bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does the impact of a multidomain intensive lifestyle intervention on cognitive function depend on baseline frailty?
Authors: Simpson Felicia R , Carmichael Owen T , Hayden Kathleen M , Hugenschmidt Christina , McCaffery Jeanne , Ojeranti Daniel , Pajewski Nicholas M , Roman‐Ashby Glorian , Yasar Sevil , Espeland Mark A 
Published: December 2020

AbstractBackgroundType 2 diabetes and obesity, separately and in combination, are known to accelerate cognitive decline, increasing one’s risk of dementia. While lifestyle interventions may be expected to mitigate cognitive decline and dementia risk through multiple pathways, the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial found no overall benefit from 10 years of multidomain intensive lifestyle intervention (ILI) compared to diabetes support and education (DSE). However, there was some evidence that the impact of the intervention on cognitive outcomes was heterogeneous, ranging from benefit for individuals with lower body mass index and no history of cardiovascular disease to harm for the heaviest individuals with a history of cardiovascular disease history. We hypothesized that the impact of the intervention on cognitive function may vary among individuals grouped according to a geroscience construct for biological aging, the Rockwood deficit accumulation frailty index (FI).MethodA standardized battery of cognitive function tests was administered to 3,708 Look AHEAD participants, 10‐13 years after they had been randomized to 10 years of ILI or the DSE control condition. Participants, who were aged 45‐76 at baseline, were grouped according to tertiles of a 38‐item FI calculated from baseline characteristics. Analyses of covariance with interaction terms were used to assess the consistency of any intervention effects among FI tertiles.ResultThe median FI score was 0.20 at baseline, with 12% classified as frail (FI>0.21). Greater baseline FI was associated with poorer cognitive function in domains related to attention, processing speed, and executive function (all p<0.01), but not memory. Assignment to ILI was not associated with better cognitive functioning in any domain, and this finding was consistent across FI tertiles and inverse probability weighted analyses.ConclusionA 10‐year multidomain intensive lifestyle intervention that produced marked and sustained improvements in weight and physical activity did not provide cognitive benefits regardless of frailty at study entry. Although intervention effects on cognitive function were heterogeneous across the range of obesity and cardiovascular disease history, this heterogeneity was not evident across the range of deficit accumulation seen in the cohort.
Sex‐related differences in cognitive trajectories in older individuals with type 2 diabetes and overweight or obesity and the role of APOE4: Findings from the Look AHEAD and Look AHEAD‐MIND studies
Authors: Espeland Mark A , Bennett Wendy , Carmichael Owen T , Chao Ariana , Dutton Gareth , Hayden Kathleen M , Hugenschmidt Christina E , Kahn Steven , Luchsinger Jose , Neiberg Rebecca H , Roman‐Ashby Glorian , Olson Kayloni , Yassine Hussein N 
Published: December 2020

AbstractBackgroundWomen’s cognitive performance, particularly in the domains of verbal learning and memory, generally exceeds that of men. Among older individuals with diabetes and overweight/obesity, two conditions known to accelerate cognitive aging, it is unknown how these sex‐related differences in cognitive functioning unfold over time, i.e. whether any advantages seen in women result from less steep trajectories of cognitive decline than men, and whether any differences in rates of decline are moderated by the APOE4 genotype.MethodA standardized battery of cognitive function tests was administered 2 to 4 times over the course of up to 10 years (mean 5.3 years) among 2583 adults (62% women) who averaged 68 years of age at their first assessment. Mixed effects models were used to compare cognitive function scores (verbal learning, executive function, and processing speed) at the first assessment and rates of cognitive decline over time between women and men, with covariate adjustment for potentially confounding risk factors for cognitive decline.ResultAt their first assessment, women significantly outperformed men on tasks of verbal memory and processing speed (both p<0.001), but not executive function (p=0.38). These differences were evident for those both with and without the APOE4 genotype. Over follow‐up, women and men had similar rates of cognitive decline in these domains, overall and among those without the APOE4 genotype (all p>0.05). However, the APOE4 genotype was associated with significantly greater rates of decline among women than men for verbal learning (37% vs 8% increase, p=0.04) and processing speed (28% increase vs 5% decrease, p=0.004), but similar increased rates of decline in executive function (p=0.67).ConclusionFemale sex is associated with better cognitive functioning than male sex in key domains among older individuals with diabetes and overweight/obesity. Overall, this relative advantage is maintained over time among women without the APOE4 genotype. However, among those with the APOE4 genotype, rates of decline in verbal learning and processing speed are greater among women compared with men.
Assessment of brain iron accumulation in Alzheimer's disease with quantitative susceptibility mapping
Authors: Fan Xiang , Liu Xueru , Yan Lirong , Mok Vincent C. T. , Li Kuncheng 
Published: December 2020

AbstractBackgroundEmerging evidence suggests that regional iron accumulation is involved in the early pathology of Alzheimer’s Disease (AD), which can be evaluated using quantitative susceptibility mapping (QSM). Therefore, the purpose of this study was to evaluate QSM as an early imaging biomarker in AD by comparing regional iron accumulation using QSM in patients with AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects.MethodThirty‐seven patients with AD, twenty patients with MCI, and forty‐three CU subjects were recruited. All subjects received MRI QSM scans. All QSM images were reconstructed using NMEDI method. Using one‐way analysis of variance (ANOVA) test, the difference in regional iron accumulation between the three groups was studied in the regions of interest (ROI) including bilateral caudate nucleus and putamen. Pairwise multiple comparison was implemented using the least significant difference (LSD) method. For whole brain analysis, we applied a voxel‐based analysis using ANOVA followed by a post hoc analysis. A significant level of family‐wise error (FWE) corrected p < 0.05 with a cluster size of 30 voxels was applied to locate brain regions with significant differences among three groups. We used paired sample t test within 6‐month follow‐up data to see if there is any difference.ResultBased on ROI analysis, average susceptibility of the bilateral caudate and left putamen was significantly different among groups (p<0.001, respectively). Maximal susceptibility of the left caudate was significantly different among groups (p<0.001). For the whole brain analysis, significant difference in iron accumulation among AD, MCI and CU was found in parahippocampus, caudate, putamen, insula, cingulate gyrus, cuneus, precuneus, angular gyrus, thalamus, fusiform, lingual gyrus, corpus callosum, cortex and subcortical white matter, some cerebellum structures and so on. No significant difference was detected with the follow‐up data in each group.ConclusionThis study described brain iron accumulation patterns using QSM during AD progression. This may reveal secondary neuronal changes due to pathologic processes (e.g. oxidative stress) in AD. In addition, this study is the first to observe QSM changes in certain cerebellar regions. Further study is needed to confirm this finding.
Principal component analysis of brain metabolism in symptomatic Alzheimer's disease patients: A positron emission tomography with 18F‐fluorodeoxyglucose (PET‐FDG) study
Authors: Demey Ignacio , Mendez Patricio Alexis Chrem , Bérgamo Yanina , Urrutia Leandro , Campos Jorge , Falasco German , Sevlever Gustavo , Allegri Ricardo F , Vazquez Silvia 
Published: December 2020

AbstractBackgroundPatients with symptomatic Alzheimer's Disease (AD) usually present alterations in their cerebral metabolism measured by Positron Emission Tomography with 18F‐fluorodeoxyglucose (PET‐FDG). In the amnestic AD phenotype, the regional differences reported between patients with Mild Cognitive Impairment due to Alzheimer's Disease (MCI‐AD) and AD Dementia (ADD) have not been consistent. Within the ATN scheme, this study detects Neurodegeneration (N). There are no published studies that correlated the metabolic value of each cortical region and the quantification of cognitive performance. Objective: To analyze brain metabolism by regions measured by Positron Emission Tomography with PET‐FDG in patients with MCI‐AD and ADD, and correlate the regional metabolic values with the severity of neuropsychological clinical variables.MethodIn this cross‐sectional study, 24 patients with MCI‐AD and 22 with ADD were included , all right‐handed and PET–PIB positive, matched by sex, age, and education, with differences in different cognitive variables (p<0.01). All were studied with PET‐FDG with automated parcellation using the Klein and Tourville atlas. Differences between groups (Anova) were analyzed, and a Principal Component (PC) analysis was performed to summarize the vectors of higher variability. Vectors were compared through diagnoses and correlated with neuropsychological evaluation and other clinical aspects.ResultPatients with ADD showed lower metabolism than patients with MCI‐AD (p<0.05) in different regions of interest. Four PCs were identified that summarized 84.77% of the metabolism variability of the cortices analyzed. No significant differences were found in the magnitude of the CP between MCI‐AD and ADD patients (p>0.05). The first CP represented the magnitude of the overall metabolism and correlated with the age of the patients (p:0.04), the second CP weighted negatively frontal and positively occipital metabolism, and correlated negatively with semantic fluency (p:0.02), phonological fluency (p:0.04) and TMT‐A (p:0.003). The third CP considered parahippocampal regions and correlated with recognition in verbal episodic memory (p:0.01).ConclusionDimension reduction analysis represents a novel approach to summarize neuroimaging data. In this sample of patients with PET‐PIB positive and symptomatic AD, CP extraction demonstrates a close correlation between regional metabolism and performance in neuropsychological tests associated with those regions.
Actigraphy as a proxy biomarker for motoric agitation in Alzheimer disease
Authors: Burhan Amer M. , Knuff Amber , Seitz Dallas 
Published: December 2020

AbstractBackgroundAgitation is an important symptom of dementia and is commonly assessed using clinician and/or caregiver rated scales. These scales are useful but they rely on a mixture of direct and indirect observations and therefore are subject to limited reliability and validity depending of factors such as staffing. Actigraphy is a tool to assess motoric activity, a core feature of agitation. There is a growing interest in using Actigraphy as a tool to diagnose and monitor agitation of dementia. We previously published a report demonstrating feasibility and a correlation between Actigraphy and informant‐based rating of physical agitation in a sample of hospital and nursing home patients with Alzheimer in moderate level of cognitive impairment from Kingston Ontario, Canada.MethodThis is an extension to our previous observational, cohort study now involving a sample of older adults with Alzheimer disease and agitation from London Ontario, Canada in hospital and nursing home with severe level of cognitive impairment. Measurements: Baseline characteristics included demographics, severity of cognitive impairment, medical comorbidity, and agitation symptoms assessed using CMAI and NPI. Actigraphy was measured over several continuous days.ResultsTwenty participants were enrolled (mean age=81.3/years, SD=7.97; Male=12; mean MMSE=6.3, SD=5.7; mean CMAI score=66.83, SD=10.79). Pearson correlation coefficient was explored between agitation and Actigraphy measures. We found that total CMAI scores correlated with 24‐hours Actigraphy data (r(18)= 51, p= .02), further analysis showed that only physical non‐aggressive agitation correlated with 24‐hours actigraphy measures (r(18)= 0.49, p=.03), this was mainly related to day‐time and evening‐time Actigraphy but not overnight.ConclusionsActigraphy was correlated significantly and moderately with informant‐based methods for measuring physical agitation in individuals with dementia and showed a temporal pattern of activity. Further studies are required to understand the application of Actigraphy as a biomarker for motoric agitation in this population.
Activation of distinct synaptic populations regulates extracellular release of ILEI⁄FAM3C and Aβ
Authors: Nakano Masaki , Mitsuishi Yachiyo , Watanabe Naoki , Hibino Emi , Saito Takashi , Saido Takaomi C. , Suzuki Toshiharu , Nishimura Masaki 
Published: December 2020

AbstractBackgroundPreviously, we reported a novel role of the secretory protein ILEI (also referred to as FAM3C) in modulation of APP metabolism. ILEI binds to the γ‐secretase complex and destabilizes APP C–terminal fragments (CTFs) to suppress Aβ production without inhibiting γ‐secretase activity. ILEI is localized in the trans–Golgi network and the endocytic vesicles where Aβ is produced from PS1:APP–CTFβ complexes. Synaptosome fractionation analysis further indicated that ILEI is colocalized with APP and the γ‐secretase complex at the synaptic vesicle. In this study, we investigated how activation or suppression of a specific synapse population affects extracellular release of ILEI and Aβ.MethodIn order to measure ILEI concentration, we first generated monoclonal antibodies against recombinant ILEI and setup sandwich ELISA. ILEI and Aβ concentrations in the interstitial fluid of cerebral cortex of freely moving mice were monitored by microdialysis. Using humanized mutant APP–knockin mice, we examined an effect of selective agonist or antagonist for a specific population of neurotransmitter receptors on ILEI and Aβ secretion.ResultMicrodialysis study using APP–knockin mice revealed that interstitial fluid concentration of ILEI was fluctuated and roughly parallel with a level of locomotor activity but not with that of Aβ. Reverse dialysis treatment with anesthetics, tetrodotoxin and tetanus toxin markedly decreased both of ILEI and Aβ in the interstitial fluid. On the other hands, treatment with agonist (diazepam) and antagonist (picrotoxin) for GABAA receptor decreased and increased both ILEI and Aβ, respectively.ConclusionOur results suggest that presynaptic ILEI and Aβ are similarly released into the extracellular space in a synaptic activity–dependent manner. Especially, ILEI secretion is largely dependent on GABAA receptor activity.
Ribosomal protein synthesis is decreased in tauopathy as revealed by noncanonical amino acid labelling
Authors: Evans Harrison Tudor , Benetatos Joseph , Bodea Liviu Gabriel , Götz Jürgen 
Published: December 2020

AbstractBackgroundTau is a scaffolding protein which serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Recently we demonstrated that amyloid‐b, the second hallmark of AD, induces de novo protein synthesis of tau, with this activation being found to be tau‐dependent. This raised the question of whether FTD‐tau by itself affects protein synthesis.MethodIn order to examine protein synthesis, we optimised non‐canonical amino acid (NCAA) labelling to label newly synthesised proteins in vivo in the K369I tau transgenic K3 mouse model of FTD. Combining this technique with either fluorescent non‐canonical amino acid tagging (FUNCAT) or bio‐orthogonal non‐canonical amino acid tagging (BONCAT), we were able to visualise and purify newly synthesised proteins from mouse brain tissue. We also used polysome profiling in primary neurons to further explore the effect of tau on ribosome biogenesis.ResultOur analysis reveals massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding we confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identify alterations in the synthesis of 247 proteins in de novo proteome of K3 mice, including the decreased synthesis of the ribosomal subunit proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. We also demonstrate that there is a decrease in overall abundance of one of these proteins, RPL23, and that this decrease correlated with the levels of both total and AT8 phosphorylated tau. Lastly, we recapultate these findings in human tissue, with FTD‐brains showing significantly lower levels of RPL23 than healthy controls.ConclusionTogether, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.
Polygenic effect of cholesterol metabolism pathway‐accelerated pathological changes and disrupted default mode network trajectory across the Alzheimer’s disease spectrum
Authors: Zang Fei Fei , Zhu Yao , Liu Yi Xin , Fan Dan Dan , Wang Qing , Zhang Qian Qian , He Cancan , Zhang Zhijun , Xie Ming Chun 
Published: December 2020

AbstractBackgroundThe cumulative genetic effect of cholesterol metabolism (CM) pathway may be a candidate cause for disrupted brain network and impaired cognitive phenotypes, dependent on the pathological changes of Alzheimer’s disease (AD) spectrum. We aim first to explore the relation of polygenic scores (PGS) underlying CM pathway with cerebrospinal fluid (CSF) biomarkers and cognition of AD, and second to investigate the role of genetic protective scores (GPS), genetic risk scores (GRS) and relative risk scores (RRS) of CM pathway on the anterior and posterior default mode network (aDMN and pDMN) trajectories across the AD spectrum.MethodWe analyzed data of 113 participants of AD spectrum from the Alzheimer's disease Neuroimaging Initiative database, with demographic, global cognitive, genetic, CSF, and resting‐state functional MRI images at baseline available. Then PGS were calculated based on the odds ratio of minor allele. Linear and nonlinear regression were employed to explore the relationship between pairs of PGS, cholesterol metabolites in the blood, CSF biomarkers, and cognitive performance, and multivariate linear regression to investigate the main and interactive effect of PGS×disease on the DMN.ResultPGS of CM pathway were significantly correlated with levels of CSF biomarkers but not cognition directly. Several cholesterol metabolites were associated with t‐Tau but not p‐Tau and Aβ levels of CSF biomarkers, and the latter of which could impact cognitive performance in a nonlinear manner. In addition, CM related blood biomarkers could influence cognitive function directly. Further, accumulative effects of GPS, GRS, and RRS on the aDMN and pDMN were in absolutely diverse trajectories across the AD spectrum. However, brain regions of PGSΧdisease effects were mainly concentrated in the cortical frontal‐parietal network and subcortical basal ganglia network. There was also a certain rule for the brain maps of cholesterol metabolites associated with DMN, where sensory‐motor network and posterior cingulate cortex occupied.ConclusionThe cumulative genetic effect of CM pathway could affect DMN and cognition dependent on the pathological levels of AD and firstly demonstrated that protective genes, risky genes and relative risk within CM pathway had different trajectories effects on the subsystems of DMN across the AD spectrum.
The clinical risk factors of cerebral microbleeds and its relationship with cognitive dysfunction
Authors: Yuan Junliang , Li Xuanting , Hu Wenli 
Published: December 2020

AbstractBackgroundTo explore the risk factors of cerebral microbleeds (CMBs) and the relationship between CMBs and cognitive impairment, and to provide more theoretical basis for the prevention and treatment of CMBs and vascular cognitive impairment.MethodThe CMBs group was classified according to the number and location. The basic clinical data were collected and the subjects all received the cognitive tests using Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and the Neuropsychological Assessment Scales.ResultA total of 138 subjects [71 participants in CMBs group and 67 as control] were enrolled, with an average age of 64.36±10.14 years. Ordered logistic regression analysis showed diastolic blood pressure (OR=1.05, 95% CI: 1.01‐1.09), history of ischemic stroke and transient ischemic attack (TIA) (OR=7.74, 95% CI: 2.74) ‐21.88), white matter hyperintensities (OR = 2.01, 95% CI: 1.46‐2.78) are independently associated with CMBs (P<0.05). Spearman correlation analysis showed that MMSE, MoCA, memory and executive function were correlated with CMBs (MMSE r=‐0.24, P=0.005; MoCA r=‐0.32, P<0.001; memory r=‐0.28, P=0.001; execution function r = ‐0.33, P<0.001). Multivariate linear regression analysis showed that MoCA score, memory and executive function were negatively correlated with CMBs number after adjusting for gender, age, years of education, other imaging biomarkers of cerebral small vessel disease and vascular risk factors (MoCA β=‐0.88, P=0.012; memory β = ‐0.22, P = 0.002; executive function β = ‐0.13, P = 0.001). As for the location, the results showed that the executive function of patients with strict lobe CMBs was lower than that of control group (P=0.046). In terms of speed and motion control, the differences between deep group and control group (P=0.037), deep group and infratentorial group (P=0.005) were statistically significant.ConclusionDiastolic blood pressure, history of ischemic stroke / TIA, white matter hyperintensities were independent risk factors for CMBs. CMBs are associated with cognitive dysfunction. CMBs in the strict lobe area are associated with the decline of executive function, and CMBs in the deep area are associated with the decline of speed and motor control ability.