Faculty Bibliography

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, the National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in 3 cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in 3 broad areas: (1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; (2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and (3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.

Hippocampal sharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memory consolidation and action planning. The duration of ripples shows a skewed distribution with a minority of long-duration events. We discovered that long-duration ripples are increased in situations demanding memory in rats. Prolongation of spontaneously occurring ripples by optogenetic stimulation, but not randomly induced ripples, increased memory during maze learning. The neuronal content of randomly induced ripples was similar to short-duration spontaneous ripples and contained little spatial information. The spike content of the optogenetically prolonged ripples was biased by the ongoing, naturally initiated neuronal sequences. Prolonged ripples recruited new neurons that represented either arm of the maze. Long-duration hippocampal SPW-Rs replaying large parts of planned routes are critical for memory.

The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clinical trials.

INTRODUCTION/BACKGROUND:Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA. METHODS:Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. RESULTS:A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). CONCLUSION/CONCLUSIONS:This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

STUDY OBJECTIVES/OBJECTIVE:To determine the effect of self-reported clinical diagnosis of Obstructive Sleep Apnea (OSA) on longitudinal changes in brain amyloid-PET and CSF-biomarkers (Aβ42, T-tau and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) elderly. METHODS:Longitudinal study with mean follow-up time of 2.52±0.51 years. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI and 325 AD elderly. Main Outcomes were annual rate-of-change in brain amyloid-burden (i.e. longitudinal increases in florbetapir-PET uptake or decreases in CSF-Aβ42 levels); and tau-protein aggregation (i.e. longitudinal increases in CSF total-tau (T-tau) and phosphorylated-tau (P-tau)). Adjusted multi-level mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate-of-biomarker-change differed between participants with and without OSA. RESULTS:In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B=.06, 95% CI .02, .11 and B=.08, 95% CI .05, .12 respectively) and decrease in CSF-Aβ42 levels (B=-2.71, 95% CI -3.11, -2.35 and B=-2.62, 95% CI -3.23, -2.03, respectively); as well as increases in CSF T-tau (B=3.68, 95% CI 3.31, 4.07 and B=2.21, 95% CI 1.58, 2.86, respectively) and P-tau (B=1.221, 95% CI, 1.02, 1.42 and, B=1.74, 95% CI 1.22, 2.27, respectively); compared to OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group. CONCLUSIONS:In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N-methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age-related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal-lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.-Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

During non-rapid eye movement (NREM) sleep, neuronal populations in the mammalian forebrain alternate between periods of spiking and inactivity. Termed the slow oscillation in the neocortex and sharp wave-ripples in the hippocampus, these alternations are often considered separately but are both crucial for NREM functions. By directly comparing experimental observations of naturally-sleeping rats with a mean field model of an adapting, recurrent neuronal population, we find that the neocortical alternations reflect a dynamical regime in which a stable active state is interrupted by transient inactive states (slow waves) while the hippocampal alternations reflect a stable inactive state interrupted by transient active states (sharp waves). We propose that during NREM sleep in the rodent, hippocampal and neocortical populations are excitable: each in a stable state from which internal fluctuations or external perturbation can evoke the stereotyped population events that mediate NREM functions.

In this issue, Wester et al. (2019) examine the obligate relationship between cortical interneurons and pyramidal neurons. By genetically converting superficial IT pyramidal cells into PT-like deep-layer pyramidal cells, they alter the position, connectivity, and gene expression within CGE-derived interneurons.

Delusions, a core symptom of psychosis, are false beliefs that are rigidly held with strong conviction despite contradictory evidence. Alterations in inferential processes have long been proposed to underlie delusional pathology, but previous attempts to show this have failed to yield compelling evidence for a specific relationship between inferential abnormalities and delusional severity in schizophrenia. Using a novel, incentivized information-sampling task (a modified version of the beads task), alongside well-characterized decision-making tasks, we sought a mechanistic understanding of delusions in a sample of medicated and unmedicated patients with schizophrenia who exhibited a wide range of delusion severity. In this novel task, participants chose whether to draw beads from one of two hidden jars or to guess the identity of the hidden jar, in order to minimize financial loss from a monetary endowment, and concurrently reported their probability estimates for the hidden jar. We found that patients with higher delusion severity exhibited increased information seeking (i.e. increased draws-to-decision behaviour). This increase was highly specific to delusion severity as compared to the severity of other psychotic symptoms, working-memory capacity, and other clinical and socio-demographic characteristics. Delusion-related increases in information seeking were present in unmedicated patients, indicating that they were unlikely due to antipsychotic medication. In addition, after adjusting for delusion severity, patients as a whole exhibited decreased information seeking relative to healthy individuals, a decrease that correlated with lower socioeconomic status. Computational analyses of reported probability estimates further showed that more delusional patients exhibited abnormal belief updating characterized by stronger reliance on prior beliefs formed early in the inferential process, a feature that correlated with increased information seeking in patients. Other decision-making parameters that could have theoretically explained the delusion effects, such as those related to subjective valuation, were uncorrelated with both delusional severity and information seeking among the patients. In turn, we found some preliminary evidence that subjective valuation (rather than belief updating) may explain group differences in information seeking unrelated to delusions. Together, these results suggest that abnormalities in belief updating, characterized by stronger reliance on prior beliefs formed by incorporating information presented earlier in the inferential process, may be a core computational mechanism of delusional ideation in psychosis. Our results thus provide direct empirical support for an inferential mechanism that naturally captures the characteristic rigidity associated with delusional beliefs.

Identify correlates of nicotine dependence [lifetime (l) and ongoing (o)] in adults with attention-deficit/hyperactivity disorder (ADHD) in childhood. We conducted a 33-year prospective follow-up of boys (mean age 8) with combined type ADHD (n = 135/207, 65% original sample). Correlates of nicotine dependence in adulthood were selected from characteristics obtained in childhood and adolescence. Among selected childhood features, only immature behavior was significantly related to nicotine dependence (OR(o) = 0.29, p = 0.02), indexing decreased risk. In contrast, several adolescent variables significantly correlated (p < 0.01) with nicotine dependence at mean age 41, including alcohol substance use disorder (SUD, OR(l) = 4.97), non-alcohol SUD (OR(o) = 4.33/OR(l) = 10.93), parental antisocial personality disorder (OR(l) = 4.42), parental SUD (OR(l) = 3.58), dropped out of school (OR(l) = 2.29), impulsivity (OR(o) = 1.53/OR(l) = 1.59), hyperactivity (OR(o) = 1.38), and number of antisocial behaviors (OR(o) = 1.10/OR(l) = 1.14). Results highlight the role of adolescent psychopathology in the development of nicotine dependence, motivating prospective longitudinal efforts to better define the developmental trajectories of risk and protection.