bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Cognitive Function with Mortality and Cardiovascular Risk
Authors: Melgarejo Jesus D , Charisis Sokratis , Patil Dhrumil , Vatcheva Kristina P. , Mejia‐Arango Silvia , Mena Luis Javier , Alliey‐Rodriguez Ney , Satizabal Claudia L , Chavez Carlos A , Gaona Ciro , Silva Egle , Calmon Gustavo , Lee Joseph H. , Terwilliger Joseph D. , Gutierrez Jose , Seshadri Sudha , Maestre Gladys E.
Published: January 2025

Background

Cognitive impairment is associated with mortality. However, evidence using population‐based studies is scarce, is limited to one cognitive assessment, and lacks the inclusion of non‐fatal adverse health outcomes. Therefore, we aimed this study to (i) investigate the association of cognitive function with mortality and cardiovascular risk and (ii) determine whether cognitive tests improve the risk‐stratification of endpoints beyond conventional risk factors.

Methods

We analyzed 946 participants aged ≥55y from a population‐based study who underwent cognitive function and were followed for fatal and nonfatal endpoints between 2001‐2016. Conventional risk factors included age, sex, education, body mass index, smoking, alcohol, antihypertensive treatment, office systolic and diastolic blood pressure, serum total cholesterol, diabetes mellitus, and previous history of cardiovascular diseases. Cognitive function examination included the mini‐mental state examination (MMSE) and selective reminder tests ([SRT], total retrieval, long‐term retrieval, and delayed recall). Our primary endpoint was total mortality and major adverse cardiovascular endpoints (MACE). Statistics included Cox proportional models and the generalized R
2 statistic to test model fit.

Results

The mean age was 66.3±7.5 years old and 640 (67.6%) were women. During a median follow‐up of 8.5 years, 267 participants died and 187 experienced MACE. The incidence of mortality and MACE per quartiles of MMSE and SRT ranged from 13.1 (95% confidence interval [CI], 8.7‐18.9) to 23.8 (95% CI, 18.3‐30.4) among participants with the highest quartile and from 28.8 (95% CI, 14.9‐47.7) to 43.8 (26.3‐66.2) among participants with the lowest quartile. A lower MMSE score was associated with a higher risk of mortality (hazard ratios [HR] per each ‐4.3 lower MMSE, 1.23; 95% CI, 1.02‐1.48) and MACE (HR, 1.27; 95% CI, 1.09‐1.47). A lower SRT‐delayed recall score was associated with 1.19 (95% CI, 1.04‐1.37) and 1.24 (95% CI, 1.04‐1.46) higher folds of mortality and MACE endpoints. On top of conventional risk factors, the inclusions of MMSE and SRT improved the model performance (R
2 ranged from 0.51% to 1.65%; P≤0.028).

Conclusions

In this population‐based study, cognitive impairment is associated with mortality and CV risk. Given the aging global population, the assessment of cognitive function might help reduce the risk of major preventable health outcomes.
Longitudinal cortical atrophy in cases of AT concordance and discordance
Authors: Ioannou Konstantinos , Mohanty Rosaleena , Poulakis Konstantinos , Leuzy Antoine , Muehlboeck J‐Sebastian , Rodriguez‐Vieitez Elena , Westman Eric , Chiotis Konstantinos
Published: January 2025

Background

Although β‐amyloid and tau PET positivity (A+T+) has been related to neurodegeneration and cognitive decline in Alzheimer’s disease (AD), the driving force of neurodegeneration in discordant AT cases remains controversial. We investigated the impact of AT status on longitudinal rates of cortical atrophy and cognitive decline.

Method

A subset of 349 individuals (cognitively unimpaired [CU; n=230], cognitively impaired [CI; n=119]) with β‐amyloid and tau PET (a priori baseline), longitudinal MRI (interval; Mean=4.5±3.3 years, scans/individual; Median=3, IQR=[2, 8]), and a cognitive follow‐up ≥2 years, was selected from the ADNI dataset. We classified the individuals based on their AT PET status (A+; global β‐amyloid ≥20 CL, T+; composite temporal region ≥1.34 SUVR) and clustered them based on their annual rates of cognitive decline on the ADAS‐Cog13 (fast vs. slow decliners [FDs vs. SDs]). Baseline AD‐signature cortical thickness was compared across AT groups. We employed a linear mixed‐effects model to assess the interaction between AT status and longitudinal cortical thickness across all cortical regions.

Results

Demographic characteristics were similar across AT groups (A‐T‐; n=192, A‐T+; n=5, A+T‐; n=106, A+T+; n=46). Most A+T+ individuals (70%) were CI, whereas most A+T‐ (71%), A‐T+ (80%), and A‐T‐ (71%) individuals were CU. Similarly, most A+T+ individuals (85%) were characterized as FDs, whereas most A+T‐ (74%), A‐T+ (60%), and A‐T‐ (88%) individuals were characterized as SDs. A+T+ individuals showed significantly lower AD‐signature cortical thickness (MeanA+T+=2.78±0.19 mm) compared to A+T‐ (MeanA+T‐=2.89±0.15 mm; P=0.0023) and A‐T‐ (MeanA‐T‐=2.89±0.15 mm; P<0.001) individuals, and the highest Aβ burden (Mean=85.3±30.6 CL; P<0.0001) at baseline. AT status significantly influenced longitudinal cortical thickness. A+T+ individuals showed significantly steeper cortical thinning rates compared to A‐T‐ individuals, primarily in temporoparietal areas. Despite similar group‐level cortical thinning rates with A‐T‐ individuals, A+T‐ individuals showed heterogeneous patterns of cortical atrophy at the individual level. These findings remained consistent even when conducting separate analyses for CU and CI individuals.

Conclusion

Unlike AT discordance, concordant AT positivity exhibited homogeneous cortical atrophy patterns consistent with AD. Considering the concurrent high prevalence of mixed pathologies in neuropathological AD, we further aim to explore the underlying neurodegenerative force in discordant AT cases.
Accelerated aging elevates the risk for mortality in persons with dementia: the Age, Gene/Environment Susceptibility‐ Reykjavik Study cohort
Authors: Asefa Nigus G. , Li Zhiguang , Hu Yi‐Han , Romero Jorge M. , Meirelles Osorio , Gudnason Vilmundur , Launer Lenore J.
Published: January 2025

Background

Epigenetic age acceleration (EAA) is a valuable tool for predicting all‐cause mortality and assessing disease risk. Differences in EAA reflects biologic aging (BA) and suggests underlying differences in morbidities. We examined whether EAA moderated the association of dementia to mortality risk.

Method

Analyses are based on data from the Age, Gene/Environment Susceptibility‐ Reykjavik Study (AGES‐RS) study (n = 2602, 57.5% females, mean age = 75.8 years, 30% demented). Data were collected from 2002 to 2006, with mortality data available until 2015. EAA was computed with the DunedinPACE algorithm and grouped as follows: EAA scores > 1 SD of the mean were labeled as ‘fast’, EAA < 1 SD as ‘slow’, and EAA scores within ±1 SD as ‘average’. Dementia was ascertained in a study exam or through follow‐up of health records. Cox proportional hazard analysis was used to evaluate the hazard ratio (HR, 95%CI) of mortality and the interaction between EAA and dementia. Models were adjusted for sex, chronological age, education, smoking, diabetes and stroke.

Result

Fast agers had higher mortality HRs than average agers (Figure 1A). Fast agers with dementia had a significantly increased risk of death (interaction p‐value = 4.08×10−2) compared to non‐demented average agers (Figure 1C); this interaction was reduced after adjusting for total brain volume (Figure 1B). Conversely, slow aging was associated with reduced mortality risk (HR = 0.71, 95% CI: 0.52‐0.98, p‐value = 3.62×10−2); however slow agers with dementia had risk estimates similar to non‐demented average agers (interaction p‐value = 1.14×10−1) but lower than demented fast agers. Controlling for total brain volume reduced the differences between slow and average agers with and without dementia.

Conclusion

Individuals aging at a faster rate than their chronological age were at a higher risk for death. The rate of BA had an effect on the association between dementia and mortality. The association was partially explained by brain atrophy, suggesting other factors related to dementia contributing to mortality risk in people with dementia.
Discordance between CSF and PET biomarkers of amyloid pathology are associated with distinct pathophysiologic process in early stages of Alzheimer’s disease
Authors: An Binchong , Li Danni , Men Lu
Published: January 2025

Background

Alzheimer’s disease (AD) pathophysiology is complex. Decrease in CSF soluble Aβ42/40 and accumulation of amyloid plaques (by amyloid PET) are two distinct biomarkers of amyloid pathology. However, the pathophysiologic process associated with each biomarker is not clear. To this end, we examined CSF protein difference across biological stages defined by biomarkers, with emphasize on early stages of AD where CSF and amyloid PET evaluations are discordant.

Method

392 nondemented participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were biologically defined based on CSF Aβ42, amyloid PET, and CSF p‐tau into four groups (controls [Aβ42‐/ PET‐], Stage 1a [Aβ42+/ PET‐], Stage 1b [Aβ42‐/ PET+], Stage 2 [Aβ42+/ PET+]). Of note, Abnormal CSF Aβ42(+) was defined as < 976.6 pg/mL and normal (‐) as ≥ 976.6 pg/mL; abnormal brain amyloid by PET (+) was defined as 18F‐florbetapir > 1.11 SUVR and normal (‐) as ≤ 1.11 SUVR. All 4 groups had normal CSF p‐tau (defined as ≤ 26.47 ng/mL). SomaScan was used to measure over 7000 proteins in CSF proteome.

Result

There was no significant protein difference between controls (Aβ42‐/PET‐) and Stage 1b (Aβ42‐/ PET+), or between Stage 1a (Aβ42+/ PET‐) and Stage 2 (Aβ42+/ PET+), after Benjamini‐Hochberg adjustment. We found 1462 proteins differentially expressed between controls (Aβ42‐/PET‐) and Stage 1a (Aβ42+/PET‐) related to abnormality in CSF soluble Aβ42. This number was much higher than 62 proteins differed between Stage 1b (Aβ42‐/ PET+) and Stage 1a (Aβ42+/PET‐) related to abnormality in amyloid PET. GO enrichment analysis of biological pathways and cellular components suggested neuropeptide signaling pathway and extracellular process are the most significant pathway and cellular components related to amyloid PET; whereas numerous pathways in neuron, synapse, axon were enriched and represented by protein differences related to CSF soluble Aβ42.

Conclusion

Our results reveal distinct pathophysiologic process associated with decrease in CSF soluble Aβ42 and increase in amyloid plaques measure by amyloid PET. Decrease in CSF Aβ42 appears to be more neurotoxic and are associated with more pathophysiological changes than increase in amyloid plaques at the early stages of AD.
Place and Space: How does the hospital environment influence the inclusion of care partners of hospitalized people living with dementia?
Authors: Still Catherine , Hoel Sydney , Strayer Andrea , Thuemling Teresa , Werner Nicole , Fields Beth
Published: January 2025

Background

Care partners of hospitalized people living with dementia (PLWD) are particularly vulnerable in the hospital setting and may feel invisible during hospitalization of the PLWD they care for. Hospital initiatives for dementia friendly spaces emphasize providing a safe and supportive environment. However, literature is scarce regarding how the hospital’s physical environment influences care partners' inclusion. Therefore, we aimed to explore how the physical environment influences care partners’ inclusion in hospital‐based dementia care.

Method

Using a descriptive qualitative design and a multi‐methods approach to data collection, our team conducted direct observations in a large academic hospital’s trauma/medical surgical unit, orthopedic unit, family practice unit, and neuroscience/stroke unit. We also interviewed care partners and clinicians to gain insight into the impact the hospital environment has on the inclusion of care partners. Observational data were analyzed using a well‐known systems engineering framework, and interview data were analyzed thematically.

Result

Direct observation (27 hours), care partner (15) and clinicians interviews (23) yielded insights into underutilized physical environment elements in the hospital and opportunities to enhance care partner inclusion through environmental modification. Underutilized physical environment elements included family‐designated spaces and communication tools like caregiving education bulletin boards and patient whiteboards. Care partner inclusion could be enhanced by having enough space for the care partner to be in the patient’s room comfortably, increasing opportunity to personalize spaces, and making parking more accessible.

Conclusion

Our findings demonstrate a need to augment the physical environment of the hospital setting. To facilitate the inclusion of care partners to PLWD, health systems must consider ways to improve their physical environment to increase care partners’ comfort and accessibility. Enhancing the physical environment of the hospital setting has potential to increase the satisfaction, health, and well‐being of both PLWD and their care partners.
Neurofilament Light and Cognition in community dwelling non‐Hispanic Blacks
Authors: Abdullah Lubnaa R
Published: January 2025

Background

No large‐scale characterizations of neurofilament light chain (NfL) and cognitive outcomes have been conducted in community dwelling non‐Hispanic Blacks.

Method

Baseline data were analyzed among n = 283 non‐Hispanic Blacks (NHB) from the multi‐ethnic Health and Aging Brain Study‐ Health Disparities (HABS‐HD). Plasma NfL was measured on the Simoa platform. Linear regression models were conducted, covarying for age, gender, and education.

Result

The majority of study participants (72%) were Cognitively Unimpaired (CU), with 21 % having mild cognitive impairment (MCI), and 6.7 % with Alzheimer’s Disease (AD). In adjusted models among the entire sample, significant associations existed between NfL and Trails A (P < .0001), Trails B (p < .0001), phonemic (FAS) and semantic (Animals) fluency (p = 0.03), and Symbol Digit Substitution (p < .001). When separated by diagnostic classification, significant associations were removed for functions involving executive functions for all diagnostic groups. Higher levels of NfL were positively associated with cognitive diagnosis, older age, and less education.

Conclusion

Plasma NfL levels are significantly associated with measures of executive functioning, which elucidate NfL as a non‐specific marker of neurodegeneration associated with efficiency of brain functions involving attention, processing, and generativity. NfL may be a sensitive measure for the detection of alterations in cognitive processing before the onset of phenotypic functional changes of neurodegeneration.
Soluble epoxide hydrolase (sEH) is a novel anti‐inflammatory target and a first‐in‐class, picomolar sEH inhibitor (EC5026) improves cognition in a mouse model of Alzheimer’s disease
Authors: Li Yichen , Hou Yuan , McReynolds Cindy , Pieper Andrew A. , Leverenz James B , Cummings Jeffrey L. , Hammock Bruce D. , Cheng Feixiong
Published: January 2025

Background

Although investment in biomedical and pharmaceutical research has increased significantly over the past two decades, there are no oral disease‐modifying treatments for Alzheimer’s disease (AD).

Method

We performed comprehensive human genetic and multi‐omics data analyses to test likely causal relationship between EPHX2 (encoding soluble epoxide hydrolase [sEH]) and risk of AD. Next, we tested the effect of the oral administration of EC5026 (a first‐in‐class, picomolar sEH inhibitor) in a transgenic mouse model of AD‐5xFAD and mechanistic pathways of EC5026 in patient induced Pluripotent Stem Cells (iPSC) derived neurons. 5xFAD mice were treated with 3 mg/kg EC5026 in drinking water for 3 months starting at 3 months of age. We evaluated the effect of EC5026 treatment on cognition using the novel object recognition test, Morris water maze and a fear conditioning test.

Result

We identified elevated sEH protein level (protein expression quantitative trait loci [pQTL] from the AD knowledge portal) is significantly associated with increased AD risk across all five large‐scale AD genome‐wide association studies (GWAS). A genome‐wide significant, protein‐coding SNP rs2741342 on EPHX2 is replicated in three pQTL datasets from the ROSMAP biobank. Further genetic and eQTL/pQTL co‐localization and fine‐mapping analyses confirmed that EPHX2 was a causal target in AD. We found that EC5026 reduced tau hyper‐phosphorylation (pTau205) in AD patient iPSC‐derived neurons. The 3 months oral administration of EC5026 significantly improved the cognition of 5xFAD transgenic mice on novel object recognition, Morris water maze and a contextual fear conditioning test. Bulk and single‐cell RNA‐sequencing analysis of EC5026‐treated brain sections revealed potential anti‐inflammatory mechanistic pathways and brain target engagement to be tested in future clinical trials.

Conclusion

In summary, we demonstrate that EPHX2 (sEH) is a promising novel anti‐inflammatory target for AD and the EC5026 (a first‐in‐class, picomolar sEH inhibitor) significantly improves cognition in the 5xFAD mouse model. Future functional observations and clinical trials are warranted to validate the causal relationship of EC5026 in potential treatment of AD.
Inflammation and daily memory lapses among older adults in the Einstein Aging Study: Associations by mild cognitive impairment status and gender
Authors: Harrington Erin E. , Bogart Karina Van , Graham‐Engeland Jennifer E. , Mogle Jacqueline A. , Katz Mindy J. , Lipton Richard B. , Sliwinski Martin J. , Engeland Christopher G.
Published: January 2025

Background

Inflammation is a risk factor for cognitive decline, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). While past research in laboratory settings suggests that inflammation relates to cognitive decline and MCI status, more research is needed to examine such associations in everyday life. The present work addressed this gap by examining MCI and gender stratified links between circulating inflammatory biomarkers and self‐reported prospective memory (PM; i.e., memory for future events) and retrospective memory (RM; i.e., memory for past events/information) lapses measured at the end of each day via daily dairies.

Method

Older adults (n=270, Mage=76.97, 68% female) enrolled in the Einstein Aging Study were classified with or without MCI using Jak/Bondi criteria. Participants completed a two‐week protocol, including two blood draws (at the start and end of the protocol) from which circulating (basal) cytokines were quantified (interleukin [IL]‐1b, IL‐4, IL‐6, IL‐8, IL‐10, tumor necrosis factor‐alpha [TNF‐α]). Each night, participants completed reports of PM and RM lapses that had occurred that day via smartphones. Correlations between inflammatory markers (averaged across the two draws) and memory lapses stratified by MCI status and gender were estimated.

Results

Among those with MCI, men (n=23) exhibited higher levels of circulating IL‐10 in association with more frequent PM lapses (r=.47, p=.025) and women (n=55), exhibited higher circulating IL‐6 in association with more frequent RM lapses (r=.28, p=.035). Among those without MCI higher levels of IL‐8 correlated with more frequent PM lapses only in men (n=64; r=.39, p=.002). Findings held when controlling for BMI, age, and education.

Conclusion

The present research suggests that MCI‐ and gender‐dependent links between inflammation and everyday memory lapses may be restricted to certain inflammatory cytokines. IL‐10 and IL‐6 may play a role in MCI‐related daily forgetting among men and women, respectively. However, these findings should be replicated within a larger sample of individuals experiencing MCI. Additionally, longitudinal research is needed to determine whether IL‐8 is indicative of early cognitive decline prior to MCI in men. Longitudinal examinations will better elucidate the links between inflammation, memory lapses, and MCI, and might ultimately inform early risk detection for MCI and AD.
A Multidimensional Comprehensive Cognitive Intervention Training Program: Introduction of a Non‐Pharmacological Digital Therapeutic and Preliminary Results of Effectiveness on Cognitive Function
Authors: Li Yatian , Wu Jingnan , Zhou Zhixing , Chen Nan , Xia Huanhuan
Published: January 2025

Background

Older adults with cognitive impairments will benefit from multicomponent interventions include cognitive training, exercise, and lifestyle modifications. However, many existing digital therapeutic products predominantly focus on computerized cognitive training, lacking effective approaches to other crucial interventions. We proposed a multidimensional comprehensive cognitive intervention training program – Brain and Body Rehab Training (BBRT), which integrates multidomain cognitive training with physical‐cognitive training and multidimensional lifestyle interventions and developed the digital therapeutic product – BBRT‐online based on WeChat mini‐program. The present study was to assess the effectiveness of BBRT in older adults with subjective memory impairments.

Method

Using the WeChat mini‐program platform, we developed the BBRT‐online digital therapeutics product. Prior to the intervention, users undergo Game‐based Cognitive Assessment – Three‐Minute Version (G3). Subsequently, an individualized training program is assigned consisting of completing four to five daily tasks, including cognitive training, physical‐cognitive training, lifestyle interventions, chronic disease/diet/sleep/emotion management, and traditional Chinese medicine non‐pharmacological interventions among others (Figure 1). The intervention duration ranges 15‐25 minutes per day, and task difficulty is dynamically adjusted based on individual task performance and periodic cognitive assessments. Additionally, remote online administration services and internet communities are strongly recommended to offer emotional support and enhance intervention effectiveness. Sixty older adults reporting subjective memory complaints were recruited, with 30 assigned to receive BBRT‐online training and the remainder serving as the control group. Cognitive function was evaluated using the G3 at baseline and three months later. T‐tests were conducted to assess the impact of BBRT‐online on cognitive function.

Result

At baseline, there was no significant difference in G3 scores between the BBRT group (53.5±10.87) and the control group (55.1±11.77, p = 0.583). Following three months of intervention, the BBRT group demonstrated a significantly higher G3 score (61.5±6.85) compared to baseline (p<0.001, Figure 2). Conversely, no such difference was observed in the control group (55.5 ± 9.34, p = 0.911).

Conclusion

The BBRT digital therapeutics enabled cognitive assessment and individualized cognitive interventions and significantly improved cognitive function in older adults. Further studies are required to evaluate its effectiveness.
Design of a dimeric‐nanobody specific for Aß1‐42 oligomers: the Dimeric‐DesAb‐O
Authors: Napolitano Liliana , Vadukul Devkee , Chiti Fabrizio , Cecchi Cristina , Cascella Roberta , Aprile Francesco
Published: January 2025

Background

Small, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents in Alzheimer’s disease (AD). In the last few years, Aprile and co‐workers designed and purified a single‐domain antibody (sdAb), called DesAb‐O, with high specificity for Aβ1‐42 oligomeric conformers. Recently, Cascella and co‐workers showed that DesAb‐O can selectively detect synthetic Aβ1‐42 oligomers both in vitro and in cultured cells, neutralizing their associated neuronal dysfunction. DesAb‐O can also identify Aβ1‐42 oligomers in the cerebrospinal fluid (CSF) of AD patients, with respect to healthy individuals, preventing cell dysfunction induced by the administration of CSFs to neuronal cells. Given the extraodinary potentialities of this nanobody, we design a dimeric‐structure of DesAb‐O, with the aim to increase its avidity and affinity for toxic Aβ1‐42 oligomers.

Method

We designed the dimeric‐DesAb‐O structure by linking two DesAb‐O monomeric domains with a flexible linker region (GGGGS)3. Once expressed and purified the protein, we characterised its molecular weight by mass spectrometry and its secondary structure by Circular Dichroism. Then, we performed an aggregation assay to monitor its ability to interfere with the Aβ1‐42 aggregation process and a Real‐Time based ELISA assay to study its binding for Aβ1‐42 oligomers.

Result

The Dimeric‐DesAb‐O is able to interfere with the Aβ1‐42 aggregation process to a greater extent than DesAb‐O. Furthermore, the dimeric structure of DesAb‐O showed a higher specificity and affinity for Aβ1‐42 oligomers compared to DesAb‐O.

Conclusion

The Dimeric‐DesAb‐O appears to be a promising tool for the future development of sdAbs‐based immunodiagnostic tests for the early diagnosis of AD.
Development of the Canadian Coalition for Seniors' Mental Health Canadian Guidelines on the Assessment and Management of Behavioural and Psychological Symptoms of Dementia
Authors: Hatch Stacey E , Watt Jennifer , Bruneau Marie‐Andrée , Ewa Vivian , Feldman Sid , Goldberg Yael , Goodarzi Zahra , Herrmann Nathan , Colborne Debbie Hewitt , Henri‐Bhargava Alexandre , Ismail Zahinoor , Kirkham Julia G , Kumar Sanjeev , Lanctôt Krista L. , Thompson Wade , Porter Jennifer , Seitz Dallas
Published: January 2025

Background

Behavioural and psychological symptoms in dementia (BPSD) are common, can be distressing for persons living with dementia (PLWD), and challenging for caregivers and clinicians. There are few updated clinical practice guidelines available to assist clinicians with the assessment and management of BPSD, including deprescribing of medications. The Canadian Coalition for Seniors’ Mental Health (CCSMH) developed Canadian clinical practice guidelines on the assessment and management of BPSD to address these needs.

Methods

We used the Guideline International Network process for development of the BPSD guidelines. A multidisciplinary guideline panel was formed including representatives from geriatric psychiatry, geriatric medicine, family medicine, nursing, pharmacy, and psychology. Surveys identified priority topic areas for the guidelines. A review of existing guidelines, systematic reviews and primary evidence reviews was undertaken to identify evidence to create the guideline recommendations. The guideline panel members framed guideline questions using the PICO format (patient, intervention, comparator, and outcome). Guideline recommendations were created using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) tool and assigned a strength of recommendation (strong or conditional) and quality of evidence (high, moderate, low, and very low). The final guideline recommendations were voted on by the guideline panel with consensus considered to be 80% agreement.

Results

The guideline panel met a total of 14 times. A total of 74 recommendations reached consensus and were included in the guideline. These included recommendations on general principles of BPSD assessment and management, BPSD diagnosis, detection, and pharmacological and non‐pharmacological management of BPSD syndromes. The following topic areas and recommendations per topic were: general principles of BPSD assessment and management (n = 11), agitation (n = 30), psychosis (n = 5), depression and depressive symptoms (n = 13), anxiety (n = 6), sexual expressions with associated risk (n = 4), and deprescribing (n = 5).

Conclusions

The CCSMH Canadian Guidelines on the Assessment and Management of BPSD provide healthcare providers with recommendations based on current evidence from a Canadian context. These guidelines will help inform care for the growing number of people living with dementia who may be affected by BPSD.
Underutilization of biomarker testing and DMT treatment among patients with MCI due to suspected Alzheimer’s disease
Authors: Stabb Margaret , Soucy Sarah
Published: January 2025

Background

Disease‐modifying therapies (DMTs) such as lecanemab and aducanumab are recommended for the treatment of patients with confirmed Alzheimer’s disease (AD) within the mild cognitive impairment (MCI) or mild stages of dementia. Biomarker testing is required to confirm the presence of amyloid beta for prescription of DMTs. Confirmatory diagnosis at the MCI stage is important to take advantage of the narrow treatment window of currently available DMTs. We aimed to understand the current utilization and drivers/barriers for confirmatory biomarker testing and DMT treatment among MCI patients.

Method

We analyzed clinical chart information and physician verbatim rationale for biomarker testing and DMT treatment decisions for 1,015 patients submitted by 151 US‐based physicians (79 Neurologists, 56 primary care physicians, 16 Geriatricians) through an online market research study. Sample composition includes 417 MCI, 416 mild dementia, and 182 moderate dementia patients based on physician assessments; patients with severe dementia were excluded from the study.

Result

Patients with MCI were slightly less likely to have been tested for biomarkers (49%) than patients with mild dementia (55%); p=.09. Patients with moderate dementia were significantly less likely to have been tested compared to either group (36%); p<.05.

Similarly, DMT prescribing or planning was more common among patients with mild dementia (63%) than MCI (51%) or moderate dementia (46%); p<.05.

According to an analysis of verbatim responses from physicians, top physician barriers to proceeding with biomarker testing and/or DMT treatment in MCI include the perception that MCI is too early or mild (40%) or uncertainty about DMT risk/benefit profiles (29%).

Among MCI patients who discussed biomarker testing with their physician but were not ultimately tested, the patient made the final decision not to test in 75% of cases. The top physician‐reported patient barrier was cost/coverage concerns associated with testing and/or DMTs (55%).

Conclusion

This research showed limited use of biomarker testing and DMT prescribing among MCI patients.

To address physician‐identified barriers, education for physicians and patients is needed to highlight the importance of early identification and treatment of AD. Expanded insurance coverage and support for confirmatory testing could help ease financial barriers.
Piloting the Elder Abuse Suspicion Index – long‐term care (EASI‐ltc©): A Mixed Methods Feasibility Study
Authors: Wilchesky Machelle , Couture Mélanie , Yaffe Mark J , Ballard Stephanie A. , Soulières Maryse , Israel Sarita , Milgram Ilanah
Published: January 2025

Background

Long‐term care (LTC) residents are a previously untested and highly vulnerable population at risk of elder abuse (EA) and its many negative health outcomes. The detection of elder abuse within the LTC context is urgent and time‐sensitive.

Objective

The overarching aim of this study is to evaluate the feasibility of implementing the Elder Abuse Suspicion Index – long‐term care (EASI‐ltc©): the first comprehensive detection tool of its kind designed specifically to identify the abuse of cognitively‐apt persons living in LTC. Preliminary tool validity will also be evaluated.

Methods

This observational pilot study is taking place within seven LTC institutions in Montreal Canada. It begins with the administration of the EASI‐ltc on a random sample of eligible LTC residents. Residents subsequently undergo a follow‐up assessment led by a trained and experienced social worker, which is used as the ‘silver standard’ reference for validation. Residents are asked to reflect on their own experiences as participants in one on‐one interviews, and key stakeholders (e.g., administrators, staff members, family, companions, and friends) are asked to provide retroactive feedback via an online survey. Survey respondents are also invited to participate in interviews to clarify their responses. Potential harmful consequences arising from EASI‐ltc administration is being evaluated.

Results

Results pertaining to tool validity, feasibility, and acceptability obtained from data collected during the first 8 months will be presented.

Conclusion

The EASI‐ltc is the first published comprehensive tool to detect elder abuse in this vulnerable population. This ongoing study responds to an urgent need to provide tools to identify abuse and give a voice to LTC residents locally, nationally, and beyond.
NINDS‐supported biospecimen repositories: BioSEND and NHCDR
Authors: Price Rebecca
Published: January 2025

Background

Access to biospecimens is an oft cited challenge to the progress in research on neurological disorders. Access to clinical biospecimens for development of validated biomarkers and improved cellular models of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) are cited as priorities across several NIH AD/ADRD Research Implementation Milestones (https://www.nia.nih.gov/research/milestones). The National Institute of Neurological Disorders and Stroke (NINDS) is committed to providing high quality biospecimens for NINDS‐mission relevant disorders, including AD/ADRDs.

Method

The NINDS human biospecimen repository, BioSpecimen Exchange for Neurological Disorders (BioSEND), acquires, maintains, and distributes NINDS biospecimen collections for biomarker research in neurological disorders. The NINDS Human Cell and Data Repository (NHCDR) acquires, maintains, and distributes fibroblast, induced pluripotent stem cell (iPSC), and edited iPSC lines from neurological disorders. Samples from BioSEND and NHCDR can be distributed to academic and commercial entities globally to further research from basic to translational stages.

Result

At BioSEND, current biospecimen collections include Parkinson’s Disease, Lewy Body Dementia, Huntington’s Disease, Myalgic Encephalomyelitits/Chronic Fatigue Syndrome, Frontotemporal Dementia, Spinocerebellar Ataxia, and Traumatic Brain Injury. Biospecimen types included DNA, RNA, plasma serum, cerebrospinal fluid (CSF), whole blood, urine, and saliva. At NHCDR, iPSC and fibroblast lines are available from control subjects and patients with various genetic mutations in Alzheimer’s Disease, Amytrophic Lateral Sclerosis, Ataxia‐Telangiectasia, Dystonia, Frontotemporal Dementia, Huntington’s Disease, Lewy Body Dementia, Mild Cognitive Impairment, Myotonic Dystrophy, Parkinson’s Disease, Parkinsonisms, Spinal Muscular Atrophy, Spinal‐Bulbar Muscular Atrophy, and Spinocerebellar Ataxia.

Conclusion

Access to biospecimens is a critical need across all stages of research. The NINDS repositories, BioSEND and NHCDR, provide biofluid and patient‐derived cell lines from various neurological disorders, including AD/ADRDs. Both repositories continue to expand available cohorts which are available to researchers worldwide. More information about BioSEND and available cell lines can be found at https://biosend.org/index.html. More information about NHCDR and available cells, including ordering, can be found at https://stemcells.nindsgenetics.org/.
Sildenafil is a candidate drug for Alzheimer’s disease: Real‐world patient data observation and functional validation in patient iPSC‐derived neurons and the 5xFAD mouse model
Authors: Li Yichen , Gohel Dhruv , Zhang Pengyue , Pieper Andrew A. , Cummings Jeffrey L. , Cheng Feixiong
Published: January 2025

Background

Our previous study identified that Sildenafil (a phosphodiesterase type 5 [PDE5] inhibitor) is a candidate repurposable drug for Alzheimer’s Disease (AD) using in silico network medicine approach. However, the clinically meaningful size and mechanism‐of‐actions of sildenafil in potential prevention and treatment of AD remind unknown.

Method

We conducted new patient data analyses using both the MarketScan® Medicare with Supplemental database (n = 7.23 million older [>65 years] subjects) and the OPTUM database (n = 11.52 million older subjects) to further test the real‐world evidence of sildenafil with AD incidence. We utilized the AD patient‐induced pluripotent stem cells (iPSC)‐derived neuron models (5 iPSC lines from both familial and sporadic AD patients) to investigate mechanism‐of‐action of sildenafil’s protective effects on AD. We also treated a transgenic AD mouse model (5xFAD) with 15 mg/kg sildenafil and conducted behavioral tests, immunofluorescence staining on mouse brain sections, and single‐cell RNA‐seq to evaluate the sildenafil’s efficacy and brain target engagement.

Result

We found that sildenafil usage is significantly associated with reduced likelihood of AD across all four new drug cohorts (bumetanide, furosemide, spironolactone, and nifedipine). Specifically, sildenafil vs. spironolactone was associated with a 46% reduced prevalence of AD in MarketScan (HR = 54%, 95% CI 0.32‐0.66, p‐value = 3.33×10‐5) and a 30% reduced prevalence of AD in OPTUM (HR = 70%, 95% CI 0.49‐1.00, p‐value = 0.05). Sildenafil treatment reduces phosphorylated tau (pTau181 and pTau231), phosphorylated GSK‐3b and CDK5 in the AD patient‐iPSC‐derived neuron model. The 3 months sildenafil treatment significantly improved the cognition of 5xFAD transgenic mice on novel object recognition, Morris water maze and contextual fear conditioning test, supporting its therapeutic effects in AD from real‐world patient data and patient iPSC model findings. RNA‐seq analysis (bulk and single‐cell) revealed potential biomarkers and brain target engagement to be tested in future clinical trials.

Conclusion

Those real‐world data, patient iPSC‐derived mechanic, and in vivo transgenic mouse model observations suggest that sildenafil offers a potential repurposable treatment for AD. However, future clinical trials are warranted to validate the causal relationship of sildenafil in potential prevention and treatment of AD.
An Investigational RNAi Therapeutic for Tau Lowering
Authors: Farley Jonathan E , Haines Jeffery D , Gannon Sean , Nguyen Tuyen , Tymon Roxanne , Cha Diana , Schlegel Mark , Castoreno Adam , Bisbe Anna , Zlatev Ivan , Rollins Jeff , Avbersek Andreja , Macdonald Lynn , Gao Min , Brown Kirk
Published: January 2025

Background

The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a group of progressive, neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia, progressive supranuclear palsy, and Alzheimer’s Disease. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs.

Method

Here, using our clinically validated C16‐siRNA CNS delivery platform, we have identified potent molecules targeting the MAPT gene.

Result

We have identified potent molecules that durably reduce MAPT mRNA and Tau protein in both in vitro and in vivo model systems. Furthermore, in a non‐human primate study, we demonstrated robust, sustained reduction of MAPT transcript and tau protein in disease relevant brain tissue that was well‐tolerated through 16‐weeks.

Conclusion

Together, these results suggest that Tau‐lowering via C16‐siRNAi may provide a novel strategy to reduce, and potentially reverse, accumulation of intracellular and extracelluar Tau aggregates. This approach has advanced into in IND‐enabling development.
Using a Bayesian workflow approach to define the optimal level of anatomy/functionality voxels clustering for the prediction of tau propagation and cortical loss in Alzheimer’s disease
Authors: Soucy Jean‐Paul , Belasso Clyde J , Cai Zhengchen , Bezgin Gleb , Stevenson Jenna , Rahmouni Nesrine , Tissot Cécile , Lussier Firoza Z , Rosa‐Neto Pedro , Rivaz Hassan J , Benali Habib
Published: January 2025

Background

Tau aggregates in Alzheimer’s disease (AD) induce loss of synapses and neurons, leading to cognitive impairment. Predicting tau and neurodegeneration temporal evolution could be used for prognostication and for assessing results of therapeutic trials. Tau PET and MRI volumetry are reliable markers of disease stage, but cost and radiation protection considerations limit research measurement frequency, lowering the accuracy of disease progression modeling. Here, we evaluate, using Bayesian analysis, whether models based on limited numbers of observations can be refined to better predict the temporal trajectory of pathology.

Method

Imaging data comes from subjects (113; 68 females; 18 AD dementia, 23 MCI and 72 cognitively normal) of the TRIAD cohort (McGill University) who have been evaluated at least twice ( 1 year interval) with both tau PET ([18F]MK‐6240) and structural MRI. Four probability models were evaluated: 1‐ a basic one, assuming that all data points come from 1 data distribution; 2‐ one where subjects' observations are clustered within anatomical ROIs, where an independent distribution is hypothesized; 3‐ data is clustered within known physiological networks, each networks’ distribution parameters having their own specific values ; 4‐ a model assuming that subjects’ observations are described by a distribution of voxel parameters dictated by both the ROI and network(s) in which they lay. Bayesian data analysis was used to compare the predictive accuracy of those models for progression at 1 year from baseline of tau PET and MRI data.

Result

Model 4 was the most accurate model for both tau and cortical thickness prediction. We therefore used it to perform posterior predictions across hemispheres, showing that the prediction curves of the left and right hemispheres for the pericalcarine cortex differ. We also noticed a decreasing trend in the CN tau curve for the left hemisphere as the rate of cortical thinning increases. In contrast, there is an increasing trend in the AD tau curve as the rate of cortical thinning increases.

Conclusion

The model that incorporated both ROI‐level and network‐level information was the best predictor of progression, and such an approach can reveal underappreciated properties of the disease (i.e., laterality).
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.
Predicting Neurodegenerative Diseases: Unveiling the Interplay of Genetics and Social Determinants
Authors: Escudero Stefanie Danielle Pina , Migeot Joaquín , Hernandez Hernan , Acosta‐Uribe Juliana , Cochran J. Nicholas , Taylor Jared W , Funes José Alberto Ávila , Matallana Diana , Lopera Francisco , Custodio Nilton , Behrens María Isabel , Chonchol Andrea Slachevsky , Bruno Martin Alejandro , Brusco Luis Ignacio , Takada Leonel Tadao , de Paula Elisa , Resende França , Reyes Pablo A , Gelvez Nancy , Franco Teresita Ramos , Bruna Bárbara , Ponce Daniela P , Durón Dafne Estefania , Montesinos Rosa , Millon Maria Beatriz Bistue , Maito Marcelo Adrian , Javandel Shireen , Godoy Maria Eugenia , Vitale Dan , Pantazis Caroline , Nalls Mike A , Singleton Andrew , Miller Bruce L. , Ibañez Agustin , Kosik Kenneth S. , Yokoyama Jennifer S. ,   Multi‐Partner Consortium to Expand Dementia Research in Latin America (ReDLat)
Published: January 2025

Background

Predicting Alzheimer's disease (AD) and frontotemporal dementia (FTD) using polygenic risk scores (PRS) for late‐onset forms holds promise, but its accuracy might be influenced by social determinants of health (SDOH). This study explores how considering SDOH alongside genes can improve prediction, focusing on potential differences for each disease.

Methods

Employing logistic regression in 677 individuals (287 AD, 102 FTD, and 288 controls) aged 40‐80 from the ReDLat study across six Latin American countries, we investigated the potential for SDOH to modify the association between PRS and susceptibility to AD and FTD. Analyses were adjusted for a probabilistic score derived from models comparing disease groups to controls with SDOH data (education, occupation, economic stability, healthcare access and quality, and social context) and APOE ε4 carrier status to account for confounding effects.

Results

Although univariate association tests revealed robust links between PRS and both diseases, adjusted models presented a nuanced picture. In AD, the SDOH score and APOE ε4 carrier status significantly attenuated the PRS effect (p=0.14), suggesting these factors modify genetic risk. In FTD, however, SDOH did not influence the PRS contribution. These findings highlight the potentially distinct roles of social factors in different neurodegenerative pathways.

Conclusion

The significant modification of PRS effects in AD by SDOH and APOE ε4 underscores the need for comprehensive approaches in future research and interventions in Latin America. Conversely, the unaltered PRS contribution in FTD emphasizes distinct intricacies in gene‐environment interactions. These findings necessitate considering both realms in future efforts, paving the way for targeted strategies in AD and FTD prevention and treatment.