Faculty Bibliography

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (beta=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 x 10-8, PFDR=2.48 x 10-3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (beta=8.24, 95% CI: 4.45-12.01, P=3.84 x 10-5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.Molecular Psychiatry advance online publication, 1 December 2015; doi:10.1038/mp.2015.177.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.Molecular Psychiatry advance online publication, 24 November 2015; doi:10.1038/mp.2015.172.

Response inhibition deficits are widely believed to be at the core of Attention-Deficit Hyperactivity Disorder (ADHD). Several studies have examined neural architectural correlates of ADHD, but research directly examining structural correlates of response inhibition is lacking. Here we examine the relationship between response inhibition as measured by a Go/No Go task, and cortical surface area and thickness of the caudal inferior frontal gyrus (cIFG), a region implicated in functional imaging studies of response inhibition, in a sample of 114 young adults with and without ADHD diagnosed initially during childhood. We used multiple linear regression models to test the hypothesis that Go/No Go performance would be associated with cIFG surface area or thickness. Results showed that poorer Go/No Go performance was associated with thicker cIFG cortex, and this effect was not mediated by ADHD status or history of substance use. However, independent of Go/No Go performance, persistence of ADHD symptoms and more frequent cannabis use were associated with thinner cIFG. Go/No Go performance was not associated with cortical surface area. The association between poor inhibitory functioning and thicker cIFG suggests that maturation of this region may differ in low performing participants. An independent association of persistent ADHD symptoms and frequent cannabis use with thinner cIFG cortex suggests that distinct neural mechanisms within this region may play a role in inhibitory function, broader ADHD symptomatology, and cannabis use. These results contribute to Research Domain Criteria (RDoC) by revealing novel associations between neural architectural phenotypes and basic neurobehavioral processes measured dimensionally.

Psychostimulants such as methylphenidate and amphetamine are the first-line pharmacologic treatments for Attention-Deficit/Hyperactivity Disorder (ADHD). They are considered prototypical cognitive enhancers but their effects on standard laboratory indices of cognitive function are modest when administered acutely, and even less substantial chronically. However, large-scale observational studies in patients with ADHD have detected stimulant-associated decreases of criminal acts, transportation accidents, slightly improved academic performance, and possible protection against drug abuse. These effects likely reflect modulation of broader domains such as emotional regulation and motivation which have been under-examined. Efforts to clarify the ontological relations between cognitive tasks and their underlying constructs should be incorporated into the Research Domain Criteria project and similar harmonization initiatives.

Objective: To assess group-differences in movement measures in published studies contrasting Attention-Deficit/Hyperactivity Disorder (ADHD) vs. controls. Background: ADHD diagnoses continue to be completely based on clinical history, which is subjective and subject to recall bias. In response, investigators have proposed incorporating objective measures such as locomotor activity which can be measured with actigraphy or with a high spatial and temporal resolution infrared camera. In May 2014, the United States Food and Drug Administration cleared an example of the latter, the Qb-Test, as a device to be used in supporting the diagnosis of ADHD. A review of the literature did not reveal any prior meta-analyses of such data. Methods: We performed a systematic review and meta-analysis of published studies on motion measures contrasting individuals diagnosed with ADHD and healthy controls. Two authors reviewed a total of 89 abstracts culled from an initial search of 356. After applying inclusion and exclusion criteria, 13 papers were included in our analyses of actigraphy and five papers in analyses of motion tracking systems. Results: The combined sample sizes were 406 patients with ADHD versus 359 controls with actigraphy data and 164 patients with ADHD versus 156 controls with motion tracking system data. Meta-analyses revealed medium effect sizes for actigraphy (standardized mean difference [SMD]: 0.64, 95 % CI: 0.43, 0.85) and large effects for motion tracking systems (SMD: 0.92, 95 % CI: 0.65, 1.20) in differentiating individuals with ADHD from controls. Conclusions: When measured objectively, locomotor hyperactivity robustly differentiates groups of patients with ADHD from healthy controls. Inclusion of objective locomotion measures is likely to be useful in circumstances in which ancillary information is not available, such as when evaluating adults with possible ADHD. However, even the relatively large effect sizes reported to date are unlikely to yield clinically actionable information for individual patients on their own. How to best incorporate such objective data in the diagnostic process remains unclear

To date, only one study has examined test-retest reliability of resting state fMRI (R-fMRI) in children, none in clinical developing groups. Here, we assessed short-term test-retest reliability in a sample of 46 children (11-17.9 years) with attention-deficit/hyperactivity disorder (ADHD) and 57 typically developing children (TDC). Our primary test-retest reliability measure was the intraclass correlation coefficient (ICC), quantified for a range of R-fMRI metrics. We aimed to (1) survey reliability within and across diagnostic groups, and (2) compare voxel-wise ICC between groups. We found moderate-to-high ICC across all children and within groups, with higher-order functional networks showing greater ICC. Nearly all R-fMRI metrics exhibited significantly higher ICC in TDC than in children with ADHD for one or more regions. In particular, posterior cingulate and ventral precuneus exhibited group differences in ICC across multiple measures. In the context of overall moderate-to-high test-retest reliability in children, regional differences in ICC related to diagnostic groups likely reflect the underlying pathophysiology for ADHD. Our currently limited understanding of the factors contributing to inter- and intra-subject variability in ADHD underscores the need for large initiatives aimed at examining their impact on test-retest reliability in both clinical and developing populations.

Working memory (WM) is central to the acquisition of knowledge and skills throughout childhood and adolescence. While numerous behavioral and task-based functional magnetic resonance imaging (fMRI) studies have examined WM development, few have used resting-state fMRI (R-fMRI). Here, we present a systematic R-fMRI examination of age-related differences in the neural indices of verbal WM performance in a cross-sectional pediatric sample (ages: 7-17; n=68), using data-driven approaches. Verbal WM capacity was measured with the digit span task, a commonly used educational and clinical assessment. We found distinct neural indices of digit span forward (DSF) and backward (DSB) performance, reflecting their unique neuropsychological demands. Regardless of age, DSB performance was related to intrinsic properties of brain areas previously implicated in attention and cognitive control, while DSF performance was related to areas less commonly implicated in verbal WM storage (precuneus, lateral visual areas). From a developmental perspective, DSF exhibited more robust age-related differences in brain-behavior relationships than DSB, and implicated a broader range of networks (ventral attention, default, somatomotor, limbic networks) - including a number of regions not commonly associated with verbal WM (angular gyrus, subcallosum). These results highlight the importance of examining the neurodevelopment of verbal WM and of considering regions beyond the "usual suspects".