bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower novelty‐related locus coeruleus function is associated with entorhinal tau‐mediated memory decline in older individuals.
Authors: Prokopiou Prokopis C. , Engels Nina , Schneider Christoph , Schultz Aaron P. , Sepulcre Jorge , Riphagen Joost M. , Koops Elouise A. , Papp Kathryn V. , Fakhri Georges El , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L. 
Published: December 2022

AbstractBackgroundThe locus coeruleus (LC) is considered one of the earliest regions accumulating hyperphosphorylated tau before this pathology emerges in the entorhinal cortex (EC). Recent animal work suggested that LC phasic activity, which can be induced with exposure to novelty, can protect the cognitive downstream effects of tauopathy. Here we investigate whether activity of the LC during novelty is associated with memory decline and whether this association is mediated by EC‐tau deposition.Method92 participants (51 F, mean age at imaging (baseline) = 69.55±10.17 years) from the Harvard Aging Brain Study underwent both longitudinal memory testing (mean follow‐up = 4.8±1.9 years) and PiB(Aβ)‐, FTP(tau)‐PET, and 3T task‐fMRI scans performed within 1 year of each other (mean time difference = 0.29±0.24 years). The fMRI‐task consisted of novel and repeated face‐name pairs that the participants were instructed to remember. Voxel‐wise mixed‐effects analyses were performed to detect regions exhibiting significant novelty‐related activation. Vertex‐wise linear regression analyses were used to detect significant associations between LC activity and cortical tau deposition. Both analyses were adjusted for age, sex and multiple comparisons (pcl<0.05). The association between LC activity and memory decline (composite, Fig. 3 caption) was evaluated using linear regression adjusted for age, sex and education. Mediation analyses were performed using a quasi‐Bayesian bootstrap (n = 1000) approach to investigate whether EC‐tau mediates the association and whether this mediation effect is moderated by Aβ status.ResultWe observed greater novelty‐related activation within the bilateral LC, amygdala, hippocampus, and fusiform and insular cortices (Fig. 1). LC activation was associated with tau in the EC, inferior‐temporal and fusiform cortices (confirmed by EC‐ROI analyses‐Fig. 2). Lower LC activation was associated with steeper memory decline (p<0.05‐Fig. 3a), and this association was found to be mediated by EC‐tau (p<0.05‐Fig. 3b). This mediation effect was significantly stronger for the Aβ+ compared to the Aβ– group (p<0.05‐Fig. 3c).ConclusionThis work demonstrates that lower LC activity is associated with tau deposition in the medial‐ and inferior‐temporal lobe, consistent with the spatial patterns of tau observed in preclinical Alzheimer’s disease. Moreover, our observation that EC‐tau mediates the relationship between LC activity and memory decline suggests that lower LC function may indicate risk associated with Alzheimer’s‐related processes.
Inactivity is associated with worse cognition and neurodegeneration in aging adults
Authors: Gogniat Marissa A. , Khan Omair A. , Li Judy , Park Chorong , Robb W Hudson , Moore Elizabeth E. , Houston Michelle , Pechman Kimberly R. , Liu Dandan , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L. 
Published: December 2022

AbstractBackgroundGreater physical activity is known to be beneficial for healthier brain aging outcomes. However, less is known about how inactivity might influence the aging brain. Inactivity is highly prevalent in older adulthood and may be an important modifiable risk factor. We examined how inactivity relates to cognitive performance and structural imaging variables in community‐dwelling older adults, particularly among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐e4 carriers).MethodVanderbilt Memory and Aging Project (n = 265, 74±8 years, 37% female) participants completed at least 7 days of wrist actigraphy, neuropsychological assessment, and 3T brain MRI. Actigraphy data was processed using the GGIR package. Linear regression analyses related average daily minutes spent in inactivity during wake periods to cognition and brain structure adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile score, APOE‐e4 status, cognitive status, actigraphy wear time, and intracranial volume (for MRI outcomes). Models were repeated testing interactions with APOE‐e4 status.ResultThe total sample was inactive for 14±2 hours/day. More minutes of inactivity related to worse episodic memory performance (β = ‐0.001, p = 0.03), a smaller AD‐signature composite of cortical thickness (β = ‐0.0002, p = 0.008), and lower occipital lobe grey matter volume (β = ‐10.01, p = 0.01). Inactivity time interacted with APOE‐e4 status on naming (β = ‐0.01, p = 0.01) and visuospatial performances (β = ‐0.02, p = 0.04); total grey matter volume (β = ‐201.40, p<0.001); and frontal (β = ‐96.24, p = 0.001), temporal (β = ‐27.13, p = 0.03), and parietal lobe volumes (β = ‐54.72, p<0.001). In stratified models, more minutes of inactivity related to worse neuropsychological performance and smaller brain volumes among APOE‐e4 carriers. All stratified models in non‐carriers were null (p‐values>0.12).ConclusionAmong community‐dwelling older adults, more time spent inactive each day related to worse episodic memory performance and lower cortical thickness in regions susceptible to AD‐related neurodegeneration. Results were stronger among APOE‐e4 carriers. This study supports the importance of not just increasing physical activity but also reducing the time spent inactive each day, particularly among aging adults at genetic risk for AD.Funding: IIRG‐08‐88733, P20‐AG068082, R01‐AG034962, K24‐AG046373
ICU hospitalization and incident dementia in community‐based cohorts of older adults
Authors: James Bryan D , Grodstein Francine , Barnes Lisa L. , Marquez David X. , Bennett David A 
Published: December 2022

AbstractBackgroundCritical illness and intensive care unit (ICU) hospitalization in older patients have been shown to increase risk of long‐term cognitive impairment. However, most data come from patients recruited from the ICU without controls or information on pre‐ICU cognition. We are not aware of a community‐based sample that allows examination of how ICU hospitalization changes risk for dementia.MethodWe used data from 5 diverse epidemiologic cohorts at the Rush Alzheimer’s Disease Center (RADC) linked to Medicare claims data from 1991 to 2018 to observe ICU hospitalizations (both prior to RADC enrollment and during RADC follow‐up) in older adults enrolled without known dementia. Incident Alzheimer’s and all type dementia was assessed using standardized annual cognitive assessment. The association of ICU hospitalization with incident dementia was tested in a time‐varying Cox model allowing hazard rate to change at time of ICU hospitalization during follow‐up. All models were adjusted for age, sex, education, and race. Fully adjusted models also included terms for baseline measures of hypertension, diabetes, BMI, vascular risk factors, vascular disease burden, other chronic medical conditions, functional disabilities, depression, and physical activity.ResultParticipants (n = 3,822; mean age = 77.3, SD = 7.5) were followed for an average of 7.8 years (SD = 5.5) from study enrollment. ICU hospitalization was experienced by 1,992 (52.1%) of participants; 1031 (27.0%) before RADC enrollment, and 961 (25.1%) during follow‐up. In models adjusted for demographics, ICU hospitalization was associated with an increased risk of Alzheimer’s (HR = 1.63, 95% CI = 1.41, 1.88) and all type dementia (HR = 1.71, 95% CI = 1.48, 1.97). In fully adjusted models, the association was stronger with ICU associated with double the risk of Alzheimer’s (HR = 2.10, 95% CI = 1.66, 2.65) and all type dementia (HR = 2.20, 95% CI = 1.75, 2.77).ConclusionWe found that ICU hospitalization was associated with double the risk of dementia in community‐based older adults compared to those who did not experience ICU hospitalization using standardized annual cognitive assessment. These findings could be significant given the high rate of ICU hospitalization in older persons, and rising ICU hospitalizations more recently during the COVID‐19 pandemic.
Neurotrophic and growth factor response to acute exercise across the lifespan
Authors: Morris Jill K. , Kueck Paul J. , Kemna Riley E. , Green Zachary D. , John Casey S. , White Dreu , Billinger Sandra A , Vidoni Eric D 
Published: December 2022

AbstractBackgroundThere is evidence that aerobic exercise is beneficial to the brain and may reduce risk for cognitive decline and dementia. However, clinical trials have shown the benefits of exercise programs vary amongst individuals. This variability may occur in part due to differences in the physiological biomarker response to acute exercise. Characteristics such as age, sex, and apolipoprotein E4 (APOE4) genotype may affect these responses, but differences in blood processing protocols may introduce additional variability into the measures.MethodWe characterized the blood biomarker response to acute exercise in 80 individuals, including older adults (n=62, mean age 73y) and 18 young controls (n=18, mean age 37). Participants engaged in an acute, 15 minute bout of moderate intensity exercise (45‐55% HRR) following a 5 minute warm‐up. Blood was collected immediately prior to exercise, immediately post exercise, and 40 minutes post exercise. After collection, each timepoint sample was immediately processed for plasma and platelet poor plasma and frozen; this was done to limit release of growth factors from activated platelets post‐blood draw. Time course responses of brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), insulin like growth factor 1 (IGF1) were measured using ELISA in platelet poor plasma. Lactate was measured in plasma (YSI 2500).ResultLinear mixed modeling performed with age, sex, and APOE4 genotype as covariates revealed a significant change in BDNF (p<0.001) and lactate (p<0.001) over time, with the highest levels of lactate observed immediately post‐exercise, while BDNF was elevated at 40 minutes post‐exercise in both young and older adults. There was no significant change with either VEGF or IGF1 over time in response to exercise, although older adults had significantly higher VEGF (p=0.01) and lower IGF1 (p<0.001) compared to young controls across all timepoints.ConclusionWe report here that analysis of the acute exercise response reveals a significant increase in circulating BDNF and lactate, but not VEGF or IGF1, following aerobic exercise in both young controls and older adults. Further investigation into the mechanisms that contribute to these changes and the relevance to additional fluid and imaging brain health biomarkers in this cohort is ongoing.
Relationship between the metabolic hormone response and plasma biomarkers of Alzheimer’s Disease and Related Dementias
Authors: Kueck Paul J. , John Casey S. , Green Zachary D. , Johnson Chelsea N. , Kemna Riley E. , Burns Jeffrey M. , Morris Jill K. 
Published: December 2022

AbstractBackgroundInsulin resistance is a known risk factor for Alzheimer’s Disease and related dementias (ADRD). While the role of insulin on peripheral tissue is well understood, it’s effect on the brain remains unclear. Insulin and other gastrointestinal peptides can cross the blood‐brain barrier to form ligands in areas involved in metabolic response. Thus, it’s important to understand the relationship between systemic metabolic outcomes, such as meal‐stimulated hormone responses, and plasma biomarkers of ADRD.Method67 Participants (27 ADRD) completed a clinical and cognitive (Uniform Data Set 2.0) examination, meal tolerance test, and MRI scan. Cognitive scores were standardized to z‐scores and averaged to yield a global z‐score. EDTA plasma samples collected during the meal tolerance test were analyzed for glucose and insulin, and responses of peptide tyrosine tyrosine (PYY) and gastric inhibitory polypeptide (GIP) were analyzed in plasma from a subset of samples (n=53) containing DPP4 inhibitor. Further characterization of amyloid beta (Aβ42), pTau 181, Neurofilament light (NFL), and glial fibrillary acidic protein (GFAP) was performed using non‐fasted EDTA plasma on the Simoa HD‐X (Quanterix). We then assessed the relationship between the early metabolic and hormone responses to a mixed meal and baseline plasma ADRD biomarkers.ResultThe study sample consisted of 53.7% females and 43.3% APOE4 carriers with an average age of 74.9±6.3 and 16±3 years of education. All analyses were controlled for age and sex. Aβ42/pTau181, pTau 181, NFL, and GFAP were significantly elevated in ADRD compared to CH individuals (p<0.05) and tracked linearly with global cognitive z score (p=0.004, p<0.001, p<0.01, p=0.02, respectively). Linear regression revealed that both pTau 181 (β=0.334, p=0.009) and NFL (β=0.320, p=0.003) tracked significantly with the early PYY response (0‐30 minute), but not other metabolic responses, across the entire cohort. pTau181 and the Aβ42/pTau181 ratio each tracked significantly with global cognitive z score (p<0.001, p=0.01, respectively).ConclusionEarly PYY response to a mixed meal tracks with pTau181 and NFL, plasma biomarkers of ADRD neuropathology and neurodegeneration, respectively. The relationship between gut and brain biomarkers warrants additional study, and further characterization of cross‐sectional and longitudinal relationships with other meal‐related hormone responses is ongoing.
Factors associated with high intensity of end‐of‐life care for decedents with dementia in a Medicare Advantage plan
Authors: Nguyen Huong Q , Duan Lewei , Lee Janet S , Wang Susan E , Hou Anthony , Browne Tarah , Carrol Jarrod , Borson Soo 
Published: December 2022

AbstractBackgroundThere are limited data on end‐of‐life care (EOL) for decedents with dementia enrolled in Medicare Advantage plans. The purpose of this descriptive analysis is to compare socio‐demographic and clinical characteristics and patterns of healthcare utilization for decedents who were hospitalized in the last 30 days of life versus those who were not.MethodsData were extracted from electronic health records (EHR) of individuals aged 65+ who had at least one coded ADRD diagnosis and died in 2018‐2019. Decedents with one or more hospital stays in the last 30 days of life were categorized as receiving high‐intensity EOL care (n = 6299, 45%); those with no hospitalizations were classified as receiving low‐intensity EOL care (n = 7571, 55%). We compared socio‐demographic and clinical characteristics and healthcare utilization, including life care planning (LCP) and palliative and hospice care between the two cohorts.ResultsThe high‐intensity cohort was minimally younger (85±7.6 vs. 86.6±7.6) and included more men (48% vs. 41%) and people of color (47% vs. 38%) compared to the low‐intensity cohort. Co‐morbidities were also higher in this group (Elixhauser: 11.5±3.6 vs. 9.9±3.7) and dementia was more often first documented in the EHR very “late” [median: 586 (IQR:85.0, 1521.0) vs. 1062 (IQR:391.0, 2012.0) days prior to death]. The high‐intensity group used more outpatient (primary care and specialty visits, 10.3 vs. 6.5), emergency visits (2.7±3.0 vs. 1.8±2.3), and inpatient (1.6±2.2 vs. 1.1±1.5) care in the prior year. Moreover, the first LCP conversation occurred much closer to death in the high‐ vs. low‐intensity group [median: 35 (IQR:10.0, 139.0) vs. 105 (IQR:45.0, 234.0) days from first conversation to death]; an advance directive or POLST were less likely to be completed (71% vs. 81%) as was receipt of home palliative care or hospice (62% vs. 82%) than in the low‐intensity cohort. All comparisons between the two cohorts were significant, p<.01.ConclusionsWe found notable differences in socio‐demographic and clinical characteristics, and utilization patterns in the year prior to death between decedents with dementia who were hospitalized in the last 30 days of life vs. those who were not. Further analyses will assess key, potentially modifiable drivers of high‐intensity EOL care.
Correlation between quantitative and qualitative assessments of white matter hyperintensities inpatients from a multicentric memory clinic population
Authors: dos Santos Clarisse Longo , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Schwarz Adam J. ,   MEMENTO study group
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMH) can be visualized as abnormal T2 signal in the periventricular, deep and subcortical white matter on Magnetic Resonance Imaging (MRI). WMH increase with age and are associated with stroke, cognitive decline and dementia. The most common visual rating scale used to assess WMH in the clinical setting is the Fazekas scale (Fazekas et al., 1987). The current study investigated the relationship between WMH volume (expressed as a % of intra‐cranial volume (ICV)) calculated using an automated method included in the QyScore® medical device, and Fazekas scores in a multicentric memory clinic population at baseline.Method1959 participants from the MEMENTO cohort (Age 71.02 +/‐ 8.61, 1218 Female, MMSE 27.95 +/‐ 1.91) had 3DT1 and T2 FLAIR MRI scans analyzed with QyScore®, an FDA‐approved and CE‐marked image analysis software. 814 had amyloid status from CSF or PET, of which 216 were Amyloid+. WMH volumes are reported in mL, corrected for %ICV. Correlation between Fazekas deep white matter (DWM) scores and quantitative WMH measurements was ascertained by Spearman’s rank correlation.ResultThere was a significant positive correlation between Fazekas DWM scores and WMH %ICV (0.76 p<0.001) for the total sample, amyloid positive (0.81 p<0.001) and negative (0.72 p<0.001) patients. The correlation was also strong when separated by clinical diagnosis: patients with Subjective Cognitive Complaint (SCC, N= 305, AGE: 69.87 +/‐ 8.03, 197 female, MMSE: 28.86 +/‐ 1.17) and MCI (N = 1638, Age: 71.2 +/‐ 8.69, 1014 Female, MMSE: 27.8 +/‐ 1.95) presented Fazekas DWM scores correlated with WMH %ICV (0.66 p<0.001 for SCC; 0.77 p<0.001 for MCI).ConclusionThe automated quantification of ICV‐corrected WMH were well‐correlated to Fazekas DWM scores. Considering that visual rating of WMH is time consuming and suffers from intra and inter‐operator variability, the quantitative assessment of WMH load provided by QyScore® may improve the assessment of patients with cognitive impairment.
Increased Bridging Characteristics in Social Networks are Associated with Increasing Amygdala Volume and Grey Matter Density
Authors: Manchella Mohit K. , Logan Paige E. , Perry Brea L , Peng Siyun , Risacher Shannon L. , Saykin Andrew J. , Apostolova Liana G. 
Published: December 2022

AbstractBackgroundSocial connectedness has been linked to decreased rates of cognitive decline particularly among older adults (Fratiglioni et al., 2004). Several studies have demonstrated that access to an expansive network of diverse, and loosely connected individuals (i.e., social bridging) plays a particularly unique role in conferring resilience against cognitive decline (Perry et al., 2021). We explored the association of social bridging with cortical atrophy measured by gray matter density (GMD) in cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s Disease (AD) participants from the Social Networks and Alzheimer’s Disease (SNAD) at the Indiana Alzheimer Disease Research Center.Method:We analyzed baseline data of 176 SNAD participants (63 CN, 54 SCD, 47 MCI, 12 AD). Social bridging metrics were collected via in‐person interviews of egocentric social network data. MCI and AD were combined into a cognitively impaired group, resulting in 3 diagnostic groups (CN, SCD, CI). Demographic and biomarker differences across groups were analyzed using ANOVA. Pooled linear regressions were run with ROIs as the dependent variables and diagnosis, age, sex, education, and social bridging as regressors. A voxel‐wise multiple linear regression of GMD images in SPM12 yielded statistical maps across the pooled sample.ResultTable 1 shows the demographic and biomarker comparisons of all groups. The linear regression showed greater social bridging was associated with larger left and right amygdala volume (both p=0.01), and trending larger left frontal thickness (p=0.055), and left and right insula thickness (both p=0.09). Figure 1 and Figure 2 show scatterplot distribution of significant and trending brain regions versus bridging by diagnostic group with regression p‐values and lines. Statistical maps show increasing social bridging is associated with increasing GMD lateralized to the left hemisphere with a frontotemporoparietal pattern (Figure 3).ConclusionWe found that the effects of particular social enrichment on GMD, such as social bridging, are localized to regions primarily involving motivation and emotion. The left lateralization suggests this hemisphere’s propensity for protection against cognitive decline via social mechanisms. Future work should investigate potential associations between social bridging and amyloid and tau deposition.
Genetic contribution to grey matter network disruptions and Alzheimer disease cerebrospinal fluid markers
Authors: Dicks Ellen , Tomassen Jori , ten Kate Mara , Teunissen Charlotte E. , Scheltens Philip , Barkhof Frederik , den Braber Anouk , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2022

AbstractBackgroundGrey matter covariance networks become disrupted early in Alzheimer’s disease (AD), when amyloid starts aggregating, and before the onset of irreversible atrophy. However, the precise relationship of grey matter network breakdown and the AD pathophysiological process remains unclear. Here, we studied to what extent shared familial (genes and family environment) or environmental factors unique to a twin contribute to these relationships in a sample of older monozygotic twins with intact cognition.MethodFrom the EMIF‐AD PreclinAD study we included monozygotic twins who had at least an MRI scan (n=197) and CSF available (n=124). We assessed the upper limit of genetic contribution to grey matter network measures (size, degree, connectivity density, clustering, path length, small‐world measures) with within‐twin pair correlations. Associations between CSF AD markers (Aβ42/40, t‐tau, p‐tau) and other markers related to AD pathophysiology (neurogranin, Aβ38, Aβ40, BACE1) with grey matter network disruptions were assessed with linear mixed models. Twin analyses (cross‐twin cross‐trait, twin difference analyses) were used to assess the contribution of shared familial and/or unique environmental factors to these associations.ResultTwenty individuals (16%) had abnormal CSF Aβ42/40 levels. Grey matter network measures were highly correlated within twin pairs (r=0.54‐0.97; all p<0.001, Fig.1), suggesting a moderate to strong genetic background. Across the whole sample, more abnormal Aβ42/40 ratios were moderately related to lower connectivity density (β±SE = 0.176±0.09, p=0.055, Fig.2). The strongest associations with grey matter network measures were observed for t‐tau and p‐tau levels (range β=‐0.344‐0.182), followed by Aβ production markers (Aβ38, Aβ40, BACE1) (range β=‐0.202‐0.165). We observed no relationships between neurogranin and grey matter network measures. Cross‐twin cross‐trait analyses showed that levels for t‐tau, p‐tau and Aβ38 in one twin were associated with grey matter network measures in their co‐twin (r=‐0.27 to ‐0.21; p range=0.02 to 0.07, Fig.3). Within‐pair differences in BACE1 were related to within‐pair differences in normalized path length values (r=0.35; p=0.01; Fig.4).ConclusionOur results suggest a shared familial background for the relationship of grey matter network disruptions and AD‐related processes as measured in CSF. In addition, unique environmental factors influencing BACE1 may also affect grey matter network disruptions.