bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mediation of Physical Activity Patterns between Whiter Matter Microstructure Alteration and Cognitive Decline According to the Progression of Alzheimer's Disease
Authors: Kim Narae , Roh Hyun Woong , Son Sang Joon , Park Bumhee 
Published: January 2025

AbstractBackgroundWe aimed to clarify the role of physical activity patterns on cognitive function decline caused by white matter structure alteration following the progression of Alzheimer’s disease(AD). Physical activity has been reported as having a close association with various pathological factor of dementia, especially it has been proved as a protective factor of disease advancement. Comparing the mediating models between Mild Cognitive Impairment (MCI) and AD, we aspire to elucidate how activity patterns, as a biomarker, undergo progression in the pathogenesis of the disease.MethodData from Biobank Innovation for chronic Cerebrovascular disease With ALZheimer’s disease Study (BICWALZS, N=131, 93 females, age = 71.66 ± 7.51) were used and we divided the cohort into three subtype groups of dementia; MCI with Amyloid beta negative(MCI‐), MCI with Amyloid beta positive(MCI+) and AD. Fractional Anisotropy (FA) was extracted from 48 regions as defined at JHU atlas and 6 activity pattern parameters (L5, M10, IS, IV, kRA, kAR) were calculated. Mediation analysis was conducted regional FA values as a predictor, a standardized score of Mini‐Mental State Examination as a response variable and the physical activity parameters as a mediator for each group separately.ResultWe found significant mediation effect in the MCI+ group after adjusting age, sex, and education year (FDR corrected P < 0.05). 20 white matter regions showed significant mediation effect with mean physical activity intensity during most active 10 hours (M10) and 24 regions showed significant mediation effect of Intraday variability (IV). Although there was similar result in AD group, but the only one region showed, and the effect size of mediation path was quite small. There was not any significant result in the MCI‐ group.ConclusionSumming up, these results can be interpreted as that the protective effects of physical activity on the cognitive decline caused by white matter alteration is far larger to patient with amyloid deposition and the effects can be decreased after the onset of AD. Therefore, enhancing physical activity patterns can be an effective strategy to slow down the progression of the disease, particularly in amyloid‐positive patients, prior to the onset of AD.
Sex differences in the association between amygdala volumes and non‐emotional memory retrieval performance
Authors: Esiaka Darlingtina , Willis Emily , Broster Lucas , Powell David K , Jicha Gregory A , Jiang Yang 
Published: January 2025

AbstractBackgroundPast studies show that amygdala atrophy may be involved in the early stages of Alzheimer's disease (AD). AD is characterized by progressive cognitive decline, and changes in the amygdala—interconnected with various brain regions involved in cognition—could contribute to memory and emotional processing impairments. Specifically, changes in amygdala volumes may affect these neural networks, contributing to cognitive decline through disrupted communication between brain regions. The present study tests the association between amygdala volumes and non‐emotional memory retrieval and the sex differences in the association.MethodParticipants (mage= 77.05, SD = 7.48; 25 females) from the University of Kentucky Alzheimer’s Disease Center cohort completed two trials of delayed match to sample task inside the 3T Siemens magnetic resonance imaging scanner.ResultWe found that increased volume in the left hippocampus (p < .05, r = .31) and left amygdala (p < .05, r = .30) were associated with faster non‐match distractor response times (RTs) in the second trial. The result further shows significant sex differences whereby there was a significant negative association between the left hippocampus volume and RTs of non‐match distractors in the first trial (r = .40, p < .05) in females but not in males. Also, in females, the left amygdala volume had a significant positive association with accuracy (R2 = .40, p < .05) and a negative association with RTs of non‐match distractors for both trials (Trial 1: r = .43, p < .05; Trial 2: r = .47, p < .05).ConclusionInvestigating correlations between amygdala volumes and non‐emotional memory retrieval has implications for understanding cognitive processes, identifying markers of neurological disorders, addressing individual differences, and advancing both clinical and basic neuroscience research.
Multimodal Perspective on the Influence of Physical Activity on Alzheimer’s Disease
Authors: Haeger Alexa , Romanzetti Sandro , Hohenfeld Christian , David Shari , Costa Ana Sofia , Haberl Luisa , Hildebrand Frank , Schulz Jörg B. , Reetz Kathrin 
Published: January 2025

AbstractBackgroundPhysical exercise presents a viable low‐cost, low‐risk, individual, and widely available non‐pharmacological treatment candidate in cognitive decline such as in Alzheimer’s disease (AD). There are even indications that it can reduce the risk of developing dementia in the first place (Livingston et al., The Lancet, 2020). However, the impact of physical activity and fitness on the multimodal facets of AD, encompassing brain function, cognition and metabolism is still poorly understood.MethodIn the Dementia‐MOVE pilot trial (Multi‐Objective Validation of Exercise), 46 patients diagnosed with Alzheimer’s disease were initially included, randomized to either an intervention arm comprising a 6 months‐supervised sports program or a control condition with a psychoeducational program at the RWTH Aachen University Hospital. Participants underwent a comprehensive multimodal assessment of AD relevant parameters, including multimodal MRI, fitness and activity, neuropsychological assessments, blood examinations and the assessments of neuropsychiatric symptoms (Haeger et al., Alzheimers’s & Dementia TRCI, 2020).ResultIn the intervention group, cardiorespiratory fitness change, i.e. ΔVO2max, showed a positive association with changes in the Montreal Cognitive Assessment (MoCA), in the executive functions score, and in volumes of the temporal lobe. It also showed a negative correlation with baseline cognitive levels (see also Figure 1 on the multiple regression analysis). High physical activity levels were associated with improved quality of life in the overall sample. In functional MRI using resting state and graph theory (n = 20 subjects), we found prediction by ΔVO2max for changes on the degree, betweenness, triangles, transitivity, hubness, closeness and Katz centrality, with the last showing the most effects in regions in the temporal lobe. Metabolic MRI comprising 23Na‐MRI and 31P‐MRS pointed to possible associations of VO2max and/or group attribution with changes in brain sodium concentrations/cerebral metabolites.ConclusionWe show that cardiorespiratory fitness and physical activity examined during an intervention with physical activity can have an impact on different aspects of AD, from cognition, to structural, functional, and metabolic brain alterations. Our results suggest that even patients who are more severely affected by the disease could benefit from interventions in these domains.
Hepatic fat is related to neurodegeneration in midlife obesity
Authors: Kasani Sara Hosseinzadeh , Dolatshahi Mahsa , Naghashzadeh Mahshid , Commean Paul K. , Rahmani Farzaneh , Liu Jingxia , Lloyd LaKisha , Nguyen Caitlyn , Hantler Nancy , McBee‐Kemper Abby , Ly Maria , Yu Gary Z , Ippolito Joseph E. , Weeks Jake , Ceriani Lael , Sirlin Claude , Morris John C. , Benzinger Tammie L.S. , Raji Cyrus A. 
Published: January 2025

AbstractBackgroundObesity in midlife, defined as body mass index (BMI) of 30 kg/m2 or higher in those between 40‐60 years, is related to higher Alzheimer’s disease (AD) later in life. Non‐alcoholic fatty liver disease, as a complication of obesity is associated with impaired cognitive function. We investigated the relationship between hepatic fat quantification by use of MRI‐derived Positron Density Fat Fraction (PDFF) and brain cortical thickness in cognitively normal midlife individuals.MethodOverall, 63 cognitively normal middle‐aged participants (Age: 50.46±6.19 years, female: 22 (71%), obesity: 32 (50.28 %), BMI: 36.46±4.9 kg/m2) underwent brain and abdominal 3T MRI. PDFF values were calculated using a trained U‐Net convolutional neural network (CNN) model to infer the hepatic PDFF maps from conventional T1‐weighted images. The CNN included the Adam optimizer for training with a learning rate of 1e‐4. Visceral and subcutaneous adipose tissue (VAT, SAT) were automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas, followed by visual inspection and if needed, manual editing. A multivariable linear regression analysis was carried out to test the association of PDFF, VAT, SAT, and BMI with brain cortical thickness, with age and sex as covariates.ResultWe observed a statistically significant association between PDFF and VAT (p=3e‐7), BMI (p=2e‐4), and insulin resistance (1e‐4). Among late‐onset AD (LOAD) cortical regions, there was a significant inverse correlation (Adjusted R²=0.19, p<0.001) between left temporal pole thickness and PDFF. Similarly, higher VAT was associated with thinning in left temporal pole (Adjusted R²=0.22, p<0.001) and middle temporal lobe (Adjusted R²=0.12, p=0.014).ConclusionOverall, our data suggest a potential role of hepatic fat fraction in promoting neurodegeneration in cognitively normal midlife individuals. These findings lend insight into a pathway that can be utilized for future AD risk reduction.
Multisite Chronic Pain Accelerates Cognitive Decline Particularly in APOE e4 Allele Carriers
Authors: Bell Tyler R. , Franz Carol E. , Lerman Imanuel , Fennema‐Notestine Christine , Panizzon Matthew S. , Bennett David A. , Elman Jeremy A. , Kremen William S. 
Published: January 2025

AbstractBackgroundChronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vulnerability to cognitive decline, particularly in those at elevated risk for Alzheimer’s disease. We examined how multisite chronic pain relates to cognitive decline in older adults, the possible moderating role of APOE‐ε4 allele status, and—in a postmortem subsample—associations with amyloid and tau.MethodWe examined 751 participants without dementia at baseline from the Religious Orders Study/Rush Memory and Aging Project (ROSMAP; Mean age = 79.47, SD = 6.93, Mean education = 6.42, SD = 3.63; 64% women) followed for up to 30 years with repeated cognitive testing measuring episodic memory, working memory, perceptual orientation, and processing speed (Mean years followed = 7.32, SD = 4.51). Individuals with multisite chronic pain, defined as joint pain in >2 body regions over the first 2 study waves, were compared to those without pain. Amyloid‐beta and tau were measured in a postmortem subsample assessed around 10 months after their last clinical evaluation using computer‐assisted immunoreactivity assays across 8 regions associated with Alzheimer’s disease (hippocampus; entorhinal cortex; midfrontal cortex; inferior temporal; angular gyrus; calcarine cortex; anterior cingulate cortex; superior frontal cortexResultMultisite chronic pain (n = 105) was associated with accelerated decline in episodic memory (b = ‐.03, p = .016) and processing speed (b = ‐.06, p<.001), particularly in APOE‐ε4‐positive individuals (bs = ‐.05 and ‐.04, respectively, ps<.01). Only APOE‐ε4‐positive individuals with multisite chronic pain showed significant decline in perceptual orientation (b = ‐.08, p = .015). Only APOE‐ε4‐positive individuals with multisite chronic pain had higher levels of amyloid‐beta load compared to those without chronic pain (b = .51, p<.001). No differences in tau burden were detected. People with single‐site chronic pain showed no significant differences from people without chronic pain.ConclusionThe results suggest that multisite chronic pain exacerbates cognitive decline, particularly in those at genetic risk for Alzheimer’s disease. In addition, the postmortem analyses suggest that early treatment of multisite chronic pain—a modifiable risk factor—might help to reduce amyloid accumulation.
Does attachment get under our skin? Midlife attachment style predicts mild cognitive impairment and cumulative deficit frailty in old age
Authors: Buchholz Erik , Franz Carol E. ,   Vietnam Era Twin Study of Aging (VETSA) group
Published: January 2025

AbstractBackgroundPoor social relations of older adults have been linked to cognitive decline, dementia risk, morbidity and mortality. However, this history of poor social relations may have started earlier in life and may be related to personality traits. Here we investigate how attachment style, a personality trait, can function as a protective factor for Alzheimer’s Disease and overall health. Specifically, we evaluated whether attachment style at midlife predicted two types of frailty in early old age: cognitive frailty and cumulative deficit frailty. Furthermore, to better understand these pathways, we have investigated several mediators: perceived stress, smoking, alcohol consumption, doctor visits, and social isolation.MethodParticipants were 1275 community‐dwelling men from the Vietnam Era Twin Study of Aging (VETSA) at average ages 56, 62, and 68. Attachment style was assessed at age 56, health mediators at age 62. Frailty at age 68 included cognitive frailty (operationalized as mild cognitive impairment; MCI) and cumulative deficit frailty, a frailty index (FI) comprising 37 items assessing multiple physiological systems. Structural Equation Modeling (SEM) assessed mediators between attachment style and FI/MCI.ResultAge 56 attachment avoidance predicted age 68 MCI (β = 0.132); attachment anxiety predicted age 68 FI (β = 0.179). In mediation models, age 62 social isolation mediated associations between attachment avoidance (β = 0.169) and FI (β = 0.192). Attachment avoidance directly predicted MCI (β = 0.134). Age 62 perceived stress, doctor visits, and smoking acted as mediators between attachment anxiety (βs = 0.400, 0.069, 0.088, respectively) and FI (β = 0.284, 0.278, 0.134, respectively). Perceived stress mediated associations between attachment anxiety (β = 0.400) and MCI (β = 0.230). There was no direct effect of attachment anxiety on MCI.ConclusionPersonality traits involving viewing others as trustworthy and dependable may function as protective factors against frailty in old age. Attachment avoidance and anxiety influence frailty through different pathways, such as social isolation compared to perceived stress and smoking. Thus, to mitigate risk for either cognitive or cumulative deficit frailty, clinicians may wish to evaluate personality characteristics related to the quality of interpersonal relationships (e.g., attachment style) in addition to health factors.
Associations of education and modifiable lifestyle factors with CSF biomarkers of neurodegeneration, neuroinflammation, and Alzheimer’s disease
Authors: Planalp Beth M. , Hulle Carol A. Van , Bendlin Barbara B. , Blennow Kaj , Quijano‐Rubio Clara , Engelman Corinne D. , Kollmorgen Gwendlyn , Ma Yue , Okonkwo Ozioma C , Carlsson Cynthia M. , Johnson Sterling C. , Zetterberg Henrik , Merten Natascha 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) and related dementias can have long preclinical phases; thus, midlife intervention and prevention methods could prove efficacious. Multiple health‐related lifestyle factors have been associated with risk for AD. However, research on lifestyle factors has focused on clinical outcomes such as cognitive decline, mild cognitive impairment and/or AD dementia; their associations with potential early changes in cerebrospinal fluid (CSF) biomarkers are less understood. Our aim was to determine whether key lifestyle factors are associated with CSF biomarkers for neurodegeneration, glial activation, and neuroinflammation.MethodParticipants were N=653 adults (aged 43—93 years) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center, two on‐going, longitudinal studies of preclinical AD. We assessed CSF biomarkers using the NeuroToolKit (NTK), a panel of robust prototype biomarker assays (Roche Diagnostics International, Switzerland). Participants completed demographic and health questionnaires and a physical assessment (Table 1). Linear regression models assessed standardized effects of associations between lifestyle factors (education, smoking, obesity, and physical activity) and CSF biomarkers, adjusting for age and sex.ResultAfter correcting for false discovery rate, preliminary results (Table 2) showed that participants with more years of education had higher CSF Aβ42/40 and lower pTau181 concentrations (Est. = 0.006, or 1 unit increase in Aβ42/40 per year increase in education, 95% confidence interval: 0.001–0.011; p =.008, adjusted p = .061; Est.= ‐0.007, or 1 unit decrease in pTau181 per year increase in education, 95% confidence interval: ‐0.013–‐0.002; p=.026, adjusted p=.061). No other biomarker associations withstood correction for multiple comparisons.ConclusionEducation has been discussed as an early modifiable risk factor for AD, likely through a mechanism of cognitive resilience. We found that higher education was associated with less AD proteinopathy (e.g. better Ab42/40 and pTau181 profiles). Future studies should explore the potential underlying mechanisms for this association. Longer follow‐up will help to understand how these findings relate to biomarker levels and cognitive changes at a later stage of disease progression.
Association of Chronic pain with Alzheimer’s‐related brain structure and plasma biomarkers in older men
Authors: Bell Tyler R. , Franz Carol E. , Fennema‐Notestine Christine , Panizzon Matthew S. , Lyons Michael J. , Elman Jeremy A. , Kremen William S. 
Published: January 2025

AbstractBackgroundChronic pain leads to tau accumulation and hippocampal atrophy in mice. Tau accumulation in the locus coeruleus (LC) precedes medial temporal accumulation in humans. Here we provide one of the first human studies examining the association of chronic pain with hippocampal volume, LC integrity, and Alzheimer’s Disease (AD)‐related plasma biomarkers. We predicted associations with rostral‐middle, but not caudal, LC because the former is more aging‐ and Alzheimer’s‐related.MethodData were from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) at average ages 56, 62, and 68. Chronic pain was defined as moderate‐to‐severe pain occurring >2 waves. At wave 3, 424 participants (mean age = 67.06) underwent LC‐sensitive MRI scans from which we calculated an LC contrast‐to‐noise ratio (LCCNR), an index of LC integrity. We measured hippocampal volume with traditional structural MRI. At wave 3, biomarkers were obtained from fasting blood draws taken the morning of the medical interview and cognitive testing, typically a day prior to the MRI exam. Immunoassays calculated levels of plasma total tau, beta‐amyloid (Aβ) 40, Aβ42, Aβ42/Aβ40 ratio, and neurofilament light (NfL). All biomarkers were log‐transformed and adjusted for site and storage time. Analyses accounted age, major health conditions, depressive symptoms, and opioid use.ResultMen with chronic pain had smaller hippocampal volume (β=‐0.24, p=.039) and lower rostral‐middle LCCNR (β=‐0.38, p=.004) but not caudal LCCNR (p=.750). Men with chronic pain also had higher levels of plasma total tau (β=‐0.32, p=.047), Aβ42 (β=.42, p=.033), and Aβ40 (β=.31, p=.032) compared to men without chronic pain. However, men with chronic pain did not differ from men without chronic pain on Aβ42/Aβ40 ratio (p=.979) or NfL (p=.313).ConclusionExtending the animal model, these findings suggest that chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected very early in the development of AD. Increases in individual Aβ measures associated among those with chronic pain but lack of association with the Aβ42/Aβ40 ratio may reflect non‐AD‐specific health‐related factors rather than brain amyloid, or alternatively, might be due to the relatively young age of the sample or the sensitivity of the assay.
Analyzing Attention Focus in the Cookie TheftPicture Description Task Using Word Alignment
Authors: Favaro Anna , Thebaud Thomas , Dehak Najim , Butala Ankur , Oh Esther S , Moro‐Velazquez Laureano 
Published: January 2025

AbstractBackgroundVisuospatial problems are one of the possible signs of Alzheimer’s Disease (AD). Notably, various studies on eye movement in static image searches reveal that individuals with dementia fixate on fewer Areas of Interest (AoIs) for a significantly shorter duration than normal controls (CTLs). Building on prior works on speech and eye movement, in this study we examined word timestamps to infer each subject’s focus of attention while describing the Cookie Theft picture. Namely, we computed various interpretable features encoding attention focus and compared them across different neurological disorders.MethodCookie Theft Picture description tasks were recorded from subjects with AD (n=20), Parkinson’s Disease (PD) (n=43), Parkinson’s disease mimics (PDM) (n=16), and CTLs (n=33). First, speech transcriptions and word timestamps were generated using WhisperX automatic speech recognizer. The following features were then computed using word timestamps: time spent in the AoIs, time to approach the first AoI, number of visits to the AoIs, transition time from one AoI to another, and time elapsed between the first and last AoI mentioned. Features were computed considering all the animate AoIs, all the inanimate AoIs, and all AoIs collectively. Completed the feature extraction, non‐parametric pair‐wise Mann‐Whitney U tests of significance were conducted to determine whether there were significant differences between experimental groups for each feature. To control the False Discovery Rate, we applied the Benjamini–Hochberg correction.ResultResults from the statistical analysis showed that subjects with AD reported a significantly fewer number of visits to the AoIs and a shorter amount of time spent on inanimate external AoIs than CTLs. The AD group also reported a greater variability in the transition time from one AoI to another. Moreover, the PDM group spent significantly more time (on average) than the PD group on animate AoIs but reported a fewer number of visits to inanimate AoIs located internally to the house than PDs.ConclusionOur preliminary analysis confirmed the difficulties of subjects with cognitive decline to voluntarily direct attention to central cues and maintain attention focus on given AoIs. Our future work will include eye‐tracking technology to analyze the relationship between attention focus from speech and eye movement.