bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic risk score for Alzheimer’s disease and its association with eye movement performance
Authors: Coors Annabell , Imtiaz Mohammed Aslam , Aziz N. Ahmad , Ettinger Ulrich , Breteler Monique M.B. 
Published: December 2020

AbstractBackgroundMany neurodegenerative disorders are characterised by changes in specific eye movement (EM) outcomes. Individuals with Alzheimer’s disease (AD) make more antisaccade errors and correct a lower proportion of those errors compared to controls. EM impairments occur at an early stage of neuropathological changes and have, therefore, been discussed as a potential biomarker. Despite high test‐retest correlations for measures of EM performance and an estimated heritability of >40% for antisaccade performance, genetic association studies identified only a few single‐nucleotide polymorphisms (SNPs) related to EM performance. Polygenic risk scores (PRSs) are advantageous as they summarize the effects of many SNPs into a single score. Therefore, we assessed whether higher genetic risk for AD in healthy participants was associated with higher antisaccade error rate and lower correction rate of antisaccade errors.MethodThe analyses were based on data of the first 2,000 participants (aged 30‐95) of the Rhineland Study, a community‐based prospective cohort study in Bonn, Germany. Genotyping was performed on Omni 2.5 exome arrays. We created PRS for AD by including all SNPs that reached genome‐wide significance at a threshold of p=5x10‐7in stage one of the GWAS of the “IGAP consortium”. Missing SNPs were imputed using the 1000 Genomes reference panel. We examined the association between genetic risk for AD and antisaccade error rate using multivariable regression with PRS as predictor and antisaccade error rate as outcome variables. For antisaccade correction rate we used a one‐inflated beta regression model as the residuals were severely skewed. Ancestry, age, age2, sex, visual acuity and education were added as covariates in both regression models.ResultPolygenic risk for AD was associated with neither antisaccade error rate nor the proportion of uncorrected errors in those who did not correct all of their errors. However, a higher PRS for AD was associated with a lower odds of correcting all mistakes (odds ratio=0.85 (95%‐CI:0.73‐1.00) per one standard deviation increase in PRS).ConclusionPolygenic risk for AD was associated with error correction rate in healthy individuals. Our findings suggest that eye movement performance may be a potential biomarker for early‐stage AD‐related neuropathological changes in the general population.
Red cell distribution width (RDW) and the risk of dementia in the oldest‐old: The Monzino 80‐plus population‐based study
Authors: Galbussera Alessia A , Tettamanti Mauro , Riva Emma , Mandelli Sara , Forloni Gianluigi , Lucca Ugo 
Published: December 2020

AbstractBackgroundThe red cell distribution width (RDW) is one of the routine parameters of a complete blood count measuring the range of variation of red cell volume, with higher values indicating greater heterogeneity in cell size. Higher RDW has been associated with poorer cognitive performance, prevalent dementia, and severity of leukoaraiosis in middle‐aged and older adults. Elevated RDW has been linked with systemic inflammatory processes, dysfunction of microcirculation, indices of oxidative stress. Existing literature on the subject is however very scanty. Objective of the present study was to explore the association of RDW with prevalent and incident dementia among the oldest‐old participants in the Monzino 80‐plus study.MethodA RDW measurement was available for 812 participants in a door‐to‐door, prospective population‐based study on the prevalence and incidence of dementia among 80‐years and older residents in the province of Varese, Italy. Diagnosis of dementia was made according to DSM‐IV criteria. Potential confounders included in "fully”‐adjusted models: age, sex, education, smoking history, alcohol consumption, hospital admission during the previous year, history of diabetes, hypertension, myocardial infarction, heart failure, respiratory failure, renal failure, stroke, TIA, parkinsonism, cancer.ResultParticipants were on average 90.7 (5.3) years old, 74.5% women, and had a mean (SD) 5.0 (2.4) years of education. Mean RDW increased with age (p for trend <0.0001). Compared to the lowest quartile of RDW (≤12.8%), the highest (≥14.4%) was significantly associated with increased odds of having dementia (age‐, sex‐, and education‐adjusted OR: 1.64; 95%CI: 1.05‐2.56; p=0.0310). When the model was fully‐adjusted, the association was no longer significant (OR: 1.39; 95%CI: 0.86‐2.25; p=0.1795). Over a 15‐year follow‐up 225 subjects were diagnosed with dementia out of 465 participants without at baseline. Oldest‐old in the highest quartile of RDW did not have a significantly increased risk of incident dementia with respect to those in the lowest (univariate analysis, HR: 1.29; 95%CI: 0.87‐1.93; p=0.2109). Similar results were obtained using RDW as a continuous variable in both cross‐sectional and longitudinal analyses.ConclusionIn the present prospective population‐based study in the oldest‐old, elevated RDW was not significantly associated with an increased risk of developing dementia.
Low plasma cortisol and large hippocampal volume are associated with reduced risk of clinical progression in MCI
Authors: Huijbers Willem , Kirschbaum Clemens , Wirth Miranka ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundHigh cortisol concentration, a biomarker of hypothalamic‐pituitary‐adrenal (HPA) axis activation, and low hippocampal volume have been linked to increased risk for Alzheimer’s disease (AD). This longitudinal study evaluates the impact of baseline plasma cortisol levels on hippocampal atrophy and on clinical progression in patients with mild cognitive impairment (MCI).MethodParticipants with mild cognitive impairment (MCI, n=305) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) based on measures of plasma cortisol (at baseline) and hippocampal volume. We assessed relationships between plasma cortisol levels, hippocampal volume, and risk of progression to clinical AD over a variable study period of up to 100 months.ResultHigher plasma cortisol levels were related to greater decline in hippocampal volume in MCI patients, adjusting for baseline volume (Figure 1, left). Hippocampal volume at baseline predicted progression to clinical AD, while plasma cortisol alone did not. Plasma cortisol interacted with hippocampal volume (Figure 1, right), such that MCI patients with relatively large hippocampal volumes and low plasma cortisol levels at baseline were less likely to progress to clinical AD.ConclusionThis study demonstrates the involvement of plasma cortisol in hippocampal degeneration and risk of clinical progression in MCI patients. Our findings suggest that regulation of HPA axis activation may be protective against neural degradation and clinical decline in these high‐risk individuals.
Multimodal phenotyping of synaptic damage along the Alzheimer disease continuum
Authors: Jelic Vesna 
Published: December 2020

AbstractBackgroundDysfunction of brain neuronal connections is one of the earliest and best correlates of cognitive deficits in patients with Alzheimer disease (AD), preceding neuronal cell death. There is no established biomarker test for early synaptic pathology. In this context, EEG and novel CSF synaptic markers are of great interest as they complementarily mirror functional and molecular aspects of synaptic dysfunction.MethodQEEG power, synchronisation, microstates and topographical analysis of generators of EEG activity were calculated from a naturalistic Memory Clinic cohort consisting of 637 individuals with different stages of cognitive impairment from subjective cognitive decline (SCD), mild cognitive impairment (MCI) and AD dementia, as well as 308 healthy elderly controls from the Swedish national aging study. Patients performed lumbar puncture and CSF was analysed for routine AD biomarkers and saved for further analysis of novel synaptic markers. In 67 MCI and AD patients FDG‐PET was performed.ResultIn patients, Global Field Power (GFP) in slow delta and theta frequency has inverse correlation with amyloid pathology while GFP in fast alpha and beta frequencies correlate with markers of neurodegeneration, Figure 1 a. A similar pattern of association between CSF biomarkers and Global Field Synchronisation (GSF) was found in fast alpha and beta frequencies, Figure 1b. Analysis of resting EEG microstates topography revealed association between CSF Aβ42 levels and alterations in the topography of symmetrical microstate class C, while alterations in the topography of asymmetrical microstate class B was associated with CSF p‐tau levels. There is a significant gradient‐like increase in mean contributions of asymmetrical classes A and B and decrease in contribution of symmetrical classes C and D with the more severe stage of cognitive impairment, Figure 2. In AD and MCI patients with CSF verified amyloid pathology brain glucose hypometabolism in temporoparietal lobes is significantly associated with altered EEG functional connectivity and “disconnection” of the same regions of interest on standardized EEG functional imaging technique sLORETA.ConclusionThere is a selective association of qEEG power, global and regional connectivity and microstates parameters with molecular AD pathology. Ongoing study is exploring if there is a similar association with novel CSF synaptic marker neurogranin.
Brain free‐water increases mediate the association of blood cardiovascular biomarkers with longitudinal cognitive decline in prodromal and clinical dementia
Authors: Ji Fang , Pasternak Ofer , Chai Yuek Ling , Liu Siwei , Ong Marcus Qin Wen , Tan Boon Yeow , Richards Arthur Mark , Kan Cheuk Ni , Venketasubramanian Narayanaswamy , Chen Christopher , Lai Mitchell Kim Peng , Zhou Juan Helen 
Published: December 2020

AbstractBackgroundThere is increasing awareness of the “Heart‐Brain Connection”, where cardiovascular function may potentially contribute to cognition. Brain free‐water (FW) increases, a novel imaging marker reflecting extracellular water molecule alteration, has been associated with cerebrovascular disease (CeVD) and cognitive impairment. We have previously shown an association between blood cardiovascular biomarkers (BCBs) and cognitive impairment. However, no study has examined the association between FW and BCBs. We hypothesized that FW would be related to BCB and would mediate the effects of BCBs on cognition.MethodBCBs (N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high sensitivity cardiac troponin T (hs‐cTnT), growth differentiation factor 15 (GDF‐15)) were measured in 232 patients (134 cognitive impairment no dementia, and 98 dementia with and without CeVD), who also underwent T1 and diffusion MRI. The FW method was applied to derive individual FW maps from diffusion MRI. We tested the association of BCBs with skeletonised white matter (WM)‐FW or surfaced grey matter (GM)‐FW by regression. Moreover, we measured the mediation effects of FW on the association of BCBs with baseline cognition and longitudinal decline by path analysis.ResultHigher BCBs were associated with widespread WM‐FW increases (Figure‐1) and GM‐FW increases primarily in the default mode, executive control and somatomotor networks (Figure‐2). Both higher WM‐FW and GM‐FW mediated the associations of BCBs with baseline (cross‐sectional) global cognitive impairment (Figure‐3A) and longitudinal decline over 5 years (Figure‐3B). For individual cognitive domains, the higher mean WM‐FW and network‐specific GM‐FW mediated the associations of higher BCBs with baseline memory and executive function deficits (not shown) and longitudinal decline (Figure‐4). Specifically, higher GM‐FW in the executive control network was responsible for executive function impairment, while GM‐FW in the default mode network mediated the relationship with memory dysfunction, both cross‐sectionally and longitudinally.ConclusionThis is the first report of an association between BCBs and FW. Importantly, we found that markers of cardiovascular dysfunction could affect baseline cognition and longitudinal cognitive changes through widespread WM and GM network‐specific FW abnormalities in memory‐clinic patients. Further research is needed to investigate if the use of such accessible cardiovascular blood biomarkers could facilitate management and treatment of cognitive impairment and dementia.
Mediterranean versus western diet effects on cerebral cortical thickness and volume in cynomolgus macaques
Authors: Shively Carol A. , Frye Brett M. , Register Thomas C. , Andrews Rachel N. , Appt Susan E. , Vitolins Mara Z. , Uberseder Beth , Silverstein‐Metzler Marnie G. , Chen Haiying , Whitlow Christopher T. , Barcus Richard A. , Lockhart Samuel N. , Corbitt Sarah E. , Craft Suzanne 
Published: December 2020

AbstractBackgroundAssociations between diet, cognitive decline and neurodegenerative disease, including Alzheimer’s Disease (AD), have been reported, but whether these relationships are causal is difficult to determine in human studies. Cynomolgus macaques (Macaca fascicularis), like humans, are omnivorous, have complex central nervous systems, and are susceptible to diet‐induced diseases. Similar to humans, these nonhuman primates accumulate amyloid and tauopathies with age, and diabetes accelerates age‐related amyloid accumulation. Thus, these primates are appropriate models for investigations of diet effects on the brain.MethodUsing structural magnetic resonance imaging, we examined diet effects on brain anatomy by measuring the thicknesses and volumes of AD‐signature cortical regions of interest (ROIs) in 38 middle‐aged females, at baseline and after consumption of either a Mediterranean (MED) or Western (WEST) diet for 36 months (∼ equivalent to a 9‐year follow up in humans).ResultUsing repeated measures analysis, cortical thicknesses were significantly increased in the WEST diet group in the angular gyrus (p<0.001), inferior temporal gyrus (p<0.001), middle temporal gyrus (p<0.001), superior temporal gyrus (p<0.001), supramarginal gyrus (p<0.001), fusiform gyrus (p<0.01), precuneus (p<0.001), parahippocampal gyrus (p<0.01), and an AD meta‐ROI (p<0.001). WEST diet also resulted in increases in total brain volume (p<0.02) and gray matter (p<0.01) and decreases in cerebrospinal fluid (p<0.01), white matter (p<0.01), and deep gray matter (striatum and thalamus) (p<0.05). In contrast to the patterns observed in the WEST diet group, thicknesses and volumes generally remained unchanged between baseline and 31 months treatment in animals consuming the MED diet.ConclusionTaken together, these findings demonstrate that WEST diets likely induce widespread structural shifts, which may increase risk of cognitive decline and neuropathology; whereas MED diets may exact a stabilizing influence on the brain. This study provides important insights about the significance of diet on brain structure, and lays the groundwork for future investigations to uncover the molecular underpinnings of diet‐induced changes in the brain.
Sleep disturbance and incident Alzheimer’s disease: A UK Biobank study of 502,538 middle‐aged to older participants
Authors: Gao Lei , Li Peng , Cui Longcong , Wong Patricia M , Johnson‐Akeju Oluwaseun , Lane Jacqueline , Saxena Richa , Scheer Frank , Hu Kun 
Published: December 2020

AbstractBackgroundRecent cross‐sectional studies have suggested a link between sleep disturbance and worse neurocognitive function. We hypothesized that sleep disturbance traits (short/long habitual sleep duration, insomnia, daytime somnolence, and napping), and sleep apnea were linked to the development of incident Alzheimer’s disease (AD) in a large, prospective cohort spanning over a decade.MethodWe studied 502,538 participants from the UK Biobank, free from AD at baseline (mean age 57, range: 37‐73), who have been followed for up to 12 years. AD date of diagnosis was obtained through algorithmic combinations of coded information from hospital admissions (diagnoses and procedures) and death registries. Cox proportional hazards models were performed to examine the association between sleep disturbance with incident AD during follow‐up. Sleep disturbance traits include: self‐reported sleep duration (short <6hrs/intermediate 6‐9h/long>9h), daytime somnolence (often/rarely), napping (usually/rarely). Sleep apnea presence was derived from ICD‐10 diagnosis and/or self‐report. Our core models with individual sleep disturbance traits were adjusted for age, sex, education, and ethnicity. The full model adjusted for major comorbidities [the Townsend deprivation index ‐ a measure of socioeconomic status, body mass index, physical activity, major cardiovascular diseases and risk factors (hypertension, high cholesterol, smoking, diabetes, AF, angina/MI, peripheral vascular disease), neurological diseases (stroke/TIA, dementia, Parkinson’s), respiratory diseases (COPD, fibrosis), alcohol use, depression/anxiety, and medication use (benzodiazepines, sedatives/sleep aides, antipsychotics, steroids and opioids)].ResultIn total, 932 developed AD after 6.4 years (SD=1.9). In our full model, long habitual sleep (>9h), but not short sleep (<6h), saw a two‐fold increased risk (HR 2.04, 95% CI: 1.55‐2.67 p<0.0001) compared to intermediate sleep (6‐9h) duration. Daytime somnolence was independently predictive of AD (HR 1.56, 95% CI: 1.18‐2.03, p=0.001). These effects remained after controlling for sleep apnea, which was only predictive in the core model (HR 2.05, 95% CI: 1.23‐3.42, p=0.006).ConclusionLong habitual sleep duration and daytime somnolence may be early, independent markers of AD. Further work examining objective measures of sleep duration and sleep disturbance within this population is ongoing, and may help confirm our findings. If replicated, future trials may be warranted to test whether optimizing sleep health reduces the risk of developing AD.
Evaluating vascular cognitive impairment and dementia due to small‐vessel disease using plasma levels of PLGF and VEGF‐A
Authors: Winder Zachary , Lee Tiffany , Fardo David W , Cheng Qiang , Goldstein Larry , Nelson Peter T. , Schmitt Frederick A. , Jicha Gregory A. , Wilcock Donna M. 
Published: December 2020

AbstractBackgroundVascular Cognitive Impairment and Dementia (VCID) refers to cerebrovascular disease‐associated cognitive disorders. VCID may manifest clinically with mild cognitive impairment (MCI) or dementia. Depending on diagnostic criteria, dementia may be attributed to VCID in about 20% of cases. Arteriolosclerosis, microinfarctions, and microhemorrhages characterize a major subgroup of VCID pathologies, collectively referred to as small‐vessel disease (SVD). In this study, we evaluated the association of SVD with plasma levels of PLGF and VEGF‐A. We hypothesize that up‐regulation of these molecules in blood are part of the mechanism and/or reaction of the brain to SVD due to their roles in blood‐brain‐barrier breakdown and aberrant angiogenesis.MethodPlasma samples from participants in the University of Kentucky Alzheimer’s Disease Center’s prospective cohort study were collected and analyzed using Meso Scale Discovery and Quanterix Simoa digitized immunoassay techniques to measure angiogenic and inflammatory biomarker levels. Unsupervised clustering analysis was used to identify unique subsets within the MCI patient population based on their plasma biomarker profile. Paired t‐tests were used to compare plasma levels of PLGF and VEGF‐A in patients diagnosed with VCID‐SVD and age‐matched controls. Supervised machine learning was then used to classify patients into groups based on the severity of their chronic vascular pathology using plasma angiogenic and inflammatory biomarkers.ResultClustering analysis identified a subset of MCI participants with elevated levels of VEGF‐A (p < 0.001), MMP1 (p < 0.001), and IL8 (p < 0.001). Whereas participants with VCID‐SVD had significantly elevated levels of PLGF compared to age‐matched controls (p < 0.01), a non‐significant increase in VEGF‐A was also found. Additionally, supervised classification analysis yielded a model with 52.4% accuracy in assigning patients to one of three groups of chronic vascular grading on cross validation.ConclusionThese experiments provide evidence for the utility of using plasma biomarkers such as PLGF and VEGF‐A in assessing SVD in patients with varied stages of VCID, ranging from MCI to dementia. In the future, analyzing plasma PLGF and VEGF‐A levels alongside imaging biomarkers may improve the accuracy of the diagnosis of VCID, monitoring of disease progression, and potentially provide a biomarker to assess therapeutic response.
Relationship between cerebrovascular reactivity and cognition among people with risk of cognitive decline
Authors: Kim Donghoon , Hughes Timothy M. , Hugenschmidt Christina E. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D. , Whitlow Christopher T. , Okonmah‐Obazee Stephanie , Bobinski Matthew , Jung Youngkyoo 
Published: December 2020

AbstractBackgroundIt has been shown that cerebrovascular reactivity (CVR) is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal is not straight‐forward since other physiological parameters, such as oxygen utilization and blood volume, also contribute to its measurements. In this study, we measured cerebral blood flow (CBF) using a dynamic arterial spin labeling (ASL) technique during a hypercapnia challenge and tested if CVR is related to risk factors of cognitive decline and cognitive performance.MethodSixty‐three subjects (age: 70.17±7.09 yrs, M/F: 18/45; BMI: 27.63±5.07; years in education: 15.79±2.38 yrs; 7 diabetes; 17 hypertension; MMSE score: 28.49±1.40) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including ASL during a hypercapnia challenge with a RespirAct computer‐controlled gas blender, targeting 10mmHg higher end‐tidal CO2 level than the baseline while end‐tidal O2 level is maintained. Pseudo‐continuous ASL (PCASL) was collected during a 3‐minute baseline and a 2‐minute hypercapnic period. The whole brain CVR was obtained by calculating a percent change of CBF per the end‐tidal CO2 elevation in mmHg between the baseline and the hypercapnic challenge (Figure 1). A partial volume correction on CVR and baseline CBF was applied and the whole brain gray matter CVRgm and CBFgm were calculated. Linear regression analyses were performed (CVRgm or CBFgm ∼age+sex+BMI+years of education+diabetes+hypertension+MMSE) to examine the relationship between CVRgm or CBFgm and global cognitive performance (MMSE score).ResultCVRgm is positively associated with the MMSE scores (β=0.208, p=0.016) independent of other covariates (Figure 2). CBFgm is negatively associated with age (β=‐0.552, p=0.013) and BMI (β=‐0.623, p=0.037) with the adjustment for all other covariates (Figure 3).ConclusionThis study demonstrated that CVRgm is related to lower MMSE scores, while resting CBFgm showed significant relationships with age and BMI. Therefore, CVRgm may be a sensitive imaging parameter relating vascular and cognitive function.