bluuebunny/crossref_metadata_2025_split huggingface dataset:
Young adult cognitive ability moderates effects of lifestyle behaviors on brain aging in late midlife: A longitudinal study of cognitive reserve
Authors: Franz Carol E. , Hatton Sean N. , Lyons Michael J. , Puckett Olivia K. , Whitsell Nathan , Kremen William S. 
Published: December 2020

AbstractBackgroundRecent studies have reported significant associations between modifiable lifestyle factors and dementia (Licher et al, 2019; Lourida et al, 2019). We sought to extend those findings by examining whether the effect of lifestyle on brain age, a possible risk factor for dementia, is moderated by one’s level of general cognitive ability (GCA). Additionally, we examined associations between brain aging and mild cognitive impairment (MCI).MethodAt mean age 68 (SD 2.6; range 61‐72), 356 participants from the Vietnam Era Twin Study of Aging (VETSA) underwent structural MRI which was used to create predicted brain age difference (PBAD) scores (Liem et al., 2017). MCI at age 68 was determined using Jak/Bondi criteria. At mean age 40 (SD 2.7; range 34‐44), a positive lifestyle index was created comprising three self‐reported behaviors: not smoking, ≤ moderate alcohol consumption, and high social engagement. GCA at mean age 20 was assessed with the Armed Forces Qualification Test. Linear mixed models included GCA, lifestyle and their interaction as IVs, and adjusted for age, ethnicity, APOE genotype, height, and family membership.ResultAge 20 GCA and age 40 lifestyle were significantly associated with PBAD [F=5.83; p=.02 and F=15.14; p<.001, respectively]. Having a higher GCA or more positive lifestyle behaviors predicted having less advanced brain age. The GCA‐lifestyle interaction was significant, indicating moderation. Having both lower GCA and few positive behaviors predicted having an older brain age relative to chronological age [F=5.00; p=. 03], but GCA made no difference when more positive behaviors were present (Figure 1). At age 68, non‐amnestic MCI participants had significantly more advanced brain aging compared with cognitively normal or amnestic MCI participants [F=3.10; p=.05].ConclusionRisk reduction remains a major component in the fight to prevent/delay dementia. Early positive lifestyle behaviors appeared to be protective against brain aging nearly three decades later for those with low or moderate GCA. High GCA appeared to be protective regardless of lifestyle behaviors. These results suggest that the negative effects of lifestyle start early, particularly for those who have lower cognitive reserve. Early intervention may help promote healthier brain aging and possibly delay dementia onset.
Study partner‐ and self‐reported difficulties in cognitively complex everyday activities in participants without objective cognitive impairment
Authors: Verrijp Merike , Dubbelman Mark A , Nijhuis Elke W , Visser Leonie NC , Zwan Marissa D , Jutten Roos J , Van Hout Hein PJ , van Der Flier Wiesje , Scheltens Philip , Sikkes Sietske AM 
Published: December 2020

AbstractBackgroundStudy partner report is used to assess cognitively complex everyday activities, or instrumental activities of daily living (IADL). Because a study partner is not always available, the question arises whether IADL can also be evaluated using self‐report. The aim of this study is to investigate the relationship between study partner‐ and self‐report IADL in individuals without objective cognitive impairment, and to explore its associated factors.MethodParticipants (N=3,295; mean age 61.0±12.1 years, 70.3% female; Table 1.) and their study partners (N=1,225) were recruited from the Dutch Brain Research Registry. They completed self‐ and study partner‐report versions of the Amsterdam IADL Questionnaire. For the 1,225 dyads, linear regression analyses were used to investigate the relationship between self‐ and study partner report. Age, sex, cohabitation, marital status, education and subjective memory complaints were explored as potential confounders and effect‐modifiers.ResultA total of 1,544 (46.9%) participants and study partners (n=497, 40.6%) reported an increased level of difficulty in at least one IADL activity (Figure 1). Absolute agreement between self and study partner on item level was high, ranging from 93.3–99.2%. Participants self‐reported more IADL difficulties (M=65.9±SD=4.7), compared to their study partners (M=66.1±SD=4.6; p<0.05). The study partner‐ and self‐ reported IADL scores were significantly associated (B=0.54). When participants experienced memory complaints, both the participant and study partner reported more IADL difficulties (both p<0.001, Figure 2). Furthermore, we found an interaction effect indicating that the association between self and study partner was lower for those without memory complaints (B= 0.42, Figure 3). In addition, the association between self‐ and proxy was slightly lower for highly educated participants (B=0.47).ConclusionSubtle difficulties in IADL were present in about half of the population, and a high level of agreement between self and study partner was observed on both item and scale level IADL. We found several factors influencing the level of agreement, and in a next step we will include objective cognitive markers to explore the etiology of these differences. These findings provide support for the use of IADL self‐report in cognitively unimpaired individuals, in particular for use in primary or secondary prevention trials.
Identification of differential regulation of European versus African local ancestry haplotypes surrounding ApoEε4
Authors: Vasquez Marina Lipkin , Celis Katrina , Van Booven Derek , Hofmann Natalia K. , Rajabli Farid , Griswold Anthony J. , Brown Christopher D. , Pericak‐Vance Margaret A , Nuytemans Karen , Vance Jeffery M. 
Published: December 2020

AbstractBackgroundThe risk for late‐onset Alzheimer disease (AD) in ApoEε4 carriers differs between ancestral groups. ApoEε4 Non‐Hispanic White (NHW) homozygotes have an odds ratio of 14.9 while the risk is much lower in Africans (AF) (OR 2.2‐5.7). Local ancestry (LA) analyses in ApoEε4 carrier populations have shown the protective effect in Africans relative to NHW is due to factors lying in the LA surrounding ApoEε4. No coding differences between genes in the LA have been observed between AF and NHW ancestries. Thus regulatory differences in LA non‐coding regions are most likely involved in the protective factor(s) lowering the risk for AF carriers of ApoEε4. Enhancers are the most common regulatory element, and thus we sought to identify if any of these variants had functional enhancer effects between the two ancestries. Little functional characterization of genetic regulation in AF ancestries has been investigated.MethodWe identified 56 significant sequence differences among AF and ApoEε4 haplotypes from the 1000 genomes in a topologically associated area (56kb) surrounding ApoE. None of these differences were identified to be protein coding. We applied Massively Parallel Reporter Assay (MPRA) supplemented with single variant reporter assays using Promega Dual Glo‐Luciferase System in AD relevant cell lines to identify the regulatory potential of these variants and their surrounding regions and to assess the differential effect sizes of the variant alleles on enhancer activity.ResultFor MPRA and complementary single variants reporter assays, we generated ∼900bp PCR fragments surrounding these variants to ensure full representation of potential regulatory elements. MPRA vector library or single reporter vectors were transfected in three cell lines (SHY‐SY5Y neuronal cells, U‐118 astrocytes and HMC3 microglia). We identified evidence for differential regulation between AF and EU variant haplotypes in intron 5 of PVRL2, TOMM40 intronic regions and a large region located 3’ of APOC1. The latter encompasses a putative enhancer identified through ENCODE analyses in brains with NHW ancestry.ConclusionOur results indicate several areas of differential regulation in this LA region on ApoEε4 haplotypes. Follow‐up of the identified regulatory regions is currently ongoing using publicly available data and in‐house iPSC derived cell lines.
Urine dicarboxylic acids reflect loss of energy capacity and hippocampal volume in pre‐symptomatic Alzheimer's disease
Authors: Castor Katherine , Tran Thao , King Kevin , Chui Helena C. , Fonteh Alfred N. , Harrington Michael G 
Published: December 2020

AbstractBackgroundNon‐invasive biomarkers will expedite widespread screening and early diagnosis of Alzheimer’s disease (AD). We hypothesized that the considerate loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD.MethodsStudy participants (> 70 years) classified as cognitively healthy (CH, n=64) or AD (n=26) after neuropsychological assessment were recruited into HMRI’s Brain Aging Study. Urine dicarboxylic acids (DCA) of carbon length 3‐10 that reflect oxidative damage and energy generation or balance that may reveal changes in brain function were quantified using gas chromatography coupled with negative ion chemical ionization mass spectrometry. Brain volumes were obtained using a GE 3 or 1.5 Tesla MRI scanner. MRI data was analyzed using Freesurfer 6.0 to obtain left and right volumes (mm3) of seven brain regions including the hippocampus.ResultsMean C4‐C5 DCAs were lower and mean C7‐C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4‐C5 DCAs were lower and mean C7‐C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aβ42, while C7‐C10 DCAs negatively corelated with CSF Aβ42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7‐C10 DCAs with hippocampal volume (p<0.01), while there was no significant correlation with the occipital volume. Urine measure of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau.ConclusionsThese data suggest that urine measures of increased lipid oxidation and dysfunctional energy balance reflect early AD pathology manifest by brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness and monitor the efficacy of therapies in clinical trials.
Ascertaining perturbations in microglial expression profiles using single‐nuclei RNA‐seq from human brains
Authors: Brase Logan , Del‐Aguila Jorge L. , Benitez Bruno A. , Karch Celeste M. , Cruchaga Carlos , Harari Oscar 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a complex and heterogeneous trait in which multiple molecular pathways are disrupted in different cell‐types culminating in disease. Genetic variants in TREM2, a gene expressed in microglia, have been associated with high‐risk with AD, and similarly soluble TREM2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with AD. In a previous Genome‐wide association study (GWAS) of CSF sTREM2 levels, a genetic variant near the MS4A gene cluster accounted for 6 percent of the protein’s variance (rs1582763 p = 1.15 × 10−15). This finding suggests that TREM2 is involved in AD risk in the general population, beyond TREM2 risk‐variant carriers, as the minor allele frequency of rs1582763 > 0.30. rs1582763 is also a cis‐eQTL for both MS4A4A and MS4A6A genes in bulk RNA‐seq of blood.MethodWe generated unsorted single‐nuclei RNA‐seq from human brain tissue from the Knight‐ADRC brain bank. We collected the parietal lobe for 30 AD brains (19 are carriers of the rs1582763 minor allele), 18 autosomal dominant AD brains (ADAD) (9 carriers) and 7 neuropath‐free (6 carriers) for a total of 55 brains (34 carriers). Using the 10X Chromium 3’ chemistry v3 we generated high quality data for over 287,000 nuclei from 54 brains (after QC) to identify the transcriptomic effects of this variant at a cell specific resolution. We identified 13,880 microglial nuclei to analyze microglial subtypes, activation states, cell‐type specific eQTLs, and differential gene expression between carriers and non‐carriers of rs1582763.ResultWe identified microglia expression states that are specific to ADAD subjects, an increased proportion of total microglia on controls, and a shift in microglia expression state for AD subjects that are carriers of rs1582763. Using linear mixed models to account for subject of origin, we will analyze these nuclei to determine which subset of genes are differentially expressed.ConclusionBoth ADAD status and rs1582763 status in AD subjects alter microglia gene expression states.
Effects of cognitive training program on brain connectivity in older adults with subjective cognitive complaints and mild cognitive impairment
Authors: Soto Marcio , Vilca Brenda Nadia Chino , Camlla Rosangela , Dengri Lucia , Fernández Ricardo Bruña , Maestú Fernando , Parra Mario A 
Published: December 2020

AbstractBackgroundCognitive intervention programs have achieved improvements at the behavioral level at different stages of dementia, especially in the preclinical phases, what is not yet clear is the neurophysiological correlate of these improvements, especially at the level of resting brain connectivity. Our objective was to analyze the changes at the neurophysiological level after the application of a cognitive training program in pre‐clinical phases of dementia using high density electroencephalography (hdEEG).MethodAn intrasubject design was applied. All subjects underwent clinical and cognitive measurements and resting state records in a hdEEG at baseline and 3 months later when the cognitive training sessions ended. The final sample was composed of 7 older adults with subjective cognitive complaints (mean age = 62.08, SD = 6.48) and 8 with mild cognitive impairment (mean age = 62.93, SD = 6.75); whom were evaluated with a large neuropsychological battery which include the domains of executive function and memory. Electrophysiological signals were recorded with a high density EEG (160 channels). The cognitive training program lasted 24 sessions distributed in 8 sessions for each cognitive domain (attention, executive function and memory).ResultThe results show a significant improvement of the cognitive domains trained and a greater clustering and a more efficient processing of the default brain network. These changes seem to be associated with greater efficiency in information processing and a reduction in random physiological activation in preclinical stages of dementiaConclusionThese programs show clear evidence of changes at the brain level due to cognitive intervention, it is recommended to do follow‐up studies to assess their stability over time.
Brain bioavailable microbiome derived flavonoid metabolite attenuates neuroinflammation in C9orf72 associated frontotemporal dementia
Authors: Iqbal Umar Haris , Smith Chad , Trageser Kyle J. , Pasinetti Giulio Maria 
Published: December 2020

AbstractBackgroundFamilial frontotemporal dementia (FTD) has been associated with mutations in the G4C2 promoter of C9orf72 leading to production of dipeptide protein repeats (DPRs), the most neurotoxic being Glycine‐Arginine (GR). Previous studies have found a parallel relationship with the accumulation of DPRs and a neuroinflammatory response. Specifically, studies have determined microglia proliferation and persistent activation plays a role in disease progression and neurodegeneration. The current study investigated the effect of the bioavailable microbiome derived flavonol metabolite, 3‐hydroxybenzoic acid (3‐HBA) (Wang D. et al, 2015), on microglia morphology and proliferation in mice harboring the AAV9‐GFP(GR)100 virus in the brain recapitulating FTD type neuropathology and behavior.MethodMice were divided into three groups: GFP control, GR100, and GR100 with 3‐HBA. The GFP control group was transfected with AAV9‐GFP through intra‐cerebroventricular injection, whereas the other two groups were transfected with AAV9‐GFP(GR)100. The virus was administered on postnatal day 0, and the treatment of 3‐HBA began on day 28 for a period of 10 weeks. Immunofluorescence staining of microglia was performed on sections spanning the prelimbic/infralimbic cortex, primary somatosensory cortex (S1), and the hippocampus in order to stereologically quantify microglia proliferation and to reconstruct the microglia in 3D using the imaging software Imaris.ResultStereological counting determined an increase in microglia density of approximately 40% (p < 0.05) in the S1 of mice transfected with AAV9‐GFP(GR)100. In addition, there was approximately 30% (p < 0.0001) reduction in S1, and hippocampal volume in groups transfected with AAV9‐GFP(GR)100. 3D reconstruction and Sholl analysis determined a change in microglia morphology from a surveilling state, as seen in the GFP control group, to that of activation characterized by increased branching closer to the soma, as observed in the GR100 group. This increased complexity/activation was found to be attenuated with the administration of 3‐HBA which was associated with a significant reduction in branch complexity compared to both the control and GR100 group.ConclusionThis study identifies a novel microbiome derived polyphenol that displayed potential in attenuating microglia activation, and hence reducing the neuroinflammatory response in FTD.
Prevalence of FTD clinical diagnostic features in patients with TDP‐43 pathology
Authors: Chatterjee Atri , Hirsch‐Reinshagen Veronica , Ducharme Blake , Leung Bonnie , Mousavi Ali , Hsiung Ging‐Yuek Robin , Mackenzie Ian R. 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) is a heterogeneous syndrome which includes three main clinical subtypes, behavioural variant FTD (bvFTD) and the non‐fluent and semantic variants of primary progressive aphasia (nfvPPA, svPPA). The pathology underlying clinical FTD, referred to as frontotemporal lobar degeneration (FTLD), is also heterogenous with transactive response DNA binding protein Mw 43 (FTLD‐TDP) present in ∼50%. In this study we investigate the proportion of FTLD‐TDP cases that fulfil diagnostic criteria for each of the clinical FTD subtypes.MethodWe retrospectively reviewed charts of patients with autopsy proven FTLD‐TDP. Patients with additional pathology, (e.g. Alzheimer’s disease, AD), were excluded. We extracted clinical data regarding behaviour, language and cognition, and compared these against the current FTD clinical diagnostic criteria.ResultFifteen of 24 patients (62.5%) with autopsy‐confirmed FTLD‐TDP pathology met diagnostic criteria for possible bvFTD (n=9), nfvPPA (n=3) or svPPA(n=3). The clinical diagnosis of the nine patients who did not match criteria for any of the three FTD syndromes included FTD with motor neuron disease (n=5), AD type dementia (n=3), progressive supranuclear palsy (n=1), corticobasal syndrome (n=1) and FTD with Parkinsonism linked to chromosome 17 (n=1). Patients with motor neuron disease developed 1 (n=2) or 2 (n=3) diagnostic features of bvFTD.Among the bvFTD diagnostic features, executive dysfunction was the commonest (79.2%), followed by apathy (37.5%) and disinhibition (33.3%). 70.8% of all patients and 42.9% of bvFTD patients developed clinical features of aphasia. Cognitive screening tests revealed a high prevalence of impaired short‐term recall (79.2%) and language dysfunction (83.3%) irrespective of the clinical diagnosis.ConclusionbvFTD is the commonest presentation of FTLD‐TDP; however, a significant proportion of patients do not match diagnostic criteria for FTD. Additionally, the high prevalence of impaired short‐term recall suggests it may not be practical to use this as an exclusionary criteria for FTD. We recognize the selection bias in our sample which was derived exclusively from a dementia clinic population.
Association of cardiovascular risk and sex with cortical tau deposition in cognitively normal and at‐risk Alzheimer’s subjects
Authors: Kleniuk Julia , Edison Paul 
Published: December 2020

AbstractBackgroundEpidemiological data shows co‐incidence of cardiovascular (CV) disease and Alzheimer’s disease (AD), however the relationship between CV risk and specific AD biomarkers is not clear. Both CV disease and AD affect men and women differently. Here, we investigated the relationship between CV risk and cortical tau deposition in two regions, the entorhinal cortex (ETC) and the inferior temporal cortex (ITC). We hypothesised that high CV risk will be associated with increased cortical tau deposition.MethodCross‐sectional data of 197 subjects (mean age 78.4, 113 male, 84 female, 107 cognitively normal) who underwent AV‐1451 tau PET imaging were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. CV risk was calculated using the Framingham Heart Study 10‐year risk score for Cardiovascular Disease (FHS‐CVD) modified for age. Regional AV‐1451 uptake between the low‐risk (bottom 25% of the sample) and high‐risk (top 25%) subjects was compared.ResultHigh‐risk men showed significantly higher AV‐1451 uptake than their low‐risk counterparts in both the ETC (p=0.002) and in the ITC (p=0.02). After adjusting for age as a covariate, the difference remained significant for the ETC, but not the ITC. High‐risk and low‐risk women did not differ significantly in AV‐1451 uptake in neither of the regions studied.ConclusionThe results show that high CV risk is associated with increased cortical tau deposition in men, but not in women. These findings highlight the sex differences in AD trajectory and the need for stratification of subjects by sex in clinical trials.