bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduction in Alzheimer’s disease brain atrophy by MRI measures in a phase 2a clinical trial of Lomecel‐BTM
Authors: Ramdas Kevin N. , Agafonova Nataliya , Hare Joshua M. , Naioti Eric , Kopcho Steven , Carballosa Raul , Patel Paayal , Brody Mark , Herskowitz Brad , Fuquay Ana , Rodriguez Savannah , Botbyl Jeffrey , Rash Brian , Oliva Anthony A. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive atrophy of the cerebral cortex and hippocampus, with concomitant increase in ventricular volume. Lomecel‐B is a novel cell‐based therapeutic approach to AD that targets neuroinflammation, microvascular dysfunction, and has the potential to stimulate endogenous tissue regeneration. We conducted MRI analysis of brain morphology in the CLEAR‐MIND study, a 49‐patient proof‐of‐concept study that tested 3 different dosing regimens of Lomecel‐B vs placebo in patients with mild AD dementia.MethodsThis double‐blind, randomized, placebo‐controlled 45‐week proof‐of‐concept trial (ClinicalTrials.gov: NCT05233774) enrolled patients (60‐85 yrs.) with mild AD dementia (MMSE score 18‐24); with evidence of amyloid on positron‐emission tomography (PET) and brain MRI consistent with AD. There were 4 study arms of Lomecel‐B intravenous infusion: 25 million (25M) cells once followed by 3 infusions of placebo (N = 13); 25M cells (N = 13) or 100 million (100M) cells (N = 11) monthly for 4 months; 4 IV infusions of Placebo (N = 12). Lomecel‐B treatment groups were evaluated for individual and pooled (25Mx1, 25Mx4, 100Mx4) groups vs placebo, n = 32.ResultsPatients receiving Lomecel‐B exhibited slowing of whole brain atrophy (pooled: reduced by 48% vs placebo, p = 0.005). Lomecel‐B exhibited reduced left, right and bilateral hippocampal atrophy by 62%, p = 0.021, 53%, p = 0.073 and 59%, p = 0.013, respectively. At Week 39, left, right and bilateral ventricular enlargement were reduced in Lomecel‐B pooled group by up to 34%, p = 0.097, 40%, p = 0.044 and 37%, p = 0.066 respectively, compared to placebo. Moreover, diffuse tensor imaging (DTI) used to index neuroinflammation indicated increased inflammation in AD placebo but substantial reduction in the Lomecel‐B pooled group, particularly the cingulate cortex (100% reduction, p = 0.002).ConclusionBrain MRI in this proof‐of‐concept study with small sample size reveals that Lomecel‐B was associated with measurable neuroanatomical and neuroinflammatory improvements compared with progressive AD pathology observed in placebo. Accordingly, these findings support further development of Lomecel‐B in a larger dose‐finding study.
Community‐based centers for people living with dementia and family caregivers: implementation and adaptation from pilot to national policy
Authors: Gajardo Jean , Aubert Josefina , Moreno Ximena , Aravena Jose M , Carcamo Felipe , Barrientos Carolina , Abusleme Maria T , Mascayano Franco 
Published: January 2025

AbstractBackgroundCommunity‐based centers for people living with dementia (PLWD) have been implemented as part of the National Plan of dementia in Chile, delivering a multicomponent and multiprofessional intervention to support the PLWD and their families, integrating social and clinical aspects. We sought to examine the implementation and adaptation of these centers, transitioning from adult day services to a community‐based dementia care model that has escalated to a public policy.MethodWe conducted a realistic evaluation using multiple qualitative data collection strategies and informants to analyze complex interventions, in 4 of a total of 9 centers. Key informants of the centers’ implementation were identified and participated in individual interviews or focus groups, at different levels (macro‐level of centralized policy, n:4; meso‐level of intervention deliverers and center coordinators, n: 27; and micro‐level of user family caregivers, n:14). Interviews and focus groups were audio‐recorded and transcribed. Rapid qualitative analysis was used with predetermined codes describing implementation according to the Active Implementation Frameworks and Implementation Outcomes.ResultAt a macro‐level of implementation, the centers have not experienced relevant transformations, and fidelity is tensioned due to lack of updated centralized technical orientations. At a meso‐level, the centers’ intervention has been adapted to improve sustainability and appropriateness, which has enhanced their scalability. Engagement with the local service network and tailoring according to geographic and cultural context, emerged as implementation drivers. Relevant points of agreement and disagreement regarding implementation among actors were identified.ConclusionThe implementation of community centers for PLWD in Chile, at a policy macro‐level the program has been continuous and stable. Most relevant implementation drivers and adaptations are identified at a meso‐level, which stresses the need to identify core components and processes for standardization and later evaluation and monitoring. Points of agreement and disagreement among the three levels are key for understanding priorities for improvement and impact.
Broadband access may influence variation in Alzheimer’s disease and related dementias prevalence in Central Appalachia
Authors: Rajczyk Jenna , Wing Jeffrey , Burke James , Xu Wendy Yi 
Published: January 2025

AbstractBackgroundGeographical differences in the burden of Alzheimer’s disease and related dementias (ADRD) exist in the US. Rural and Appalachian areas are characterized by limited access to primary and specialty health care in comparison to their urban and non‐Appalachian counterparts. Better access to telehealth can improve detection of ADRD in remote regions but it highly relies on availability of broadband services. Our objective is to evaluate the influence of county‐level broadband availability on Appalachian and rural variation in ADRD prevalence in Central Appalachia.MethodCounty‐level ADRD prevalence among fee‐for‐service Medicare beneficiaries in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia) was estimated using 2015‐2018 Centers for Medicare and Medicaid Services Public Use Files. Broadband availability was defined as county‐level measures of broadband presence (FCC Broadband Deployment Data 2015‐2019), proportion of households with broadband, household device ownership, household internet access (American Community Survey 2015‐2019), and broadband usage (Microsoft 2019). ADRD prevalence by Appalachian Regional Commission’s Appalachian/non‐Appalachian designation, and by rural/urban classification (Rural‐Urban Continuum Codes) was estimated using sequential negative binomial regression models: (1) crude; (2) adjusted for age, education, and care access (PCP and neurology visits); (3) additionally adjusted for all broadband measures.ResultAmong all Central Appalachian counties, 52%‐97% had broadband access throughout the study period (Figures 1‐2). The proportions of urban (61%) and non‐Appalachian counties (60%) with broadband access were higher relative to rural (39%) and Appalachian (40%) counties. Appalachian counties had higher prevalence in both rural (Prevalence Ratio (PR): 1.02; 95% CI: 1.00, 1.04) and urban (PR: 1.03; 95% CI: 1.02, 1. 05) areas, but this was mostly explained by socio‐demographics in rural areas (PR: 1.00, 95% CI: 0.98, 1.02; Table). Variation in urban counties persisted after adjustments for demographics, access, and broadband (PR: 1.01; 95% CI: 1.00, 1.03).ConclusionVariation in ADRD prevalence was largely explained by socio‐demographics and care access but not broadband availability. However, the role of broadband access on ADRD prevalence needs to be clarified. Greater broadband access may reflect improved telemedicine access and higher diagnoses, yet the inconsistency in rural counties challenges this hypothesis and other explanations should be considered.
Tau accumulation mediates β‐amyloid effects on hippocampal atrophy and memory in early Alzheimer’s disease
Authors: Fernandez‐Lozano Sofia , Fonov Vladimir S , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Poltronetti Nina Marguerita , Rosa‐Neto Pedro , Collins D Louis 
Published: January 2025

AbstractBackgroundWhile we know dementia in Alzheimer’s disease (AD) results from the accumulation of β‐amyloid (Aβ), tau pathology, and hippocampus atrophy (HC), it is still unclear how these factors impose cognitive decline.MethodWe used Structural Equation Models (SEM; lavaan R package) to explore the complex relationships between the neurobiological factors in the early stages preceding AD dementia in the TRIAD cohort. Our sample comprised 333 timepoints of neuropsychological evaluation (MoCA), structural MRI, Aβ ([18F]AZD4694), and tau ([18F]MK6240) PET of cognitively healthy (NC) and mild cognitive impaired (MCI) participants. We measured neurodegeneration with an inverted HC‐to‐Ventricle ratio (HVR), i.e. 1‐HVR, an integrity measure composed of the ratio of the HC volume and the sum of the volumes of HC and the temporal horn of the lateral ventricle.We used a feature selection algorithm (Boruta R package) to select the most important Regions of Interest (ROIs) from the CerebrA atlas relating Aβ & Tau to memory. We then used SEM to explore the mediation of Aβ and Tau on HC‐atrophy and memory using 1) the average Aβ & Tau SUVR of all ROIs and 2) separate models using the Aβ & Tau SUVR for each of the ROIs. Age, sex and education were treated as covariates. For ease of comparison, we calculated the standardized coefficients in our models.ResultThe demographic data of our sample is presented in Table 1.The selected ROIs were: bilateral amygdala, hippocampus, and parahippocampal gyrus; right fusiform gyrus and orbitofrontal cortex (lateral and medial portions); and left middle temporal gyrus.The full SEM with all ROIs show full mediation between Aβ, Tau and HC‐atrophy, and partial mediation between all biomarkers (Figure 1). On the distinct models by ROI, Amyloid’s effect on MoCA is almost always indirect through Tau (Figure 2).ConclusionWe show that, even in the early stages of AD, Aβ aggregation alone has no effect on HC atrophy, and only a weak effect on cognitive decline; interactions with tau pathology is required to modulate the effects of Aβ aggregation on both HC atrophy and memory loss.
Association between autonomic function, depressive symptoms, and cognitive function in cognitively normal older adults in U.S. POINTER trial
Authors: Shaltout Hossam A , Garcia Katelyn R , Baker Laura D , Snyder Heather M , Papp Kathryn V , Bailey Margie J , Brinkley Tina E 
Published: January 2025

AbstractBackgroundAutonomic dysfunction and depression are among the most common causes of disability in high‐income countries and depression has been associated with deficits in various cognitive domains. The degree to which depression associates with autonomic function and modifies risk for Alzheimer’s disease (AD) in older adults is unknown. We investigated the association between depression status and autonomic function measures in 398 participants enrolled in the U.S. POINTER trial (mean age: 68.0±5.3 years, 61% female, 32% people of color).MethodsContinuous blood pressure and ECG recordings were used to assess baroreflex sensitivity (BRS), blood pressure variability (BPV), heart rate variability as measured by root mean square of successive differences (rMSSD) and standard deviation of beat to beat interval (SDNN), and sympathovagal balance (LF/HF ratio). Participants were classified as depressed if their geriatric depression scale (GDS) score was >4 or if they used antidepressants, or as non‐depressed if their GDS score was ≤4. Autonomic variables were compared according to depression status. Linear regression was used to examine cross‐sectional associations between the outcomes of interest adjusting for age, sex, race/ethnicity, education, and site.ResultsThe prevalence of depression was 27% (n = 110). Depressed individuals were more likely to be female (p = 0.0021), have higher cholesterol levels (p = 0.0056), and have lower BRS (p = 0.0016), rMSSD (p = 0.009) and SDNN (p = 0.0003), with a trend for higher LF/HF ratio (p = 0.12). GDS score was negatively associated with BRS (p<0.05), rMSSD (p = 0.04), and SDNN (p = 0.008). Meanwhile, LF/HF ratio positively correlated with measures of global cognition (p = 0.0045), executive function (p = 0.003), and processing speed (p = 0.008), while rMSSD and SDNN positively correlated with the mini‐mental state examination score. SDNN positively correlated with global cognition and executive function (p<0.05). Adjusting for GDS score did not alter the association between autonomic function and cognition.ConclusionsIn this population of older adults at risk for AD, measures of autonomic function were positively associated with cognitive function and negatively associated with depression. Further studies are needed to assess if early diagnosis and treatment of depression in this population could delay the development of AD.
Beyond GWAS: Investigating Structural Variants and Their Segregation in Familial Alzheimer’s Disease
Authors: Gunasekaran Tamil Iniyan , Reyes‐Dumeyer Dolly , Corvelo André , Clarke Wayne E. , Evani Uday S. , Byrska‐Bishop Marta S. , Basile Anna O. , Runnels Alexi , Musunuri Rajeeva O. , Narzisi Giuseppe , Faber Kelley M. , Goate Alison M. , Boeve Brad F. , Cruchaga Carlos , Pericak‐Vance Margaret A. , Haines Jonathan L. , Rosenberg Roger N , Tsuang Debby W , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Sweet Robert , Bennett David A. , Wilson Robert S. , Foroud Tatiana M. , Dalgard Clifton L. , Mayeux Richard , Zody Michael , Vardarajan Badri N 
Published: January 2025

AbstractBackgroundLate‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated.MethodWe analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset.ResultWe identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene.ConclusionOur findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.
More Cumulative Time Spent Pregnant is Associated with Thicker Cerebral Cortex in Postmenopausal Women
Authors: Bramen Jennifer E. , Popa Emily S. , Kwon Dayoon , Chang Marcus , Raj Sonel , Crandall Carolyn , Espeland Mark A. , Porter Verna R. , Siddarth Prabha , Fox Molly 
Published: January 2025

AbstractBackgroundMatrescence, like adolescence, is a critical period for neurodevelopment characterized by hormonal changes that reshape the brain in preparation for new experiences and subsequent learning. Women exhibit greater age‐matched Alzheimer’s disease (AD) risk than men, yet little is known about long‐term neurological health consequences of reproduction (Buckley, 2019), the defining biological difference between the sexes. We tested the hypothesis that greater number of months pregnant would be positively associated with cortical thickness (CT), particularly in regions within the default mode network (DMN). DMN disruption is well‐established in AD pathology (Dennis, 2014). Research also indicates that synaptic pruning within the DMN during pregnancy is related to improved maternal attachment and reduced hostility toward the infant, with these changes persisting post‐partum (Hoekzema, 2017; Garcia, 2021). Moreover, in late life, beneficial changes due to motherhood have been shown in the DMN (Orchard, 2021).MethodWe used data from 1004 older women from the Women’s Health Initiative Magnetic Resonance Imaging (MRI) study (Coker, 2009) (Table 1). CT was estimated from T1‐weighted MRI using FreeSurfer. The effect of cumulative pregnancy duration on mean CT was assessed using a linear mixed model, controlling for parity (number of complete pregnancies), breastfeeding duration, age, reproductive span, estrogen, and progestogen hormone therapies (HT) and duration, and time since HT cessation. Cortical surface analyses used linear regression, accounting for the same confounders, and were corrected for multiple comparisons using cluster‐wise probability.ResultsThe number of months a woman was pregnant was positively associated with global cortical thickness (b = 0.002, p = 0.002). Cortical surface analysis revealed only positive regional associations with CT, including most regions of the DMN (Figure 1; Table 2), as well as several clusters outside the DMN. Notably, the anterior cingulate (ACG) did not show a significant association.ConclusionsThis work supports the hypothesis that pregnancy may be beneficial for late‐life brain health, particularly in regions important to AD‐pathology such as the DMN, with benefits extending beyond the effect of parity and breastfeeding. Future directions of this work include subcortical analysis and examining whether genetic risk for AD (such as APOE) modifies the relationship between pregnancy and cortical atrophy.
Marital Status and Gender among the Oldest Old: Implications for Cognitive Decline in the Life After 90 Study
Authors: Lee Elisa S , Whitmer Rachel A. , Gilsanz Paola , Meunier Claire C. , Lor Yi , Chen Nancy X , Corrada María M. M. , Posis Alexander Ivan B. , Mungas Dan M. , Decarli Charles , Kawas Claudia H. , George Kristen M. 
Published: January 2025

AbstractBackgroundWidowhood is associated with cognitive impairment, which is salient for the oldest‐old, who are at high risk of cognitive decline and spousal loss. We assessed the association of marital status with cognitive decline in the LifeAfter90 Study (LA90) and examined effect modification by gender.MethodLA90 enrolled participants aged 90+ who were long‐term members of Kaiser Permanente Northern California. Analyses included participants identifying as married, separated, or widowed (excluding single and never married individuals due to small numbers). At 6‐month intervals, the Spanish and English Neuropsychological Assessment Scale (SENAS) measured executive function (EF) and verbal episodic memory (VEM), standardized to baseline. Linear mixed models estimated the association of marital status with EF and VEM adjusting for baseline age, race/ethnicity, gender, education, depression, social and emotional support, interview mode and practice effects. Gender stratified models assessed differences between men and women.ResultParticipants (n = 943) had a mean age of 92.4±2.3, 61% were women, 61% were widowed, 29% were married, and 10% were separated. Women were more likely to be separated or widowed. Compared to widows, separated participants had higher average baseline EF (βEF (95% CI):0.14(‐0.07,0.35)) while married participants had lower (βEF: ‐0.13(‐0.29,0.03)), though these differences were not statistically significant. Over 1.8±1.35 years of follow‐up, married and separated participants had non‐significant faster decline in EF (Married pEF = 0.33; Separated pVEM = 0.55; Figure 1) and VEM (Married pEF = 0.34; Separated pVEM = 0.07; Figure 1) compared to widows. While associations were not significant in sex‐stratified models, married vs. widowed men had lower baseline EF (βEF:‐0.16(‐0.37,0.04)), separated vs. widowed men had better EF (βEF:0.29(‐0.19,0.76)), and separated vs. widowed women had better EF (βEF:0.12(‐0.13,0.36)). There were no significant differences in decline in sex‐stratified models, though slopes for separated men appeared slightly steeper (Figure 2).ConclusionIn this diverse cohort of adults ages 90+, there were no significant differences in marital status and cognitive decline, though findings suggested separated participants may average better baseline cognition and steeper decline compared to widowed and married oldest old adults. Further research is necessary to assess the importance of marital status on cognitive aging and decline.
Animal protein intake is associated with frailty but not with cognition: an ELSI‐Brazil preliminary study of food consumption
Authors: Vasques Vivian Silveira , Borelli Wyllians Vendramini , Ferrari‐Souza João Pedro , de Freitas Núbia Alencar , Pauli Patricia , Suemoto Claudia Kimie , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundDiet is considered a complex modifiable risk factor for dementia and frailty. Some dietary patterns such as the MIND diet have been associated with a reduced risk of cognitive decline and dementia. Studies have shown mixed results with protein intake and frailty. However, the association of animal protein intake with cognitive performance and frailty is yet unclear. This study aimed to investigate the association of food group consumption with cognition and frailty in Brazilian older adults.MethodThis cross‐sectional study included baseline data from the Brazilian Longitudinal Study of Ageing (ELSI‐Brazil). The sample comprises cognitively unimpaired (CU, n = 4.155) and cognitively impaired (CI, n = 974) older adults (Table). Frailty was defined by weight loss, weakness, slow walking speed, exhaustion, and low physical activity. Cognition was calculated with a z‐score of orientation scores, animal fluency and memory recall. Individuals were defined as CI if the global cognition score was below 1SD of the sample mean. The association between food consumption and cognition was evaluated using a linear regression model corrected for age, sex, education, BMI, income, and frailty. A mediation model was developed with the association between cognition, frailty and animal protein intake (Figure).ResultCI individuals showed increased rates of frailty (47.4% vs. 26.6%, p<0.001), and presented decreased weekly intake of fruits (8.9±6.2 vs. 9.6±6.3, p = 0.03) when compared with CU. Weekly intake of vegetables and animal protein was similar between groups (Table). Linear regression model identified total weekly intake of animal protein was associated with frailty, but not with cognition (Figure). Consuming animal protein in less than 5 days per week was associated with increased cognitive scores (β = 0.24±0.08, p<0.001), but this association was not significant when analyzing subgroups of animal protein (red meat, fish or chicken).ConclusionOur results suggest that weekly animal protein intake is associated with frailty but not cognition. However, intake of animal protein less than 5 days a week may have a neuroprotective effect. Further studies should understand the complex interaction of animal protein consumption in cognition and frailty.