5 research outputs found
Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood:Findings from the DREAM BIG consortium
This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.</p
Odor identification as a biomarker for progression of pre-symptomatic Alzheimer's disease
Introduction: After several decades of research, we now understand that there is a long transition period from normal aging to dementia onset. Recently, preventive interventions have moved more upstream than ever before. This shift requires "measurement like" functional instruments or biological markers to reflect early Alzheimer neuropathological change. Previous association studies, imaging, and autopsy work had hinted that olfactory functions might be indicative of an underlying neurodegenerative disorder like AD. We sought to use odor identification as a measure of change and investigate its association with severity markers of AD in both cross-section and over time. Method: Cognitively normal adults with a first-degree relative were given serial odor identification tests, measured using the University of Pennsylvania Smell Identification Test. Total tau (t-tau), phospho-tau (P181-tau), β-amyloid (Aβ1-42) were measured for those who volunteered to do lumbar punctures. We used Kruskal-Wallis and chi-square to evaluate group differences. We used robust fit linear regression methods to evaluate the effect of multiple variables entering AD risk or severity measures iteratively. We used linear mixed-effect model to assess decline in odor identification over a 2-year period. We assessed the association of repeated odor identification and AD measurements. We evaluated the effect of baseline AD severity (CSF biomarkers, hippocampal volume, global cognition) on longitudinal OI. Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. Longitudinal analyses were adjusted for treatment assignment, and time. Results: Reduced odor identification was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau to Aβ1-42. OI declined significantly over 2 years. In analyses that investigated change scores, an increase in t-tau/Aβ1-42 predicted decreasing OI over two years at trend level. Higher baseline CSF t-tau/Aβ1-42 predicted lower OI throughout the trial at trend level. Similarly, lower baseline OI predicted higher CSF t-tau/Aβ1-42. Lower baseline immediate memory was associated with lower OI at any timepoint. Baseline global cognition and immediate memory portended declines in OI at trend level. Finally, there was no association between OI and hippocampal volumes. Conclusion: This work contributes to the understanding of how odor identification could be a measurement for AD progression. Together, the findings from healthy high-risk older individuals suggest that odor identification reflects degree of pre-symptomatic AD pathology. Olfactory functions remain an attractive and easy way to measure early Alzheimer related changes. This method shows promising cost-effectiveness. This sensori-neural function deserves more attention, and further investigation in preventative trials.Introduction: Après plusieurs décennies de recherche, nous comprenons maintenant qu'il existe une longue période de transition entre le vieillissement normal et le début de la démence. Les interventions préventives sont de plus en plus en amont que jamais auparavant. Des instruments de mesure fonctionnels et des marqueurs biologiques sont nécessaires pour mesurer des changements dans la phase précoce de la maladie d'Alzheimer (MA). Des études d'association utilisant l'imagerie cérébrale et le travail d'autopsie ont suggéré que des troubles d'identification des odeurs pourraient indiquer un trouble neurodégénératif sous-jacent comme la maladie d'Alzheimer. Ces observations nous ont poussés à utiliser l'identification des odeurs comme mesure du changement et à étudier son association avec les marqueurs de sévérité de la MA dans sa phase pré-symptomatique. Méthode : Des tests d'identification d'odeurs ont été administrés en série, en utilisant un test standardisé de l'Université de Pennsylvanie chez des adultes cognitivement normaux qui ont un parent atteint de la MA. Les niveaux de protéines tau totales (t-tau), tau phosphorylées (P181-tau) et de β-amyloïde (Aβ1-42) ont été mesurés dans un sous-groupe de volontaires chez qui des ponctions lombaires ont été effectuées afin de recueillir du liquide céphalo-rachidien (LCR). Les méthodes de Kruskal-Wallis et chi-carré ont été utilisées pour évaluer les différences entre les groupes de volontaires. Des méthodes de régression linéaire ont été appliquées pour évaluer l'effet de variables multiples en entrant des mesures de risque ou de sévérité de la MA de manière itérative (âge, cognition, éducation, sexe, statut APOE ε4, biomarqueurs du LCR). Pour évaluer le déclin de la capacité à identifier des odeurs sur une période de deux ans, un modèle linéaire à effets mixtes a été utilisé. Nous avons évalué l'association de l'identification des odeurs et des mesures de la MA répétées (biomarqueurs du LCR, volume de l'hippocampe, cognition globale) sur deux ans. Les analyses qui ont été ajustées le sont en fonction de l'âge, de la cognition, du statut APOE ε4, de l'éducation et du sexe Les analyses longitudinales ont été ajustées selon le temps et l'assignation à un traitement pharmacologique. Résultats: Une capacité réduite à identifier les odeurs est associée à un score cognitif plus faible, à un âge plus avancé, ainsi qu'à des ratios élevés de t-tau/Aβ1-42. La capacité à identifier les odeurs a diminué de façon significative en deux ans. Une augmentation du ratio t-tau/Aβ1-42 prédit une diminution de l'identification d'odeurs sur deux ans avec un faible niveau de confiance De même, une valeur initiale plus élevée du ratio t-tau/Aβ1-42 prédit une capacité moindre à identifier les odeurs tout au long de l'étude. De même, la capacité d'identifier les odeurs plus bas au début prédit un ratio t-tau/Aβ1-42 plus élevé tout au long de l'étude. Les résultats aux tests cognitifs initiaux (cognition globale ainsi que la mémoire de travail) prédisent le déclin des résultats d'identification d'odeurs. Aucune association entre les résultats d'identification d'odeurs et les volumes de l'hippocampe n'a été détectée. Conclusion: Ce travail contribue à la compréhension de la façon dont l'identification des odeurs pourrait être une mesure de la progression de la MA. Ensemble, les résultats suggèrent que l'identification des odeurs reflète le degré de pathologie présent chez des individus sain à risque de développer la MA, considérés dans la phase pré-symptomatique. La mesure des fonctions olfactives demeurent un moyen attrayant et simple pour mesurer les changements précoces liés à la maladie d'Alzheimer. Cette méthode présente un rapport coût-efficacité prometteur et mérite son inclusion dans plus de recherches afin de mieux définir son utilisation
Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood:Findings from the DREAM BIG consortium
This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.</p
Supplementary_Revised
eMethods, eTables (Table e1, Table e2, Table e3, Table e4), eFigures (Figure e1, Figure e2), eReferences (1
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Test-retest resting-state fMRI in healthy elderly persons with a family history of Alzheimer’s disease
We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled in the “Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease” (PREVENT-AD) Cohort. Subjects with a family history of Alzheimer's disease in first-degree relatives were recruited as part of an on-going double blind randomized clinical trial of Naproxen or placebo. Two pairs of scans were acquired ~3 months apart, allowing the assessment of both intra- and inter-session reliability, with the possible caveat of treatment effects as a source of inter-session variation. Using the NeuroImaging Analysis Kit (NIAK), we report on the standard quality of co-registration and motion parameters of the data, and assess their validity based on the spatial distribution of seed-based connectivity maps as well as intra- and inter-session reliability metrics in the default-mode network. This resource, released publicly as sample UM1 of the Consortium for Reliability and Reproducibility (CoRR), will benefit future studies focusing on the preclinical period preceding the appearance of dementia in Alzheimer's disease