bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower cerebral oxygen utilization is associated with Alzheimer’s disease‐related neurodegeneration on MRI and poorer cognitive performances among apolipoprotein E ε4 carriers
Authors: Robb W. Hudson , Khan Omair A. , Ahmed Humza A. , Liu Dandan , Moore Elizabeth E. , Li Judy , Cambronero Francis E. , Pechman Kimberly R. , Gifford Katherine A. , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2020

AbstractBackgroundOxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are markers of oxygen utilization and neuronal energy demands that may offer insights into normal and abnormal changes in aging. This study cross‐sectionally related OEF and CMRO2 to cognitive and structural neuroimaging variables among older adults. Because apolipoprotein E (APOE)‐ε4 status is an Alzheimer’s disease (AD) genetic risk factor and a molecular mediator of vascular damage, we tested whether APOE‐ε4 status modified associations.MethodVanderbilt Memory and Aging Project participants free of stroke and dementia (n=237, 75±7 years, 37% female) underwent neuropsychological testing and multimodal 3T brain MRI, including T
1‐weighted imaging (grey matter volumes/thickness), fluid attenuated inversion recovery (white matter hyperintensities (WMHs)), T2‐relaxation‐under‐spin‐tagging (venous oxygenation (Yv)), and pseudo‐continuous arterial spin‐labeling (cerebral blow flow (CBF)). Participant‐specific Yv, arterial oxygenation, and hematocrit were used to calculate OEF, which multiplied by CBF yielded CMRO2. Linear regressions related OEF and CMRO2 individually to cognition, grey matter volumes, an AD imaging signature (Schwarz et al., 2016), and WMHs adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, Clinical Dementia Rating, APOE‐ε4 status, and (as appropriate) intracranial volume. Follow‐up models tested predictor x APOE‐ε4 status interactions on outcomes followed by APOE‐ε4 status stratification.ResultMain effects were mostly null (p‐values>0.04). APOE‐ε4 status interacted with both OEF and CMRO2 on language (p‐values<0.04), episodic memory (p<0.04), hippocampal volume (p‐values<0.03), and Schwarz AD signature (p‐values<0.05). APOE‐ε4 status also interacted with CMRO2 on total grey matter volume (p=0.04), inferior lateral ventricle volume (p=0.01), executive function (p=0.05), and visuospatial skills (p=0.01). For all interactions, lower OEF and CMRO2 related to worse cognitive performances and smaller regional grey matter structures in APOE‐ε4 carriers only.Conclusion
APOE‐ε4 status modifies associations linking cerebral oxygen metabolism markers (CMRO2, OEF) to worse episodic memory performance and smaller neuroimaging variables in regions susceptible to AD‐related neurodegeneration. Consistently, results are present in APOE‐ε4 carriers only. Congruence between cognitive and neuroimaging findings suggests that oxygen metabolism and APOE‐ε4 may interact early in the pathogenesis of AD and related neurodegeneration with important clinical consequences.
Characterization of genetic expression patterns in MCI using a multiomics approach and neuroimaging endophenotypes
Authors: Sanjay Apoorva Bharthur , Patania Alice , Yan Xiaoran , Svaldi Diana , Apostolova Liana G. 
Published: December 2020

AbstractBackgroundOur goal was to characterize gene expression patterns at the MCI stage using a multiomics approach involving the integration of neuroimaging MRI data and peripheral blood‐based gene expression data.MethodData from the ImaGene study (Imaging and Genetics Biomarkers study of Alzheimer’s Disease, UCLA) was used. This included 160 subjects clinically diagnosed with amnestic MCI (n=70), non‐amnestic MCI (n=38) and normal controls (n=52)(Table 1). Coronal T1‐weighted MPRAGE scans were processed in Freesurfer 6.0 using the standard processing pipeline and atrophy measures were obtained. Quantile‐normalized and log‐transformed mRNA levels were obtained from peripheral blood. Preliminary data reduction was performed by selecting 3420 genes whose expression was significantly associated with hippocampal volume and cortical thickness (p<0.05, linear regression model). Vertex‐wise regressions were performed in SurfStat to map the associations of peripheral blood‐based gene expression with brain atrophy. A persistent‐homology pipeline was applied on the regression‐derived beta‐coefficients to derive betti numbers characterizing the association between gene expression and brain topology (Figure 1). The betti numbers were then used in a kernel‐based clustering solution to cluster genes. PCA was used to represent each cluster by its first principal component. Clusters of genes significantly associated with disease diagnosis were identified. Significant clusters were characterized ontologically to identify enriched biological pathways within the clusters. Cluster level association of genes with brain regions was then assessed using vertex wise regressions in SurfStat (Figure 3).ResultThe 3420 genes clustered into 20 clusters with good separation (Figure 2). Three disease‐relevant significant clusters emerged (pFDR‐Corrected<0.05) and were validated using a null model. The biological processes associated with each cluster were mitochondrial fatty acid beta oxidation, as well as regulation of NF‐kappaB signaling and apoptosis (Figure 2). Cluster‐level associations with cortical thickness displayed canonical AD‐like patterns (Figure 3).The apoptosis cluster showed a very strong AD like presentation with respect to atrophy pattern.ConclusionUsing a data‐driven approach, we found a systems‐level disease‐relevant gene expression signature that is sensitive to pre‐clinical AD using peripheral blood showing an AD‐like pattern of association with cortical atrophy. This approach might be useful in developing robust risk assessment platforms.
Interactive effects of chronic health conditions and financial hardship on episodic memory among older blacks: Findings from the Health and Retirement Study
Authors: Byrd DeAnnah R , Gonzales Ernest , Moody Danielle L Beatty , Marshall Gillian L , Zahodne Laura B , Thorpe Roland J , Whitfield Keith E 
Published: December 2020

AbstractBackgroundPrevious research suggests that chronic health conditions and financial hardship robustly shape cognitive health outcomes, including ADRD risk in older Blacks. However, few studies have explored the moderating effect of financial hardship on chronic disease burden and specific cognitive domains. This study examined whether financial hardship modifies the impact of self‐reported chronic health conditions on episodic memory among a representative sample of older Blacks enrolled in the 2006 Health and Retirement Study (HRS).MethodThe study included 934 older Blacks (50+ years) who completed the psychosocial leave‐behind questionnaire in the 2006 wave of the HRS. Episodic memory included a composite standardized score of immediate and delayed recall. Six chronic health conditions (e.g., hypertension, diabetes, stroke) were summed and dichotomized (0‐1 vs. as ≥2 conditions). Financial hardship was assessed as self‐reported difficulty paying monthly bills (range: not at all=0 to very/completely=3). Weighted OLS regression models tested independent associations between chronic health conditions and episodic memory, controlling for sociodemographic characteristics. An interaction term tested moderation by financial hardship.ResultThe majority of the sample was female (39.34% male) and had less than a high school education (35.89%; Table 1). Financial hardship modified the association between chronic disease burden and episodic memory performance such that individuals who reported very little difficulty paying their monthly bills had significantly lower memory scores at high levels of disease burden compared to those reporting high financial difficulty after controlling for age, gender, education and income (F 2, 49 = 4.97, p= 0.011; see Table 2 and Figure 1).ConclusionThe present study adds to our understanding of cognitive aging among older Black Americans. Results support previous research, pointing to the independent negative effects of both chronic diseases and subjective financial burden, but also extend the literature by suggesting an interactive effect. Specifically, multimorbidity was more strongly associated with worse episodic memory functioning among older Blacks with less financial hardship, which appeared to be driven by the relatively low cognitive functioning among those with the greatest financial hardship. This pattern of results suggest that financial hardship may be just as consequential for cognitive aging as chronic diseases for older Blacks.
Young adulthood cardiovascular risk and MRI and amyloid PET in late‐life in a diverse cohort: The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: George Kristen M. , Whitmer Rachel A. , Mayeda Elizabeth Rose , Glymour M. Maria , Mungas Dan M , Gilsanz Paola , Miles Sunita , Quesenberry Charles P , DeCarli Charles 
Published: December 2020

AbstractBackgroundMid‐life cardiovascular (CVD) risk factors have been associated with cognitive impairment, but CVD risk factors in young adulthood are not well characterized. We evaluated how young adulthood CVD factors influence late‐life brain health in The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort.MethodKHANDLE is a multi‐ethnic study of 1,712 long‐term Kaiser Permanente North California members ages 65 and older. To date, 165 participants (25% Asian, 21% Black, 24% Latino, and 30% White) received MRI and PET imaging as part of an imaging sub‐study. MRI analyses included regional gray matter and total WMH volumes. Amyloid PET used AV45 and standard SUVR analysis with cerebellar gray matter as the reference region. Participants underwent neuropsychologic testing and received diagnoses of cognitively normal or dementia/mild cognitive impairment (MCI). CVD risk factors were measured during Multiphasic Health Checkups (MHC) between 1964‐1992 where body mass index (BMI), blood pressure, and total cholesterol were measured. The association of young adulthood CVD factors with imaging measures and syndrome were assessed using linear and logistic regressions with adjustment for age, years since MHC, gender, education and race/ethnicity.ResultParticipants had a mean age of 31+6 at MHC and 75+6 at KHANDLE. Being overweight or obese at MHC was negatively associated with hippocampal volume [β:‐0.42(‐0.81, ‐0.03)] and marginally associated with cerebral gray matter [β:‐0.37(‐0.75, 0.01)] and temporal cortex [β: ‐0.39(‐0.78, 0.01)] volumes. Continuous BMI was negatively associated with cerebral gray [β:‐0.07(‐0.14, ‐0.01)], hippocampal [β:‐0.07(‐0.14, ‐0.01)], and temporal cortex [β:‐0.39(‐0.78, 0.01)] volumes. Hypertension at MHC was negatively associated with cerebral [β:‐0.34(‐0.61, ‐0.06)] and occipital cortex [β:‐0.36(‐0.66, ‐0.06)] volumes. Hypercholesteremia at MHC was negatively associated with cerebral volume [β:‐0.50(‐0.81, ‐0.19)] and hippocampal volume [β:‐0.36(‐0.72, ‐0.01)]. A standard deviation increase in total cholesterol was negatively associated with hippocampal volume [β:‐0.16(‐0.31, ‐0.01)] and associated with greater amyloid burden [β:0.19(0.02, 0.36)].ConclusionCVD risk factors of overweight/obesity, hypertension, and hypercholesteremia in young adulthood were negatively associated with measures of late‐life brain health in this diverse cohort of community‐dwelling older adults.
Plasma‐based biomarkers for Aβ and tau predict longitudinal brain atrophy in cognitively healthy elderly and in patients with Alzheimer’s disease
Authors: Leuzy Antoine , Ashton Nicholas J. , Karikari Thomas K. , Simrén Joel , Mårtensson Gustav , Benedet Andréa Lessa , Hye Abdul , Schöll Michael , Mecocci Patrizia , Vellas Bruno , Tsolaki Magda , Kłoszewska Iwona , Lovestone Simon , Aarsland Dag , Mattsson Niklas , Hansson Oskar , Westman Eric , Blennow Kaj , Zetterberg Henrik 
Published: December 2020

AbstractBackgroundWhile the last two decades have seen important advances in the in vivo detection of Alzheimer’s disease (AD) pathology (i.e. β‐amyloid [Aβ] and Tau) using biomarkers (PET‐ and CSF‐based), the global use of these measures is quite limited due to high costs, insufficient availability and their invasive nature. Interest in blood‐based biomarkers for AD is growing due their greater accessibility and lower cost. We here aimed to investigate the relationship between ultrasensitive plasma‐based measures for AD and both cross‐sectional and longitudinal brain atrophy.MethodsWe evaluated cross‐sectional plasma samples for 307 participants (100 cognitively unimpaired (CU) elderly, and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) and 106 AD) from the European multicentre AddNeuroMed cohort. Single molecule array (Simoa) assays were performed for NfL, T‐tau, Aβ42, Aβ40 and GFAp. P‐tau181 was measured using an in‐house Simoa assay. Associations with longitudinal MRI (baseline, 3‐months, 12‐months) were performed using linear mixed models (adjusted for age, sex, education, APOE ε4 status, and interval between plasma and MRI). Three predefined MRI markers were selected: hippocampal volume (adjusted for intracranial volume), cortical thickness within a temporal meta‐ROI encompassing regions susceptible to AD (mean thickness in the bilateral entorhinal, inferior/middle temporal, and fusiform cortices) and whole‐brain cortical thickness.ResultsCross‐sectionally, P‐tau181 and whole‐brain cortical thickness were the only significant association for CU. In CI subjects, Aβ42/Aβ40 and P‐tau181 were significantly associated with hippocampal volume and temporal meta‐ROI/whole‐brain cortical thickness (Table 1). Longitudinally, increased baseline P‐tau181 was associated with all three MRI measures in both CU and CI subjects (Table 1). Low Aβ42/Aβ40 was also associated with all three MRI measures, though only in CI subjects. Further analyses will associate these plasma measures at the voxel level.ConclusionThese results suggest that plasma‐based measurements of Aβ42/Aβ40 and P‐tau181 are associated with cross‐sectional atrophy levels and, more importantly, can predict brain atrophy over time, both in patients with AD and in CU elderly individuals. These findings add to a growing number of studies suggesting that these markers hold great promise, both as diagnostic tools as well as in research and clinical trials.
Depressive symptoms are associated with hippocampal neurodegeneration in preclinical autosomal dominant Alzheimer’s disease
Authors: Gatchel Jennifer R. , Lopera Francisco , Fox‐Fuller Joshua T. , Guzman‐Velez Edmarie , Bocanegra Yamile , Pardilla‐Delgado Enmanuelle , Vila‐Castelar Clara , Schoemaker Dorothee , Baena Ana , Torrico‐Teave Heirangi , Munera Diana , Vannini Patrizia , Hanseeuw Bernard , Johnson Keith A. , Sperling Reisa A. , Marshall Gad A. , Quiroz Yakeel T. 
Published: December 2020

AbstractBackgroundIncreasing evidence suggests that depressive symptoms may be among early behavioral changes in Alzheimer’s Disease (AD). However, the neurobiology of these symptoms in the preclinical stages of AD remains unclear, particularly in relation to markers of neurodegeneration. Studying depression in individuals who carry mutations for autosomal dominant AD (ADAD) is a compelling way to characterize depressive symptoms in preclinical AD, as virtually all ADAD mutation carriers develop dementia and have a well‐characterized trajectory from pre‐symptomatic to clinical disease stages.MethodWe evaluated cross‐sectional associations between the 15‐item Geriatric Depression Scale (GDS) and neurodegeneration of the hippocampus, one of the most vulnerable brain regions in ADAD and depression, in 27 cognitively unimpaired PSEN1 E280A mutation carriers and 26 matched non‐carrier family members of a Colombian kindred with ADAD. Global cognition was measured by the Mini‐Mental State Examination (MMSE); hippocampal volume was assessed by structural MRI. A general linear model with dependent variable GDS, predictor hippocampal volume, and covariates, age, sex, MMSE, and intracranial volume (ICV), was employed.Result
PSEN1 E280A carriers and non‐carriers did not differ in GDS (carriers:2.2±2.6, non‐carriers:2.9±3.5; p=0.64), sex (carriers:70% females, non‐carriers:88% females; p=0.24), age (carriers:35.9±8.2 years, non‐carriers:37.0±6.5; p=0.56), ICV (carriers:1.4 x106 ±1.1 x 105 mm3, non‐carriers:1.4 x 106 ±1.3 x 105 mm3; p=0.16), or hippocampal volume (carriers: 3867±569 mm3, non‐carriers: 4090±371 mm3; p=0.20). Compared to non‐carriers, carriers had lower MMSE scores (carriers: 28.3±2.9, non‐carriers: 29.7±0.5; p=0.03). In carriers, GDS was negatively associated with hippocampal volume (β= ‐0.71, t= ‐2.6, p=0.02), but not with age, sex, MMSE, or ICV. This association between GDS and hippocampal volume was not observed in non‐carriers (β= ‐0.26, t= ‐1.2, p=0.25).ConclusionDepressive symptoms in cognitively‐unimpaired carriers of an ADAD mutation are significantly associated with early hippocampal neurodegeneration, years before the estimated onset of dementia. This provides some of the first evidence of a region‐specific neurodegenerative basis of depressive symptoms in preclinical ADAD. Future longitudinal investigation is needed to characterize the temporal sequence of depressive symptoms in relation to markers of brain pathology and cognitive decline in AD. Findings may have implications for early interventions to reduce depressive symptoms in individuals who have AD risk factors.
Double‐blind placebo‐controlled trial of the safety and efficacy of GM‐CSF/sargramostim in subjects with mild‐to‐moderate Alzheimer’s disease
Authors: Potter Huntington , Woodcock Jonathan H. , Boyd Timothy , Sillau Stefan H. , O'Shaugnessy John R. , Borges Thomas T , Thaker Ashesh A. 
Published: December 2020

AbstractBackgroundRheumatoid arthritis (RA) patients have a reduced risk of developing Alzheimer’s disease (AD), originally hypothesized to be attributable to their use of non‐steroidal anti‐inflammatory drugs (NSAIDs). However, clinical trials with NSAIDs were unsuccessful in both AD and Mild Cognitive Impairment (MCI) subjects. We hypothesized that intrinsic innate immune system factors associated with RA itself may underlie the AD protective effect(s). We tested several cytokines upregulated in RA blood and found that 20 daily injections of 5 μg granulocyte‐macrophage colony stimulating factor (GM‐CSF) reduced cerebral amyloidosis by greater than 50% and completely reversed the cognitive impairment of transgenic AD mice. In a retrospective study, we found that short‐term treatment with sargramostim/Leukine® (recombinant human GM‐CSF) plus G‐CSF improved cognition of leukemia patients following bone marrow chemoablation/hematopoietic cell transplant compared to patients who received G‐CSF alone.MethodA double blind Phase II safety and efficacy trial of sargramostim in 40 mild‐to‐moderate AD subjects, half receiving placebo and half receiving 250 μg/m2/day sargramostim by subcutaneous injection five days/week for three weeks with follow‐up visits at 45 and 90 days post‐treatment is complete (NCT01409915). Neurological and neuropsychological assessments and MRI and amyloid‐PET scans were performed to assess the safety and efficacy of treatment.ResultClinical and imaging analyses showed no drug‐related serious adverse events, including no amyloid‐related imaging abnormalities (ARIAs; micro‐hemorrhage or vasogenic edema). At the end of treatment, the mean Mini‐Mental State Examination (MMSE) score in the sargramostim group was improved relative to baseline (p=0.0074) and to the placebo group (p=0.037) by repeated measures mixed model analysis. The beneficial effect of sargramostim on MMSE, compared to placebo, was retained at the first follow‐up visit at 45 days after the end of treatment (p=0.0272). In contrast, there was a single poorer ADAS‐Cog‐13 (Alzheimer’s Disease Assessment Scale‐Cognitive Subscale‐13) mean score in the sargramostim group compared to placebo–at the first follow‐up visit 45 days after the end of treatment. Amyloid and volumetric brain scans are being analyzed.ConclusionThese results indicate that GM‐CSF/sargramostim shows promise as a potential treatment for AD and that our Alzheimer’s Association “Part the Cloud”‐funded 24‐week treatment trial is warranted.
Neuroprotective effects of fecal microbiota transplantation in a mouse model of Alzheimer’s disease
Authors: Holsinger R.M. Damian , Elangovan Shalini 
Published: December 2020

AbstractBackgroundThe efficacy of fecal microbiota transplantation (FMT) as a therapeutic in Alzheimer's disease was evaluated in the 5XFAD mouse model.MethodWe treated sixteen, 36‐week‐old 5XFAD transgenic mice with fecal slurry from healthy, wild‐type donors of similar age (n = 8; Old Tg‐FO) or from younger (8‐10‐week old) healthy, wild‐type donors (n = 8; Old Tg‐FY) for seven days. Mice were incubated for 21 days and were then subjected to cognitive tests to examine the effects of FMT on memory. Mice were sacrificed and brain tissue was examined for amyloid plaque load.ResultImproved spatial and recognition memory in Old Tg‐FY and enhanced recognition memory in Old Tg‐FO mice were observed when compared to Old Tg‐Control mice treated with saline. Importantly, there were significant decreases in cortical Ab loading following seven days of FMT in all treated mice.ConclusionOur results demonstrate the capability FMT in improving cognition and reducing amyloid pathology in the 5XFAD mouse model of Alzheimer’s.