The impact of the Alzheimer's Disease Neuroimaging Initiative 2: What role do public-private partnerships have in pushing the boundaries of clinical and basic science research on Alzheimer's disease?

In the growing landscape of biomedical public-private-partnerships, particularly for Alzheimer's disease, the question is posed as to their value. What impacts do public-private-partnerships have on clinical and basic science research in Alzheimer's disease? The authors answer the question using the Alzheimer's Disease Neuroimaging Initiative (ADNI) as a test case and example. ADNI is an exemplar of how public-private-partnerships can make an impact not only on clinical and basic science research and practice (including clinical trials), but also of how similar partnerships using ADNI as an example, can be designed to create a maximal impact within their fields.

Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex.

MicroRNAs (miRNAs) are critical regulators of nervous system function, and in vivo knockout studies have demonstrated that miRNAs are necessary for multiple aspects of neuronal development and survival. However, the role of miRNA biogenesis in the formation and function of synapses in the cerebral cortex is only minimally understood. Here, we have generated and characterized a mouse line with a conditional neuronal deletion of Dgcr8, a miRNA biogenesis protein predicted to process miRNAs exclusively. Loss of Dgcr8 in pyramidal neurons of the cortex results in a non-cell-autonomous reduction in parvalbumin interneurons in the prefrontal cortex, accompanied by a severe deficit in inhibitory synaptic transmission and a corresponding reduction of inhibitory synapses. Together, these results suggest a vital role for miRNAs in governing essential aspects of inhibitory transmission and interneuron development in the mammalian nervous system. These results may be relevant to human diseases such as schizophrenia, where both altered Dgcr8 levels as well as aberrant inhibitory transmission in the prefrontal cortex have been postulated to contribute to the pathophysiology of the disease.

Evaluating the role of statins in prevention of preeclampsia: deeper insights into maternal cardiometabolic changes.

Pregnant women with gestational hypertension and/or preeclampsia, have derangements of atherogenic lipids in early pregnancy. Changes in maternal lipids can promote atherogenesis through endothelial injury. These alterations in serum lipid levels have been linked to adverse pregnancy outcomes and maternal morbidity and mortality. Several recent studies have examined maternal atherogenic profiles in early pregnancy, and their relationships to preeclampsia and other adverse pregnancy outcomes. Given their effects on reduction of endothelial dysfunction, inflammation, and plaque stabilization, statin therapies may have utility in prevention and treatment of preeclampsia. We sought to investigate this further by examining the association between dyslipidemia and preeclampsia, as well as the potential role of statins in the prevention of preeclampsia. We discuss the pathophysiology of placental dysfunction in preeclampsia, the safety profile of statins in pregnancy, and evaluate the potential utility of statins in pregnancy, based on recent studies, specifically for women at high risk of developing preeclampsia. The lipid-lowering, immunomodulatory, anti-inflammatory, and pleiotropic effects of statins may make them promising candidates for the prevention and treatment of preeclampsia. However, it is important to note that the clinical use of statin therapy to prevent preeclampsia has no support from current research and is not justified. A reasonably large trial of pravastatin reported no effect on preeclampsia but used limited dosing with the intervention performed only in women at high-risk of term preeclampsia. Further research in randomized controlled trials extending the parameters of statin dosing is needed to help determine if preeclampsia can be effectively prevented.

Communication approaches to enhance patient motivation and adherence in cardiovascular disease prevention.

Preventive cardiology visits have traditionally focused on educating patients about disease risk factors and the need to avoid and manage them through lifestyle changes and medications. However, long-term patient adherence to the recommended interventions remains a key unmet need. In this review we discuss the rationale and potential benefits of a paradigm shift in the clinician-patient encounter, from focusing on education to explicitly discussing key drivers of individual motivation. This includes the emotional, psychological, and economic mindset that patients bring to their health decisions. Five communication approaches are proposed that progress clinician-patient preventive cardiology conversations, from provision of information to addressing values and priorities such as common health concerns, love for the family, desire of social recognition, financial stressors, and desire to receive personalized advice. Although further research is needed, these approaches may facilitate developing deeper, more effective bonds with patients, enhance adherence to recommendations and ultimately, improve cardiovascular outcomes.

Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia.

BACKGROUND: It is estimated that less than 10% of cases of familial hypercholesterolemia (FH) in the United States have been diagnosed. Low rates of diagnosis may in part be attributable to affected patients not meeting the clinical diagnostic criteria of the Dutch Lipid Clinic Network (DLCN), Simon Broome, or US MEDPED diagnostic criteria. OBJECTIVE: The objective of this study was to assess the utility of incorporating genetic testing into a patient's evaluation for FH. METHODS: We retrospectively reviewed patients seen in the Advanced Lipids Disorders Clinic at Johns Hopkins Hospital between January 2015 and May 2018. Between June 2018 and December 2018, patients were consented to a prospective registry. DLCN, Simon Broome, and MEDPED criteria were applied to each patient, before and after genetic testing. Genetic testing included sequencing and deletion duplication analysis of four genes (LDLR, PCSK9, APOB, and LDLRAP1). RESULTS: The retrospective review and prospective study identified 135 adult probands who were seen in our clinic for evaluation of heterozygous FH. Twenty-nine individuals (21%) were heterozygous for a pathogenic or likely pathogenic monogenic variant. Before genetic testing, using the DLCN criteria, 35 (26%) individuals met criteria for a definite diagnosis of FH. Thirty patients (22%) met criteria using Simon Broome, and 29 (21%) patients met criteria using US MEDPED before genetic analysis. Depending on the criteria, incorporating genetic testing identified 11-14 additional patients with FH. CONCLUSIONS: Incorporating genetic testing diagnosed almost 50% more patients with definite FH in comparison to classification solely on clinical grounds.

Deaths from heart failure and cancer: location trends.

BACKGROUND: Increasing utilisation of hospice services has been a major focus in oncology, while only recently have cardiologists realised the similar needs of dying patients with heart failure (HF). We examined recent trends in locations of deaths in these two patient populations to gain further insight. METHODS: Complete population-level data were obtained from the Mortality Multiple Cause-of-Death Public Use Record from the National Center for Health Statistics database, from 2013 to 2017. Location of death was categorised as hospital, home, hospice facility or nursing facility. Demographic characteristics evaluated by place of death included age, sex, race, ethnicity, marital status and education, and a multivariable logistic regression analysis was performed to analyse possible associations. RESULTS: Among 2 780 715 deaths from cancer, 27% occurred in-hospital and 14% in nursing facilities; while among 335 350 HF deaths, 27% occurred in-hospital and 30% in nursing facilities. Deaths occurred at hospice facilities in 14% of patients with cancer, compared with just 8.7% in HF (p=0.001). For both patients with HF and cancer, the proportion of at-home and in-hospice deaths increased significantly over time, with majority of deaths occurring at home. In both cancer and HF, patients of non-Hispanic ethnicity (cancer: OR 1.29, (1.27 to 1.31), HF: OR 1.14, (1.07 to 1.22)) and those with some college education (cancer: OR 1.10, (1.09 to 1.11); HF: OR 1.06, (1.04 to 1.09)) were significantly more likely to die in hospice. CONCLUSION: Deaths in hospital or nursing facilities still account for nearly half of cancer or HF deaths. Although positive trends were seen with utilisation of hospice facilities in both groups, usage remains low and much remains to be achieved in both patient populations.

A Clinician's Guide to Healthy Eating for Cardiovascular Disease Prevention.

Despite continued advances in health care, the cardiovascular disease (CVD) mortality rate has plateaued in recent years and appears to be trending upward. Poor diet is a leading cause of obesity and type 2 diabetes mellitus, which are leading contributors to CVD morbidity and mortality. Although dietary modification is a cornerstone of CVD prevention, implementation in clinical practice is limited by inadequate formal training in nutrition science. In this report, we review the individual components of a heart-healthy diet, evidence-based dietary recommendations, and the impact of diet on CVD risk factor prevention and management. Furthermore, we examine the unique difficulties of dietary counseling in low-socioeconomic-status environments and provide an evidence-based approach to better serve these populations. We utilized PubMed searches in adults with no date restriction with the following search terms: "carbohydrate," "fat," protein," "DASH," "Mediterranean," "plant-based," "vegetarian," "cardiovascular disease," "obesity," "weight loss," "diabetes," "socioeconomic status," and "race." In this review, we demonstrate that patients should focus on implementing a general diet plan that is high in fruits, whole grains, legumes, and nonstarchy vegetables while low in trans-fats, saturated fats, sodium, red meat, refined carbohydrates, and sugar-sweetened beverages. The Dietary Approaches to Stop Hypertension, Mediterranean, and vegetarian diets have the most evidence for CVD prevention. Clinicians should understand the barriers that patients may face in terms of access to healthy dietary choices. Further research is needed to determine the dietary changes that are most economically, socioculturally, and logistically feasible to reduce these barriers. Improvement in diet is a public health priority that can lead to a significant population-level reduction in CVD morbidity and mortality. It is imperative that clinicians understand current dietary practice guidelines and implement evidence-based dietary counseling in those at high risk for CVD.

Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain.

Embryonic medial ganglionic eminence (MGE) cells transplanted into the adult brain can disperse, migrate, and differentiate to neurons expressing GABA, the primary inhibitory neurotransmitter. It has been hypothesized that grafted MGE precursors could have important therapeutic applications increasing local inhibition, but there is no evidence that MGE cells can modify neural circuits when grafted into the postnatal brain. Here we demonstrate that MGE cells grafted into one location of the neonatal rodent brain migrate widely into cortex. Grafted MGE-derived cells differentiate into mature cortical interneurons; the majority of these new interneurons express GABA. Based on their morphology and expression of somatostatin, neuropeptide Y, parvalbumin, or calretinin, we infer that graft-derived cells integrate into local circuits and function as GABA-producing inhibitory cells. Whole-cell current-clamp recordings obtained from MGE-derived cells indicate firing properties typical of mature interneurons. Moreover, patch-clamp recordings of IPSCs on pyramidal neurons in the host brain, 30 and 60 d after transplantation, indicated a significant increase in GABA-mediated synaptic inhibition in regions containing transplanted MGE cells. In contrast, synaptic excitation is not altered in the host brain. Grafted MGE cells, therefore, can be used to modify neural circuits and selectively increase local inhibition. These findings could have important implications for reparative cell therapies for brain disorders.

Structural determinants of benzodiazepine allosteric regulation of GABA(A) receptor currents.

Benzodiazepine enhancement of GABA(A) receptor current requires a gamma subunit, and replacement of the gamma subunit by the delta subunit abolishes benzodiazepine enhancement. Although it has been demonstrated that benzodiazepines bind to GABA(A) receptors at the junction between alpha and gamma subunits, the structural basis for the coupling of benzodiazepine binding to allosteric enhancement of the GABA(A) receptor current is unclear. To determine the structural basis for this coupling, the present study used a chimera strategy, using gamma2L-delta GABA(A) receptor subunit chimeras coexpressed with alpha1 and beta3 subunits in human embryonic kidney 293T cells. Different domains of the gamma2L subunit were replaced by delta subunit sequence, and diazepam sensitivity was determined. Chimeric subunits revealed two areas of interest: domain 1 in transmembrane domain 1 (M1) and domain 2 in the C-terminal portion of transmembrane domain 2 (M2) and the M2-M3 extracellular loop. In those domains, site-directed mutagenesis demonstrated that the following two groups of residues were involved in benzodiazepine transduction of current enhancement: residues Y235, F236, T237 in M1; and S280, T281, I282 in M2 as well as the entire M2-M3 loop. These results suggest that a pocket of residues may transduce benzodiazepine binding to increased gating. Benzodiazepine transduction involves a group of residues that connects the N terminus and M1, and another group of residues that may facilitate an interaction between the N terminus and the M2 and M2-M3 loop domains.

GABA(A) receptor function and pharmacology in epilepsy and status epilepticus.

GABA(A) (gamma-n-aminobutyric acid) receptor dysfunction has long been implicated in the development of epilepsy and status epilepticus. Recent advances have been made in understanding the cellular, pharmacological and genetic involvement of GABA(A) receptors in seizure disorders. In particular, genetic mutations found in GABA(A) receptor subunits strongly implicate the GABA(A) receptor in idiopathic generalised epilepsies.

Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T⁺ tf/J mouse model of autism.

BACKGROUND: Autism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T⁺ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders. METHODS: We generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes. RESULTS: Six QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4. CONCLUSIONS: We identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.

Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission.

GABA synthesis is necessary to maintain synaptic vesicle filling, and key proteins in its biosynthetic pathways may play a role in regulating inhibitory synaptic stability and strength. GABAergic neurons require a source of precursor glutamate, possibly from glutamine, although it is controversial whether glutamine contributes to the synaptic pool of GABA. Here we report that inhibition of System A glutamine transporters with alpha-(methyl-amino) isobutyric acid rapidly reduced the amplitude of inhibitory post-synaptic currents and miniature inhibitory post-synaptic currents (mIPSCs) recorded in rat hippocampal area cornu ammonis 1 (CA1) pyramidal neurons, indicating that synaptic vesicle content of GABA was reduced. After inhibiting astrocytic glutamine synthesis by either blocking glutamate transporters or the glutamine synthetic enzyme, the effect of alpha-(methyl-amino) isobutyric acid on mIPSC amplitudes was abolished. Exogenous glutamine did not affect mIPSC amplitudes, suggesting that the neuronal transporters are normally saturated. Our findings demonstrate that a constitutive supply of glutamine is provided by astrocytes to inhibitory neurons to maintain vesicle filling. Therefore, glutamine transporters, like those for glutamate, are potential regulators of inhibitory synaptic strength. However, in contrast to glutamate, extracellular glutamine levels are normally high. Therefore, we propose a supportive role for glutamine, even under resting conditions, to maintain GABA vesicle filling.