scholarly journals Brain MRI Phenotypes Associated with Polymorphisms at or near the MAPT (Microtubule Associated Protein Tau) and COASY (Coenzyme A Synthase) Genes

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1246-1246
Author(s):  
Emily Chambers ◽  
Evan Hermann ◽  
Danielle Davis ◽  
Mckale Montgomery ◽  
Edralin Lucas ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Metal Accumulation ◽  
Brain Aging ◽  
Brain Mri ◽  
Brain Regions ◽  
Chromosome 17 ◽  
P Value ◽  
Candidate Snps ◽  
A Genome ◽  
Independent Association

Abstract Objectives Impaired metal homeostasis in the brain has been reported in neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease and can be detected using magnetic resonance imaging (MRI). Many factors, including genetics, affect brain metal accumulation and the risk of neurodegeneration or premature brain aging. Our objective is to uncover independent association signals at chromosome 17 associated with susceptibility-weighted MRI (swMRI) intensities in the caudate and putamen. Methods Conditional and joint association analysis by GCTA-COJO was performed on the summary statistics dataset from a genome-wide association study (GWAS) on brain swMRI phenotypes from 7778 healthy adults of European descent aged 40–69 years from the UK BioBank. Independent association signals (single nucleotide polymorphisms or SNPs) found by GCTA-COJO were grouped further by SNPclip to identify additional candidate SNPs in high linkage disequilibrium (LD) (R2 > 0.8, P < 5.0 × 10–8) with the independent lead/index SNP at each signal. Correlations were performed to show the similarity of impacts (beta) of SNPs significantly associated with MRI differences in both caudate and putamen at one locus. Results There are 2 independent and distinct loci at chromosome 17 associated with MRI differences in the putamen, whereas there is only 1 locus for the caudate. One locus for the putamen is associated with the MAPT H2 haplotype, which has been linked to different neurological diseases. Another locus for both putamen and caudate is located near the genes COASY, NAGLU, and MLX, which are all plausible candidate genes for brain metal accumulation. For one locus identified by GCTA-COJO, there are 19 SNPs in LD (R2 > 0.8) and overlapping in both the caudate and the putamen. The effects (beta) of the SNPs in the putamen and caudate are highly correlated across both brain regions (R2 = 0.907, P-value = 0.000921). Conclusions There is likely 1 signal from the COASY/NAGLU locus on chromosome 17 affecting both brain regions. The signal from the MAPT locus only affects the MRI pattern seen in the putamen. These results connect genetics with brain MRI patterns and an individual's risk for neurodegenerative diseases. Funding Sources This work was funded by grants from the Oklahoma Center for the Advancement of Science & Technology and the Oklahoma Agricultural Experiment Station.

scholarly journals Genetic Variants Correlate With Better Processing Speed

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 163-164
Author(s):  
Anastasia Gurinovich ◽  
Kaare Christensen ◽  
Marianne Nygaard ◽  
Jonas Mengel-From ◽  
Stacy Andersen ◽  
...  
Keyword(s):  
Processing Speed ◽  
Genetic Variants ◽  
Cognitive Aging ◽  
Genome Wide Association Study ◽  
Brain Aging ◽  
P Value ◽  
Digit Symbol Substitution Test ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract Some cognitive abilities, such as vocabulary, are resilient to brain aging, while others such as conceptual reasoning, memory, and processing speed, decline with age and their rate of decline is genetically regulated. Despite the strong genetic heritability of processing speed assessed by the digit symbol substitution test (DSST), previous studies have failed to identify robust common genetic variants associated with this test. The Long Life Family Study (LLFS) includes long lived individuals and their family members who maintain good DSST scores as they age and who may carry variants associated with better DSST. We therefore conducted a genome-wide association study (GWAS) of DSST in LLFS using ~15M genetic variants imputed to the HRC panel of 64,940 haplotypes with 39,635,008 sites and replicated the findings using genetic data imputed to the 1000 Genomes phase 3 reference panel combining two Danish cohorts: the Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants reaching genome-wide significance (p-value < 5x10-8), including 18 variants associated with better processing speed with large effect size. The genetic associations of rs7623455, rs9821776, rs9821587, rs78704059 in chromosome 3 were replicated in the combined Danish cohort. These genetic variants tagged two hormone receptor related genes, THRB and RARB, both related to cognitive aging. Further gene-based tests in LLFS confirmed that these two genes have protective variants associated with better processing speed.

scholarly journals Multi-Racial Normative Data for Lobar and Subcortical Brain Volumes in Old Age: Korean and Caucasian Norms May Be Incompatible With Each Other†

2021 ◽  
Vol 13 ◽  
Author(s):  
Yu Yong Choi ◽  
Jang Jae Lee ◽  
Kyu Yeong Choi ◽  
Uk-Su Choi ◽  
Eun Hyun Seo ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Normative Data ◽  
Brain Aging ◽  
Brain Structures ◽  
Brain Regions ◽  
Normative Values ◽  
Aging Brain ◽  
Intracranial Volume ◽  
Brain Volumes ◽  
Subcortical Volumes

Brain aging is becoming an increasingly important topic, and the norms of brain structures are essential for diagnosing neurodegenerative diseases. However, previous studies of the aging brain have mostly focused on Caucasians, not East Asians. The aim of this paper was to examine ethnic differences in the aging process of brain structures or to determine to what extent ethnicity affects the normative values of lobar and subcortical volumes in clinically normal elderly and the diagnosis in multi-racial patients with Alzheimer's disease (AD). Lobar and subcortical volumes were measured using FreeSurfer from MRI data of 1,686 normal Koreans (age range 59–89) and 851 Caucasian, non-Hispanic subjects in the ADNI and OASIS datasets. The regression models were designed to predict brain volumes, including ethnicity, age, sex, intracranial volume (ICV), magnetic field strength (MFS), and MRI scanner manufacturers as independent variables. Ethnicity had a significant effect for all lobar (|β| > 0.20, p < 0.001) and subcortical regions (|β| > 0.08, p < 0.001) except left pallidus and bilateral ventricles. To demonstrate the validity of the z-score for AD diagnosis, 420 patients and 420 normal controls were selected evenly from the Korean and Caucasian datasets. The four validation groups divided by race and diagnosis were matched on age and sex using a propensity score matching. We analyzed whether and to what extent the ethnicity adjustment improved the diagnostic power of the logistic regression model that was built using the only z-scores of six regions: bilateral temporal cortices, hippocampi, and amygdalae. The performance of the classifier after ethnicity adjustment was significantly improved compared with the classifier before ethnicity adjustment (ΔAUC = 0.10, D = 7.80, p < 0.001; AUC comparison test using bootstrap). Korean AD dementia patients may not be classified by Caucasian norms of brain volumes because the brain regions vulnerable to AD dementia are bigger in normal Korean elderly peoples. Therefore, ethnicity is an essential factor in establishing normative data for regional volumes in brain aging and applying it to the diagnosis of neurodegenerative diseases.

scholarly journals The Combined Effect of APOE and BDNF Val66Met Polymorphisms on Spatial Navigation in Older Adults

2020 ◽  
Vol 78 (4) ◽  
pp. 1473-1492
Author(s):  
Jan Laczó ◽  
Katerina Cechova ◽  
Martina Parizkova ◽  
Ondrej Lerch ◽  
Ross Andel ◽  
...  
Keyword(s):  
Older Adults ◽  
Verbal Memory ◽  
Medial Temporal Lobe ◽  
Brain Aging ◽  
Spatial Navigation ◽  
Memory Performance ◽  
Brain Mri ◽  
Brain Regions ◽  
Real Space ◽  
Egocentric Navigation

Background: The apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory and spatial navigation deficits. The brain-derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment in APOE ɛ4 carriers but its role in APOE ɛ4-related spatial navigation deficits has not been established. Objective: We examined influence of APOE and BDNF Val66Met polymorphism combination on spatial navigation and volumes of selected navigation-related brain regions in cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (aMCI). Methods: 187 participants (aMCI [n = 116] and CU [n = 71]) from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNFVal/Val, ɛ4–/BDNFMet, ɛ4+/BDNFVal/Val, and ɛ4+/BDNFMet. The participants underwent comprehensive neuropsychological examination, brain MRI, and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real-space human analogue of the Morris water maze. Results: Among the aMCI participants, the ɛ4+/BDNFMet group had the least accurate egocentric navigation performance (p < 0.05) and lower verbal memory performance than the ɛ4–/BDNFVal/Val group (p = 0.007). The ɛ4+/BDNFMet group had smaller hippocampal and entorhinal cortical volumes than the ɛ4–/BDNFVal/Val (p≤0.019) and ɛ4–/BDNFMet (p≤0.020) groups. Among the CU participants, the ɛ4+/BDNFMet group had less accurate allocentric and allocentric delayed navigation performance than the ɛ4–/BDNFVal/Val group (p < 0.05). Conclusion: The combination of APOE ɛ4 and BDNF Met polymorphisms is associated with more pronounced egocentric navigation impairment and atrophy of the medial temporal lobe regions in individuals with aMCI and less accurate allocentric navigation in CU older adults.

scholarly journals Associations between sleep apnea and advanced brain aging in a large-scale population study

SLEEP ◽  
2020 ◽  
Author(s):  
Antoine Weihs ◽  
Stefan Frenzel ◽  
Katharina Wittfeld ◽  
Anne Obst ◽  
Beate Stubbe ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Neurodegenerative Diseases ◽  
Brain Aging ◽  
Mediating Effect ◽  
Apnea Hypopnea Index ◽  
P Value ◽  
Subclinical Inflammation ◽  
Age Related ◽  
Obstructive Sleep ◽  
Brain Age

Abstract Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer’s dementia, and it was suggested that sleep disorders such as obstructive sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea–hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect [95% CI]: 0.07 [0.03; 0.12], p-value: 0.002; ODI std. effect [95% CI]: 0.09 [0.04; 0.13], p-value: &lt; 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.

scholarly journals Erythrocyte omega-3 index, ambient fine particle exposure, and brain aging

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e995-e1007
Author(s):  
Cheng Chen ◽  
Pengcheng Xun ◽  
Joel D. Kaufman ◽  
Kathleen M. Hayden ◽  
Mark A. Espeland ◽  
...  
Keyword(s):  
White Matter ◽  
Linear Models ◽  
Elderly Women ◽  
Brain Aging ◽  
Brain Mri ◽  
Brain Regions ◽  
Dietary Intakes ◽  
Omega 3 ◽  
Brain Volumes ◽  
Spatiotemporal Model

ObjectiveTo examine whether long-chain omega-3 polyunsaturated fatty acid (LCn3PUFA) levels modify the potential neurotoxic effects of particle matter with diameters <2.5 µm (PM2.5) exposure on normal-appearing brain volumes among dementia-free elderly women.MethodsA total of 1,315 women (age 65–80 years) free of dementia were enrolled in an observational study between 1996 and 1999 and underwent structural brain MRI in 2005 to 2006. According to prospectively collected and geocoded participant addresses, we used a spatiotemporal model to estimate the 3-year average PM2.5 exposure before the MRI. We examined the joint associations of baseline LCn3PUFAs in red blood cells (RBCs) and PM2.5 exposure with brain volumes in generalized linear models.ResultsAfter adjustment for potential confounders, participants with higher levels of RBC LCn3PUFA had significantly greater volumes of white matter and hippocampus. For each interquartile increment (2.02%) in omega-3 index, the average volume was 5.03 cm3 (p < 0.01) greater in the white matter and 0.08 cm3 (p = 0.03) greater in the hippocampus. The associations with RBC docosahexaenoic acid and eicosapentaenoic acid levels were similar. Higher LCn3PUFA attenuated the inverse associations between PM2.5 exposure and white matter volumes in the total brain and multimodal association areas (frontal, parietal, and temporal; all p for interaction <0.05), while the associations with other brain regions were not modified. Consistent results were found for dietary intakes of LCn3PUFAs and nonfried fish.ConclusionsFindings from this prospective cohort study among elderly women suggest that the benefits of LCn3PUFAs on brain aging may include the protection against potential adverse effects of air pollution on white matter volumes.

scholarly journals Genomic prediction for growth using a low-density SNP panel in dromedary camels

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morteza Bitaraf Sani ◽  
Javad Zare Harofte ◽  
Mohammad Hossein Banabazi ◽  
Saeid Esmaeilkhanian ◽  
Ali Shafei Naderi ◽  
...  
Keyword(s):  
Body Weight ◽  
Birth Weight ◽  
Sample Size ◽  
Genetic Improvement ◽  
Growth Traits ◽  
P Value ◽  
Dromedary Camels ◽  
Genome Wide ◽  
A Genome ◽  
Daily Gain

AbstractFor thousands of years, camels have produced meat, milk, and fiber in harsh desert conditions. For a sustainable development to provide protein resources from desert areas, it is necessary to pay attention to genetic improvement in camel breeding. By using genotyping-by-sequencing (GBS) method we produced over 14,500 genome wide markers to conduct a genome- wide association study (GWAS) for investigating the birth weight, daily gain, and body weight of 96 dromedaries in the Iranian central desert. A total of 99 SNPs were associated with birth weight, daily gain, and body weight (p-value < 0.002). Genomic breeding values (GEBVs) were estimated with the BGLR package using (i) all 14,522 SNPs and (ii) the 99 SNPs by GWAS. Twenty-eight SNPs were associated with birth weight, daily gain, and body weight (p-value < 0.001). Annotation of the genomic region (s) within ± 100 kb of the associated SNPs facilitated prediction of 36 candidate genes. The accuracy of GEBVs was more than 0.65 based on all 14,522 SNPs, but the regression coefficients for birth weight, daily gain, and body weight were 0.39, 0.20, and 0.23, respectively. Because of low sample size, the GEBVs were predicted using the associated SNPs from GWAS. The accuracy of GEBVs based on the 99 associated SNPs was 0.62, 0.82, and 0.57 for birth weight, daily gain, and body weight. This report is the first GWAS using GBS on dromedary camels and identifies markers associated with growth traits that could help to plan breeding program to genetic improvement. Further researches using larger sample size and collaboration of the camel farmers and more profound understanding will permit verification of the associated SNPs identified in this project. The preliminary results of study show that genomic selection could be the appropriate way to genetic improvement of body weight in dromedary camels, which is challenging due to a long generation interval, seasonal reproduction, and lack of records and pedigrees.

scholarly journals Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Joseph S. Reddy ◽  
Mariet Allen ◽  
Charlotte C. G. Ho ◽  
Stephanie R. Oatman ◽  
Özkan İş ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Transcriptome Profiling ◽  
Brain Regions ◽  
Common Finding ◽  
Amyloid Angiopathy ◽  
Genome Wide ◽  
A Genome ◽  
Male Sex

AbstractCerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

scholarly journals Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

2021 ◽  
Vol 11 (1) ◽  
pp. 59
Author(s):  
Kirsten Voorhies ◽  
Joanne E. Sordillo ◽  
Michael McGeachie ◽  
Elizabeth Ampleford ◽  
Alberta L. Wang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Significance Level ◽  
Bronchodilator Response ◽  
Genome Wide ◽  
A Genome ◽  
Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

scholarly journals Molecular and cellular pathways contributing to brain aging

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Aliabbas Zia ◽  
Ali Mohammad Pourbagher-Shahri ◽  
Tahereh Farkhondeh ◽  
Saeed Samarghandian
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Brain Aging ◽  
Neuroprotective Effect ◽  
Ros Generation ◽  
Brain Health ◽  
Cellular Pathways ◽  
Aging Mechanisms ◽  
Oxidatively Modified ◽  
Biology Of Aging

AbstractAging is the leading risk factor for several age-associated diseases such as neurodegenerative diseases. Understanding the biology of aging mechanisms is essential to the pursuit of brain health. In this regard, brain aging is defined by a gradual decrease in neurophysiological functions, impaired adaptive neuroplasticity, dysregulation of neuronal Ca2+ homeostasis, neuroinflammation, and oxidatively modified molecules and organelles. Numerous pathways lead to brain aging, including increased oxidative stress, inflammation, disturbances in energy metabolism such as deregulated autophagy, mitochondrial dysfunction, and IGF-1, mTOR, ROS, AMPK, SIRTs, and p53 as central modulators of the metabolic control, connecting aging to the pathways, which lead to neurodegenerative disorders. Also, calorie restriction (CR), physical exercise, and mental activities can extend lifespan and increase nervous system resistance to age-associated neurodegenerative diseases. The neuroprotective effect of CR involves increased protection against ROS generation, maintenance of cellular Ca2+ homeostasis, and inhibition of apoptosis. The recent evidence about the modem molecular and cellular methods in neurobiology to brain aging is exhibiting a significant potential in brain cells for adaptation to aging and resistance to neurodegenerative disorders.

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