Using Genetic Diversity to Understand Susceptibility to Cognitive Decline in Aging and Alzheimer’s Disease

An individual\u27s genetic makeup plays an important role in determining susceptibility to cognitive aging and transition to dementia such as Alzheimer\u27s disease (AD). Identifying the specific genetic variants that contribute to cognitive aging and AD may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we turned to genetically diverse mice from the BXD genetic reference panel (GRP) to overcome some of the barriers traditionally associated with human studies. Using a forward genetics screen, we first identified and validated the gene heterochromatin protein l binding protein 3 (Hp1bp3) as a novel modulator of normal cognitive aging. We then demonstrated that targeted knockdown of Hp1bp3 in the hippocampus by 50-75% was sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and AD, namely an increase in inflammatory pathways and decrease in neuronal and synaptically-localized transcripts. We also show Hp1bp3 is a translationally relevant target, as transcriptional changes induced by our targeted knockdown significantly overlapped those observed in the aging human brain. In addition, HPlBP3 itself was decreased in the hippocampus of cognitively impaired aging humans. In summary, our results suggest therapeutics designed to target either Hp1bp3 or its downstream effectors may be useful promoting cognitive longevity. We next expanded on our findings that the BXDs were variably susceptible to cognitive aging and combined the BXD GRP with a well-established transgenic mouse model of AD harboring 5 familial AD mutations, the 5XFAD model. The resulting panel, which we termed the AD-BXDs, consists of genetically diverse yet isogenic Fl mice that all harbor the same high-risk human AD mutations but who differ across the remainder of their genome. We first showed that genetic variation profoundly modified the impact of human AD mutations on both cognitive and pathological phenotypes. We then validated this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD. Genetic mapping was used to identify novel genomic loci that modified susceptibility or resilience to cognitive and pathological symptoms of AD. Finally, we used transcriptome profiling to identify gene networks present in the pre-symptomatic mouse brain that predict cognitive performance at an advanced age. Together, the candidates identified through these analyses highlight new potential drivers of susceptibility or resilience to AD and contribute significantly to our understanding of early, potentially causal disease mechanisms. In summary, work here highlights the utility of genetically diverse mice to elucidate mechanisms underlying complex human disease, namely cognitive aging and AD. In addition, we developed a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD. Data presented here provides convincing evidence that preclinical models incorporating genetic diversity may better translate to human disease. Due to the reproducible nature of the BXDs and resulting AD-BXDs, this approach creates substantial opportunities to develop improved models of human aging and AD as well as develop a better understanding of precise mechanisms underlying disease. Together, these resources may ultimately enable precision medicine approaches across a diverse population. Finally, our experimental design is likely to be broadly applicable to mouse models of human disease that incorporate a dominantly inherited high-risk genotype in the form of a transgene or other genetic perturbation, enhancing the general utility of results reported here

Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging.

Identifying genetic factors that modify an individual\u27s susceptibility to cognitive decline in aging is critical to understanding biological processes involved and mitigating risk associated with a number of age-related disorders. Recently, heterochromatin protein 1 binding protein 3 (Hp1bp3) was identified as a mediator of cognitive aging. Here, we provide a mechanistic explanation for these findings and show that targeted knockdown of Hp1bp3 in the hippocampus by 50%-75% is sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and Alzheimer\u27s disease brains. Specifically, neuroinflammatory-related pathways become activated following Hp1bp3 knockdown in combination with a robust decrease in genes involved in synaptic activity and neuronal function. To test the hypothesis that Hp1bp3 mediates susceptibility to cognitive deficits via a role in neuronal excitability, we performed slice electrophysiology demonstrate transcriptional changes after Hp1bp3 knockdown manifest functionally as a reduction in hippocampal neuronal intrinsic excitability and synaptic plasticity. In addition, as Hp1bp3 is a known mediator of miRNA biogenesis, here we profile the miRNA transcriptome and identify mir-223 as a putative regulator of a portion of observed mRNA changes, particularly those that are inflammatory-related. In summary, work here identifies Hp1bp3 as a critical mediator of aging-related changes at the phenotypic, cellular, and molecular level and will help inform the development of therapeutics designed to target either Hp1bp3 or its downstream effectors in order to promote cognitive longevity

The mental health disaster in conflict settings: Can scientific research help?

Neuner F, Elbert T. The mental health disaster in conflict settings: Can scientific research help? BMC Public Health. 2007;7(1): 275

Daring to process the trauma: using a web-based training to reduce psychotherapists’ fears and reservations around implementing trauma-focused therapy

Sansen L, Saupe L, Steidl A, Fegert JM, Hoffmann U, Neuner F. Daring to process the trauma: using a web-based training to reduce psychotherapists’ fears and reservations around implementing trauma-focused therapy. European Journal of Psychotraumatology. 2019;10(1): 1696590.Although trauma-focused interventions are the first-line therapies for patients with posttraumatic stress disorder (PTSD), they are not frequently used in clinical practice. Factors preventing therapists from applying trauma-focused methods include a lack of training and negative attitudes towards trauma-focused therapy. The aim of the present study was to investigate which factors predict willingness to carry out trauma-focused therapy and to examine whether a web-based training is able to reduce negative attitudes and reservations about these interventions. In a wait-list controlled evaluation study, therapists (N = 499) were randomized into an intervention or a wait-list control group. Results show that trauma-treatment specific competencies and overcoming pre-existing concerns towards trauma-focused therapy significantly predict therapists’ willingness to utilize trauma-focused interventions. Thus, the content alignment of the web-based course is appropriate for improving therapists’ willingness to conduct trauma-focused therapy. A retrospective examination of therapists after the training and a comparison of fears and reservations before and after the training demonstrate a significant reduction of fears and reservations. In terms of perceived contraindications, no effects of the web-based training were found. The present study provides compelling evidence that web-based training in evidence-based PTSD therapy is able to reduce reservations that may prevent therapists from applying evidence-based trauma-focused interventions

Genetic background modifies CNS-mediated sensorimotor decline in the AD-BXD mouse model of genetic diversity in Alzheimer\u27s disease.

Many patients with Alzheimer\u27s dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual\u27s ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer\u27s disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and the relationship to cognitive decline in these mice. We found that age- and AD-related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD-BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging- and AD-related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD-related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease

Association of Current Opioid Use With Serious Adverse Events Among Older Adult Survivors of Breast Cancer

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Importance National efforts to improve safe opioid prescribing focus on preventing misuse, overdose, and opioid use disorder. This approach overlooks opportunities to better prevent other serious opioid-related harms in complex populations, such as older adult survivors of cancer. Little is known about the rates and risk factors for comprehensive opioid-related harms in this population. Objective To determine rates of multiple opioid-related adverse drug events among older adults who survived breast cancer and estimate the risk of these events associated with opioid use in the year after completing cancer treatment. Design, Setting, and Participants This retrospective cohort study used 2007 to 2016 Surveillance, Epidemiology and End Results-Medicare data from fee-for-service Medicare beneficiaries with first cancer diagnosis of stage 0 to III breast cancer at age 66 to 90 years from January 1, 2008, through December 31, 2015, who completed active breast cancer treatment. Data were analyzed from October 31, 2019, to June 10, 2020. Exposures Repeated daily measure indicating possession of any prescription opioid supply in Medicare Part D prescription claims. Main Outcomes and Measures Adjusted risk ratios (aRRs), estimated using modified Poisson generalized estimating equation models, for adverse drug events related to substance misuse (ie, diagnosed opioid abuse, dependence, or poisoning), other adverse drug events associated with opioid use (ie, gastrointestinal events, infections, falls and fractures, or cardiovascular events), and all-cause hospitalization associated with opioid supply the prior day, controlling for patient characteristics. Results Among 38 310 women included in the study (mean [SD] age, 74.3 [6.3] years), there were 0.010 (95% CI, 0.008-0.011) adverse drug events related to substance misuse per 1000 person-days, 0.237 (95% CI, 0.229-0.245) other adverse drug events associated with opioid use per 1000 person-days, and 0.675 (95% CI, 0.662-0.689) all-cause hospitalizations per 1000 person-days. Opioid use was associated with increased risk of adverse drug events related to substance misuse (aRR, 14.62; 95% CI, 9.69-22.05; P < .001), other adverse drug events related to opioid use (aRR, 2.50; 95% CI, 2.11-2.96; P < .001), and all-cause hospitalization (aRR, 2.77; 95% CI, 2.55-3.02; P < .001). In a dose-response effect, individuals with high daily opioid doses had consistently higher risks of all study outcomes compared with individuals who had low opioid doses. Compared with days with no opioid exposure, the risk of any adverse drug event related to substance misuse was 3.4-fold higher for individuals with a current opioid supply ≥50 mg morphine equivalent dose per day (aRR, 3.40; 95% CI, 2.47-4.68; P < .001), while the risk was 2.3-fold higher for individuals with 1 to 49 mg morphine equivalent dose per day (aRR, 2.29; 95% CI, 1.89-2.77; P < .001). Conclusions and Relevance These findings suggest that among older adults who survived breast cancer, continued prescription opioid use in the year after completing active cancer treatment was associated with an immediate increased risk of a broad range of serious adverse drug events related to substance misuse and other adverse drug events associated with opioid use. Clinicians should consider the comprehensive risks of managing cancer pain with long-term opioid therapy

Translational approaches to understanding resilience to Alzheimer\u27s disease.

Individuals who maintain cognitive function despite high levels of Alzheimer\u27s disease (AD)-associated pathology are said to be \u27resilient\u27 to AD. Identifying mechanisms underlying resilience represents an exciting therapeutic opportunity. Human studies have identified a number of molecular and genetic factors associated with resilience, but the complexity of these cohorts prohibits a complete understanding of which factors are causal or simply correlated with resilience. Genetically and phenotypically diverse mouse models of AD provide new and translationally relevant opportunities to identify and prioritize new resilience mechanisms for further cross-species investigation. This review will discuss insights into resilience gained from both human and animal studies and highlight future approaches that may help translate these insights into therapeutics designed to prevent or delay AD-related dementia

Protein spot arrays on graphene oxide coatings for efficient single-cell capture

Biomedical applications such as cell screening or cell–cell interaction studies require placement and adhesion of cells on surfaces with controlled numbers and location. In particular, single-cell arraying and positioning has come into focus as a basis of such applications. An ideal substrate would combine biocompatibility with favorable attributes such as pattern stability and easy processing. Here, we present a simple yet effective approach to single-cell arraying based on a graphene oxide (GO) surface carrying protein (fibronectin) microarrays to define cell adhesion points. These capture NIH-3T3 cells, resulting in cell arrays, which are benchmarked against analogous arrays on silanized glass samples. We reveal significant improvement in cell-capture performance by the GO coating with regards to overall cell adhesion and single-cell feature occupancy. This overall improvement of cell-arraying combined with retained transparency of substrate for microscopy and good biocompatibility makes this graphene-based approach attractive for single-cell experiments

Coulomb plasmas in outer envelopes of neutron stars

Outer envelopes of neutron stars consist mostly of fully ionized, strongly coupled Coulomb plasmas characterized by typical densities about 10^4-10^{11} g/cc and temperatures about 10^4-10^9 K. Many neutron stars possess magnetic fields about 10^{11}-10^{14} G. Here we briefly review recent theoretical advances which allow one to calculate thermodynamic functions and electron transport coefficients for such plasmas with an accuracy required for theoretical interpretation of observations.Comment: 4 pages, 2 figures, latex2e using cpp2e.cls (included). Proc. PNP-10 Workshop, Greifswald, Germany, 4-9 Sept. 2000. Accepted for publication in Contrib. Plasma Phys. 41 (2001) no. 2-

«Smarter Medicine»: 5 Interventionen, die in der ambulanten allgemeinen inneren Medizin vermieden werden sollten

Seit 2012 befasst sich die Schweizerische Gesellschaft für Allgemeine Innere Medizin mit der Problematik der Überdiagnostik und Überversorgung in der Medizin. Nun hat sie beschlossen, eine Liste mit fünf Untersuchungen auf dem Gebiet der ambulanten allgemeinen inneren Medizin zusammenzustellen, die ohne oder mit nur geringem Nutzen bei zahlreichen Patienten durchgeführt werden, gleichzeitig jedoch unerwünschte Nebenwirkungen haben können und zum Anstieg der Gesundheitskosten beitragen