bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the impact of empathy loss on caregiver burden in behavioral variant Frontotemporal degeneration (bvFTD)
Authors: Fisher Lauren , Cousins Katheryn A Q , Rhodes Emma , Irwin David J , Massimo Lauren
Published: January 2025

Background

Behavioral variant Frontotemporal Degeneration (bvFTD) is a common form of early onset dementia characterized by prominent behavioral change, including loss of empathy. Research has demonstrated that caregivers of persons living with bvFTD (PLwFTD) are more burdened, stressed, and depressed than other dementia caregivers, and that empathy loss may contribute to this high level of burden. However, it remains unclear if empathy loss contributes to caregiver burden above and beyond other neuropsychiatric symptoms. Understanding the contribution of empathy loss in the PLwFTD to caregiver burden is important for supporting caregivers. The purpose of this study is to evaluate the impact of empathy loss on caregiver burden in the context of other common neuropsychiatric symptoms.

Methods

Participants included 111 caregivers to PLwFTD who were enrolled in research at the University of Pennsylvania Frontotemporal Degeneration Center and completed caregiver questionnaires that assess cognitive and emotional empathy (Interpersonal Reactivity Index [IRI]– Perspective Taking (PT) and Empathic Concern (EC) subscales, respectively), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), dementia severity (Clinical Dementia Rating Scale global score [CDR]), and caregiver burden (Zarit Burden Inventory [NPI]). Linear regressions were performed to evaluate the relationship between IRI subscales and caregiver burden, adjusting for dementia severity and NPI total score.

Results

For PLwFTD (n = 111), mean age was 62.8 (SD = 8.74) and predominantly white, non‐Hispanic (94.6%, 99.1% respectively), and male (59.5%). Caregiver reports of lower EC (β = ‐0.80, 95% CI: ‐0.6227806 to 0.4829205, p< 0.001) and PT (β = ‐1.29, 95% CI: ‐1.8700469 to ‐0.5882883, p<0.001) were associated with increased caregiver burden. After covarying for other neuropsychiatric symptoms (NPI total score: β = 2.28, 95% CI: 1.2032696 to 3.3532612, p<.001) and dementia severity (CDR: p = 0.25), decreased PT remained significantly associated with increasing caregiver burden (β = ‐0.77, 95% CI: ‐1.4041703 to ‐0.1321910, p<0.05), but EC was no longer significant (p = 0.57).

Conclusions

Empathy loss is a common behavioral symptom in PLwFTD that contributes to caregiver burden, even after accounting for other neuropsychiatric symptoms. In particular, we found that cognitive empathy or the inability of PLwFTD to understand their caregiver’s viewpoint is a major source of burden. These findings can inform interventions to support caregivers of PLwFTD.
Preliminary analysis reveals links between visual attention, sleep duration, and neural recruitment in Alzheimer's disease
Authors: Rempe Maggie P , Springer Seth D , Garrison Grant M , Glesinger Ryan J , Okelberry Hannah J , Petts Aubrie J , Embury Christine M , Wilson Tony W
Published: January 2025

Background

Sleep disturbances have been shown to relate to the development of Alzheimer’s disease (AD) and its associated cognitive deficits, including visual attention function. Here, we investigated the potential interactive and additive effects of sleep disruption and AD on visual attention performance and its underlying neural mechanisms.

Method

Preliminary analysis included 33 participants, 10 biomarker‐positive patients on the AD spectrum (mild cognitive impairment (MCI) and AD; 7 females; Mage: 70.24) and 23 cognitively‐healthy older adults (17 females; Mage: 67.47). Participants completed a visual search task during magnetoencephalography (MEG). Participants wore an Actigraph device on their non‐dominant wrist for a two‐week period. Actigraph data were cleaned using sleep diaries and analyzed using the Cole‐Kripke algorithm. Total sleep time (TST) was calculated for each night of sleep and averaged across all nights of sleep collected. The MEG data were transformed into the time‐frequency domain and significant task‐related oscillatory responses were source‐imaged.

Result

Behavioral analysis of the visual search task revealed a significant conditional effect (p < .001) and a significant group by TST interaction (p < .001) on RTs, revealing overall longer RTs in conjunctive trials and longer RTs in patients on the AD spectrum with shorter TST. Regarding the MEG data, we observed robust neural responses in theta, alpha, and beta frequency bands. Analysis of source‐imaged neural responses in the alpha range revealed significant conditional differences in the right posterior temporal lobe (p < .005), such that stronger responses were found in the conjunctive condition relative to the feature condition. A significant group‐by‐condition interaction was found in the right temporoparietal junction (TPJ; p < .005), revealing that patients on the AD spectrum had weaker responses during the conjunctive condition compared to controls. Finally, a group by TST interaction on conditional differences in alpha power (p < .005) in right occipital and cerebellar regions revealed that the relationship between condition‐wise neural recruitment in these regions and TST differed as a function of AD diagnosis.

Conclusion

These preliminary findings suggest key relationships between total sleep time, visual attention behavioral performance and neural recruitment, and how these relationships may differ in AD spectrum conditions.
Health care utilization and cost differences across cognitively‐defined Alzheimer’s disease subgroups
Authors: Coe Norma , Sun Chuxuan , White Lindsay , Shapiro Lily N , Taylor Janelle S , Crane Paul K.
Published: January 2025

Background

Existing studies on the health care utilization and costs associated with Alzheimer’s disease (AD) have treated individuals with AD as a homogeneous group, though recent evidence suggests individuals with AD may be classified into biologically distinct subgroups with differing genetic and clinical profiles. The objective of our study is to examine differences in healthcare utilization and costs across cognitively defined AD subgroups.

Method

We utilize data from the Adult Changes in Thought (ACT) study (1994 – 2020), a population‐based longitudinal study of aging and the incidence of and risk factors for dementia. We focus our study on individuals who developed incident AD and classify these individuals into one of six cognitively‐defined AD subgroups using previously described methods. We identify a sex‐ and birth year‐matched set of controls using a many‐to‐one matching method. Controls are assigned an index date equal to the AD onset date for their matched AD case. We examine utilization and costs in the year preceding AD onset and in the three years following. Our utilization outcomes include number of days in a month spent in a hospital inpatient, intensive care unit, or skilled nursing facility setting, and number of emergency department visits. We also examine monthly total health care costs and component costs, including outpatient, hospital inpatient, skilled nursing facility, and pharmacy costs. We utilize repeated measures generalized estimating equations to estimate health care utilization associated with each AD subgroup. To estimate the incremental costs associated with each subgroup, we use the Basu and Manning cost estimator.

Result

We find significant utilization and costs differences across the cognitively‐defined AD subgroups, driven primarily by differences in the use of hospital inpatient and skilled nursing facility services. We also find the highest utilization and costs among the group of individuals with substantial relative impairments across multiple cognitive domains.

Conclusion

Studies on the health care utilization and costs associated with AD miss important heterogeneity by examining individuals with AD in the aggregate. Our study suggests that individuals in the cognitively‐defined AD subgroups have distinct health care utilization and cost patterns leading up to and following AD onset.
Self‐awareness of cognitive impairment in a community‐based cohort
Authors: Barrett A. M. , Ang Ting Fang Alvin , Liu Yulin , Devine Sherral A. , Mez Jesse , Au Rhoda , Lin Honghuang
Published: January 2025

Background

The deficit of unawareness of cognitive impairment (cognitive anosognosia) is known to be associated with adverse health outcomes, caregiver burden, and worse cognitive outcomes. A better understanding of cognitive self‐awareness and the ability to self‐judge cognitive performance among the general population would enable a rational design of cognitive screening and improve how subjective cognitive decline and self‐reported errors at tasks like medication administration are interpreted.

Method

Participants were enrolled in the Framingham Heart Study, which is a community‐based cohort with three generations of participants. Through ancillary studies, FHS participants underwent neuropsychological assessments every 4 to 5 years. For those with possible cognitive impairment, study examiners identified, and a panel later adjudicated, a clinical diagnosis (intact, mild cognitive impairment [MCI], or dementia, and their subtypes). Before the neuropsychological testing, participants were asked, “Do you have any concerns about your memory or thinking”. If “yes,” they were further asked: “Do you think this is normal for your age?”

Result

Our study included 5,110 participants of FHS with self‐reported assessment of cognition (mean age: 67±15 years; 55.1% women, 66.2% with some college degree or above). As shown in Table 1, among 359 (7.0% of the participants) diagnosed with MCI or dementia, 47.4% (170) had a self‐report consistent with unawareness of cognitive impairment (72 or 45.0% of MCI, 98 or 49.2% of dementia). These individuals had NO self‐reported concerns at all about memory and thinking. Even more concerning, a larger group of people (p = 0.025) with MCI or dementia who DID self‐report concerns about memory/thinking (88 with MCI, or 55.0%, 101 with dementia, 50.7%), stated that they thought the problem was normal for their age (124 participants, 65.6%).

Conclusion

Most of the Framingham Heart Study participants clinically diagnosed with pathologic cognitive impairment self‐reported that they either had no memory or thinking problems, or, more often, self‐reported memory and thinking problems that they felt were normal for their age. This is consistent with cognitive anosognosia, which can represent a range of unawareness. Since subjective cognitive decline is used to identify MCI, further research could develop complementary MCI diagnosis markers.
The Effects of Aerobic‐Strength Training on Cognitive Functions and Residual Platinum Levels in Cancer Survivors
Authors: Ukropcová Barbara , Amiri Ali , Slobodova Lucia , Malenovská Karin Marček , Pechancova Radka , Rerkova Katarina , Schön Martin , Oliva Viktor , Litvakova Viera , Sedliak Milan , Krssak Martin , Pluhacek Tomas , Mego Michal , Chovanec Michal , Ukropec Jozef
Published: January 2025

Background

The risk of cognitive decline in cancer survivors may be increased by platinum‐based chemotherapy. Evidence indicates that physical exercise has a potential to reduce chemotherapy‐related toxicity. The aim of this study was to assess effects of a 6‐month aerobic‐strength training on cognitive functions, metabolic flexibility, anthropometric parameters and physical fitness in testicular germ cell tumor (TGCT) survivors, treated with platinum‐based chemotherapy.

Methods

TGCT survivors underwent 6‐month intervention (supervised aerobic‐strength training/ controls n = 20/8, age 42.1±7.6 yrs. BMI:27.7±3.8kg/m², VO2max:29.2±6.7 mlO2/kg/min, 1‐20 years post‐treatment). Cognitive functions (FACT‐Cog; computerized tests Memtrax & CogState; Auditory Verbal Learning Test/AVLT), abdominal adiposity (MRI), cardiorespiratory fitness (VO2max, spiroergometry), muscle strength (leg‐press; chair dynamometry), energy expenditure and metabolic substrate preference (indirect calorimetry), serum glycemia, insulinemia, lipid profile, plasma adiponectin (ELISA), platinum, and zinc (Inductively‐Coupled Plasma Mass Spectrometry) were assessed before and after the 6‐month intervention.

Results

Training improved delayed and short‐term memory recall (AVLT), compared to non‐active controls. Training‐induced changes in delayed memory recall positively correlated with improvements in VO2max, supporting a link between cognition and cardiorespiratory fitness. Training reduced visceral adiposity (p<0.01), increased HDL‐cholesterol (p<0.01), cardiometabolic fitness (VO2max) and muscle strength (both p = 0.01). Plasma adiponectin, glycemia and insulinemia were unaffected by exercise training (p>0.1), while intervention normalized residual plasma platinum and increased zinc levels (both p<0.01), with no change in controls. Platinum levels (P<0.001) and number of chemotherapy cycles (p = 0.06) were the best predictors of memory function in cancer survivors.

Conclusions

Aerobic‐strength exercise training reduced visceral adiposity and circulating residual levels of platinum, improved physical fitness and cognitive functions in TGCT cancer survivors. Our observations support a role for exercise as an effective complementary treatment for cancer survivors, with a potential to reduce residual chemotherapy burden and cardiometabolic risk, which could be linked to improved cognitive functions.

Funding: APVV 19‐0411, VEGA2/0164/20, VEGA 2/0076/22
Adverse childhood events and the timing of Alzheimer's Disease in Down syndrome
Authors: Hickey Emily J
Published: January 2025

Background

People with Down syndrome (DS) are genetically at‐risk for Alzheimer’s disease (AD). The age of symptomatic AD in DS varies (late‐40s‐70s). Lifestyle factors are theorized to explain some of this variability. Experiencing adverse childhood events (ACEs) is associated with later‐life cognitive decline and risk for AD in general population samples. Mechanisms underlying this association may involve biological pathways such as systemic inflammation and/or increased mental health conditions such as anxiety and depression, which are themselves risk factors for AD. Little is known about the effect of ACEs on AD pathology (PET Aβ and tau) or symptomology directly, or indirectly through inflammation or mental health in DS.

Methods

We investigated ACEs prevalence in 112 adults with DS (mean age=39.0, range 25‐61; mild ID: 60.7%) and associations with plasma markers of inflammation, informant‐reported mental health, and PET Aβ and tau, controlling for age. Inflammation was measured by a composite of plasma IL‐6 (interleukins), serum IL‐6, serum CRP (C‐reactive protein), and serum sICAM (soluble intercellular adhesion molecule) levels. Mental health problems were measured via the Anxiety, Depression, and Mood Scale (ADAMS), Glasgow Depression Scale‐Caregiver Supplement (CGDS), and Reiss Screen for Maladaptive Behaviors (RSMB). Dementia symptoms were assessed via the Down Syndrome Mental Status Exam (DSMSE).

Results

Eighty percent (n=90) of participants reported at least one ACE and 24% (n=27) reported ≥4. ACEs were positively associated with anxiety (t=2.35, p=.021), depression (t=2.64, p=.010), maladaptive behaviors (t=3.35, p=.001), and plasma inflammatory markers (t=2.40, p=.021), controlling for age. ACEs were not significantly associated with the DSMSE. ACEs were associated with tau (t=‐2.58, p=.013) and at a trend level, with Aβ (t=‐1.95, p=.057), controlling for age, although not in the expected directions.

Conclusions

People with DS are vulnerable to ACEs and experience expected associations between higher ACEs and more mental health problems and systemic inflammation, but ACEs were not related to dementia symptoms. Unexpectedly, ACEs were related to lower PET Aβ and tau relative to age. It is possible that ACEs may be linked to other AD protective factors, such as time spent in the community. Future research should look into pathways that explain this finding.
Identifying early predictors of cognitive impairment and dementia in a large nationally‐representative US sample
Authors: Hudomiet Peter , Hurd Michael D , Rohwedder Susann
Published: January 2025

Background

Dementia impacts a large and growing number of older adults in the US, and the total impact of disease is costly to individuals and society. Though many risk factors have been identified, accurately predicting future dementia remains difficult. This study aims to identify early predictors of cognitive impairment and dementia using a large US sample.

Method

We evaluated the predictive power of 181 dementia risk factors using a recently developed and validated probabilistic measure of dementia and cognitive impairment, available on 97,629 person‐year observations in the nationally representative longitudinal Health and Retirement Study in the US (Table 1). The project predicted two types of outcomes: the two‐year or four‐year incidence of dementia or cognitive impairment; and the prevalence of dementia or cognitive impairment at age 80 based on the characteristics of individuals at age 60.

Result

In line with prior literature, physical health, a prior stroke, cognitive abilities, ADL and IADL functional limitations, and genes strongly predicted future incidence and prevalence of cognitive impairment and dementia. Our statistical models identified additional predictors that have received less attention. For example, dementia prevalence at age 80 was 9.9 percentage points higher (20.5% vs. 10.6%) among those with a BMI above 35 (vs. BMI 0‐25) at age 60, and this differential reduced to 4.2 ppts but remained statistically significant when all other predictors were controlled. Other factors associated with a higher chance of having cognitive impairment or dementia in the future were: being born in the South, not having a private health insurance plan at age 60, working fewer years, diabetes at age 60, never exercising, scoring lower on various physical performance measures (e.g. pulmonary function, grip strength, walking speed, balance tests), being less conscientious, and lower engagement in hobbies and novel information activities (Figures 1 and 2).

Conclusion

The sharpened list of dementia risk factors can be used to raise awareness and target resources for prevention and early detection in the presence of health system capacity constraints. These results are suggestive that some behavioral changes and interventions might slow cognitive decline.
Unlocking Pragmatic Changes in Typically Aging Elderly: An In‐Depth Analysis
Authors: Akkunje Preetie Shetty , Archa Sasi kumar , Hegde Prasanna Suresh , Thaut Michael H
Published: January 2025

Background

The dual‐cyclical relationship between language and cognition, encapsulated in linguistic relativity, underscores the reciprocal influence of thoughts on communication and vice‐versa. This study explores the intricate changes in pragmatics, a fundamental aspect of human communication, during the aging process, considering changes in sensory abilities, cognition, and language.

Method

Sixty participants, aged ≥50 years with a minimum of five years of formal education, were included, excluding those with neurological or psychological illnesses. Participants were categorized based on Montreal Cognitive Assessment (<25 & ≥25 MOCA scores), and their demographic details, language use, and educational and occupational history were recorded. Pragmatic evaluations included 1) functional communication profile analysis (sensory, receptive language, expressive language, pragmatic language and non‐oral communication), 2) pragmatic language evaluation (verbal aspects, paralinguistic aspects, nonverbal aspects), 3) spontaneous speech evaluation using Western Aphasia Battery, 4) discourse production assessment (macrostructures–main concept analysis, correct information units, global coherence and microstructures–T unit), and 5) hearing evaluation (pure tone audiometry, speech audiometry). Statistical analysis employed SPSS version 29.0.10, utilizing descriptive statistics and Likelihood ratio or Chi‐square tests.

Results

Participants had a mean age of 66.5±9.9 years, with 58.3% females and 41.7% males. Educational distribution included 31.7% with ≤10th standard, 13.3% with 12th standard, 46.7% with a Bachelor’s degree, 6.7% with a Master’s degree, and 1.7% with a Ph.D. Regarding language proficiency, 41.7% were proficient in one language, 53.3% in two languages, and 5% in three languages. Significant relationships between pragmatic characteristics were identified among participant groups, supporting existing literature linking cognitive‐linguistic decline to aging. Higher MOCA scores correlated with superior speech discrimination and communication, while lower scores were associated with hearing loss. Likelihood Ratio Tests indicated significant associations between higher MOCA scores (≥25) and clear, specific, stimulus‐related pragmatic communication, while scores below 25 were linked to pragmatic difficulties.

Conclusion

The study highlights the robust connection between pragmatics, cognitive function, and hearing abilities in the elderly. It offers insights into communication disorders, advocating for integrated rehabilitation programs for individuals with cognitive decline and hearing loss. Additionally, it reveals the intricate relationship between education, cognitive abilities, and pragmatic skills, guiding clinical practice and intervention strategies.
Impact of Sleep on Extracellular Volume in Human Brains: A Study with Simultaneous Sodium (23Na) MRI and EEG
Authors: Chen Xingye , Lin Ying‐Chia , Kumbella Nahbila‐Malikha , Henin Simon , Rockowitz Zena , Liu Anli , Masurkar Arjun V. , Babb James , Ge Yulin , Lui Yvonne W. , Qian Yongxian
Published: January 2025

Background

Alzheimer's disease is associated with neurotoxic amyloid‐beta (Aβ) plaques. Studies in mice demonstrated that cerebrospinal fluid (CSF) clearance, if impaired, reduces Aβ clearance by 70% and that sleep enhances CSF clearance via expanding extracellular space by 60%. However, the impact of sleep on extracellular volume in human remains unclear due to lack of non‐invasive technology. In this study, we use unique sodium (23Na) magnetic resonance imaging (MRI) to measure extracellular volume fraction (ECVF) in healthy subjects while monitoring their sleep stage with MRI‐compatible electroencephalography (EEG).

Method

With IRB approval, we studied 16 cognitively‐healthy subjects (age 52.9 ± 17.6 years, ranging 27–77 years, 7 males and 9 females). The study lasted 1.5 hours, including four repeated 16‐min sodium MRIs on a clinical scanner at 3T (Prisma, Siemens), and continuous EEG recording (Brain Vision, 32‐channel, Garner, NC). The subjects were instructed to relax and fall asleep. Sleep was scored to five stages (wake, N1, N2, N3, and REM), based on American Academy of Sleep Medicine (AASM) Manual (v2.6, 2020). Sodium MRI was performed with a dual‐tuned (1H‐23Na) birdcage coil (QED, Cleveland, OH) and a custom‐developed pulse sequence, twisted projection imaging (TPI), with parameters: FOV=220mm, matrix size=64, 3D isotropic, TE/TR = 0.5/100ms, flip angle=90°, averages=6, and TA=16min. ECVF, a
e, was calculated on the sodium images voxel‐by‐voxel, i.e., s = ΔV (aeCe + aiCi) = ΔV (145 ae + 15 ai), with ae + ai = 1.

Result

In panel P1 is the set‐up of the study, including the MRI, EEG, sodium images, and hardware set‐up. In P2 are typical EEG waveforms and spectra of sleep stages. In P3 is a representative of ECVF maps from a subject (43 years old, female). In P4 are outcomes of the study. Surprisingly, we observed a decrease in ECVF with sleep stage in the gray matter (P=0.036) and in the white matter (P=0.085, nearly significant).

Conclusion

This study surprisingly observed a decrease in ECVF with sleep stage in the gray matter of healthy subjects, and in white matter as possible. This finding is contrary to the outcome from the animal studies and needs to confirm with more human subjects.
Development of a Multi‐task Graph Neural Network for Alzheimer’s Disease Drug Repurposing
Authors: Hsieh Kang‐Lin , Plascencia‐Villa German , Lin Ko‐Hong , Perry George , Jiang Xiaoqian , Kim Yejin
Published: January 2025

Background

Developing drugs for treating Alzheimer’s disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies.

Method

To address the challenge in AD drug development, we developed a multi‐task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi‐level evidence on drug efficacy, to identify repurposable drugs and their combination candidates

Result

Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post‐treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population‐based treatment effect, and Phase 2/3 clinical trials. We experimentally validated the top‐ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations.

Conclusion

This methodology showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real‐world patient data shed light on the drug development of complex diseases.
The Alzheimer’s Association Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease – Where does Lewy body dementia stand?
Authors: Abdelnour Carla
Published: January 2025

Dementia patients often received one clinical diagnosis, yet most of these cases present multiple underlying pathologies. Bringing the transition from clinical‐based to biological‐based diagnosis holds promise with the diagnostic criteria proposed by the Alzheimer’s Association (AA) Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease and the Neuronal Synuclein Disease Integrated Staging System (NSD‐ISS). This session aims to explore the practical implications of the AA revised criteria for diagnosing and designing clinical trials in Lewy body disease (LBD).

The updated version of the AA criteria proposes 3 biomarker categories: core Alzheimer’s disease (AD) biomarkers, non‐specific biomarkers, and biomarkers for common non‐AD co‐pathologies, including synucleinopathy (asyn). Utilizing the seeding amplification assay (SAA) to detect asyn pathology expands the biomarker toolkit, historically dominated by AD biomarkers. Identifying asyn in vivo in dementia cases enables recognizing underlying LBD, potentially reducing oversight of LBD cases with concurrent AD, which are less likely to present core features (particularly females).

The AA criteria emphasize the role of clinical judgment in cases with comorbid pathology, proposing a biomarker profile for characterization. Challenges in evaluating several biomarkers in the clinical setting may be addressed using biofluid biomarkers and a stepwise process guided by clinical judgment.

Practical applications of these criteria include their role as inclusion/exclusion criteria and stratification of LBD clinical trials. Similarly, in AD clinical trials, this framework allows excluding patients with comorbid pathologies to achieve a homogeneous study population.

The AA revised criteria, along with the NSD‐ISS, serve as starting points for hypothesis testing. Future directions involve updating these frameworks with a patient‐centered approach, engaging patients and caregivers to understand the implications of biological‐based diagnosis. Longitudinal studies analyzing multiple comorbid pathologic changes are essential for determining the timeline of each pathology’s development. Finally, it is envisioned the creation of a comprehensive system to stratify disease progression of neurodegenerative diseases by incorporating biomarkers, demographic, clinical, and genetic data.
Development of the 7‐item ASK‐AD Assess Symptoms and Knowledge of Alzheimer’s Disease tool for multigenerational community dementia awareness: Findings from Old SCHOOL Hip Hop
Authors: Noble James M. , Minchala Sandra G , Hedmann Monique G , Teresi Jeanne , Ocepek‐Welikson Katja , Silver Stephanie A , Eimicke Joseph P , Ramirez Mildred , Harris Adrian , Lloyd Arthur , Chhea Kunsorya , Arango Catalina Alvarez , Lee Yejin , Sawyer Vanessa , Williams Olajide
Published: January 2025

Background

Alzheimer’s disease (AD) health literacy is low in high‐risk populations and is likely a determinant of timely care seeking behavior. Our group aimed to develop a novel brief questionnaire for use in community outreach and related studies of AD awareness.

Methods

We developed an initial 15‐item AD knowledge questionnaire “ASK‐AD (Assess Symptoms and Knowledge of AD)” following pilot study and cognitive interviews with subject matter experts along with elementary school children. The study took place in 28 elementary schools in the New York City area between 2018‐2023. Psychometric analyses explored data acquired immediately following enrollment but before randomization into either arm of the Old SCHOOL Hip Hop randomized controlled trial.

Results

Overall, 1461 diverse elementary school children including 692 (47%) fourth graders and 752 (52%) fifth graders (typically aged 9‐11 years) enrolled along with 783 of their parents. Among parents, 679 (87%) were female with 441 (56%) self‐reporting Black or African‐American race and 215 (28%) Hispanic ethnicity; 97 (12%) reported White race. Most parents were aged 36‐55 years (521 (67%), 18‐35y: 223 (29%)) with 185 (24%) having completed high school; 226 (29%) completed some college, and 182 (24%) had a bachelor’s degree. Performance metrics of 15‐, 11‐, 8‐, and 7‐ question versions were explored. The 7‐item version of the ASK‐AD evidenced optimal performance in students and parents, testing key AD concepts, including common symptoms and signs (six items) and brain localization (one item). ASK‐AD‐7 corrected item‐total correlations ranged from 0.30‐0.50 for student data and 0.24‐0.53 for parents. Psychometric property estimates were good‐to‐excellent for parent and student versions. The unstandardized Cronbach’s alpha coefficient estimate was 0.668 (standardized = 0.667) for students and 0.699 (0.701) for parents. For parents, the McDonald’s Omega estimate Total (ωt) was 0.857, ordinal alpha was 0.854, and the explained common variance (ECV) was 59.567; for students ωt = 0.801, ordinal alpha = 0.798 and ECV = 49.338. Items of AD prevention, treatment, and action plan were not retained in any reduced version.

Conclusions

The novel 7‐item ASK‐AD multigenerational community dementia awareness tool may be used in diverse, at‐risk groups. ASK‐AD could fill important gaps in ongoing AD community outreach programs.
Correlates of Cognitive SuperAging in the Mexican Health and Aging Study
Authors: Saenz Joseph , Doyle Cassidy , Andel Ross
Published: January 2025

Background

Aging is often accompanied by normative cognitive change, with memory decline typically experienced with advanced age. Some older adults reach their 80s maintaining memory performance of people 20 years younger. Little is known about these “SuperAgers” or correlates of SuperAging, particularly in low‐ and middle‐income settings. We evaluate how demographic, psychosocial, and health factors relate to odds of SuperAging in Mexico, an upper middle‐income country experiencing rapid population aging.

Method

Data came from the Mexican Health and Aging Study, a nationally representative study of adults age 50+. We defined SuperAging as being 80+ years old, having delayed recall scores at or above the median for those age 50‐64, and not having cognitive impairment or dementia. We then explored associations between demographic, psychosocial, and health factors and odds of SuperAging.

Result

Our sample included 334 individuals aged 80+ in the 2012 MHAS with no history of dementia or cognitive impairment, of whom 16% (n = 53) met criteria for SuperAging and 84% (n = 281) experienced normal cognitive aging. Women (OR: 1.90, p<0.05) were more likely to be among the SuperAgers, as were younger study participants (OR: 0.87, p<0.05), but years of education did not relate with SuperAging. Higher life satisfaction related positively with SuperAging (OR: 1.32, p<0.05) whereas other psychosocial factors (depressive symptoms and control beliefs) did not discriminate SuperAgers from their normal aging counterparts. Functional ability, chronic condition count, and self‐rated health were not related with SuperAging.

Conclusion

Some individuals aged 80 and over maintain superior memory performance, with levels consistent with their peers in their fifties and early sixties. Using data from a study of older Mexican adults, we found that women and those reporting higher life satisfaction are more likely to be SuperAgers.
Intranasal dantrolene nanoparticles abolished depression behavior and memory loss as a disease‐modifying drug in 5XFAD mice
Authors: Bhuiyan Piplu , Zhang Wenjia , Chae Rebecca , Kim Kyelee , St. Louis Lauren , Wang Ying , Liang Ge , Wei Huafeng
Published: January 2025

Background

The vicious cycle between depression and dementia increases the risk of Alzheimer’s Disease (AD) pathogenesis and pathology. This study investigates therapeutic effectiveness versus side effects and the underlying mechanisms of intranasal dantrolene nanoparticles (IDNs) to treat depression behavior and memory loss in 5XFAD mice.

Method

5XFAD and wild‐type B6SJLF1/J mice were treated with IDNs (IDN, 5 mg/kg) in Ryanodex formulation for a duration of 12 weeks. Early treatment groups (ETG) began treatment at 2 months until 5 months of age, and late treatment groups (LTG) began treatment at 9 months until 12 months of age. Behavioral assessments including depression (Tail suspension, open field), cognition (fear conditioning, Y‐ maze), olfaction (buried food test), and motor function (rotarod) were conducted between the ages of 5‐6 months in ETG and 12‐13 months in LTG. Blood and brain samples were obtained at 7 and 13 months in ETG and LTG, respectively. Blood Alanine transaminase measured by ELISA for liver function. The changes of brain proteins on Ca2+ release channels on the ER membrane (RyR‐2 and InsP3R‐1), MDA, pyroptosis regulatory proteins (NLRP3, Caspase‐1, full length or NT of Gasdermin D, cytotoxic (IL‐1β, IL‐18, IL‐6, TNF‐a) and cytoprotective (IL‐10) cytokines and PSD‐95, Synapsin‐1 determined using immunoblotting. Mice weight was measured monthly.

Result

Compared to WT mice, there were significant depression behavior and memory loss in both ETG and LTG 5XFAD mice, which were abolished by IDNs. IDNs also significantly inhibited the pathologically increased proteins expression of RyR‐2 and InsP3R‐1, MDA‐modified proteins, pyroptosis regulatory proteins (NLRP3, Caspase‐1, NT‐GSDMD), neurotoxic cytokines (IL‐1β, IL‐18, IL‐6, TNF‐α). IDNs also increased the neuroprotective cytokines (IL‐10) and synaptic proteins (PSD‐95, Synapsin‐1) in the LTG mice. IDNs did not affect blood liver function enzymes, motor or smell function, body weight in both ETG and LTG WT or 5XFAD mice.

Conclusion

IDNs robustly protect both depression behavior and memory loss in young and aged 5XFAD mice, with no adverse effects with chronic use. This was associated with its potent inhibition of inflammation, pyroptosis, and associated synapse protein loss. IDNs emerge as a promising therapeutic intervention for both depression and dementia, particularly in AD.
Area‐based socioeconomic deprivation is associated with cognitive decline in midlife to early late‐life New Zealanders without cognitive impairment
Authors: Röhr Susanne , Gibson Rosemary , Alpass Fiona
Published: January 2025

Background

Research identified individual‐level socioeconomic factors as key determinants of cognitive health. This study investigated the effect of area‐based socioeconomic deprivation on cognitive outcomes in midlife to early late‐life New Zealanders without cognitive impairment. Understanding geographical dimensions of socioeconomic determinants of cognitive health is important from an equity perspective.

Method

Data stemmed from a subsample of the New Zealand Health, Work and Retirement Study, a cohort study on ageing. In 2010, 1,001 participants aged 49‐84 years completed face‐to‐face interviews and were reassessed two years later. Cognitive functioning was measured using Addenbrooke’s Cognitive Examination–Revised, adapted for culturally acceptable use in New Zealand. Area‐based socioeconomic deprivation was assessed using the New Zealand Deprivation Index (NZDep2006). Linear mixed‐effects models analysed the association between area‐based socioeconomic deprivation and cognitive outcomes, controlling for individual‐level socioeconomic (age, age², gender, education, ethnicity [Māori, Indigenous people of New Zealand, and Non‐Māori, mostly of European descent], marital status, employment, net personal income), lifestyle and health variables (Lifestyle for Brain Health/LIBRA index, social loneliness).

Result

The analysis included 783 participants (54.7% female, mean age 62.7 years, 25.0% Māori). Individuals with cognitive impairment at baseline (n = 69) and older than 75 years were excluded (n = 79). Further attrition was due to missing data. At baseline, 39.7% resided in low deprivation areas, 39.0% in moderate, and 21.3% in high deprivation areas. The unadjusted model indicated a significant association between higher area‐based socioeconomic deprivation and lower cognitive functioning (B = ‐0.16, 95%CI: ‐0.22,‐0.10; p < .001) and cognitive decline (B = ‐0.12, 95%CI: ‐0.21;‐0.03; p = .015). The adjusted model yielded similar results for cognitive functioning (B = ‐0.08, 95%CI: ‐0.15;‐0.01; p = .050) and cognitive decline (B = ‐0.12, 95%CI: ‐0.20;‐0.04, p = .013) (Fig. 1). Influential covariates included gender, education, and lifestyle (LIBRA).

Conclusion

This study demonstrated a relationship between higher area‐based socioeconomic deprivation and lower cognitive functioning, along with cognitive decline, in cognitively unimpaired New Zealanders aged 48 to 75 years. These findings emphasize the importance of considering neighbourhood characteristics and broader socioeconomic factors in strategies aimed at mitigating cognitive health disparities and reducing the impact of dementia in disadvantaged communities.
Effects of a 4‐Month Supervised Aerobic‐Strength Training on Cognitive Functions and Clinical State of Patients with Parkinson’s Disease
Authors: Ukropec Jozef , Slobodová Lucia , Malenovská Karin Marček , Amiri Ali , Konečná Michaela , Straka Igor , Klepochová Radka , Košutzká Zuzana , Krššák Martin , Valkovič Peter , Ukropcová Barbara
Published: January 2025

Background

Physical exercise improves clinical state of patients with Parkinson’s disease (PD), and evidence from experimental models suggests it has a potential to slow down the disease progression. Improved glucose metabolism as well as exerkines, bioactive molecules released into circulation with each exercise bout, contribute to the synchronized exercise‐induced adaptive response at a systemic level. Our aim was to assess effects of exercise on clinical state and molecular changes in cerebrospinal fluid (CSF) and blood of patients with PD.

Methods

Patients with PD (H&Y score I‐III, 9F/17M; age 63.3 ± 8.4yrs; BMI 26.5 ± 5.9kg/m2) underwent supervised 4‐month aerobic‐strength training (3×1h/week). Clinical state (MDS‐UPDRS), body composition (BIA/MRI), cognitive functions (CogState, ACE‐R, TMT‐A&B, DSST, RAVL test), VO2max (Rockport 1 mile walk test), muscle strength (dynamometry), resting metabolic rate, metabolic substrate flexibility (indirect calorimetry), and insulin sensitivity (euglycemic hyperinsulinemic clamp) were assessed and CSF was sampled by atraumatic lumbar puncture (in a subpopulation) before / after 4‐month intervention. Extracellular vesicles (EVs) were isolated from serum and CSF by size exclusion chromatography (SEC). Proteomic analysis (mass spectrometry) of the samples is currently ongoing.

Results

Four‐month aerobic‐strength exercise improved or tended to improve clinical state (MDS‐UPDRS, p<0.05), body composition (reduced: BMI, p = 0.007; body fat, p = 0.08; visceral fat, p = 0.038) and cognitive performance (ACE‐R verbal production subscore, p = 0.029; psychomotor function, p = 0.04; visual learning & short‐term memory, p = 0.009) in patients with PD. Training reduced circulating HbA1C, improved whole‐body metabolic flexibility (substrate preference based on the substrate availability, the hallmark of healthy metabolism) and muscle strength (all p<0,05). Proteomic analysis of the samples obtained before and after training is in progress.

Conclusions

A relatively short aerobic‐strength exercise has favorable effects on cognition and clinical state in patients with PD which could be, at least in part, related to the improvements in patients’ physical fitness and metabolism. It is plausible to speculate that the specific training‐induced changes in the proteome of CSF, blood and EVs could be involved in the adaptive response underlying the exercise‐induced health benefits in PD.

Funding: APVV‐20‐0466, VEGA‐2/0076/22, ADDIT‐CE Horizon Europe 101087124
Neuroprotective effects of fosgonimeton and amyloid‐β‐targeting monoclonal antibodies against amyloid‐β toxicity in primary neuron culture
Authors: Reda Sherif M , Wu Wei , Setti Sharay E. , Berthiaume Andrée‐Anne , Taylor Robert W , Johnston Jewel L , Church Kevin J.
Published: January 2025

Background

We have previously reported the neuroprotective effects of fosgonimeton in amyloid‐β (Aβ)‐driven preclinical models of Alzheimer’s disease (AD). Fosgonimeton is an investigational small‐molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, currently under investigation for mild‐to‐moderate AD (LIFT‐AD; NCT04488419). Given the recent approvals of Aβ‐targeting monoclonal antibodies (Aβ‐mAbs) for the treatment of AD, and growing recognition that combination therapies may improve treatment outcomes, we sought to investigate the preclinical activity of fosgonimeton in the presence of Aβ‐mAbs. Here, we report the neuroprotective effects of fosgonimeton against Aβ toxicity in primary cortical neurons in the presence and absence of lecanemab, an Aβ‐targeting mAb that has received full approval for early AD.

Method

Primary rat cortical neurons were pre‐treated with the active metabolite of fosgonimeton (fosgo‐AM; 100 nM), lecanemab (25 nM), or fosgo‐AM + lecanemab for 15 minutes, and subsequently challenged with Aβ1‐42 (15 µM). In another condition, the drug treatments were co‐applied with Aβ1‐42. Following 24‐ or 48‐hour Aβ exposure, cultures were immunoassayed for microtubule‐associated protein‐2 (neuronal marker) to determine neuronal survival and neurite network length.

Result

Cortical neurons pre‐treated with fosgo‐AM and/or lecanemab exhibited a significant increase in neuronal survival and neurite network length following 24h or 48h Aβ challenge. In the Aβ1‐42 co‐application conditions, following 24h Aβ exposure, all treatments significantly promoted neuronal survival, but only the combination of fosgo‐AM + lecanemab significantly preserved neurite networks. In the Aβ1‐42 co‐application conditions, following 48h Aβ exposure, only the combination of fosgo‐AM + lecanemab significantly promoted neuronal survival, and none of the treatments had a significant effect on neurite network.

Conclusion

This study provides preliminary evidence that, on a cellular level, the neuroprotective ability of fosgonimeton against Aβ‐mediated toxicity in primary neurons is maintained in the presence of lecanemab. Furthermore, in some conditions, only the combination of fosgo‐AM and lecanemab demonstrated a significant increase in neuronal survival. While additional experiments are required to characterize these effects, these initial observations may have important implications regarding the potential of fosgonimeton as a treatment for AD, with or without Aβ‐targeting antibodies.
PET imaging utility of a novel Aβ‐tracking PET radiotracer, [18F]FC119S in aged vervet monkeys
Authors: Bhoopal Bhuvanachandra , Frye Brett M. , Bansode Avinash , Miller Mack , Damuka Naresh , Gollepalli Krishna Kumar , Barcus Richard A. , Lockhart Samuel N. , Sutphen Courtney L. , Jorgensen Matthew J. , Craft Suzanne , Register Thomas C. , Whitlow Christopher T , Shively Carol A. , Sai Kiran K. Solingapuram
Published: January 2025

Background

Older vervet monkeys are an excellent model for studying age‐associated Aβ deposition; however, they have high proportions of low‐affinity Aβ sites compared to human brains. Commonly used Aβ PET radiotracers are most useful in detecting high affinity Aβ fibrils. Measuring real‐time levels of low affinity Aβ fibrils through PET provides critical information of early AD progression. The radiotracer [18F]FC119S has high binding strength for Aβ1–42 protein aggregates (0.16 nM) and AD brain homogenates (13–15 nM). A pilot clinical trial showed significantly higher hippocampal and cortical uptake in AD patients over cognitively normal participants. Here we report the fully‐automated [18F]FC119S radiochemistry and preliminary imaging and fluid biomarker correlation data in aged vervet monkeys.

Methods

Radiochemistry followed [18F]¯‐assisted nucleophilic substitution of mesityl precursor and deprotection of Boc group. [18F]FC119S(∼0.37GBq)‐based brain PET (0‐120min) and T1‐weighted whole‐brain MRI scans were conducted in aged vervets (19‐27 y, n=14). CSF and plasma Aβ40, Aβ42, pTau181, and NfL were measured in samples taken close to the time of PET. Standard Uptake Values with cerebellum as reference (SUVr) and time‐activity‐curves (TACs) were calculated from PET/MR (Figure 1). SUVrs of anterior and posterior cingulate, hippocampus, frontal, parietal, temporal, and occipital lobes were correlated with age, MRI outcomes (grey and white matter volumes), and fluid biomarker data.

Results

[18F]FC119S production was highly reproducible (n>25 runs) in high (>97%) radiochemical purities, and molar activities (∼140 GBq/µmol). TACs showed favorable washout kinetics from all brain regions. SUVrs of hippocampus and cortical parietal lobe positively correlated with age and SUVrs of all the regions analyzed negatively correlated with MRI deep gray and white matter volumes. Among the high SUVr regions, cortical anterior cingulate SUVr was highly positively correlated (Figure 2) with CSF pTau181 (r=0.78, **p=0.002).

Conclusion

Preliminary [18F]FC119S PET evaluations agrees with human PET data in vervets with high uptake in regions associated with Aβ deposition. Among all fluid biomarkers analyzed, CSF pTau181 was the best correlate of all the brain PET SUVrs. Association of Aβ PET imaging data with synaptic density and microtubule data in the same cohort is being evaluated to explore the potential neurodegeneration pathways in aged vervet monkeys.