impairment (MCI and early dementia) and the remainder were cognitively normal. Speech features were extracted from SCS voice recordings and integrated in a dataset along with SCS scores and demographic indicators. The dataset was randomly divided into training and validation sets in a 4:1 ratio and trained in various ML models with predictive speech features examined.

Result

Among the models trained, the ML models employing SVM model, Logistic Regression, Random Forest, LightGBM, and XGBoost demonstrated higher accuracy than original SCS scores (Table 1). A ML classifier using Mel spectrograms and multimodal data fusion exhibited the highest accuracy of 0.953 (AUC = 0.967, sensitivity = 0.933, specificity = 0.933). Further analysis of the LightGBM model revealed that speech markers significantly influencing the model’s output included modal particles, standard deviation of interval time, silence duration, mean interval time, total speaking time, silence time in delayed recall test, and percentage of silence time (Figure 1). These findings align with the audio waveform characteristics (i.e., smaller amplitudes, longer intervals, greater rhythm variations, and increased silence, Figure 2) in individuals with cognitive impairments. However, the top three factors were scores of delayed recall and instant memory, as well as SCS total score.

Conclusion

The findings demonstrated speech biomarkers associated with cognitive impairments, facilitating more accurate detection of early cognitive impairment with ML techniques. Validation studies on larger sample sizes is necessary.
Providing In‐Home Helmet‐Based 40 Hz Light Therapy for Alzheimer’s Patients in Memory Care Facilities in Detroit, MI: A Proposal for a Feasibility Study to Expand Early Efficacy Data
Authors: Bart Jacob A , Attar Zechariah
Published: January 2025

Introduction

Alzheimer’s disease is the most common and costly neurodegenerative disease worldwide. Early studies of helmet‐based 40 Hz light therapy have demonstrated safety and early efficacy in targeting the pathophysiologic characteristics of Alzheimer’s disease. This intervention has shown slowing and even reversal of disease progression. An extensive literature review has demonstrated this therapy to be cost‐effective and user‐friendly with minimal side effects. Implementation of this therapy has been limited by barriers to access, illustrated by small sample sizes and poor compliance in numerous studies. Further research with larger sample sizes is essential to accelerate the rate of translation from bench to bedside by addressing implementation barriers to access, thereby optimizing patient adherence.

Hypothesis

We hypothesize that offering helmet‐based 40 Hz light therapy in a home setting will result in increased enrollment of eligible patients and compliance by providing convenience to patients and their caregivers. This approach will develop implementation guidelines while expanding on existing efficacy data.

Objective

To explore our hypothesis, we plan to conduct a feasibility study by recruiting through, and providing care at, memory care facilities in Detroit, Michigan. Changing the location of care may be an easily adaptable implementation strategy that can be applied nationally. We've identified 50 memory care facilities that house Alzheimer’s patients, with capacity for over 400 residents in Detroit alone.

Methods

We plan to assemble a mobile team of research‐clinicians to administer helmet‐based 40 Hz light therapy. Scheduled weekly appointments can be facilitated at the convenience of the patients and their care providers across all facilities that allow this therapy for their residents. These participants will be recruited via rolling admission and outcomes will be evaluated using standardized neurocognitive assessments. In summary, helmet‐based 40 Hz therapy has already been shown to be safe and effective. Studying the feasibility of implementing it in the patient’s home is an important next step in making this care accessible to those that need it most.
The Evaluation of Telehealth Provider Payment Parity on Health Service Utilization among Adults with High Risk Factors for Dementia in the US
Authors: Zhang Zhang
Published: January 2025

Background

Cardiometabolic diseases and mental health disorders, which are high‐risk factors for dementia and cognitive decline, are associated with higher mortality and morbidity with age. Interventions before age 60 may lessen the burden of cognitive and physical function in later life. Telehealth offers early intervention and solutions for their complex demands in continuous behavior monitoring and medication refilling. Telehealth has been catalyzed by the COVID‐19 pandemic and become a new norm in healthcare. One of the important factors driving this transformation is governments' temporary modifications and policies. Our study aims to evaluate the impact of telehealth payment parity mandates, which require an equal payment rate for telehealth vs. in‐person outpatient visits, on overall health service utilization among populations with high‐risk factors for dementia.

Method

Using the IBM MarketScan dataset from 2019 to 2021, we leverage a policy shock using a quasi‐experiment by a two‐way fixed effect difference‐in‐differences (DiD) estimation. Our sample includes adults with cardiometabolic risks (diabetes, hypertension, or dyslipidemia) or mental health disorders. We compare the differences between the control and treated states in changes in the outcomes of interest after the onset of the pandemic.

Result

On average, the treated group had 0.18 more telehealth visits by patient by month than the control (p<0.05). Compared to the control group, the treated group had 7 percentage points higher probability of having at least one telehealth encounter by patient by month (p<0.1) and 5 percentage points increase in the proportion of outpatient visits via telehealth by patient by month (p<0.1). In addition, the payment parity did not lead to a significant increase in in‐person outpatient visits.

Conclusion

Our results suggested that the telehealth payment parity, driven by supply‐side incentives, has effectively increased telehealth adoption during and post‐pandemic. The findings addressed the public concerns that telehealth expansion policies could induce and trigger excess demand for in‐person office visits. Our study provides evidence for policymakers to establish sustainable telehealth reimbursement policies and payment models and improve equitable telehealth access for populations with high‐risk factors for dementia in the US.
Supporting everyday cognition: Home Technology Tours with people living with dementia
Authors: Astell Arlene , Awan Hira , Pearson Danielle
Published: January 2025

Background

Current off‐the‐shelf technologies contain functionality which can support everyday cognition, such as storing telephone numbers and calendar reminders. These functions can benefit everyone, including people living with dementia. However, knowledge is limited about people living with dementia acquiring and using existing technologies and whether or how they are utilizing these functions.

Method

Technology Tours were completed in the homes of 9 individuals living with dementia, followed by semi‐structured interviews. As they went around their homes the individuals were asked to describe what technologies they used in each room, what they used them for, and how they acquired them. The tours and interviews were transcribed and analyzed using content analysis.

Result

Participants living with dementia described multiple technologies that they use in their everyday lives. These include televisions, stoves and mobility aids, alongside tablets, smart phones, and voice assistants (e.g. Alexa). Their reasons for using their devices were (i) maintaining meaningful activities, (ii) staying connected, and (iii) promoting independence, all of which influenced their well‐being. The usability of devices and safety features were also highlighted.

Conclusion

The findings indicate that people living with dementia use a wide range of technologies to support their everyday cognition. They adopt different functions for different aspects of their lives and would like to access more functionality. This is hindered by the complexity of learning to use and incorporate some potentially helpful devices into their daily lives. These findings can help to dispel myths about the interest and ability of people living with dementia to use digital tools, to encourage wider use of readily available functions and devices, and increased development of new cognitive supports.
Universal tau PET scale (Uniτ) – The HEAD Study
Authors: Povala Guilherme , Bauer‐Negrini Guilherme , Bellaver Bruna , Lussier Firoza Z , Amaral Livia , Ferreira Pamela C.L. , Zatt Bruno , Tudorascu Dana , Lopresti Brian J , Jagust William J. , Klunk William E , Lowe Val J. , Soleimani‐Meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: January 2025

Background

The HEAD study aims to collect a large dataset of multiple tau‐PET tracers to provide robust anchor values for tau‐PET harmonization. Here, we tested the hypothesis that anchoring two tau tracer uptake values using head‐to‐head measurements has the potential to generate an accurate universal tau‐PET scale, named Uniτ(tau).

Methods

We assessed 200 individuals across the aging and AD spectrum (Training:HEAD data freeze 2.0, n=185; Testing:UPitt dataset (Gogola et al.), n=15) with [18F]Flortaucipir and [18F]MK‐6240 tau‐PET. SUVRs were processed to a common 8mm FWHM, with inferior cerebellar gray matter as the reference region (Pascoal et al.). Uniτ explored two anchoring/harmonization methods. First, we examined within‐tracer anchoring by creating anchor values based on the mean SUVR of Youngs (<25 years) and 95th percentile voxels from cognitively impaired individuals. Second, we explored within‐ plus between‐tracer anchoring, employing linear (e.g., piecewise) and non‐linear regressions. To address the inherent problem of discontinuity of piecewise transformations, we implemented two smoothing methods at the inflection point between equations, transforming them into a continuous function.

Results

Uniτ scale anchoring within‐tracer resulted in similar estimates for high values, but less accurate in the lower range (Figure 1,2). Anchoring within‐ plus between‐tracer improved estimate consistency, with the piecewise transformation generating the best results. The piecewise smoothing equation yielded estimates comparable to those obtained from the piecewise method without smoothing. This allowed for the use of a single formula. In addition, this leads to more robust results when the goal is to study longitudinal changes in the scale (data not shown). UPitt testing dataset showed similar results to the training set (Figure 3).

Conclusion

Our preliminary findings suggest that anchoring tau‐PET values both within and between tracers has the potential to harmonize tau‐PET tracers, while preserving their characteristics. Currently, piecewise smoothing is the preferred method for Uniτ, but we are continuously fine‐tuning scale parameters as we acquire more data. The final scale parameters will be determined based on extensive training and testing data from multiple tracers. This cautious methodology holds the promise of delivering reliable, robust, and reproducible results, ensuring safe usage of the scale in clinical trials, and potentially paving the way for future use in clinical practice.
Lecanemab‐associated amyloid‐β protofibril is a proximal biomarker of neurodegeneration unlike other plaque‐associated biomarkers
Authors: Ono Kenjiro , Shinohara Moeko , Shuta Kazuyoshi , Murakami Hidetomo , Mori Yukiko , Komatsu Junji , Kobayashi Chizuru , Hersch Steven , Horie Kanta
Published: January 2025

Background

We developed a highly sensitive immunoassay method using lecanemab that selectively captures amyloid‐β (Aβ) protofibril (PF). To characterize Aβ‐PF in human cerebrospinal fluid (CSF), we investigated the CSF Aβ‐PF levels in patients with Alzheimer’s disease (AD) at different disease stages. We also studied the association of CSF Aβ‐PF with other AD‐related biomarkers.

Method

The participants in this study consisted of 48 cognitively unimpaired Aβ‐negative (CU‐) including 25 young normal control (YNC) and 23 age matched control (AMC) (age≥50), 8 cognitively impaired diagnosed as suspected non‐Alzheimer’s pathophysiology (CI‐), 9 cognitively unimpaired Aβ‐positive (CU+), 34 Aβ‐positive with mild cognitive impairment (MCI+) and 64 Aβ‐positive with AD dementia (AD+). CSF Aβ‐PF were analyzed by the immunoassay system using lecanemab as a tool antibody. The other CSF biomarkers were analyzed by the conventional enzyme‐linked immunosorbent assay (ELISA) or the digital ELISA system (Simoa) (Figure 1).

Result

The CSF Aβ‐PF levels significantly increased in MCI+ and AD+ compared to YNC or AMC in CU‐ group (Figure 2). CU+ also showed increase of CSF Aβ‐PF levels while CI‐ did not although the differences were not significant. In Aβ‐positive participants, the CSF Aβ‐PF was strongly correlated with “N” biomarkers such as CSF total tau (t‐tau) (Spearman rho = 0.634, p < 0.001) and neurogranin (rho = 0.434, p < 0.001) whereas the relatively lower correlations were observed for CSF Aβ42 (rho = ‐0.080, p = 0.415), Aβ42/40 (rho = ‐0.334, p < 0.001), tau phosphorylated at 181 residue (p‐tau181) (rho = 0.294, p = 0.004), and p‐tau217 (rho = 0.232, p = 0.018) which are known as plaque‐associated biomarkers.

Conclusion

This is the first report describing lecanemab‐captured Aβ‐PF species in human CSF. The CSF Aβ‐PF levels increased during AD continuum including MCI+ as well as AD+ stages. CSF Aβ‐PF showed modest correlation with plaque‐associated biomarkers in Aβ‐positive participants and stronger correlation with neurodegeneration biomarkers, suggesting that lecanemab‐associated Aβ‐PF may be a toxic species involved in the amyloid cascade and underlie the clinical effect of lecanemab in AD.
Gender differences in anticholinergic overactive bladder medication use and the risk of dementia
Authors: Richardson Kathryn , Loke Yoon , Steel Nick , Edwards Duncan , Panicker Jalesh N , Irving Stuart , Mattishent Katharina , Fox Chris , Robinson Louise , Petersen Irene
Published: January 2025

Background

Studies that report an association between anticholinergic medications and dementia often suffer from confounding by indication and rarely consider gender effects. We estimated the association between recurrent prescriptions for anticholinergic overactive bladder (OAB) medications and incident dementia, separately in men and women.

Method

We studied patients aged ≥50 years first prescribed an anticholinergic OAB drug (e.g. oxybutynin, solifenacin, tolterodine) during 1998‐2019 in England using the Clinical Practice Research Datalink Aurum (CPRD) linked to hospital admissions data. To reduce confounding by indication, we compared patients receiving a second prescription to those only prescribed one during the first year. To reduce protopathic bias, we began follow‐up for incident dementia (first diagnosis in CPRD, hospital data or prescription for a cognitive enhancer) first prescription, and censored patients at death, leaving the practice, one month before last data collection, or 31/3/2020. We excluded patients with history of dementia, cognitive impairment, serious central nervous system disorders, severe mental illness, alcohol abuse, or <12 months registration with their GP. We used Cox regression, with age as the time‐scale, to estimate hazard ratios (HR) for recurrent OAB prescription and incident dementia adjusted for many socio‐demographic and health‐related covariates, comorbidities, and concomitant medications, separately in men and women. We also examined risks by drug and cumulative defined daily doses (DDDs).

Result

We included 80,874 men and 149,930 women who initiated bladder anticholinergics with ≥3 years of subsequent follow‐up. Of these, 83,718 (received only one prescription during the first year. Receiving a second prescription was associated with a greater increased dementia incidence in men (HR = 1.23, 95%CI 1.17‐1.29) than women (HR = 1.11, 95%CI 1.08‐1.15; p = 0.002 for gender interaction). Associations increased with greater cumulative exposure, with HRs (95%CI) of 1.32 (1.24‐1.40) and 1.16 (1.11‐1.21) for >6 months of DDDs (vs ≤1 month) for men and women.

Conclusion

We observed greater increased rates of dementia for men with recurrent OAB anticholinergic prescriptions than women, and associations were dose‐dependent. Prescribers should exercise additional caution in men, and aim for alternative management options or the lowest effective dose and a limited period where possible.
Clinical‐effectiveness of DREAMS START an intervention for with people with dementia and sleep disturbance and their caregivers ‐ A single masked, phase 3, parallel arms superiority randomised controlled trial
Authors: Rapaport Penny , Amador Sarah , Barber Julie , Adeleke Mariam M , Webster Lucy A , Banerjee Sube , Charlesworth Georgina , Clarke Christopher , Espie Colin A , Kyle Simon D , Raczek Malgorzata , Walker Zuzana , Livingston Gill
Published: January 2025

Background

Sleep disturbance is common and distressing for people with dementia, with no known safe, effective treatments. We previously developed and delivered DREAMS‐START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives), a multimodal non‐pharmacological intervention, and demonstrated feasibility and acceptability. This randomised controlled trial (RCT) aimed to establish whether DREAMS‐START is clinically‐effective in reducing sleep disturbances in people with dementia at home after 8 months compared to usual care.

Methods

We conducted a two‐arm, multi‐centre, parallel arms, superiority RCT with masked outcome assessment, recruiting dyads of people with dementia and sleep disturbance, and their family caregivers, in English community settings. Those meeting inclusion criteria were randomised (1:1) to DREAMS‐START or usual treatment. DREAMS‐START is a six‐session, manualised intervention delivered by supervised, non‐clinical graduates. Strategies were tailored and included routine, comfort, increasing light exposure, relaxation, and activity. Outcomes were collected at baseline, 4 months, and 8 months. The primary outcome was the Sleep Disorders Inventory (SDI) score at 8 months and analyses were intention to treat. Secondary outcomes for people with dementia included quality of life, daytime sleepiness, and neuropsychiatric symptoms and for family caregivers ‐ quality of life, sleep disturbance, mood, and burden.

Results

Between February 2021 and March 2023, 377 participant dyads were randomised, 189 were allocated to usual treatment and 188 to intervention. Mean age of participants with dementia was 79.4 years (SD 9.0). 206 (54.6%) were women. Mean SDI score at 8 months was lower in the intervention arm versus usual treatment (15.16 [SD 12.77], n = 159, vs 20.34 [16.67], n = 163]; adjusted difference in means ‐4.70 (95% CI ‐7.65 to ‐1.74; p = 0.002). At 8 months carer sleep (difference in means 0.57 [95% CI 0.10 to 1.05]) and carer anxiety (difference in means ‐0.86 [95% CI ‐1.71 to ‐0.01]), were significantly lower in the intervention group than usual treatment.

Conclusion

To our knowledge, this is the first and largest fully powered RCT of a multicomponent non‐pharmacological intervention that improves sleep in people living at home with dementia and their caregivers, with sustained effectiveness beyond delivery. DREAMS‐START has potential to be delivered at scale in health services.
Transitions from Hospital‐to‐Home for Dementia with Multimorbidity: A Realist Review Protocol with Preliminary Findings
Authors: Lawson Lauren , Cooper Matthew , Tolley Clare , Nazar Hamde
Published: January 2025

Background

Older adults with dementia live with an average of four additional long‐term conditions (multimorbidity), and experience frequent transitions between fragmented care settings. This can compromise their safety due to an increased risk of miscommunication, errors, and delays in receiving appropriate treatment. Unsafe transitions are also associated with increases in mortality, morbidity, and preventable readmissions. The experiences of adults managing dementia alongside multimorbidity has not often been reflected in the literature. As such, it is currently unclear how dementia, alongside existing multimorbidity can influence transitions from hospital‐to‐home, and what currently works in this process. This review aims to synthesise existing literature to understand and explain how, to what extent, and under which circumstances transitions from hospital‐to‐home work for older adults with dementia and multimorbidity.

Method

This review was registered on PROSPERO and follows Realist and Meta‐narrative Evidence Syntheses: Evolving Standards. Following on from the development of an initial programme theory, six electronic databases (CINAHL/Embase/MEDLINE/PsycINFO/PubMed/Scopus/Web of Science) and two grey literature databases (HMIC/ProQuest Dissertations and Theses) were systematically searched using key terms. Eligible documents included adults aged 65 and over with dementia and at least one other long‐term condition, informal caregivers or healthcare professionals involved in their care, and investigated transitions from hospital‐to‐home. Research investigating end‐of‐life care or aged‐care facilities was excluded. Three additional, independent reviewers screened 10% of documents at each level for consistency. Realist quality appraisal will assess relevance and rigour of included documents. Deductive and inductive coding will be performed to identify prominent interactions between contexts, outcomes, and causal mechanisms.

Results

This review is iterative and ongoing. The first search identified 4,396 (database) and 43 (grey) articles. From 349 documents screened at full‐text, 73 are being reviewed for inclusion. Preliminary evidence suggests that the extent to which a transition from hospital‐to‐home works is influenced by trust, effective communication, awareness of dementia, health literacy, inconsistent use of digital health technologies, and prioritisation of non‐acute patients with dementia in hospital.

Conclusions

The final, revised programme theory and context‐mechanism‐outcome configurations produced upon completion of data synthesis will be used to develop suitable recommendations to inform improvements in transitional care pathways.
TargetTau‐1: Design of a phase 2 trial to evaluate the efficacy, safety, and tolerability of BMS‐986446, an anti‐MTBR tau monoclonal antibody, in patients with early Alzheimer’s disease
Authors: van Dyck Christopher H. , Kahl Anja , Abelian Grigor , Donovan Mark , Ahuja Manuj , Watson David , Ossenkoppele Rik , Iwatsubo Takeshi , Hansson Oskar
Published: January 2025

Background

Alzheimer’s disease (AD) is the leading cause of cognitive impairment and dementia with rising prevalence, morbidity, and mortality. Limited treatment options highlight a significant unmet need.

AD is characterized pathologically by extracellular accumulation of Aβ peptide‐containing plaques and intracellular neurofibrillary tangles containing aggregates of the microtubule‐associated protein tau, leading to neuronal and synaptic loss, neuroinflammation, and brain atrophy.

The microtubule binding region (MTBR) within the tau protein is important in the pathogenic self‐association and aggregation of higher‐order tau species and critical for neuronal uptake of neurotoxic tau species via interactions with cell surface receptors. Increased MTBR tau concentrations in cerebrospinal fluid correlate with other markers of AD clinical progression.1

BMS‐986446 (formerly PRX005) is a humanized immunoglobulin class G1 kappa monoclonal antibody that binds to the MTBR of the tau protein and represents a novel potential therapeutic for early AD.

In vitro activity studies demonstrated that BMS‐986446 and its murine parent antibody 3D6 equivalently inhibit the uptake of aggregated tau into neurons, inhibit tau‐induced neurotoxicity, and promote uptake of aggregated tau into phagocytic cells preventing further cell‐to‐cell tau transmission.2

The TargetTau‐1 study (NCT06268886) will assess efficacy, safety, and tolerability of BMS‐986446 in patients with early AD.

Methods

This phase 2, randomized, double‐blind, placebo‐controlled trial is enrolling adults aged 50 to 80 years with mild cognitive impairment or mild AD dementia (Figure). The 76‐week double‐blind treatment period is followed by a planned optional 96‐week open‐label extension. The primary endpoint is mean change from baseline in the Clinical Dementia Rating Sum of Boxes score at week 76. Primary and secondary endpoints are shown (Figure).

Results

The TargetTau‐1 study began enrollment on March 20, 2024, and aims to randomize 475 participants (4:3:3 to placebo, BMS‐986446 dose 1, or BMS‐986446 dose 2) across 14 countries in North America, Europe, and Asia‐Pacific regions.

Conclusions

The phase 2 TargetTau‐1 trial will assess efficacy, safety, and tolerability of BMS‐986446, an anti‐MTBR tau monoclonal antibody, in patients with early AD.

References:

1. Horie K et al. Nat Med 2023;29:1954‐1963.

2. Nolan P et al. Poster presented at the ADII; June 9‐11, 2022; London, United Kingdom.
Low density lipoprotein receptor related protein 1 regulates adult hippocampal neurogenesis and memory
Authors: Dietert Kristi , Marion Nicole , Kokovay Erzsebet , Sayre Naomi L.
Published: January 2025

Background

Adult neural stem cells are fundamental in allowing the brain to retain memory via hippocampal neurogenesis. In Alzheimer’s disease, patients have impaired neurogenesis, which may contribute to memory impairments. We have discovered a new player in the brain’s ability to retain memory: the protein LRP1 (low density lipoprotein receptor related protein). LRP1 is a promiscuous membrane receptor which differentially regulates cell signaling through multiple mechanisms. LRP1 is implicated in Alzheimer’s disease pathogenesis via its interaction with disease related proteins, including ApoE4, tau, and amyloid beta.

Methods

We tested a role for LRP1 in adult hippocampal neurogenesis in vivo via Cre‐mediated recombination to knockout LRP1 from adult neural stem cells. We generated mice which expressed a tamoxifen‐inducible Cre under control of the Nestin promotor which were crossed with mice with stop‐floxed inducible td‐tomato and floxed LRP1 (Nestin‐CreERt2:td‐tomatofl/fl:LRP1fl/fl). Adult (3‐month‐old) mice were subjected to tamoxifen treatment to induce Cre expression and so cause expression of td‐tomato and knockout of LRP1 in neural stem cells to generate LRP1KO mice. As a control, we used mice one generation removed which lacked floxed LRP1 (Nestin‐CreERt2:td‐tomatofl/fl:LRP1+/+). Mice (n = 10‐20 males and females) were aged to either 4‐ or 9‐months, and cognitive impairment was measured via a battery of tests including the elevated plus maze, Y maze, and the Barnes maze. Tissues were harvested for subsequent analysis.

Results

LRP1KO mice displayed significant impairments in cognition compared to control mice, including increased anxiety resulting in reduced open arm time in the elevated plus maze (p = 0.02), reduced spontaneous alterations in the Y‐maze (p = 0.01), and reduced target exploration in the Barnes maze (p = 0.02). Tissue analysis revealed that while neural stem cell proliferation was consistent between LRP1KO and control mice, greater numbers of td‐tomato positive, NeuN positive mature neurons were observed in 9‐month old mice (p<0.001), suggesting increased differentiation of these cells into neurons.

Conclusion

LRP1 regulates adult hippocampal neurogenesis in a manner which is protective of memory, and impairments to LRP1 function disrupts hippocampal neurogenesis. These findings may have significant relevance towards Alzheimer’s disease pathogenesis, as impairments to LRP1 function can occur in the context of ApoE4/amyloid beta/tau expression and in aging.
Advancing Alzheimer’s disease and related dementias (ADRD) and COVID‐19 research by linking real‐world data with a standardized longitudinal ADRD data platform
Authors: Biber Sarah A , Prado Maria G , Culhane Jessica E. , Phuong Jim , Keller Ben , Lerch Melissa , Wang Sophia , Noble James M. , Moulder Krista L. , Saykin Andrew J. , Gao Sujuan , Lai Albert , Natarajan Karthik , Kukull Walter A. , Mooney Sean , Stephens Kari
Published: January 2025

Background

Persons with Alzheimer’s disease and related dementias (ADRD) have been disproportionally impacted by the COVID‐19 pandemic, showing a significantly increased risk of infection and severe illness, including neurocognitive consequences. The National Alzheimer’s Coordinating Center collects rich longitudinal, standardized neurocognitive data from populations at high risk of COVID‐19 complications, including older adults who were cognitively normal prior to infection and those who had pre‐existing ADRD. These data, in combination with Electronic Health Records (EHR) clinic data, will be critical for understanding the complex pathophysiology and cognitive symptoms of COVID‐19 and the development of future therapeutics. To rapidly respond to the COVID‐19 epidemic, the present study developed a novel socio‐technical solution for the Alzheimer’s Disease Research Centers (ADRC) Program to expand longitudinal COVID‐19 data collection, integrate new data streams, and open the door to impactful new COVID‐19 and ADRD discoveries.

Method

We linked EHR, Medicare claims, and genetic data with rich standardized longitudinal cognitive assessment data collected from across the ADRC Program and housed at NACC. This project included the development and deployment of standardized IRB and consent language and a new data use agreement to provide access to all data steams within the LINKAGE enclave. It also leveraged an OMOP model to collect, harmonize, and integrate EHR data from participating ADRCs. The governance materials and technical pipelines developed will allow us to scale our solution across the heterogeneous consortium of 37 ADRCs.

Result

The new team science model we developed facilitates collaborations between informatics leaders and ADRD leaders within and across institutions. Our approach supports development and dissemination of best practices to advance data interoperability and will facilitate researchers asking and answering new questions at the intersection of COVID and ADRD. The projected cohort size for this pilot study across three ADRCs is: cognitively normal (1,109), mild cognitive impairment (214), and dementia (224).

Conclusion

Once scaled to the full ADRC Program, this platform will provide one of the largest and most comprehensive longitudinal multimodal datasets in the world for an age group at high risk for COVID‐19 infection. Additionally, the dataset includes valuable cognitive, behavioral, and genetic data collected prior to COVID‐19 infection.
Human cerebrospinal fluid extracellular vesicle miRNAs identify sex‐dependent changes in synaptic proteins in postmortem Alzheimer’s disease brain
Authors: Sandau Ursula S , McFarland Trevor J. , Setthavongsack Naly , Smith Sierra J , Galasko Douglas R. , Quinn Joseph F , Woltjer Randy L , Saugstad Julie A
Published: January 2025

Background

Alzheimer’s disease (AD) is the fifth leading cause of death for individuals aged 65 and older. Since FDA approved therapies have limited efficacy, there is a need to develop new treatments based on a better understand of pathological changes occurring in tissues from humans with AD. Central nervous system cells utilize extracellular vesicles (EVs) to package and secrete miRNAs where they mediate cell‐to‐cell communication. Importantly, cerebrospinal fluid (CSF) contains EVs derived from the brain whose contents – including miRNAs – reflect the originating cell’s molecular composition. Thus, we used CSF EV miRNAs to identify neurologically relevant genes and canonical pathways altered in the human AD brain.

Method

Human CSF from AD (n = 28) and controls (n = 28) was fractionated by size exclusion chromatography to separate EVs. CSF EV miRNAs were assayed by qPCR and used for target prediction and Ingenuity Pathway Analysis. Human postmortem hippocampus from AD (n = 34) and control (n = 22) were used to measure SNAP‐25, MUNC18‐1, and Reelin by immunoblot. Human hippocampal sections were co‐labeled for SNAP‐25 and miR‐16‐5p in AD (n = 4) and control (n = 3). MiR‐16‐5p puncta were analyzed using Zen Intellesis AI Segmentation software.

Result

Four miRNAs (miR‐16‐5p, ‐331‐3p, ‐409‐3p, ‐454‐3p) were significantly increased in AD CSF EVs compared to control EVs. Further, the increase in miR‐16‐5p and ‐331‐3p occurred only in AD females with APOEe3/e4 genotype. Conversely in males, miR‐16‐5p and ‐331‐3p showed no group differences. The predicted targets of miR‐16‐5p include mRNAs integral to synaptic transmission (SNAP‐25, MUNC18‐1, Reelin), which were significantly decreased in the hippocampus of AD females, compared to control females. While in males these protein targets were not changed in AD. Co‐labeling of human brain sections demonstrated that miR‐16‐5p and SNAP‐25 are both expressed in cortical grey matter and preliminary analysis shows a trend of increased miR‐16‐5p in AD.

Conclusion

We demonstrate that the miRNA cargo of CSF EVs is impacted by AD, sex, and APOE4 status. Also, CSF EV miRNAs have the potential to identify therapeutic targets to treat or cure AD. These data also demonstrate pathological changes in AD are sex‐ and genotype‐dependent, which may need to be considered for drug development and/or treatment strategies.