Genome-wide Association Studies in Alzheimer’s Disease: A Review

Over the past decade, research aiming to disentangle the genetic underpinnings of late-onset Alzheimer’s disease has mostly focused on the identification of common variants through genome-wide association studies. The identification of several new susceptibility genes through these efforts has reinforced the importance of amyloid precursor protein and tau metabolism in the cause of the disease and has implicated immune response, inflammation, lipid metabolism, endocytosis/intracellular trafficking, and cell migration in the cause of the disease. Ongoing and future large-scale genome-wide association studies, translational studies, and next-generation whole genome or whole exome sequencing efforts, hold the promise to map the specific causative variants in these genes, to identify several additional risk variants, including rare and structural variants, and to identify novel targets for genetic testing, prevention, and treatment

Progression of extrapyramidal signs in Alzheimer's disease. clinical and neuropathological correlates

Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions

Exploring the effect of an augmented reality literacy programme for reading and spelling difficulties for children diagnosed with ADHD

AbstractChildren diagnosed with attention deficit hyperactivity disorder (ADHD) experience a variety of difficulties related to three primary symptoms: hyperactivity, inattention and impulsivity. The most common type of ADHD has a combination of all three symptom areas. These core symptoms may negatively impact the academic and social performance of children throughout their school life. The AHA (ADHD-Augmented) project focused specifically on the impact of digital technologies' intervention on literacy skills of children that participated in the pilot study and were diagnosed with ADHD prior to the intervention. Existing research has shown that augmented reality (AR) can improve academic outcomes by stimulating pupils' attention. AHA project aimed at implementing an evidence-based intervention to improve ADHD children's reading and spelling abilities through the enhancement of an existing literacy programme with AR functionality. The present paper reports preliminary findings of the pilot study aimed at evaluating the effectiveness of the AHA system in promoting the acquisition of literacy skills in a sample of children diagnosed with ADHD compared to the literacy programme as usual. Background information on the main characteristics and difficulties related to the teaching and learning process associated with children diagnosed with ADHD are first introduced; the design and methodology of the AHA project intervention are also described. The preliminary findings have shown that AHA project succeeded in delivering an AR solution within an existing online literacy programme, which integrates a set of specific technologies and supports interactive educational content, services, assessment, and feedback

Promjene biokemijskih pokazatelja u preponskih konja za vrijeme simuliranih skokova.

The modifications of some biochemical parameters and serum electrolytes after a simulated show jumping test were evaluated. On seven clinically healthy Italian saddle horses, heart rate (HR), lactate concentration, serum concentrations of alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT), creatine kinase (CK), gamma glutamil transferase (γGT), lactic dehidrogenase (LDH), creatinine, urea, total bilirubin, glucose, chloride (Cl-), potassium (K+) and sodium (Na+) were analysed at rest, after the warm up, immediately after the simulated show jumping and 45 minutes after the end of the exercise. One-way repeated measures analysis of variance (ANOVA) showed a significant effect of sampling time (P<0.05) on HR, lactate concentration, ALP, AST, ALT, CK, γGT, creatinine, glucose and K+. These results suggest that by knowing the biochemical changes during a simulated jumping test, the veterinarian could better judge the horses with electrolytes and metabolic disturbances in a competition.Prosuđivane su promjene određenih biokemijskih pokazatelja i serumskih elektrolita nakon simuliranog preponskog jahanja u sedam talijanskih jahačkih konja. Izmjerena je frekvencija bila, koncentracija laktata, alkalne fosfataze, aspartat aminotransferaze, alanin aminotranferaze, kreatin kinaze, gama-glutamiltransferaze, laktat dehidrogenaze, zatim kreatinina, ureje, ukupnog bilirubina, glukoze, klorida, kalija i natrija u serumu za vrijeme odmora, nakon zagrijavanja, neposredno nakon simuliranog preponskog skakanja i 45 minuta nakon završetka vježbe. Analiza varijance ponavljanih mjerenja pokazala je znatan utjecaj vremena uzorkovanja (P<0,05) na frekvenciju bila, koncentraciju laktata, alkalne fosfataze, aspartat aminotransferaze, alanin aminotransferaze, kreatin kinaze, gama-glutamiltransferaze, kreatinina, glukoze i kalija. Rezultati upućuju na zaključak da poznavanje biokemijskih promjena za vrijeme simuliranog testa skakanja može pridonijeti boljoj procjeni elektrolitičkih i metaboličkih poremećaja tijekom natjecanja

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico

Objective: To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population. Method: Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease. Results: The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively). Conclusions: Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype

Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools

BackgroundImputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH).MethodsWe evaluated imputation accuracy in CH (N = 1,000), focusing on rare (0.1% ≤ minor allele frequency (MAF) ≤ 1%) and ultra-rare (MAF &lt; 0.1%) variants. We used two reference panels, the Haplotype Reference Consortium (HRC; N = 27,165) and 1000 Genome Project (1000G phase 3; N = 2,504) and multiple phasing (SHAPEIT, Eagle2) and imputation algorithms (IMPUTE2, MACH-Admix). To assess imputation quality, we reported: (a) high-quality variant counts according to imputation tools’ internal indexes (e.g., IMPUTE2 “Info” ≥ 80%). (b) Wilcoxon Signed-Rank Test comparing imputation quality for genotyped variants that were masked and imputed; (c) Cohen’s kappa coefficient to test agreement between imputed and whole-exome sequencing (WES) variants; (d) imputation of G206A mutation in the PSEN1 (ultra-rare in the general population an more frequent in CH) followed by confirmation genotyping. We also tested ancestry proportion (European, African and Native American) against WES-imputation mismatches in a Poisson regression fashion.ResultsSHAPEIT2 retrieved higher percentage of imputed high-quality variants than Eagle2 (rare: 51.02% vs. 48.60%; ultra-rare 0.66% vs. 0.65%, Wilcoxon p-value &lt; 0.001). SHAPEIT-IMPUTE2 employing HRC outperformed 1000G (64.50% vs. 59.17%; 1.69% vs. 0.75% for high-quality rare and ultra-rare variants, respectively, Wilcoxon p-value &lt; 0.001). SHAPEIT-IMPUTE2 outperformed MaCH-Admix. Compared to 1000G, HRC-imputation retrieved a higher number of high-quality rare and ultra-rare variants, despite showing lower agreement between imputed and WES variants (e.g., rare: 98.86% for HRC vs. 99.02% for 1000G). High Kappa (K = 0.99) was observed for both reference panels. Twelve G206A mutation carriers were imputed and all validated by confirmation genotyping. African ancestry was associated with higher imputation errors for uncommon and rare variants (p-value &lt; 1e-05).ConclusionReference panels with larger numbers of haplotypes can improve imputation quality for rare and ultra-rare variants in admixed populations such as CH. Ethnic composition is an important predictor of imputation accuracy, with higher African ancestry associated with poorer imputation accuracy

Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

OBJECTIVE: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. METHODS: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ε4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. RESULTS: Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. CONCLUSIONS: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers

Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study

Background: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. Methods and results: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance (P\u3c5×10-8) (top single-nucleotide polymorphism, rs7921574; β=0.06 [P=1.54×10-8]). This locus mapped to an intron of CNNM2. A trans-ancestry genome-wide association study meta-analysis identified 2 more loci at NT5C2 (rs10748839; P=2.54×10-8) and AS3MT (rs10786721; P=4.97×10-8), associated with global BAD. In addition, 2 single-nucleotide polymorphisms colocalized with expression of CNNM2 (rs7897654; β=0.12 [P=6.17×10-7]) and AL356608.1 (rs10786719; β=-0.17 [P=6.60×10-6]) in brain tissue. For the posterior BAD, 2 variants at one locus mapped to an intron of TCF25 were identified (top single-nucleotide polymorphism, rs35994878; β=0.11 [P=2.94×10-8]). For the anterior BAD, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). Conclusions: The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health

Chromosome 10Q2432 Variants associate With Brain arterial Diameters in Diverse Populations: a Genome-Wide association Study

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance ( CONCLUSIONS: The current study reveals 3 novel risk loci