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1.
Carlos Cruchaga Jorge L. Del-Aguila Benjamin Saef Kathleen Black Maria Victoria Fernandez John Budde Laura Ibanez Yuetiva Deming Manav Kapoor Giuseppe Tosto Richard P. Mayeux David M. Holtzman Anne M. Fagan John C. Morris Randall J. Bateman Alison M. Goate Oscar Harari 《Alzheimer's & dementia》2018,14(2):205-214
Objective
To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD).Methods
Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.Results
We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10?7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10?7) and sLOAD (OR = 1.40; P = 1.21 × 10?3). The PRS was associated with cerebrospinal fluid ptau181-Aβ42 on eADAD (P = 4.36 × 10?2).Conclusion
Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset. 相似文献2.
Sophie E. Holmes Rainer Hinz Silke Conen Catherine J. Gregory Julian C. Matthews Jose M. Anton-Rodriguez Alexander Gerhard Peter S. Talbot 《Neuropsychopharmacology》2018,83(1):61-69
Background
Major depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation in vivo using positron emission tomography and TSPO-specific radioligands.Methods
We used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts.Results
Multivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (p = .005). The elevation was of large effect size and significant in the ACC (p = .022, Cohen’s d = 0.95), with smaller nonsignificant elevations in the prefrontal cortex (p = .342, Cohen’s d = 0.38) and insula (p = .466, Cohen’s d = 0.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (p = .008) and insula (p = .023).Conclusions
We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder. 相似文献3.
Sameer Jauhar Mattia Veronese Matthew M. Nour Maria Rogdaki Pamela Hathway Sridhar Natesan Federico Turkheimer James Stone Alice Egerton Philip McGuire Shitij Kapur Oliver D. Howes 《Neuropsychopharmacology》2019,85(1):79-87
Background
Elevated striatal dopamine synthesis capacity has been implicated in the etiology and antipsychotic response in psychotic illness. The effects of antipsychotic medication on dopamine synthesis capacity are poorly understood, and no prospective studies have examined this question in a solely first-episode psychosis sample. Furthermore, it is unknown whether antipsychotic efficacy is linked to reductions in dopamine synthesis capacity. We conducted a prospective [18F]-dihydroxyphenyl-L-alanine positron emission tomography study in antipsychotic naïve/free people with first-episode psychosis commencing antipsychotic treatment.Methods
Dopamine synthesis capacity (indexed as influx rate constant) and clinical symptoms (measured using Positive and Negative Syndrome Scale) were measured before and after at least 5 weeks of antipsychotic treatment in people with first-episode psychosis. Data from a prior study indicated that a sample size of 13 would have >80% power to detect a statistically significant change in dopamine synthesis capacity at alpha = .05 (two tailed).Results
A total of 20 people took part in the study, 17 of whom were concordant with antipsychotic medication at therapeutic doses. There was no significant effect of treatment on dopamine synthesis capacity in the whole striatum (p = .47), thalamus, or midbrain, nor was there any significant relationship between change in dopamine synthesis capacity and change in positive (ρ = .35, p = .13), negative, or total psychotic symptoms.Conclusions
Dopamine synthesis capacity is unaltered by antipsychotic treatment, and therapeutic effects are not mediated by changes in this aspect of dopaminergic function. 相似文献4.
Structural Brain Connectivity in Childhood Disruptive Behavior Problems: A Multidimensional Approach
Koen Bolhuis Ryan L. Muetzel Argyris Stringaris James J. Hudziak Vincent W.V. Jaddoe Manon H.J. Hillegers Tonya White Steven A. Kushner Henning Tiemeier 《Neuropsychopharmacology》2019,85(4):336-344
Background
Studies of white matter connectivity in children with disruptive behavior have yielded inconsistent results, possibly owing to the trait’s heterogeneity, which comprises diverse symptoms like physical aggression, irritability, and delinquency. This study examined associations of global and specific white matter connectivity with childhood disruptive behavior problems, while accounting for their complex multidimensionality.Methods
In a large cross-sectional population-based study of 10-year-old preadolescents (n = 2567), we assessed four previously described empirically derived dimensions of disruptive behavior problems using the Child Behavior Checklist: physical aggression, irritability, disobedient behavior, and delinquent behavior. Global and specific white matter microstructure was assessed by diffusion tensor imaging.Results
Global fractional anisotropy and mean diffusivity were not associated with broad measures of disruptive behavior, e.g., Child Behavior Checklist externalizing problems scale. Global fractional anisotropy was negatively associated with delinquent behavior (β = ?.123, pfalse discovery rate adjusted = .028) and global mean diffusivity was positively associated with delinquent behavior (β = .205, pfalse discovery rate adjusted < 0.001), suggesting reduced white matter microstructure in preadolescents with higher levels of delinquent behavior. Lower white matter microstructure in the inferior longitudinal fasciculus, superior longitudinal fasciculus, cingulum, and uncinate underlie these associations. Global white matter microstructure was not associated with physical aggression, irritability, or disobedient behavior.Conclusions
Delinquent behavior, a severe manifestation of childhood disruptive behavior, was associated with lower white matter microstructure in tracts connecting frontal and temporal lobes. These brain regions are involved in decision making, reward processing, and emotion regulation. This study demonstrated that incorporating the multidimensional nature of childhood disruptive behavior traits shows promise in advancing the search for elucidating neurobiological correlates of disruptive behavior. 相似文献5.
Nathalie MacKinnon Mila Kingsbury Liam Mahedy Jonathan Evans Ian Colman 《Neuropsychopharmacology》2018,83(2):100-108
Background
It has been suggested that prenatal maternal stress may increase the risk of childhood externalizing disorders, yet no large cohort study has investigated this association across a large range of acute stressors. Our objective was to estimate the association between prenatal stressful events and risk of offspring conduct disorder and hyperactivity.Methods
We used data from 10,184 mother–offspring pairs from the United Kingdom–based Avon Longitudinal Study of Parents and Children. Mothers self-reported 42 prenatal stressful life events at 18 weeks’ gestation. Symptoms of conduct disorder and hyperactivity in their offspring were measured at 6, 9, 11, 13, and 16 years of age using the Strengths and Difficulties Questionnaire. The primary outcome was membership in high-symptom trajectories of 1) conduct disorder and 2) hyperactivity throughout childhood, identified using latent class growth modeling. Multinomial logistic regression models estimated the association between prenatal stress and both conduct disorder and hyperactivity, after adjusting for sex, parental education, low birth weight, preterm birth, parental social class, maternal smoking and drinking, maternal mental health, offspring stressful life events, and offspring depressive and anxious symptoms.Results
Those exposed to the highest quartile of prenatal stress were more likely to belong to the high symptom trajectory for hyperactivity (B = 0.46, p < .05) and conduct disorder (B = 0.88, p < .01), respectively. Prenatal stress further demonstrated a positive, dose–response relationship with symptoms of externalizing disorders at independent time points.Conclusions
The findings suggest that prenatal stressful events may be an independent risk factor for offspring externalizing symptoms, regardless of maternal mental health and offspring internalizing. 相似文献6.
Luke J. Norman Stephan F. Taylor Yanni Liu Joaquim Radua Yann Chye Stella J. De Wit Chaim Huyser F. Isik Karahanoglu Tracy Luks Dara Manoach Carol Mathews Katya Rubia Chao Suo Odile A. van den Heuvel Murat Yücel Kate Fitzgerald 《Neuropsychopharmacology》2019,85(9):713-725
Background
Error processing and inhibitory control enable the adjustment of behaviors to meet task demands. Functional magnetic resonance imaging studies report brain activation abnormalities in patients with obsessive-compulsive disorder (OCD) during both processes. However, conclusions are limited by inconsistencies in the literature and small sample sizes. Therefore, the aim here was to perform a meta-analysis of the existing literature using unthresholded statistical maps from previous studies.Methods
A voxelwise seed-based d mapping meta-analysis was performed using t-maps from studies comparing patients with OCD and healthy control subjects (HCs) during error processing and inhibitory control. For the error processing analysis, 239 patients with OCD (120 male; 79 medicated) and 229 HCs (129 male) were included, while the inhibitory control analysis included 245 patients with OCD (120 male; 91 medicated) and 239 HCs (135 male).Results
Patients with OCD, relative to HCs, showed longer inhibitory control reaction time (standardized mean difference = 0.20, p = .03, 95% confidence interval = 0.016, 0.393) and more inhibitory control errors (standardized mean difference = 0.22, p = .02, 95% confidence interval = 0.039, 0.399). In the brain, patients showed hyperactivation in the bilateral dorsal anterior cingulate cortex, supplementary motor area, and pre-supplementary motor area as well as right anterior insula/frontal operculum and anterior lateral prefrontal cortex during error processing but showed hypoactivation during inhibitory control in the rostral and ventral anterior cingulate cortices and bilateral thalamus/caudate, as well as the right anterior insula/frontal operculum, supramarginal gyrus, and medial orbitofrontal cortex (all seed-based d mapping z value >2, p < .001).Conclusions
A hyperactive error processing mechanism in conjunction with impairments in implementing inhibitory control may underlie deficits in stopping unwanted compulsive behaviors in the disorder. 相似文献7.
Mascha van &#x;t Wout-Frank M. Tracie Shea Victoria C. Larson Benjamin D. Greenberg Noah S. Philip 《Brain stimulation》2019,12(1):41-43
Background
Facilitating neural activity using non-invasive brain stimulation may improve extinction-based treatments for posttraumatic stress disorder (PTSD).Objective/hypothesis
Here, we examined the feasibility of simultaneous transcranial direct current stimulation (tDCS) application during virtual reality (VR) to reduce psychophysiological arousal and symptoms in Veterans with PTSD.Methods
Twelve Veterans with PTSD received six combat-related VR exposure sessions during sham-controlled tDCS targeting ventromedial prefrontal cortex. Primary outcome measures were changes in skin conductance-based arousal and self-reported PTSD symptom severity.Results
tDCS + VR components were combined without technical difficulty. We observed a significant interaction between reduction in arousal across sessions and tDCS group (p = .03), indicating that the decrease in physiological arousal was greater in the tDCS + VR versus sham group. We additionally observed a clinically meaningful reduction in PTSD symptom severity.Conclusions
This study demonstrates feasibility of applying tDCS during VR. Preliminary data suggest a reduction in psychophysiological arousal and PTSD symptomatology, supporting future studies. 相似文献8.
Cecilia S. Lee Eric B. Larson Laura E. Gibbons Aaron Y. Lee Susan M. McCurry James D. Bowen Wayne C. McCormick Paul K. Crane 《Alzheimer's & dementia》2019,15(1):34-41
Introduction
Identifying ophthalmic diseases associated with increased risk of Alzheimer's disease (AD) may enable better screening and understanding of those at risk of AD.Methods
Diagnoses of glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) were based on International Classification of Diseases, 9th revision, codes for 3877 participants from the Adult Changes in Thought study. The adjusted hazard ratio for developing probable or possible AD for recent (within 5 years) and established (>5 years) diagnoses were assessed.Results
Over 31,142 person-years of follow-up, 792 AD cases occurred. The recent and established hazard ratio were 1.46 (P = .01) and 0.87 (P = .19) for glaucoma, 1.20 (P = .12) and 1.50 (P < .001) for AMD, and 1.50 (P = .045) and 1.50 (P = .03) for DR.Discussion
Increased AD risk was found for recent glaucoma diagnoses, established AMD diagnoses, and both recent and established DR. People with certain ophthalmic conditions may have increased AD risk. 相似文献9.
Kumar B. Rajan Jennifer Weuve Lisa L. Barnes Robert S. Wilson Denis A. Evans 《Alzheimer's & dementia》2019,15(1):1-7
Introduction
The trends in prevalence and incidence of Alzheimer's disease (AD) dementia remain uncertain.Methods
A sample of 2794 participants with a clinical diagnosis for AD dementia were included.Results
The 2010 census standardized prevalence of AD dementia was 14.5% (95% CI = 13.7–15.3), and annual incidence was 2.3% (1.7–2.9). Both prevalence and incidence showed substantial variation over time, but no secular trends. The prevalence of AD dementia did not change significantly from 14.6% (95% CI = 13.0, 16.2) in 1994–1997 to 14.7% (95% CI = 13.2, 16.2) in 2010–2012 (P = .84). The annual incidence of AD dementia was 2.8% (95% CI = 2.2, 3.2) in 1998–2000 and 2.2% (95% CI = 1.6, 2.8) in 2004–2006 (P = .20) and remained steady in 2010–2012. The prevalence and incidence among African Americans were approximately twice than those among European Americans.Conclusions
The prevalence and incidence of AD dementia showed substantial variation between 1994 and 2012, but no secular trend. 相似文献10.
Background
While previous studies have investigated the effect of repetitive transcranial magnetic stimulation (rTMS) in treating Tourette syndrome (TS), the results remain inconclusive.Objective
We aim to systematically review the existing literature related to the efficacy of rTMS in TS and synthesize the results through meta-analysis.Methods
We searched for PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases without language restriction through January 1, 2018, and included randomized-controlled and open-label trials that assessed the treatment effect of rTMS for tic symptoms. We used a random-effects model to pool effect sizes, which were expressed as Hedges' g and 95% confidence intervals (CIs). The outcomes include symptom improvement of tic, obsessive-compulsive (OC), and attention-deficit hyperactivity disorder. Distribution of sex, age, and differences of rTMS protocol were examined as potential moderators.Results
Eight studies were included in the meta-analysis. rTMS significantly improved tic (g?=??0.61; CI: ?0.94 to ?0.29) and OC (g?=??0.48; CI: ?0.83 to ?0.14) symptoms in TS patients, compared to baseline. However, active rTMS was not effective in tic or OC symptoms among patients with TS when controlled for placebo. Furthermore, stimulation of the bilateral supplementary motor areas was more effective in tic symptoms than that of other areas (g?=??0.70; CI: ?1.11 to ?0.30 vs. g?=??0.36; CI: ?0.84 to 0.14). Moreover, a younger age was associated with a better treatment effect (coefficient?=?0.03, p?=?0.027).Conclusion
Current study indicates that rTMS has a significant effect on tic and OC symptoms in TS patients. 相似文献11.
Cecilie N. Lydholm Ole Köhler-Forsberg Merete Nordentoft Robert H. Yolken Preben B. Mortensen Liselotte Petersen Michael E. Benros 《Neuropsychopharmacology》2019,85(4):317-325
Background
Previous studies have shown associations between maternal infections during pregnancy and increased risks of schizophrenia and autism spectrum disorder in the offspring. However, large-scale studies investigating an association between parental infections both during and outside the pregnancy period and the risk of any mental disorder in the child are lacking.Methods
A nationwide Danish cohort study identified 1,206,600 children born between 1996 and 2015 and followed them to a maximum of 20 years of age. Exposure included all maternal and paternal infections treated with anti-infective agents or hospital contacts before, during, or after pregnancy. The main outcome was a diagnosis of any mental disorder in the child. Hazard ratios (HRs) were calculated using Cox regression analysis.Results
Maternal infections during pregnancy treated with anti-infective agents (n = 567,016) increased the risk of mental disorders (n = 70,037) in the offspring (HR, 1.09; 95% confidence interval [CI], 1.06–1.12), which was more elevated (p < .001) than after paternal infections (n = 350,835; HR, 1.01; 95% CI, 0.98–1.03). Maternal hospital contacts for infections (n = 39,753) conferred an increased HR of 1.21 (95% CI, 1.14–1.28), which was not significantly (p = .08) different from the risk after paternal infections (n = 8559; HR, 1.07; 95% CI, 0.95–1.20). The increased risks observed during pregnancy were not different from the similarly increased risks for maternal and paternal infections before and after pregnancy. The risk of mental disorders increased in a dose-response relationship with the number of maternal infections treated with anti-infective agents, particularly during and after pregnancy (both p < .001).Conclusions
Maternal infections were associated with an increased risk of mental disorder in the offspring; however, there were similar estimates during and outside the pregnancy period. 相似文献12.
Thomas H. McCoy Sheng Yu Kamber L. Hart Victor M. Castro Hannah E. Brown James N. Rosenquist Alysa E. Doyle Pieter J. Vuijk Tianxi Cai Roy H. Perlis 《Neuropsychopharmacology》2018,83(12):997-1004
Background
Relying on diagnostic categories of neuropsychiatric illness obscures the complexity of these disorders. Capturing multiple dimensional measures of neuropathology could facilitate the clinical and neurobiological investigation of cognitive and behavioral phenotypes.Methods
We developed a natural language processing–based approach to extract five symptom dimensions, based on the National Institute of Mental Health Research Domain Criteria definitions, from narrative clinical notes. Estimates of Research Domain Criteria loading were derived from a cohort of 3619 individuals with 4623 hospital admissions. We applied this tool to a large corpus of psychiatric inpatient admission and discharge notes (2010–2015), and using the same cohort we examined face validity, predictive validity, and convergent validity with gold standard annotations.Results
In mixed-effect models adjusted for sociodemographic and clinical features, greater negative and positive symptom domains were associated with a shorter length of stay (β = ?.88, p = .001 and β = ?1.22, p < .001, respectively), while greater social and arousal domain scores were associated with a longer length of stay (β = .93, p < .001 and β = .81, p = .007, respectively). In fully adjusted Cox regression models, a greater positive domain score at discharge was also associated with a significant increase in readmission risk (hazard ratio = 1.22, p < .001). Positive and negative valence domains were correlated with expert annotation (by analysis of variance [df = 3], R2 = .13 and .19, respectively). Likewise, in a subset of patients, neurocognitive testing was correlated with cognitive performance scores (p < .008 for three of six measures).Conclusions
This shows that natural language processing can be used to efficiently and transparently score clinical notes in terms of cognitive and psychopathologic domains. 相似文献13.
Kang Ik K. Cho Yoo Bin Kwak Wu Jeong Hwang Junhee Lee Minah Kim Tae Young Lee Jun Soo Kwon 《Neuropsychopharmacology》2019,85(1):70-78
Background
Disruption in the thalamus, such as volume, shape, and cortical connectivity, is regarded as an important pathophysiological mechanism in schizophrenia. However, there is little evidence of nuclei-specific structural alterations in the thalamus during early-stage psychosis, mainly because of the methodological limitations of conventional structural imaging in identifying the thalamic nuclei.Methods
A total of 37 patients with first-episode psychosis and 36 matched healthy control subjects underwent diffusion tensor imaging, diffusion kurtosis imaging, and T1-weighted magnetic resonance imaging. Connectivity-based segmentation of the thalamus was performed using diffusion tensor imaging, and averages of the diffusion kurtosis values, which represent microstructural complexity, were estimated using diffusion kurtosis imaging and were compared in each thalamic nucleus between the groups.Results
The mean kurtosis values in the thalamic regions with strong connections to the orbitofrontal cortex (F1,70 = 8.40, p < .01) and the lateral temporal cortex (F1,70 = 8.46, p < .01) were significantly reduced in patients with first-episode psychosis compared with those of the healthy control subjects. The mean kurtosis values in the thalamic region with strong connection to the orbitofrontal cortex showed a significant correlation with spatial working memory accuracy in patients with first-episode psychosis (r = .36, p < .05), whereas no significant correlation between these variables was observed in the healthy control subjects.Conclusions
The observed pattern of reduced microstructural complexity in the nuclei not only highlights the involvement of the thalamus but also emphasizes the role of the higher-order nuclei in the pathophysiology beginning in the early stage of schizophrenia. 相似文献14.
W. Robert Bell Yang An Yusuke Kageyama Collin English Gay L. Rudow Olga Pletnikova Madhav Thambisetty Richard O&#x;Brien Abhay R. Moghekar Marilyn S. Albert Peter V. Rabins Susan M. Resnick Juan C. Troncoso 《Alzheimer's & dementia》2019,15(1):8-16
Introduction
Primary age-related tauopathy (PART) is a recently described entity that can cause cognitive impairment in the absence of Alzheimer's disease (AD). Here, we compared neuropathological features, tau haplotypes, apolipoprotein E (APOE) genotypes, and cognitive profiles in age-matched subjects with PART and AD pathology.Methods
Brain autopsies (n = 183) were conducted on participants 85 years and older from the Baltimore Longitudinal Study of Aging and Johns Hopkins Alzheimer's Disease Research Center. Participants, normal at enrollment, were followed with periodic cognitive evaluations until death.Results
Compared with AD, PART subjects showed significantly slower rates of decline on measures of memory, language, and visuospatial performance. They also showed lower APOE ε4 allele frequency (4.1% vs. 17.6%, P = .0046).Discussion
Our observations suggest that PART is separate from AD and its distinction will be important for the clinical management of patients with cognitive impairment and for public health care planning. 相似文献15.
Oluwole O. Awosika Marco Sandrini Rita Volochayev Ryan M. Thompson Nathan Fishman Tianxia Wu Mary Kay Floeter Mark Hallett Leonardo G. Cohen 《Brain stimulation》2019,12(3):628-634
Background
Ambulation is an essential aspect of daily living and is often impaired after brain and spinal cord injuries. Despite the implementation of standard neurorehabilitative care, locomotor recovery is often incomplete.Objective
In this randomized, sham-controlled, double-blind, parallel design study, we aimed to determine if anodal transcutaneous spinal direct current stimulation (anodal tsDCS) could improve training effects on locomotion compared to sham (sham tsDCS) in healthy subjects. Methods: 43 participants underwent a single backwards locomotion training (BLT) session on a reverse treadmill with concurrent anodal (n = 22) or sham (n = 21) tsDCS. The primary outcome measure was speed gain measured 24 h post-training. We hypothesized that anodal tsDCS + BLT would improve training effects on backward locomotor speed compared to sham tsDCS + BLT. A subset of participants (n = 31) returned for two additional training days of either anodal (n = 16) or sham (n = 15) tsDCS and underwent (n = 29) H-reflex testing immediately before, immediately after, and 30 min post-training over three consecutive days.Results
A single session of anodal tsDCS + BLT elicited greater speed gain at 24 h relative to sham tsDCS + BLT (p = 0.008, two-sample t-test, adjusted for one interim analysis after the initial 12 subjects). Anodal tsDCS + BLT resulted in higher retention of the acquired skill at day 30 relative to sham tsDCS + BLT (p = 0.002) in the absence of significant group differences in online or offline learning over the three training days (p = 0.467 and p = 0.131). BLT resulted in transient down-regulation of H-reflex amplitude (Hmax/Mmax) in both test groups (p < 0.0001). However, the concurrent application of anodal-tsDCS with BLT elicited a longer lasting effect than sham-tsDCS + BLT (p = 0.050).Conclusion
tsDCS improved locomotor skill acquisition and retention in healthy subjects and prolonged the physiological exercise-mediated downregulation of excitability of the alpha motoneuron pool. These results suggest that this strategy is worth exploring in neurorehabilitation of locomotor function. 相似文献16.
Thomas H. McCoy Victor M. Castro Kamber L. Hart Amelia M. Pellegrini Sheng Yu Tianxi Cai Roy H. Perlis 《Neuropsychopharmacology》2018,83(12):1005-1011
Background
Genetic studies of neuropsychiatric disease strongly suggest an overlap in liability. There are growing efforts to characterize these diseases dimensionally rather than categorically, but the extent to which such dimensional models correspond to biology is unknown.Methods
We applied a newly developed natural language processing method to extract five symptom dimensions based on the National Institute of Mental Health Research Domain Criteria definitions from narrative hospital discharge notes in a large biobank. We conducted a genome-wide association study to examine whether common variants were associated with each of these dimensions as quantitative traits.Results
Among 4687 individuals, loci in three of five domains exceeded a genome-wide threshold for statistical significance. These included a locus spanning the neocortical development genes RFPL3 and RFPL3S for arousal (p = 2.29 × 10?8) and one spanning the FPR3 gene for cognition (p = 3.22 × 10?8).Conclusions
Natural language processing identifies dimensional phenotypes that may facilitate the discovery of common genetic variation that is relevant to psychopathology. 相似文献17.
Joanna Martin Raymond K. Walters Ditte Demontis Manuel Mattheisen S. Hong Lee Elise Robinson Isabell Brikell Laura Ghirardi Henrik Larsson Paul Lichtenstein Nicholas Eriksson 《Neuropsychopharmacology》2018,83(12):1044-1053
Background
Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.Methods
We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).Results
Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98–1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11–1.18], p = 1.5E-15).Conclusions
Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence. 相似文献18.
Alexis E. Cullen Scarlett Holmes Thomas A. Pollak Graham Blackman Dan W. Joyce Matthew J. Kempton Robin M. Murray Philip McGuire Valeria Mondelli 《Neuropsychopharmacology》2019,85(1):35-48
Background
A relationship between non-neurological autoimmune (NNAI) disorders and psychosis has been widely reported but not yet subjected to meta-analysis. We conducted the first meta-analysis examining the association between NNAI disorders and psychosis and investigated the effect of 1) temporality (as determined by study design), 2) psychiatric diagnosis, and 3) specific autoimmune disorders.Methods
Major databases were searched for articles published until April 2018; 31 studies, comprising data for >25 million individuals, were eligible. Using random-effects models, we examined the overall association between all NNAI disorders and psychosis; rheumatoid arthritis was examined separately given the well-established negative association with psychosis. Stratified analyses investigated the effect of temporality, psychiatric diagnosis, and specific NNAI disorders.Results
We observed a positive overall association between NNAI disorders and psychosis (odds ratio [OR] = 1.26; 95% confidence interval [CI], 1.12–1.41) that was consistent across study designs and psychiatric diagnoses; however, considerable heterogeneity was detected (I2 = 88.08). Patterns varied across individual NNAI disorders; associations were positive for pernicious anemia (OR = 1.91; 95% CI, 1.29–2.84), pemphigoid (OR = 1.90; 95% CI, 1.62–2.24), psoriasis (OR = 1.70; 95% CI, 1.51–1.91), celiac disease (OR = 1.53; 95% CI, 1.12–2.10), and Graves’ disease (OR = 1.33; 95% CI, 1.03–1.72) and negative for ankylosing spondylitis (OR = 0.72; 95% CI, 0.54–0.98) and rheumatoid arthritis (OR = 0.65; 95% CI, 0.50–0.84).Conclusions
While we observed a positive overall association between NNAI disorders and psychosis, this was not consistent across all NNAI disorders. Specific factors, including distinct inflammatory pathways, genetic influences, autoantibodies targeting brain proteins, and exposure to corticosteroid treatment, may therefore underlie this association. 相似文献19.
Paola Gilsanz Maria M. Corrada Claudia H. Kawas Elizabeth Rose Mayeda M. Maria Glymour Charles P. Quesenberry Catherine Lee Rachel A. Whitmer 《Alzheimer's & dementia》2019,15(4):497-505
Introduction
Little is known about dementia incidence in diverse populations of oldest-old, the age group with highest dementia incidence.Methods
Incident dementia diagnoses from 1/1/2010 to 9/30/2015 were abstracted from medical records for 2350 members of an integrated health care system in California (n = 1702 whites, n = 375 blacks, n = 105 Latinos, n = 168 Asians) aged ≥90 in 2010. We estimated race/ethnicity-specific age-adjusted dementia incidence rates and implemented Cox proportional hazards models and Fine and Gray competing risk of death models adjusted for demographics and comorbidities in midlife and late-life.Results
Dementia incidence rates (n = 771 cases) were lowest among Asians (89.9/1000 person-years), followed by whites (96.9/1000 person-years), Latinos (105.8/1000 person-years), and blacks (121.5/1000 person-years). Cox regression and competing risk models estimated 28% and 36% higher dementia risk for blacks versus whites adjusting for demographics and comorbidities.Discussion
Patterns of racial/ethnic disparities in dementia seen in younger older adults continue after the age of 90 years, though smaller in magnitude. 相似文献20.
Anna Marseglia Laura Fratiglioni Grégoria Kalpouzos Rui Wang Lars Bäckman Weili Xu 《Alzheimer's & dementia》2019,15(1):25-33