Faculty Bibliography

Patients with complex chronic diseases usually must make multiple lifestyle changes to limit and manage their conditions. Numerous studies have shown that education alone is insufficient for engaging people in lifestyle behavior change, and that theory-based behavioral approaches also are necessary. However, even the most motivated individual may have difficulty with making lifestyle changes because of the information complexity associated with multiple behavior changes. The goal of the current Healthy Hearts and Kidneys study was to evaluate, different mobile health (mHealth)-delivered intervention approaches for engaging individuals with type 2 diabetes (T2D) and concurrent chronic kidney disease (CKD) in behavior changes. Participants were randomized to 1 of 4 groups, receiving: (1) a behavioral counseling, (2) technology-based self-monitoring to reduce information complexity, (3) combined behavioral counseling and technology-based self-monitoring, or (4) baseline advice. We will determine the impact of randomization assignment on weight loss success and 24-hour urinary excretion of sodium and phosphorus. With this report we describe the study design, methods, and approaches used to assure information security for this ongoing clinical trial. Clinical Trials.gov Identifier: NCT02276742.

OBJECTIVE:To test the hypothesis that localization-related epilepsy is associated with widespread neuronal dysfunction beyond the ictal focus, reflected by a decrease in patients' global concentration of their proton MR spectroscopy (1H-MRS) observed marker, N-acetyl-aspartate (NAA). METHODS:Thirteen patients with localization-related epilepsy (7 men, 6 women) 40±13 (mean±standard-deviation)years old, 8.3±13.4years of disease duration; and 14 matched controls, were scanned at 3 T with MRI and whole-brain (WB) 1H MRS. Intracranial fractions of brain volume, gray and white matter (fBV, fGM, fWM) were segmented from the MRI, and global absolute NAA creatine (Cr) and choline (Cho) concentrations were estimated from their WB 1H MRS. These metrics were compared between patients and controls using an unequal variance t test. RESULTS:Patients' fBV, fGM and fWM: 0.81±0.07, 0.47±0.04, 0.31±0.04 were not different from controls' 0.79±0.05, 0.48±0.04, 0.32±0.02; nor were their Cr and Cho concentrations: 7.1±1.1 and 1.3±0.2 millimolar (mM) versus 7.7±0.7 and 1.4±0.1mM (p>0.05 all). Patients' global NAA concentration: 11.5±1.5 mM, however, was 12% lower than controls' 13.0±0.8mM (p=0.004). CONCLUSIONS:These findings indicate that neuronal dysfunction in localization-related epilepsy extends globally, beyond the ictal zone, but without atrophy or spectroscopic evidence of other pathology. This suggests a diffuse decline in the neurons' health, rather than their number, early in the disease course. WB 1H-MRS assessment, therefore, may be a useful tool for quantification of global neuronal dysfunction load in epilepsy.

A fundamental problem in the field of obstructive sleep apnea (OSA) and memory is that it has historically minimized the basic neurobiology of sleep's role in memory. Memory formation has been classically divided into phases of encoding, processing/consolidation, and retrieval. An abundance of evidence suggests that sleep plays a critical role specifically in the processing/consolidation phase, but may do so differentially for memories that were encoded using particular brain circuits. In this review, we discuss some of the more established evidence for sleep's function in the processing of declarative, spatial navigational, emotional, and motor/procedural memories and more emerging evidence highlighting sleep's importance in higher order functions such as probabilistic learning, transitive inference, and category/gist learning. Furthermore, we discuss sleep's capacity for memory augmentation through targeted/cued memory reactivation. OSA - by virtue of its associated sleep fragmentation, intermittent hypoxia, and potential brain structural effects - is well positioned to specifically impact the processing/consolidation phase, but testing this possibility requires experimental paradigms in which memory encoding and retrieval are separated by a period of sleep with and without the presence of OSA. We argue that such paradigms should focus on the specific types of memory tasks for which sleep has been shown to have a significant effect. We discuss the small number of studies in which this has been done, in which OSA nearly uniformly negatively impacts offline memory processing. When periods of offline processing are minimal or absent and do not contain sleep, as is the case in the broad literature on OSA and memory, the effects of OSA on memory are far less consistent.

Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

Background: The apolipoprotein E (APOE) gene codes for the brain's primary cholesterol carrier protein. In both humans and humanized APOE mice the Alzheimer's disease-risk APOE 4 allele (APOE4) alters the number and size of neuronal endosomes, a pathology common to several neurodegenerative disorders, including Alzheimer's disease. Given that exosomes derive from the endosomal system, we investigated the impact of APOE4 on brain-derived exosomes. Methods: Extracellular vesicles (EV) were isolated from brain tissue of neuropathologically normal humans and of APOE targeted-replacement mice at 6, 12 and 18 months of age. Antibodies against TSG101 and ALIX were used to identify the exosome population within these samples. Protein, mRNA and lipid analyses were performed on both EV and whole-brain samples. Results: We found lower exosome levels in the brains of neuropathologically normal human APOE4 carriers compared to individuals homozygous for the risk-neutral 3 allele (APOE3). In APOE4 compared with APOE3 mice, brain exosome levels were lower in an age-dependent manner: lower levels were observed at 12 and 18 but not at 6 months of age. Protein and mRNA expressions of the exosome pathway regulators TSG101 and Rab35 were also lower in APOE4 compared with APOE3 mouse brains at 12 months of age, arguing for decreased exosome biosynthesis and secretion, respectively, from the endosomal pathway. Cholesterol and ganglioside levels were higher in brain exosomes isolated from 12-month-old APOE4 compared with APOE3 mice. Summary/Conclusion: Our findings show an APOE4-driven downregulation of brain exosome biosynthesis and release that is associated with altered lipid homeostasis. Failure to maintain proper functioning of the interdependent endosomal-exosomal pathways during aging, which is essential for diverse homeostatic and catabolic cellular processes, is likely to contribute to neuronal vulnerability in neurodegenerative disorders, including Alzheimer's disease

Oxytocin is a hypothalamic neuropeptide first recognized as a regulator of parturition and lactation which has recently gained attention for its ability to modulate social behaviors. In this chapter, we review several aspects of the oxytocinergic system, focusing on evidence for release of oxytocin and its receptor distribution in the cortex as the foundation for important networks that control social behavior. We examine the developmental timeline of the cortical oxytocin system as demonstrated by RNA, autoradiographic binding, and protein immunohistochemical studies, and describe how that might shape brain development and behavior. Many recent studies have implicated oxytocin in cognitive processes such as processing of sensory stimuli, social recognition, social memory, and fear. We review these studies and discuss the function of oxytocin in the young and adult cortex as a neuromodulator of central synaptic transmission and mediator of plasticity.

Cortical mechanisms that regulate acute or chronic pain remain poorly understood. The prefrontal cortex (PFC) exerts crucial control of sensory and affective behaviors. Recent studies show that activation of the projections from the PFC to the nucleus accumbens (NAc), an important pathway in the brain's reward circuitry, can produce inhibition of both sensory and affective components of pain. However, it is unclear whether this circuit is endogenously engaged in pain regulation. To answer this question, we disrupted this circuit using an optogenetic strategy. We expressed halorhodopsin in pyramidal neurons from the PFC, and then selectively inhibited the axonal projection from these neurons to neurons in the NAc core. Our results reveal that inhibition of the PFC or its projection to the NAc, heightens both sensory and affective symptoms of acute pain in naïve rats. Inhibition of this corticostriatal pathway also increased nociceptive sensitivity and the aversive response in a chronic neuropathic pain model. Finally, corticostriatal inhibition resulted in a similar aversive phenotype as chronic pain. These results strongly suggest that the projection from the PFC to the NAc plays an important role in endogenous pain regulation, and its impairment contributes to the pathology of chronic pain.

Vanishing white matter (VWM) disease is an autosomal genetic leukodystrophy caused by mutations in subunits of eukaryotic translation initiation factor 2B (eIF2B). The clinical symptoms exhibit progressive loss of white matter in both hemispheres of the brain, accompanied by motor functions deterioration, neurological deficits, and early death. To date there is no treatment for VWM disease. The aim of this work was to expedite rational development of a therapeutic opportunity. Our approach was to design a computer-aided strategy for an efficient and reliable screening of drug-like molecules; and to use primary cultures of fibroblasts isolated from the Eif2b5^R132H/R132H VWM mouse model for screening. The abnormal mitochondria content phenotype of the mutant cells was chosen as a read-out for a simple cell-based fluorescent assay to assess the effect of the tested compounds. We obtained a hit rate of 0.04% (20 hits out of 50,000 compounds from the selected library). All primary hits decreased mitochondria content and brought it closer to WT levels. Structural similarities between our primary hits and other compounds with known targets allowed the identification of three putative cellular pathways/targets: 11β-hydroxysteroid dehydrogenase type 1, Sonic hedgehog (Shh), and Sigma-1-Receptor (S1R). In addition to initial experimental indication of Shh pathway impairment in VWM mouse brains, the current study provides evidence that S1R is a relevant target for pharmaceutical intervention for potential treatment of the disease. Specifically, we found lower expression level of S1R protein in fibroblasts, astrocytes, and whole brains isolated from Eif2b5^R132H/R132H compared to WT mice, and confirmed that one of the hits is a direct binder of S1R, acting as agonist. Furthermore, we provide evidence that treatment of mutant mouse fibroblasts and astrocytes with various S1R agonists corrects the functional impairments of their mitochondria and prevents their need to increase their mitochondria content for compensation purposes. Moreover, S1R activation enhances the survival rate of mutant cells under ER stress conditions, bringing it to WT levels. This study marks S1R as a target for drug development toward treatment of VWM disease. Moreover, it further establishes the important connection between white matter well-being and S1R-mediated proper mitochondria/ER function.