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- Ip, H. F., et al.
(author)
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Genetic association study of childhood aggression across raters, instruments, and age
- 2021
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Journal article (peer-reviewed)abstract
- Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGG(overall). The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from r(g)= 0.46 between self- and teacher-assessment to r(g)d= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range r(g): 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r(g)=-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |r(g)| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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- Alemany, S., et al.
(author)
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Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals
- 2021
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In: Environment International. - : Elsevier BV. - 0160-4120. ; 157
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Journal article (peer-reviewed)abstract
- Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-beta (A beta) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of A beta 42, A beta 40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO2,) and particulate matter (PM2.5, PM2.5 abs, PM10). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF A beta status and APOE-epsilon 4 carriership was also assessed. Results: A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain A beta deposition, while greater exposure to PM10 and PM(2.5)was associated with higher levels of CSF NfL. Most associations were driven by individuals that were A beta-positive. Although APOE-epsilon 4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-epsilon 4 carriers. Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.
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- Lopes Alves, Isadora, et al.
(author)
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Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging
- 2021
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In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13
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Journal article (peer-reviewed)abstract
- Background: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer’s disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. Methods: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database (www.oasis-brains.org). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. Results: Although highly correlated to DVR (ρ =.96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). Conclusion: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.
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- Mila-Aloma, M., et al.
(author)
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Cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF biomarker profile
- 2021
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Journal article (peer-reviewed)abstract
- Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-beta (A beta) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF A beta 42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and alpha-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F-18]-FDG, and [F-18]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of A beta pathology: (1) positive CSF A beta 42/40 and < 30 Centiloids in A beta PET, (2) positive CSF A beta 42/40 and negative A beta PET visual read, and (3) 20-40 Centiloid range in A beta PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding A beta-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the A beta-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful A beta-downstream effects in individuals with a low burden of A beta pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of A beta pathology for clinical trials.
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- Vilor-Tejedor, N., et al.
(author)
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Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum
- 2021
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Journal article (peer-reviewed)abstract
- Background Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys (R) immunoassays were used to measure CSF A beta 42, A beta 40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and alpha-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by A beta status (positivity defined as A beta 42/40 < 0.071). Results The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of A beta positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in A beta negative participants. Conclusions Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
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