bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of an electronic health record 3‐year risk model for diagnosis of dementia with and without Mini‐Cog scores
Authors: Hanson Leah R , Crain A Lauren , Gustafson Sally K , Werner Ann M , Svitak Aleta L , O'Keefe Lauren R , O'Connor Patrick J , Rossom Rebecca C 
Published: January 2025

AbstractBackgroundThe number people living with Alzheimer’s disease and related dementias is expected to triple by 2050, contributing to decreased quality of life, increased medical care utilization, and additional burden on an already stressed primary care system. Many clinicians lack confidence to assess, diagnose and manage cognitive impairment (CI), and more than 50% of patients with CI are undiagnosed. A tool to better identify patients at risk of CI could lead to earlier detection and diagnosis in primary care.MethodA prediction model was developed and validated to estimate the risk of dementia diagnosis within three years using two machine learning approaches, R SuperLearner and LASSO. Patients were 65 years or older without a CI diagnosis and seen at a 2017 primary care index visit. A subgroup of patients had Mini‐Cog (MC) screening data available. Variable selection was carried out in the full population, and again in the MC subgroup. Both machine learning approaches selected variables from >1,000 features calculated from broad categories of electronic health record (EHR) and MC data documented between 2012 and the index date. Features considered came from categories including Annual Wellness Questionnaire, cognitive screens, diagnoses, encounter history, vitals, labs, medications, procedures, patient reported outcomes, social history, and vaccinations. Dementia diagnosis between index and 12/31/2020 was the outcome. Diagnostic measures were calculated from logistic regression models fit using the selected variables.ResultThe full population prediction model included data from N = 100,998 patients (training n = 70,699; validation n = 30,299), 6.0% of whom developed dementia. In the MC subgroup (training n = 47,478; validation n = 20,807) 3.6% developed dementia. Maximum predictive accuracy (AUC) was obtained using the LASSO approach. The full population model retained 33 predictors with AUC = 0.80 (95% CI 0.79 – 0.81) in the training and validation datasets. The MC prediction model retained 32 predictors and AUC = 0.83 (95% CI 0.82‐0.84) in both datasets.ConclusionUsing MC and readily available EHR data, we were able to predict future dementia diagnoses with high accuracy. Next, we are implementing this model into an algorithm‐driven clinical decision support system and testing the system’s ability to improve diagnosis rates via a cluster‐randomized trial.
The Association between the Body Fat Localization, Insulin Resistance, and Amyloid Burden in Midlife
Authors: Dolatshahi Mahsa , Commean Paul K. , Naghashzadeh Mahshid , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , McBee‐Kemper Abby , Weeks Jake , Sirlin Claude , Ceriani Lael , Yifei Xu , Mittendorfer Bettina , Liu Jingxia , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A. 
Published: January 2025

AbstractBackgroundObesity in midlife is a risk factor for developing Alzheimer disease later in life. However, the metabolic and inflammatory effects of body fat varies based on its anatomical localization. In this study, we aimed to investigate the association of MRI‐derived abdominal visceral and subcutaneous adipose tissue (VAT and SAT), liver proton‐density fat fraction (PDFF), thigh fat‐to‐muscle ratio (FMR), and insulin resistance with whole‐brain amyloid burden in cognitively normal midlife individuals.MethodA total of 49 cognitively normal midlife individuals (Age: 50.65±5.77 years, 61.2% female, BMI: 32.0±67.34, 57.1% obese) underwent brain PET scan, body MRI, and metabolic assessment. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) was used for measuring insulin resistance. Dynamic amyloid imaging was performed with a bolus injection of ∼15mCi [11C]PiB, followed by a 60‐min scan. Data from the 30–60 minute post‐injection window was used for calculating whole‐brain amyloid centiloid. VAT and SAT were semi‐automatically segmented using an in‐house MATLAB‐based software. A trained U‐Net convolutional neural network (CNN) model was used to calculate the hepatic PDFF maps from abdominal T1‐weighted images. After preprocessing and N4ITK bias correction on mid‐thigh slices between the ischial ramus and the medial knee condyle, a MATLAB program was used for segmenting thigh total fat including subcutaneous, inter‐, and intra‐muscular fat, and muscle volumes. Total thigh fat‐to‐muscle ratio (FMR) was calculated. Using Spearman correlation test, the association between whole‐brain amyloid centiloid and BMI, HOMAIR, VAT, SAT, PDFF, and FMR was assessed, with age and sex as covariates.ResultObese individuals had a higher amyloid burden compared to the non‐obese (p=0.011). Whole‐brain amyloid centiloid values were significantly associated with VAT (rho=0.62, p<0.0001) and HOMAIR (rho=0.56, p=0.013), but not other fat metrics. A mediation analysis showed significant direct effect of VAT (p=0.02) on amyloid burden, while the indirect VAT effects mediated by HOMAIR were non‐significant (p=0.28).ConclusionObesity, higher visceral fat and insulin resistance, but not BMI, subcutaneous abdominal fat, liver fat, or thigh fat, are associated with higher whole‐brain amyloid burden in midlife. This highlights the importance of anatomical characterization of body fat for Alzheimer disease risk, where visceral fat shows a strong relationship with amyloid pathology.
The Black Male Dementia Caregiver Study: An Analysis of the Relationship between Informal Caregiving, Sleep, Depression, and Cognitive Functioning
Authors: Ali Amani L , Delong Alexander , Turner Robert W 
Published: January 2025

AbstractBackgroundStress associated with caregiving for a person with Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/RD) has negative health implications. However, little is known about the implications of stress on non‐Hispanic Black (NHB) informal male caregivers. This study aims to examine the relationship between sleep, depression, and cognitive function in a sample of NHB informal male caregivers in the metropolitan Washington, D.C. area.MethodThis cross‐sectional study (n = 68) included informal caregivers and non‐caregivers who participated in self‐perceived health questionnaires and a series of cognitive assessments. Data analysis consisted of logistic regression models to understand the relationship between caregiving, cognitive health, age, education, sleep (Pittsburgh Sleep Quality Index), and depression (Center for Epidemiological Studies Depression Scale).ResultThree variables were used to explore caregiving: caregiver status, caregiver tenure, and hours per week spent caregiving. Tenure was positively associated with hours per week spent caregiving (p = 0.031). Poorer sleep was associated with caregiver status (p = 0.030) and weekly time spent caregiving (p = 0.002), while depression was associated with caregiver status (p = 0.024). Additionally, there was an association between caregiver status and the Verbal Fluency Test (VFT) (p = 0.050) and the Verbal Naming Test (VNT) (p = 0.035), which became stronger when adjusting for sleep and depression (p = 0.023). Additional hours spent per week providing care was associated with poor performance on the Number Span Test (NST) (p = 0.012), which is exacerbated when adjusting for sleep and depression (p = 0.009). Caregiver tenure was associated with lower scores on the VFT (p = 0.003), unimpacted by adjusting for sleep or depression.ConclusionIn this study of NHB male informal caregivers, poor sleep was associated with lexical retrieval deficits, with caregiver tenure exacerbating this. Hours spent giving care per week is also associated with decreased sleep and attentivity. The results from this pilot study indicate a need for interventions to improve sleep quality among caregivers, thus reducing cognitive burden. Given this group’s unique cultural perspectives on sleep, curating targeted cognitive behavioral sleep interventions should be examined.
Associations of plasma phospho‐Tau217 with amyloid‐PET and cognitive status in adults with Down syndrome
Authors: Bettcher Brecca , Janelidze Shorena , McLachlan Max , Zammit Matthew D , McVea Andrew K , DiFilippo Alexandra H , Betthauser Tobey J. , Laymon Charles M , Tudorascu Dana , Cohen Annie , Garimella Arun , Price Julie C , Keator David B. , Brickman Adam M. , Lao Patrick J. , Klunk William E , Rosas H. Diana , Zaman Shahid , Hartley Sigan L , Head Elizabeth , Mapstone Mark , Krinsky‐McHale Sharon J. , Johnson Sterling C. , Lai Florence , Ances Beau , Handen Benjamin L , Hansson Oskar , Christian Bradley T. 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers able to detect atypical neuropathology could serve as a cost‐effective and noninvasive screening to include participants with Down syndrome (DS) in anti‐amyloid clinical trials. Accurately placing these novel biomarkers on the AD pathological cascade as proposed by the AT(N) framework informs relative disease progression of individuals. This work examines associations between plasma pTau217 accumulation, PET amyloid positivity, and cognitive status in adults with Down syndrome.MethodParticipants were recruited from the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS) study (Table 1). Amyloid positivity was determined by [11C]PiB or [18F]florbetapir (A+: Centiloids > 18) PET imaging from U01 cycle 1. Participants were classified as cognitively stable, mild cognitive impairment (MCI), or dementia (D). Plasma pTau217 concentration was measured using Lilly’s immunoassay for the Meso Scale Discovery platform. The threshold for ptau217 abnormality was derived using a subsample of amyloid negative participants. Youden’s Index (YI) was optimized to assess ptau217 sensitivity to PET A+ individuals. The time offset between PET amyloid positivity (18 CL) and ptau217 sensitivity was based on amyloid chronicity trajectories (Zammit et al, 2023). A second analysis was performed with respect to varying PET A+ thresholds.ResultAmyloid positive participants showed elevated pTau217 levels compared to amyloid negative participants (A+: 0.82 pg/ml, A‐: 0.44 pg/ml, p < 0.05). With a data derived pTau217 threshold of 0.78 pg/ml, optimization of YI identified an optimal cut point of 48.5 CL. In a ROC analysis, AUC increased with increasing PET A+ thresholds (Figure 1). A significant separation of pTau217 with cognitive status was observed (cognitively stable: 0.51 pg/ml, MCI: 0.88 pg/ml, D: 1.50 pg/ml) (Figure 2).ConclusionConcordance was high between plasma pTau217 using Lilly’s immunoassay and amyloid PET status after reaching elevated amyloid levels of 48.5 CL or ∼6 years PET A+. This work suggests that elevated pTau217 levels follows Aβ neuropathology detected by PET and trends with clinical progression.
Preliminary grip strength data from an 8‐week pilot trial of creatine monohydrate supplementation in Alzheimer’s disease patients
Authors: Smith Aaron N. , Sullivan Debra K , Kelly Emma , Arora Tanu N , Waitsman Faith N , Taylor Matthew K 
Published: January 2025

AbstractBackgroundDiminished muscle function and strength are linked to an increased risk and accelerated progression of Alzheimer’s disease (AD). Although these are direct consequences of the disease, recent preclinical evidence suggests decreased muscle function and strength may directly influence AD risk and progression via the muscle‐brain axis. Therefore, interventions to improve muscle strength may prevent functional decline related to AD. However, such specific interventions in AD are lacking. In this context, creatine monohydrate (CrM), a dietary supplement that boosts muscle strength, presents a promising intervention. This single‐armed pilot study explores the potential effects of an 8‐week creatine monohydrate supplementation on handgrip strength in AD.MethodData from 16 participants with AD who completed a one‐arm, 8‐week trial examining the feasibility and preliminary efficacy of 20 g/day of CrM in AD were analyzed. Handgrip strength, a reliable measure of muscle strength, was assessed on the dominant hand at baseline and at the end of the study on a calibrated hand dynamometer, measured in kilograms (kg) of force. At baseline and 8 weeks, 3 measurements were taken; the highest value was selected. We conducted a paired t‐test to test for an 8‐week change in mean handgrip strength. Statistical analyses were performed using R (v. 4.3.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.ResultParticipants were 56% male with a mean age of 72.1 ± 6.4 years at baseline. The mean hand grip strength and body mass index (BMI) at baseline were 33.6 ± 11.6 kg and 25.4 ± 3.6 kg/m2, respectively. After 8 weeks of CrM supplementation, mean handgrip strength improved by 2.6 kg (36.1 ± 12.1 kg, p < 0.001). BMI did not change.ConclusionIn this study, 20 g/day of CrM supplementation for 8 weeks was associated with improved handgrip strength in individuals with AD. Our pilot data suggests that CrM may be valuable for maintaining or preventing AD‐related functional decline by improving muscle strength.
Effects of Self‐Perceptions of Cognitive Decline on Cognitive Assessment Outcomes in the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic
Authors: Kaplan Nikki L , Post Emily , Levine Taylor F , Caldwell Jessica ZK 
Published: January 2025

AbstractBackgroundThe Women’s Alzheimer’s Movement Prevention Center (WAMPC) at Cleveland Clinic evaluates women’s risk factors for developing Alzheimer’s disease and provides personalized recommendations for reducing risk. Previous research has established that up to 40% of Alzheimer’s disease (AD) cases might be prevented when modifiable risk factors are addressed. To better understand individual risk profiles, a wealth of information is collected, including self‐reported health conditions (both personal and familial), lifestyle factors (e.g. alcohol and tobacco use, exercise, social support), a brief cognitive test battery, and blood tests. WAMPC takes a holistic approach in helping women combat modifiable risks for AD.Method207 women from the WAMPC who consented to have their clinical data used for research purposes were assessed (mean age = 53.39, SD = 9.53). Requirements for participation include normal cognition and family history of Alzheimer’s disease. Patients completed the Mini Mental State Exam (MMSE), selected tests from the NIH Toolbox (Oral‐Symbol Digit, Processing Speed, Picture Vocabulary, Card Sort, and Flanker), Controlled Oral Word Association Test‐FAS (COWAT: FAS, Animal Naming), and the Trail Making Test Part B. Patients also completed the Subjective Cognitive Decline Questionnaire (SCDQ), a self‐report assessment of perceived cognitive changes. We transformed SCDQ total scores into cohort‐based z‐scores to create three SCDQ groups (“fewer cognitive concerns” = bottom third, “average cognitive concerns” = middle third, and “above average cognitive concerns” = top third. We evaluated the relationship between performance on cognitive tests and women’s perceived cognitive decline on SCDQ. We ran 9 individual ANCOVAs, one for each cognitive test, using education and age as covariates.ResultOf the tests evaluated, the SCDQ significantly predicted scores on Animal Naming (F(2,190) = 3.602, p = .029) and NIH Toolbox Card Sorting (F(2,190) = 3.597, p = .029). No other tests demonstrated significant relationships with self‐perceptions of cognitive decline per the SCDQ.ConclusionPerceived cognitive decline in daily life predicted concurrent poorer performance on selected tests of language and executive function, in women who are cognitively normal, yet at increased risk for AD based on family history. Further work is needed to understand whether subjective cognitive concerns may represent risk for cognitive decline in this cohort of women with family history of AD.
Making meaning through cultural embeddedness: Advancing culture‐sensitive training for Alzheimer’s Disease and Alzheimer’s Disease Related Dementia Caregivers in Ibadan, Nigeria
Authors: Adedeji Isaac Akinkunmi , Lawal Saheed Akinmayowa , Ogunniyi Adesola , Henderson David C , Farombi Temitope Hannah , Elugbadebo Olufisayo Oluyinka 
Published: January 2025

AbstractBackgroundLimited knowledge exists about the cultural approaches to managing the psychological and behavioral outcomes (PBO) of Alzheimer’s Disease and Alzheimer’s Disease‐Related Dementia (AD/ADRD) in Africa. Specifically, to develop a culture‐sensitive training framework for AD/ADRD caregivers, we explored AD/ADRD caregivers’ cultural embeddedness in managing people living with AD/ADRD (PLWAD/ADRD) in Ibadan, Nigeria.MethodUsing hermeneutic phenomenological qualitative research design, we interviewed 23 caregivers providing care to PLWAD/ADRD in Ibadan, a Yoruba‐speaking ethnic group of Nigeria. Caregivers participated in in‐depth interviews (IDI) to share their experiences in managing AD/ADRD PBO. To capture the interpretive value of the caregivers’ experiences, we developed inductive and deductive codes and applied them to caregivers’ narratives using Nvivo 14. Based on the reflexivity of the multidisciplinary research team, themes, and sub‐themes about the cultural elements of caregivers' response to the PBO of PLWAD/ADRD were developed.ResultAmong the 23 caregivers, 16 were female; five received a monthly salary; two were non‐members of the Yoruba ethnic group. We found five culturally sensitive themes, broadly categorized into cultural universals and specifics. The Yoruba‐specific aspects included (1) respect and filial piety, (2) non‐verbal cues, and (3) communal living arrangements and rotational care. Meanwhile, the cultural universals centered on (4) reciprocity/fear of retribution and (5) patience. Caregivers showed respect and filial piety by staying quiet, speaking in a low tone, minimizing correction, and refraining from commenting on PLWAD/ADRDs' self‐efficacy. Non‐verbal cues, like facial expressions, played a crucial role. The communal living arrangement proved valuable in managing negative behaviors like wandering. Reciprocity and retribution were embedded beliefs, and patience was a culturally universal approach requisite in the care of PLWAD/ADRD.ConclusionThe five cultural themes are important training areas for managing the behavioral and psychological outcomes of AD/ADRD. Mixed‐methods studies are required to explore the dimensions and generalizability of the five cultural constructs to strengthen Africa’s AD/ADRD caregiving workforce.
Antisense‐mediated APP suppression as potential therapeutic for Down Syndrome Alzheimer’s Disease
Authors: Zhao Hien T , Chen Xu‐Qiao , Das Utpal , Zuo Xinxin , Ford Brittany T , Kordasiewicz Holly B , Mobley William C. 
Published: January 2025

AbstractBackgroundIncreased APP gene dosage is both necessary and sufficient to result in Down Syndrome Alzheimer’s Disease (DSAD) in humans and AD‐related degenerative changes in mouse models of DS.MethodWe tested antisense oligonucleotides (ASOs) designed to suppress APP expression via RNAseH1‐mediated degradation in the Dp(16)1Yey or Dp(16) model of Down Syndrome. Dp(16) is trisomic for human chromosome 21 syntenic regions on murine chromosome 16, containing 115 genes including APP. To evaluate efficacy of APP suppression, Dp16 and 2N euploid mice at 6‐8 months of age were treated with a mouse App ASO, and endosomal pathology and downstream pathological processes were evaluated.ResultAPP suppression reverses not only Rab5 hyperactivation in this model, but also abnormal hyperactivation of other Rab GTPases such as Rab7 and Rab11. Furthermore, tau hyperphosphorylation was ameliorated, and neurotrophin signaling was restored following APP suppression.ConclusionTaken together, these data support the hypothesis that APP suppression should restore normal endosomal function and neurotrophic signaling and benefit disease, and the potential of antisense‐mediated APP suppression as a disease‐modifying therapy for DSAD.
Biomarkers evaluation in olfactory neuroepithelial cells isolated from Mexican patients with and without Mild Cognitive Impairment
Authors: Silva‐Lucero Maria‐del‐Carmen , Gomez‐Virgilio Laura , Gutierrez‐Malacara Andres‐Ivan , Lora‐Marin Obed‐Ricardo , Cardenas‐Aguayo Maria‐del‐Carmen 
Published: January 2025

AbstractBackgroundMild cognitive impairment may increase the risk of Alzheimer's disease (AD) or probably accelerate the progression. AD is the most common cause of dementia, substantial neuronal loss, and neuropathological lesions can damage many brain regions. Symptoms of the disease begin with mild memory difficulties and evolve towards cognitive impairment. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use, but may be expensive approaches, here we propose a more affordable approach to detect biomarkers in cells isolated from the olfactory neuroepithelium.MethodOlder adults with signs of Mild Cognitive Impairment and healthy individuals of the same age were recruited. We performed a MoCA Test, a medical interview, and an olfactory test for each volunteer. A noninvasive nasal exudate was performed to obtain, isolate, and characterize Olfactory Epithelial Precursor Cells. Once the cultures were established, different biomarkers were evaluated using the Western Blot technique. We selected the biomarkers studied through a bioinformatic DEG’s analysis previously carried out by our research group.ResultA cohort of 3 patients with cognitive impairment and 3 healthy controls were recruited. We obtained from all volunteers their clinical history, a MOCA‐cognitive test, blood samples, and the culture of the Olfactory Epithelial Precursor Cells of each patient was established. The following markers were analyzed by Western Blot Amyloid precursor protein, total tau (T‐tau) and phospho‐tau217 (p‐tau217), as well as the AD biomarkers selected by our bioinformatics analysis: calcineurin subunit, a serine/threonine phosphatase under the control of Ca2+/calmodulin; β‐synuclein, which is associated with synaptic degeneration; a‐synuclein; and FKBP prolyl isomerase 1B (FKBP1B), a chaperone involved in age‐related Ca2+ dysregulation in the brain. Our data showed no correlation between p/tau217 and cognitive impairment.ConclusionThe search for altered genes in mild cognitive impaired patient‐derived peripheral cells will allow us to identify potential early biomarkers of AD that could be validated in blood samples from patients with AD, as a possible affordable diagnostic tool.