Faculty Bibliography

Objectives: The goals of this study are to describe long-term clinical and functional outcomes in the New York Study of hyperactive children who were followed prospectively for 33 years and identify possible predictors that influence these outcomes. Methods: White hyperactive boys (N = 207 probands) were recruited in childhood and followed in adolescence (mean age 18 years), early adulthood (mean age 25 years), and mid-adulthood (mean age 41 years). In late adolescence, 178 comparison participants were recruited. At the final followup in mid-adulthood, a total of 135 probands and 136 comparison participants (65.2 and 76.4 percent of original cohort, respectively) were assessed. Outcome measures included occupational, economic, and educational attainment and marital history, occupational and social functioning, ongoing and lifetime psychiatric disorders, hospitalizations, obesity, risk-taking behaviors, and criminal behaviors. Results: Compared with peers without ADHD, probands showed greater persistence of ADHD, along with greater prevalence of CD/antisocial personality disorder (APD) and SUD in late adolescence. These dysfunctions continued into early adulthood, even when ADHD remitted for the majority of the sample group, and were associated with deficits in educational and occupational attainment, leading to a relative economic disadvantage. Furthermore, the disproportionally high rate of CD/APD and SUD in probands versus comparison participants translated to significantly higher rates of criminality, risk-taking behavior, and risk-related medical outcomes in adulthood. Probands also showed elevated obesity rates in relation to comparison participants but no differences in mood or anxiety disorders. Conclusions: There is heterogeneity in the clinical and functional outcomes of children with ADHD. This study's findings show that childhood ADHD does not preclude adequate functioning in various life domains. However, it does predispose to maladjustment in adolescence and adulthood in a subset of these children, particularly those who develop CD/APD, an important predictor of long-term outcome

Objectives: Organizational Skills Training (OST), is a 10-week psychosocial intervention found effective in improving organizational, time management, and planning (OTMP) skills in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Little is known about the feasibility of identifying brain markers for treatment response. Using resting state fMRI (R-fMRI), we aimed to examine neuronal correlates of post-treatment change as a first step toward larger controlled studies of objective predictors of treatment response. Methods: We examined pre- and post-OST R-fMRI data of 15 children (12 males; mean age: 9+/-1 year) with ADHD and significant impairments in OTMP skills indexed by total scores on Children's Organizational Skills Scales-Parent (COSS-P) or Teacher (COSS-T). Our primary outcome measure was the change in COSS-P scores. As secondary summary outcome measure, we used prepost Z-score differences averaged across COSS-T, Homework Problems Checklist, Academic Progress Report and Academic Performance Rating scales. We selected a priori the intrinsic functional connectivity (iFC) of the dorsal anterior cingulate cortex (dACC), based on its role on cognitive control. Multivariate distance matrix regression (MDMR) analysis additionally allowed for whole-brain explorations. Follow-up iFC analyses were conducted on regions with significant within-subject post-OST differences by MDMR analysis. Results: COSS-P decreased significantly (t=7.1, p< 0.0001). In a cluster involving striatum bilaterally, dACC iFC decreased post-OST; these decreases were positively correlated with COSS-P improvements (r=.34, NS) and to improvements in the summary outcome (r=.63; p<0.03). MDMR analyses revealed iFC changes in the right medial and lateral precentral cortex. Followup seed-based iFC analyses of this region showed significant decreases in cortico-striatal iFC post-OST. Conclusions: Results support the feasibility of identifying changes in brain iFC after OST. Two distinct analysis converged on decreased corticosubcortical iFC post-treatment which related to change in clinical measures. As decreases in striato-cortical iFC characterize typical development, results suggest regionally-specific enhanced maturational effects of OST

Background: The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SP) and neurofibrillary tangles (NFTs). Passive immunization with anti-Abeta antibodies is a promising therapeutic approach for AD with several on-going clinical trials; however, toxicity with amyloid related imaging abnormalities (ARIA) is problematic in many of these trails. This toxicity is in part related to the effector function of the antibodies used. Recently, an affibody molecule that lacks effector function, but binds to monomeric Abeta peptides, with aggregation inhibition capacity, was generated and tested in AD model transgenic fruit flies, demonstrating abolition of Abeta related neurotoxic effects and restoration of their life span. Here we assessed the efficacy of passive immunization with the affibody in a mouse model of AD. Methods: APP/ PS1 transgenic AD model mice were injected intraperitoneally twice a week with the Abeta-binding ZSYM73-ABD Affibody molecule from the age of 6 months (at a point where the mice already have amyloid deposition). Control mice received a non-Abeta binding affibody. Their behavior was assessed at 9 months of age and brain tissue subsequently was harvested for analysis of treatment efficacy. Results: The treated (Abeta-binding ZSYM73-ABD) mice didn't show a significant difference from controls on locomotor testing. ZSYM73- ABD treated-mice performed the same as wild-type mice. The amyloid burden of in treated animals was reduced by 49 % in the cortex and 50% in the hippocampus. There was no significant difference in astrogliosis or microhemorrhages between treated and control mice. Conclusions: These results indicate that passive immunization with an Affibody molecule can significantly decrease the amyloid burden and improve cognitive function in a transgenic mouse model of AD

Background: We have previously demonstrated that anti-beta-sheet conformational monoclonal antibodies (mAbs) recognize pathological oligomeric forms of Abeta and Tau in tissue samples of human Alzheimer's Disease (AD) brains and in AD mouse models (Goni et al 2015, Alzheimer & Dementia pp 845-6). We have now tested one of our mAbs in aged 3xTg AD animals with extensive preexisting Abeta and Tau related pathology with weekly injections of the TABP1 mAb. Methods: Two groups of 16 months old 3xTg AD animals were inoculated i.p. biweekly for three weeks and weekly thereafter for 5 weeks with either 100 mug of TABP1 in 100 muL of sterile saline or with 100 muL of vehicle alone. Radial Arm Maze behavioral analysis was performed after the treatment, followed by sacrifice and harvesting of the brains for immuno-histochemical and biochemical analyses. Results: No adverse reactions were demonstrated during the treatment. The TABP1 infused animals showed significant cognitive rescue compared to the controls. No significant differences were noted with the immunohistochemical quantitation of amyloid plaques or tau pathology; although there was a trend for reduced deposition in the infused animals. However, there was a significant decrease of the soluble and oligomeric Abeta (mainly Abeta1-42) and pathological Tau in the infused animals versus the controls. Conclusions: Anti-conformational monoclonal antibodies infused i.p. can ameliorate behavioral deficits in AD model mice. The mechanism is likely related to reductions of the levels of soluble oligomeric forms of Abeta and Tau; these species have been most closely linked to the cognitive deficits in AD patients. The results are encouraging for the further testing of humanized versions of these mAbs in clinical trials

Background/Purpose: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and European Union at 200 mg daily dose in combination with a xanthine oxidase inhibitor (XOI) for treatment of hyperuricemia associated with gout in patients unable to achieve target serum uric acid on XOI (allopurinol or febuxostat) alone. Approval of lesinurad was based on three pivotal, placebo-controlled, 12-month phase III (core) studies evaluating lesinurad 200 mg (LESU200) and 400 mg (LESU400) in combination with XOI. Patients completing core studies were eligible to enter extension studies, continuing LESU+XOI at the same dose or randomized from placebo to LESU200 or LESU400 plus XOI. Methods: Renal-related and kidney stone safety data were pooled from core studies to compare LESU200+XOI and LESU400+XOI with XOI alone and from core studies + extension studies to evaluate the impact on renal safety of extended LESU+XOI treatment. Renal-related treatment-emergent adverse events (TEAEs) were a customized list of 36 preferred terms selected from the Medical Dictionary for Regulatory Activities (MedRA) Renal and Urinary Disorders System Organ Class (SOC), the Investigations SOC and the Acute Renal Failure MedRA Standardized MedRA Query (SMQ). Descriptive statistics are provided for patients receiving >1 dose of study medication. To adjust for varying treatment duration, TEAEs are expressed as exposure-adjusted incidence rates (EAIRs; subjects with events per 100 person-years). Results: In the core studies, EAIRs for any renal-related TEAE, serious renal-related TEAEs, and renal-related TEAEs leading to discontinuation were similar with XOI alone and LESU200+XOI and lower than with LESU400 +XOI (Table 1). Similar results were found for kidney stone and serious kidney stone TEAEs. The most common renal-related TEAE was increased serum creatinine (sCr). EAIRs for sCr elevations >1.5x baseline were higher with LESU+XOI than XOI alone (Table 1). Overall, 75% and 84% of sCr elevations in the XOI alone and LESU+XOI groups, respectively, were resolved at last study assessment; 75% and 66% resolved without interruption of medication. Exposure to extended LESU+XOI treatment in core+extension studies did not show an increase from core studies in EAIRs for any renal-related or kidney stone adverse event category (Table 2). Conclusion: Lesinurad at the approved dose of 200 mg once-daily combined with XOI demonstrated comparable rate of adverse events to XOI alone. There was no clinically relevant increase in these adverse events with the extension of treatment beyond 1 year. (Table presented)

BACKGROUND: Methylphenidate and atomoxetine are commonly prescribed for treating attention deficit hyperactivity disorder (ADHD). However, their therapeutic neural mechanisms remain unclear. METHOD: After baseline evaluation including cognitive testing of the Cambridge Neuropsychological Test Automated Battery (CANTAB), drug-naive children with ADHD (n = 46), aged 7-17 years, were randomly assigned to a 12-week treatment with methylphenidate (n = 22) or atomoxetine (n = 24). Intrinsic brain activity, including the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo), was quantified via resting-state functional magnetic resonance imaging at baseline and week 12. RESULTS: Reductions in inattentive symptoms were related to increased fALFF in the left superior temporal gyrus and left inferior parietal lobule for ADHD children treated with methylphenidate, and in the left lingual gyrus and left inferior occipital gyrus for ADHD children treated with atomoxetine. Hyperactivity/impulsivity symptom reductions were differentially related to increased fALFF in the methylphenidate group and to decreased fALFF in the atomoxetine group in bilateral precentral and postcentral gyri. Prediction analyses in the atomoxetine group revealed negative correlations between pre-treatment CANTAB simple reaction time and fALFF change in the left lingual gyrus and left inferior occipital gyrus, and positive correlations between pre-treatment CANTAB simple movement time and fALFF change in bilateral precentral and postcentral gyri and left precuneus, with a negative correlation between movement time and the fALFF change in the left lingual gyrus and the inferior occipital gyrus. CONCLUSIONS: Our findings suggest differential neurophysiological mechanisms for the treatment effects of methylphenidate and atomoxetine in children with ADHD.

Many decisions involve uncertainty, or 'risk', regarding potential outcomes, and substantial empirical evidence has demonstrated that human aging is associated with diminished tolerance for risky rewards. Grey matter volume in a region of right posterior parietal cortex (rPPC) is predictive of preferences for risky rewards in young adults, with less grey matter volume indicating decreased tolerance for risk. That grey matter loss in parietal regions is a part of healthy aging suggests that diminished rPPC grey matter volume may have a role in modulating risk preferences in older adults. Here we report evidence for this hypothesis and show that age-related declines in rPPC grey matter volume better account for age-related changes in risk preferences than does age per se. These results provide a basis for understanding the neural mechanisms that mediate risky choice and a glimpse into the neurodevelopmental dynamics that impact decision-making in an aging population.

Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.

Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5-20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5-20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5-20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-alpha (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD.