bluuebunny/crossref_metadata_2025_split huggingface dataset:
How timings of being physically active in adulthood relate to later‐life cognition: over 30 years of follow up in the 1946 British Birth Cohort
Authors: Chiou Yu‐Jie , Schott Jonathan M , Richards Marcus , James Sarah‐Naomi 
Published: December 2022

AbstractBackgroundWe aim to assess how the timing of being physically active in adulthood is associated with later‐life cognitive function; and estimate to what extent these effects are explained by pathways including earlier life influences, cardiovascular and mental health.MethodData from participants (n = 1417, 53% female) in the British 1946 birth cohort were included. Physical activity was assessed across adulthood at ages 36, 43, 53, 60 and 69 by interviews and categorised into: 0)Not active; 1)Moderately active (participated in physical activity 1‐4 times per month); 2) Most active (participated 5+ times per month). Responses were additionally binarized and summed to create a cumulative exposure of adulthood physical activity. Cognition at age 69 was assessed by the Addenbrooke’s Cognitive Examination (ACE‐III)). Regression analyses examined associations between physical activity measures and later‐life cognition, adjusting for childhood cognition; childhood socioeconomic position (SEP); education; cardiovascular health (Framingham risk score at age 69); emotional symptoms (general health questionnaire at age 69); and APOE‐e4 status. A structural equation modelling analysis further tested the life course models of sensitive period and accumulation for describing how physical activity was best related to later‐life cognition.ResultCompared to those not active, those who were moderately and most physically active, at every age, had higher ACE‐III scores at age 69 (Figure 1). Being physically active across different periods was associated with better cognitive state, in a dose‐response manner (Figure 1). Adjusting for childhood cognition, childhood SEP and education largely attenuated these effects but results mainly remained significant at the 5% level; adjustment for cardiovascular risk, mental health and APOE‐e4 status did not attenuate associations (Figure 1). An accumulation model of physical activity was the best fit (Table 1).ConclusionWe provide evidence from two complementary analyses that maintaining physical activity across different periods of adulthood is related to better later‐life cognitive state in a dose response manner, even after adjustment for variables that predict physical activity and later‐life cognition, such as childhood cognition, education and SEP. These relationships were independent of cardiovascular and mental health and APOE‐E4 status.
Brain‐Wide Monitoring of Antibody Therapeutics Crossing the Blood‐Brain‐Barrier
Authors: Redd Chase , Guanzon Nathaniel , Gallegos Yessenia , Weiss Jacob , Jensen Camilla Stampe , Vergo Sandra B. , Wheeler Damian G. 
Published: December 2022

AbstractBackgroundRecent advances in optical clearing and light sheet imaging have opened an exciting new avenue for brain‐wide, cellular resolution immunostaining at the forefront of a dimensional shift from 2D to 3D histology. Providing access to the intricate anatomy of the whole intact brain, tissue clearing offers neuroscientists unbiased and complete views of brain anatomy and function. One area where these methods have particular utility is in the development of CNS therapeutics where they can be used to examine the regional distribution of the therapeutic in the brain as well as brain‐wide target engagement and phenotypic efficacy.MethodWe have developed an optimized iDISCO‐based clearing method and with our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image cellular‐resolution immunoreactivity across entire mouse brains in ∼25 min. Here we examined whether our technology can detect antibody therapeutics crossing the blood‐brain‐barrier. To do this, we took advantage of a bispecific antibody engineered to bind to the Alzheimer’s Disease target, BACE1, as well as the transferrin receptor (TfR1), which helps shuttle the antibody across the brain endothelium and into the brain parenchyma. Twenty‐four hours after dosing we perfusion‐fixed the brains and performed our modified iDISCO‐based clearing and staining protocol using 3 different anti‐human IgG secondary antibodies.ResultWe found anti‐human antibodies revealed high levels of the bi‐specific antibody in the brain vasculature and parenchyma. Importantly, in brains dosed with a monospecific control antibody that does not bind TfR1, immunoreactivity was at background levels, similar to that seen in control mice that were not dosed with antibody. These data are consistent with binding to TfR1 localizing the bispecific antibody in the vasculature and enabling transport into the brain parenchyma. Importantly, the pattern of immunoreactivity in the cleared brain matched the pattern seen with traditional 2D slice immunohistochemistry. But unlike traditional methods, we were able to examine the concentration of the bi‐specific antibody throughout the entire brain and assess whether the pattern matched that of the therapeutic target.ConclusionTogether, these data provide a clear demonstration of the utility of tissue clearing methods for quantitative brain‐wide monitoring of therapeutic antibody exposure.
Role of neurochemistry in amyloid pathology using 5xFAD transgenic mouse model of AD: A single‐voxel Magnetic Resonance Spectroscopy (MRS) study
Authors: Shahid Syed Salman , Paraiso Hallel C , Yu Ivorine , Wu Yu‐Chien 
Published: December 2022

AbstractBackgroundChanges in cerebral metabolic concentrations are markers of aging and are also associated with various neurological disorders. Neurotransmitter and membrane metabolisms are affected in Alzheimer’s disease (AD). These metabolic alterations are suggested to occur in the hippocampus and rhinal cortex during the early stages of AD pathology. Higher levels of glutamine (Gln) in the blood and cerebral spinal fluid are associated with an increased risk of developing AD. Since Gln is capable of crossing the blood‐brain barrier and is involved in the metabolic cycle with glutamate (Glu), elevated levels of Gln in the presence of Aβ pathology may suggest a protective role of Gln in the early stage of the disease. Therefore, alteration in Glu/Gln cycle may serve as an early biomarker in the pathogenesis of AD. Choline‐containing compounds (tCho) are essential for phospholipid synthesis and degradation of cell membranes. Abnormal alterations of tCho levels are indicative of imbalanced cell membrane phospholipid metabolism. At the early stage of Aβ pathology, high levels of tCho in conjunction with elevated levels of Gln may suggest the involvement of compensatory mechanisms to counter declining acetylcholine. Thus, investigating metabolic changes in the hippocampus may improve our understanding of metabolic mechanisms associated with Aβ pathology.MethodMale 5xFAD mice (N=4) at 6‐months‐old and age‐matched littermates (N=5) were used in this study. Single‐voxel MRS was acquired on a 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. STEAM spectra was acquired from a 2mm3 voxel positioned on the left hippocampus region. Glu, Gln, tCho and total Creatine (tCr) levels were estimated with LC Model. A general linear model (GLM) was used to estimate group‐wise differences in Glu/Gln ratio, tCho.Gln and tCr.ResultCerebral metabolic concentration levels suggest group‐level differences between wild‐type (WT) and 5xFAD mice. Glu/Gln ratio was significantly higher in WT mice than 5xFAD (pFWE<0.05; d=3.4) and tCho.Gln was significantly lower in WT than 5xFAD (pFWE<0.05; d=2.8).ConclusionSingle‐voxel MRS in the hippocampus region can identify the neurochemical profile of multiple cerebral metabolites, which may be sensitive to the Aβ burden at the early stages of the pathology.
Cardiorespiratory fitness attenuates the deleterious effects of sleep apnea on cerebral structure, perfusion, and risk of Alzheimer’s disease in the Wisconsin Sleep Cohort study
Authors: Edmunds Kyle J , Driscoll Ira , Hagen Erika W , Barnet Jodi H , Ravelo Laurel A , Plante David T , Gaitán Julian M. , Lose Sarah R , Motovylyak Alice , Okonkwo Ozioma C. , Peppard Paul E 
Published: December 2022

AbstractBackgroundEmerging evidence suggests that age‐related changes in cerebral structure and perfusion—hallmark features of preclinical Alzheimer’s disease (AD)—may be sensitive to vascular risk modifiers such as physical exercise and sleep quality. Here, we examine whether cardiorespiratory fitness modifies the effects of obstructive sleep apnea (OSA) on cerebral structure, perfusion, and AD risk.MethodUsing data from a sample of participants (n=134 for analyses of imaging outcomes and n=1,182 for analyses examining AD outcomes) in the Wisconsin Sleep Cohort (WSC) study, we examined cross‐sectional associations between OSA severity, estimated cardiorespiratory fitness (eCRF), and their interaction with MRI‐assessed total and regional gray (GM) and white matter (WM) volumes, WM hyperintensities (WMHs), total lesion volume, and arterial spin labeling cerebral blood flow (CBF), using multiple linear regression models adjusted for age, sex, BMI, hypertension, and education level. We further assessed whether eCRF modifies the associations between OSA and risk of AD using Cox proportional hazard models.ResultOSA severity was associated with greater total lesion volume, reduced total GM volume, and greater WMHs among less‐fit, but not among more‐fit, subjects. Perfusion models likewise revealed significant regional differences in CBF between fitness groups. OSA severity was likewise associated with greater risk of AD among less‐fit individuals, but there was no significant association among the more‐fit.ConclusionThis work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging and AD.
Type 2 diabetes and cortical thickness in older Mexican Americans and non‐Hispanic Whites
Authors: Braskie Meredith N , Hazra Nalini , Kothapalli Deydeep , Cho HyungJin , Lester Jacob , Rogers Jessica N , Palmer Raymond F. , Vintimilla Raul , Johnson Leigh , Yaffe Kristine , Toga Arthur W. , O'Bryant Sid E. 
Published: December 2022

AbstractBackgroundType 2 diabetes mellitus (T2DM) at midlife increases dementia risk. Metabolic factors contribute more to Alzheimer’s disease (AD) risk in Mexican Americans (MA) than in non‐Hispanic Whites (NHW). However, most work relating T2DM to brain structure in older adults has been performed in NHWs. We evaluated how T2DM related to regional cortical thickness in cognitively intact older MA or NHW adults. We hypothesized that T2DM would relate more to regional cortical thickness in MA.MethodWe assessed 819 cognitively intact controls (344 MA, mean age=62.2; 475 NHW, mean age =68.8) in the Health and Aging Brain‐Health Disparities (HABS‐HD) cohort who had 1) a T1‐weighted structural brain MRI (3T Siemens Magnatom Skyra) 2) type 2 diabetes diagnostic assessment and 3) successful FreeSurfer (v5.3.0) cortical segmentations (34 cortical regions on the right and left). Regions that failed visual quality checks were imputed using MICE (R studio). We related mean bilateral regional cortical thickness to T2DM diagnosis, covarying for age and sex and controlling for multiple comparisons (Bonferroni correction.) For regions significantly associated with T2DM diagnosis, we evaluated the relationship of HbA1c and fasting blood insulin to cortical thickness, controlling for age and sex.ResultT2DM was significantly associated with cortical thickness in bilateral gyri: supramarginal, precuneus, superior and middle temporal, banks of the superior temporal sulcus, transverse temporal, temporal pole, lingual, pericalcarine, and left lateral occipital (Table 1). HbA1c levels, but not fasting insulin, were significantly correlated with cortical thickness in all identified regions after Bonferroni correction (p<0.0012). There was a significant effect of ethnicity in most of these regions, after controlling for education and household income (Table 2). Supramarginal gyrus, precuneus, transverse temporal gyrus, and left lateral occipital thickness showed a nominally significant interaction (p<0.05) between ethnicity and T2DM, with stronger T2DM effects in MA. Ethnicity interaction effects were diminished in all regions when HbA1c was added to the model.ConclusionT2DM is associated with cortical thickness in temporal, parietal, and occipital regions. Those effects are stronger in MA than NHW, independent of age, sex, and economic status, but may be partly explained by differences in blood glucose level control.
Purpose in life may promote cognitive resilience through default‐mode network connectivity in middle‐aged adults
Authors: Abellaneda‐Pérez Kilian , Cattaneo Gabriele , Cabello‐Toscano María , Sánchez Javier Solana , Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Bargalló Núria , Tormos‐Muñoz Josep Mª , Pascual‐Leone Alvaro , Bartrés‐Faz David 
Published: December 2022

AbstractBackgroundDisease‐modifying agents to counteract cognitive impairment in aging remain elusive, and identifying modifiable factors promoting brain reserve is paramount. In AD, education, occupation, and physical activity represent typical reserve proxies (Stern et al. Alzheimers Dement.2020;16(9):1305‐1311), but psychological factors are increasingly being recognized, as their operating biological mechanisms are elucidated (i.e., Arenaza‐Urquijo et al. Neurology 2020;95:e1571). Purpose in life (PiL), one of the pillars of psychological well‐being, was found to reduce the deleterious effects of AD‐related pathological changes on cognition (Boyle et al., Arch Gen Psychiatry. 2012;69(5):499‐505). However, whether PiL operates as a cognitive resilience factor in middle‐aged individuals, as well as its associated neural mechanisms remains unknown.MethodData was obtained from 573 middle‐aged adults (mean age 54.28±7.2; 275 women) from the Barcelona Brain Health Initiative cohort (Cattaneo et al. Front Aging Neurosci. 2018;10:321). Individuals with lower (LP; N = 131) and higher (HP; N = 94) PiL rates, according to the division of this variable into quintiles, were compared in terms of cognitive status; a measure reflecting brain burden (MRI‐derived white matter hyperintensities; WMHs); and resting‐state functional connectivity (rs‐FC), examining system segregation (SyS) using 14 brain circuits (Shirer et al. Cereb Cortex. 2012;22(1):158‐165).ResultsNeuropsychological status and WMHs burden did not differ between PiL groups. However, only in the LP group, greater WMHs entailed a negative impact on speed of processing and logical reasoning (Fig.1A‐B). Subjects in the HP group showed lower SyS on the dorsal DMN (dDMN), indicating lesser segregation of this network from other brain circuits (t = 2.423, p = 0.016; Fig.1C). Specifically, HP individuals had greater inter‐network connectivity between dDMN nodes and the rest of the brain. Conversely, subjects in the LP group exhibited more connectivity across DMN‐like regions. Notably, in the HP group, greater functional connectivity was positively correlated with cognitive function previously related to WMHs, while the opposite pattern was observed in the LP group (Fig.1D‐F).ConclusionExpanding previous findings on AD‐pathology and advanced age, present results suggest that higher rates of PiL may promote cognitive resilience already in middle age. Possible neurobiological mechanism by which PiL might operate could imply greater integration between the DMN and other brain areas.
Pupil and eye tracking measures as a tool for detection and intervention in neurodegeneration
Authors: O’Callaghan Claire , Hezemans Frank H , Ye Rong , Orlando Isabella , Passamonti Luca , Rowe James B 
Published: December 2022

AbstractBackgroundThe locus coeruleus–noradrenaline system plays an extensive role in cognition and behaviour. It is among the earliest and most prominent sites of pathology in neurodegenerative diseases of ageing, including Alzheimer’s and Parkinson’s disease. Improving our ability to detect changes in this system in vivo has implications for early diagnosis and for tracking treatment interventions.MethodMy talk will focus on pupil and oculomotor measures as a biomarker to detect changes in the locus coeruleus–noradrenaline system. I will discuss results from a study in Parkinson’s disease patients (N=19) who underwent a pharmacological challenge using the noradrenergic reuptake inhibitor atomoxetine (40mg). In this study, we characterised the locus coeruleus using ultra‐high‐field 7T MRI and tested patients on and off atomoxetine, using a suite of oculomotor eye tracking tasks and a learning task combined with pupillometry.ResultWe show that atomoxetine improves cognitive performance and saccadic reaction times. Crucially, atomoxetine led to larger pupil responses that varied as a function of locus coeruleus integrity.ConclusionTogether, these results show that pupil and eye tracking measures are an effective biomarker for the locus coeruleus–noradrenaline system, and they are sensitive to pharmacological interventions. I will discuss the implications of these results for early detection and monitoring of subcortical changes in Alzheimer’s disease.
Rural/Urban Disparities in PQIs Among Patients with ADRD – Evidence of Hospital‐based HIT and Enabling Services
Authors: Chen Jie , Wang Nianyang , Buchongo Portia 
Published: December 2022

AbstractBackgroundTo examine urban and rural disparities in potentially preventable hospitalizations (PPH) among patients with Alzheimer’s Disease and Related Dementias (ADRD) and the use of health information technology (HIT) and enabling services as mediators.MethodWe merged 2017 100% Medicare Fee‐For‐Service (FFS) claims with the Medicare Beneficiary Summary File, American Community Survey, and American Hospital Association Annual Survey to construct a dataset containing patient, hospital, and community‐level data. Logistic regression was applied to examine differences in PPH by HIT and enabling services.ResultThe rates of PPHs related to acute and chronic conditions for rural and micropolitan patients with ADRD were significantly higher compared to the rates among urban patients with ADRD. Having both telehealth post‐discharge and enabling services significantly decreases the odds of PPH due to acute (OR: 0.93, 95% CI: 0.89‐0.98, p‐value <0.01) and chronic conditions (OR: 0.96, 95% CI: 0.92‐1.00, p‐value = 0.07) compared to not having these available. The presence of both telehealth post‐discharge and enabling services significantly decreased the odds of PPH in patients with ADRD in rural (acute PPH OR: 0.56, 95% CI: 0.41‐0.77, p‐value <0.01; chronic PPH OR: 0.73, 95% CI: 0.55‐0.97, p‐value = 0.03) and micropolitan (acute PPH OR: 0.65, 95% CI: 0.57‐0.73, p‐value <0.01; chronic PPH OR: 0.83, 95% CI: 0.74‐0.93, p‐value <0.01) areas compared to urban patients with ADRD.ConclusionResults suggest that the combination of HIT telehealth post‐discharge and enabling services are important interventions in helping to reduce preventable hospitalizations among patients with ADRD living in rural and micropolitan areas.
The association between bilingual semantic fluency and episodic memory among bilingual Mexican American older adults.
Authors: Briceno Emily M , Renteria Miguel Arce , Chang Wen , Lewandowski‐Romps Lisa , Heeringa Steven G , Garcia Nelda M , Morgenstern Lewis B 
Published: December 2022

AbstractBackgroundBilingualism is increasingly common in older adults in the US and may impact the expression and course of Alzheimer’s Disease and related dementias (ADRD). Optimal methods for assessing cognition in population‐based studies of bilingual older adults are not established. Given that declines in semantic fluency are associated with declines in episodic memory in ADRD, we examined the degree to which animal naming in English and Spanish is associated with memory performance in a sample of bilingual Mexican American (MA) older adults.MethodThe Brain Attack Surveillance in Corpus Christi‐Cognitive study is a population‐based study of cognition in MA and non‐Hispanic white adults 65+ in south Texas. We included US‐born, bilingual MA participants who completed in‐person neuropsychological assessment in their preferred language (English) with the Harmonized Cognitive Assessment Protocol. We added a Spanish animal naming trial to the standard animal naming trial in English. We used the delayed recall score from a word list as the indicator of memory performance. We performed a series of regression analyses with delayed recall as the dependent variable and the English and Spanish animal naming scores as the independent variables, with age, sex, years of education, and a self‐reported bilingualism index score to account for level of bilingualism (range 0–1; 0 indicates monolingual Spanish; 1 indicates monolingual English) as covariates.ResultNinety‐six participants were included (Mage = 73yrs±6; Meducation = 11±4; 60% women; Table 1). In separate regression models including covariates, English animal naming (b = 0.25, p<.0001) and Spanish animal naming (b = 0.20, p <.05) were each associated with delayed recall. When considered together, English animal naming (b = 0.24, p = <.0001) and not Spanish animal naming (b = 0.03, p = .69) was associated with delayed recall, after accounting for age, sex, years of education, and level of bilingualism (Table 2). Results were consistent when the analysis was restricted to balanced bilinguals (Table 3).ConclusionSemantic fluency in English and Spanish were each related to episodic memory among bilingual MA older adults assessed in English, although the Spanish trial did not add unique information in its association with episodic memory. Future studies should evaluate how bilingual semantic fluency is associated with longitudinal cognitive decline in ADRD.
LDLR, VLDLR and APOBR in the pathophysiology of sporadic Alzheimer’s disease
Authors: Flores Isabel Sierra , Picard Cynthia , Poirier Judes 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) and cholesterol homeostasis have long been linked, most notably by the identification of apolipoprotein E‐ε4 allele as the strongest risk factor. Yet the mechanism by which its pathogenic isoform ε4 impacts AD has remained elusive. Different GWA studies have identified other potential risk factors, many of which are also involved in the maintenance, homeostasis, mobilisation, and distribution of cholesterol. The aim of this study was to analyse three candidate genes involved in cholesterol metabolism, which showed preliminary significance and are strongly related to cholesterol processes and APOE neurobiology.MethodThe three candidates are the receptors LDLR, VLDLR and APOBR which were analysed using neocortical mRNA data from the Religious Orders study/ Memory and Aging Project ROSMAP cohort’s dataset. The receptor mRNA levels were contrasted against several AD pathological markers, such as Braak and CERAD stages. Other apolipoprotein mRNA levels were also analysed for significance. Age, Sex and ApoE4 genotype were also tested for effect.ResultPreliminary analyses showed significant correlation between mRNA levels of these receptors (most strongly VLDLR) and Braak stages (VLDLR p < 0.008), CERAD stages (VLDLR p < 0.001) as well as several proteins known to be involved in AD pathophysiology. VLDLR expression levels did not correlate with APOE mRNA levels (VLDLR; R2=0.176, p > 0.05) and were only significant in APOε4 negative subjects when split for APOε4 genotype (VLDLR Braak p < 0.003).ConclusionThe three receptors analysed so far appear to be involved at some level with AD pathophysiology. They will be further studied and investigated in both, symptomatic and pre‐symptomatic AD. The relationship between the receptors and APOE pathophysiology in sporadic AD remains unclear.