bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal Functional Organization Mediates the Impact of the Cortical Iron on the Cognition in Women with Suspected Coronary Microvascular Dysfunction
Authors: Silemek Arzu C Has , Wertheimer Jeffrey C , Wei Janet , Dumitrascu Oana M , Kremen Sarah , Xie Yibin , Li Debiao , Nelson Michael D , Tan Zaldy S , Merz Noel Bairey , Sati Pascal , Gao Wei 
Published: January 2025

AbstractBackgroundWomen with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer’s disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain’s functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).Material and MethodsTwenty‐seven women with suspected CMD [Age; median (range) = 54 (29‐76)], drawn from ongoing cohorts (3R01HL146158‐04S1,3U54AG065141‐04S1), underwent a 3T MRI protocol, including submillimeter T2* 3‐dimensional echo‐planar‐imaging for assessing iron deposition with high‐resolution quantitative susceptibility mapping (QSM) and resting‐state fMRI (rs‐fMRI). Iron content was quantified by total‐generalized‐variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.ResultsMost of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure 1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p=0.005, adjusted‐r2=0.19) (Figure 1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient=531.09) as well as language functions and crystalized abilities (p=0.036, coefficient=362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = ‐254.54 /‐ 213.06) (Figure 1C).ConclusionsOur results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.
Association of lifestyle activities with cognitive function and Alzheimer’s disease CSF biomarkers: an examination of cognitively normal adults in the Stanford Aging and Memory Study (SAMS)
Authors: Lu Olivia , Mormino Elizabeth , He Zihuai , Carr Valerie A , Trelle Alexandra N. , Young Christina B. , Romero America , Vossler Hillary , Park Jennifer , Skylar‐Scott Irina Anna 
Published: January 2025

AbstractBackgroundIt is increasingly clear that delaying the onset of Alzheimer’s disease (AD) dementia by several years can meaningfully lower its prevalence. The goal of the present study is to examine the relationship between lifestyle activities and cognition function as well as cerebrospinal fluid (CSF) biomarkers of AD to determine whether these activities can serve as protective factors for AD resistance and resilience.Methods173 cognitively normal older individuals (mean ± SD, 69 ± 6.4 years) were recruited to the Stanford Aging and Memory Study (SAMS) and completed the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire regarding current social, cognitive, and physical activity (Table 1). They also underwent APOE genetic testing and a detailed neuropsychological evaluation. The following cognitive domains were evaluated after conversion to z‐scores: global cognition (cognitive composite), executive function, working memory, attention, episodic memory, visuospatial function, and language (see Table 2 for definitions). 127 participants completed lumbar punctures, and levels of Aβ‐40, Aβ‐42, p‐tau181, and total tau were measured in the CSF. Cross‐sectional regression models included age, sex, years of education, and APOE status as co‐variates. Benjamini‐Hochberg corrections for multiple hypotheses were completed.ResultsThere was a significant association between social activity (frequency/week) and global cognition (β = 0.20, p = 0.03), executive function (β = 0.15, p<0.05), and working memory (β = 0.26, p = 0.01) but not episodic memory, visuospatial function, or language function. There was also a significant association with attention prior to correction for multiple hypotheses (β = 0.17, p = 0.04) but not afterward (Table 2). Additionally, there was a significant association between cognitive activity (hours/week) and global cognition (β = 0.19, p = 0.03) as well as executive function (β = 0.25, p = 0.007) but not with other cognitive domains tested (Table 3). There was no association between light or moderate caloric expenditure and cognitive measures. There was also no significant relationship between CSF biomarkers and levels of social, cognitive, and physical activity.ConclusionsIn a well‐characterized cohort of cognitively normal older adults, higher levels of social and cognitive activity were associated with higher cognitive scores on tasks of executive function but not episodic memory. The mechanism mediating this relationship appears to be independent of both Aβ and tau burden.
Associations of early‐life factors and risk of incident dementia: a cohort study of 247,841 participants
Authors: Ou Ya‐nan , Tan Lan , Yu Jin‐Tai 
Published: January 2025

AbstractBackgroundLife‐course models are increasingly recognized in dementia prevention but have too often focused on mid to later life, thereby missing major opportunities for prevention much earlier. This study aimed to reveal the associations between early‐life factors and incident dementia risk, and the underlying brain imaging alterations.MethodEight early‐life factors (maternal smoking around birth, birth weight, part of a multiple birth, breastfed as a baby, adopted as a child, comparative height at age 10, comparative body size at age 10, and child maltreatment) in the UK BioBank (UKB) were investigated. Multi‐adjusted Cox proportional hazard model and restricted cubic spline model were performed to investigate the longitudinal associations. Linear regression analysis was performed to reflect the statistical dependencies with brain imaging measurements.ResultA total of 247,841 UKB participants with a mean age of 59.9 (SD 5.5) years old and a female percentage of 57.2% were included. Over a mean of 8.7 (SD 2.7) years of follow‐up, 3,661 all‐cause dementia (ACD) were recorded. Maternal smoking around birth and shorter height at age 10 was associated with an 13%‐20% increased risk of dementia. Approximate linear relationship between birth weight and dementia risk was revealed. Maintaining the specific birth weight window (3.73‐5.00 kg) was related with lowest vascular dementia (VaD) risk. Physical neglect was related with all of the three dementia outcomes (HR:2.56 for ACD, HR:2.91 for Alzheimer’s disease [AD], HR:6.87 for VaD). Extensive associations exist between early life factors and dementia‐related brain structures, especially middle temporal lobe and hippocampus.ConclusionEarly risk factors are closely associated with late‐life dementia risk. Policies investing in early child development may contribute to improve lifelong brain health to prevent late‐life dementia.
Occupational complexity and cognitive resilience in the Framingham Heart Study
Authors: Hwang Phillip H , Feng Irena , Durape Shruti , Gurnani Ashita S. , Ang Ting Fang Alvin , Devine Sherral A. , Choi Seo‐Eun , Lee Michael L. , Scollard Phoebe , Gibbons Laura E. , Mukherjee Shubhabrata , Trittschuh Emily H. , Sherva Richard , Dumitrescu Logan C. , Hohman Timothy J. , Saykin Andrew J. , Crane Paul K. , Au Rhoda , Farrer Lindsay A. , Mez Jesse 
Published: January 2025

AbstractBackgroundGreater occupational complexity may be protective against dementia in later life, but it is unclear if it contributes to cognitive resilience and whether different aspects of occupational complexity are associated with resilience. We examined relationships between occupational complexity related to data, people, and things, and cognitive resilience to neurodegeneration.Method1,699 participants from the Framingham Heart Study Offspring cohort who were aged ≥60 years, had a plasma total tau (t‐tau) measure (a marker of neurodegeneration), and a neuropsychological (NP) exam visit within five years of the plasma t‐tau measurement were included. Plasma t‐tau was measured using the Simoa assay (Quanterix) on samples collected at Exam 8 (2005‐2008). NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. Occupational data were collected at the NP exam, from which occupational complexity was disaggregated into data complexity, people complexity, and things complexity according to the 1970 US Census Dictionary of Occupational Titles. Cognitive resilience was operationalized using a residual approach by regressing each NP factor score on the plasma t‐tau measure, adjusting for age, sex, education, time from blood draw, and APOE ε4 status. The adjusted residuals were then regressed on each type of occupational complexity, dichotomized into higher complexity versus lower complexity.ResultThe sample was, on average, 70 years of age, 53% female, and had 15 years of education. Higher data (β = 0.20, 95% confidence interval (CI) = 0.15‐0.25, p<0.001), people (β = 0.11, 95% CI = 0.07‐0.15, p<0.001), and things (β = 0.05, 95% CI = 0.01‐0.09, p = 0.015) occupational complexity were most strongly associated with resilience in executive function. Higher data (β = 0.10, 95% CI = 0.05‐0.15, p<0.001) and people (β = 0.07, 95% CI = 0.03‐0.11, p = 0.001) occupational complexity were associated with resilience in memory. Higher data (β = 0.07, 95% CI = 0.01‐0.12, p = 0.014) occupational complexity was associated with resilience in language.ConclusionSpecific types of occupational complexity contribute to resilience to neurodegeneration in specific cognitive domains differently. Occupational complexity may offer the most resilience in executive function and occupations with high data complexity may offer the most cognitive resilience.
Association Between Cumulative Anticholinergic Use and White Matter Hyperintensity Burden
Authors: Li Kevin H , Krakauer Chloe , Nelson Jennifer C , Crane Paul K. , Andre Jalal B , Curl Patti , Yuh Esther C. , Ralston James , Gray Shelly L , MacDonald Christine 
Published: January 2025

AbstractBackgroundAnticholinergic medication use has been found to be associated with higher dementia risk and cognitive decline in older adults. The presence of a biologic pathway through changes to white matter hyperintensities (WMH) remains unclear.MethodWe used the first clinically indicated magnetic resonance imaging (MRI) scan from each participant in the Adult Changes in Thought (ACT) Study—a prospective cohort study within Kaiser Permanente Washington (KPWA)—collected between January 2003 and March 2020 from participants ≥65 years old and with ≥10 years of continuous KPWA enrollment prior to the scan. Our primary cumulative exposure was total standardized daily dose (TSDD) of anticholinergic medications in the 10 years prior to the scan, grouped as non‐use, 1‐90 TSDD, 91‐365 TSDD, 366‐1095 TSDD, and ≥1096 TSDD. Neuroimaging outcomes were common data elements (CDEs) for WMH on MRI scans (Fazekas, Scheltens, Age‐Related White Matter Changes [ARWMC]). We used separate linear regression models for each outcome to estimate adjusted mean values of CDEs in each exposure group and test for differences in mean values.ResultOf the 1,043 individuals included in analyses, 28% had no use, 33% had 1‐90 TSDD, 15% had 91‐365 TSDD, 7% had 366‐1095 TSDD, and 17% had ≥1096 TSDD. The mean age at the time of the scan was 81 years among a group that was majority female (58%) and White (88%). While most individuals were exposed to antihistamines (38%) among all anticholinergic classes, 65% of TSDD were accrued from antidepressants. Compared to no use, the ≥1096 TSDD group had a higher (worse) adjusted mean Fazekas (4.0 vs. 3.4; p: <0.001), Scheltens (14.3 vs. 12.2; p: <0.001), and ARWMC (5.6 vs. 4.8; p = 0.001). A dose‐response relationship was not found, but adjusted mean outcomes values were observed to be higher (worse) in the 1‐90 TSDD group relative to the no use group.ConclusionThe highest anticholinergic burden was associated with greater WMH burden among older individuals who received an MRI due to clinical indications. The lack of a demonstrated dose‐response relationship warrants further research into biological mechanisms underlying the link between anticholinergic use and WMH burden.
Survival Disparities among Alzheimer’s Patients in Hawaii: Exploring Racial/Ethnic Disparities and Machine Learning for Survival Prediction in the Hawaii Medicare Population
Authors: Siriwardhana Chathura 
Published: January 2025

AbstractBackgroundThe survival outcomes following an Alzheimer’s disease (AD) diagnosis hold significant importance for health management, caregivers, patients, and their families. Hawaii is known as the most diverse ethnic population in the United States and there exist significant racial health disparities. This study investigates racial/ethnic disparities in survival among AD patients in Hawaii and develops Machine Learning models for overall survival prediction, utilizing Hawaii Medicare data.MethodWe utilized nine years of Hawaii Medicare data to gather information on developing AD after age 65, and followed them for capturing the all‐cause survival or until censoring. We examined the effects of race/ethnicity coupled with socioeconomic status (SE) on the risk of mortality. SE status was accessed by the surrogate marker: Medicare/Medicaid dual eligibility. Cox regression analysis was conducted on the overall survival while accounting for age at AD onset, Gender, and multiple comorbidities. Subsequently, a Survival Random Forest (SRF) was employed to predict survival within a machine learning framework, incorporating K years of longitudinal subject health profiles, including demographics, chronic disease profiles, observed acute conditions, and hospitalization history. A penalty‐based variable selection was employed for SRF development.ResultThe study included n = 9,393 AD subjects. Our analysis revealed that American Asians (AA) had a later age at AD diagnosis (p<.001), with an average age of 85.9, compared to 82.7 and 83.3 years for Whites (WH) and Native Hawaiians and Pacific Islanders (NHPI), respectively. Low SE level exhibited an increment in mortality hazard (Hazard Ratio [HR] = 1.36, p<.001). In comparison to AA with high SE (AA + high SE), increased hazards were found for AA + low SE (1.29, p<.001), WH + high SE (1.19, p<.001), WH + low SE (1.52, p<.001), and NHPI + low SE (1.39, p<.001). The SRF model with K = 2 setting demonstrated a Concordance (C) Index of 0.806 via five‐fold cross‐validation, exhibiting robust survival predictability of AD subjects. A permutation‐based study identified a list of factors influencing subject survival.ConclusionThe onset of AD development and survival are influenced by race/ethnicity and SE status. When combined with longitudinal health data, machine learning demonstrates reasonable predictability of survival.
Alzheimer’s Disease and Healthy Aging Indicators Cognitive Decline
Authors: Khuld Hamna 
Published: January 2025

AbstractBackgroundIn the United States and Puerto Rico, cognitive decline and resulting Alzheimer’s disease are major public health concerns for older adults. According to the Alzheimer’s Association (2021), by 2050, people ages 65 and above with Alzheimer’s are estimated to grow to 12.7 million—rising in prevalence and severity. The rise in Alzheimer’s prevalence is attributed to genetic, environmental, and lifestyle factors—leading to memory, judgment, language, and behavior problems. This research examines whether there is an association between race and cognitive decline as indicated by adults ages 50 and above in the United States and Puerto Rico.MethodThe Alzheimer’s Disease and Healthy Aging Indicators Cognitive Decline study is an ecological study that documents cognitive decline or memory loss among adults ages 50 and above. The data was collected from 2015 to 2019 by the Center for Disease Control, under the Behavior Risk Factor Surveillance System (BRFSS). The surveys documented cognitive decline or memory loss experienced by 16,799 older adults by age, race, sex, and state of residency.ResultThe main findings examine the association of cognitive decline by comparing races, using White, non‐Hispanic as the reference group. This analysis shows that Hispanic vs White has the highest OR of 10.35 and 95% CI of 3.128 to 34.256. Black, non‐Hispanic vs White, non‐Hispanic have the second‐highest OR at 3.130 with 95% CI at 1.277 to 7.674.Association between cognitive decline and race showed a negative inverse relationship–cognitive decline (BRFSSPRCTG) decreases depending on the race. Races such as Native Am/Alaskan Native, Hispanic, and Black, White are statistically significant. However, Asian/Pacific Islanders had on average 0.67 standard error, which is not statistically significant (alpha = 0.05).Age and its association with participants' state of residency shows that Maryland had the highest percentage of cognitive decline by either age group–ages 50‐64 years are 4.76%, and ages 65 and older are 4.50% likely to experience cognitive decline.ConclusionsIn conclusion, race is associated with cognitive decline depending on age and state of residency. Further research is needed because there was missing information on participants' education, income, zip code, socioeconomic status, etc., which may contribute to cognitive decline.
Financial toxicity of family dementia caregiving in South Korea
Authors: Yang Hyejeong , Seo Hyun‐Ju , Choi YuMi , Kim Jeong Lan , Kim Seong Min 
Published: January 2025

AbstractBackgroundOne out of every ten individuals aged 65 or above in Korea experiences dementia, with a total dementia care cost of KRW 18.7198 trillion, or approximately KRW 21.24 million per person. It was discovered that the cost of treating dementia increases annually as the severity of each patient’s condition worsens. The rise in dementia cases leads to an increased economic and social burden for care and reduced quality of life for patients and families. Therefore, we aimed to identify the prevalence of financial toxicity in dementia caregiving, its sociodemographic, and its recipients’ caregiving correlates in family caregivers in the context of South Korea.MethodWe utilized the Korean version of the Comprehensive Score for Financial Toxicity (COST) of a 12‐item questionnaire to quantify subjective financial toxicity in at least 300 primary family caregivers who are spouses, children, or siblings. The data will be collected using online platforms and paper printouts from hospital outpatient and community‐based dementia relief centers. Additionally, we will gather family caregivers’ characteristics, including general characteristics, socioeconomic factors (such as employment status and monthly income), presence of chronic diseases, and their recipient’s characteristics, including general characteristics of the recipient, treatment characteristics, resident region (urban or rural), time to since diagnosis, and dependency scale.ResultWe will present the prevalence of financial toxicity and related factors that have a significant impact on the financial toxicity experienced by these caregivers. The study results will be presented in a poster presentation at an upcoming conference.ConclusionAlthough approximately 80% of people with dementia are eligible and likely to cover long‐term care insurance in South Korea, no survey has been conducted to examine the prevalence and factors affecting the financial burden of primary family caregivers. Caregivers' perceptions of financial toxicity will increase the long‐term distress of the caregiving role. The findings of this study will help develop policy strategies to improve the financial well‐being of family caregivers of people with dementia.
Association of cardiorespiratory fitness with dementia risk across different levels of genetic predisposition: a large community‐based longitudinal study
Authors: Wang Shuqi , Xu Liyao , Yang Wenzhe , Wang Jiao , Dove Abigail , Qi Xiuying , Xu Weili 
Published: January 2025

AbstractBackgroundCardiorespiratory fitness (CRF), a proxy for cardiovascular and respiratory function, has been linked to health outcomes, but its association with cognition and dementia risk remains unclear. We aimed to investigate the association of CRF with domain‐specific cognitive function and dementia risk, taking genetic predisposition for dementia into account.MethodWithin the UK Biobank, 61,214 dementia‐free participants aged 39‐70 (mean age: 56.33 ± 8.15, 51.96% were female) were followed for up to 16 years to detect incident dementia. CRF score (measured in metabolic equivalent of task [MET] units) was estimated using a 6‐min submaximal exercise test on a stationary bike and divided into tertiles (i.e., low, moderate, and high). Tests of global and domain‐specific cognitive functions (including prospective memory, visual memory, verbal/numeric memory, and processing speed) were administered at baseline. Dementia was identified based on medical history and medical records. Genetic predisposition for dementia was estimated using the polygenic risk score for Alzheimer’s disease (PRSAD), tertiled as low, moderate, or high level. Data were analyzed using linear regression, Poisson regression, and Laplace regression.ResultThe age‐ and sex‐specific CRF ranged from ‐2.74 to 6.61 MET at baseline. In multi‐adjusted linear regression, compared to low CRF, high CRF was related to better global cognitive function (β [95% confidence interval]: 0.05 [0.04, 0.06]), prospective memory (0.06 [0.04, 0.08]), verbal/numeric memory (0.11 [0.09, 0.13]), and processing speed (0.05 [0.03, 0.07]). Over the follow‐up (median [interquartile range]: 11.52 [11.62–11.87] years), 553 individuals developed dementia. Compared to low CRF, the incidence rate ratio (IRR [95% CI]) of dementia was 0.61 (0.48–0.77) for high CRF, and the onset of dementia was delayed by 1.47 (95% CI: 0.64–2.30) years among people with high vs. low CRF. Among people with moderate/high genetic risk for dementia, high CRF can attenuate dementia risk by 35% (IRR = 0.65, 95% CI: 0.51–0.82). There was a trend of CRF to alleviate the genetic risk for dementia, but the additive interaction was not significant.ConclusionHigh CRF is associated with better cognitive performance at baseline, and lower dementia risk over follow‐up. High CRF could mitigate the impact of genetic predisposition on dementia risk by almost 40%.