Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study

An adverse outcome pathway (AOP) is a sequence of key events from a molecular-level initiating event and an ensuing cascade of steps to an adverse outcome with population-level significance. To implement a predictive strategy for ecotoxicology, the multiscale nature of an AOP requires computational models to link salient processes (e.g., in chemical uptake, toxicokinetics, toxicodynamics, and population dynamics). A case study with domoic acid was used to demonstrate strategies and enable generic recommendations for developing computational models in an effort to move toward a toxicity testing paradigm focused on toxicity pathway perturbations applicable to ecological risk assessment. Domoic acid, an algal toxin with adverse effects on both wildlife and humans, is a potent agonist for kainate receptors (ionotropic glutamate receptors whose activation leads to the influx of Na + and Ca 2+ ). Increased Ca 2+ concentrations result in neuronal excitotoxicity and cell death, primarily in the hippocampus, which produces seizures, impairs learning and memory, and alters behavior in some species. Altered neuronal Ca 2+ is a key process in domoic acid toxicity, which can be evaluated in vitro. Furthermore, results of these assays would be amenable to mechanistic modeling for identifying domoic acid concentrations and Ca 2+ perturbations that are normal, adaptive, or clearly toxic. In vitro assays with outputs amenable to measurement in exposed populations can link in vitro to in vivo conditions, and toxicokinetic information will aid in linking in vitro results to the individual organism. Development of an AOP required an iterative process with three important outcomes: a critically reviewed, stressor-specific AOP; identification of key processes suitable for evaluation with in vitro assays; and strategies for model development. Environ. Toxicol. Chem. 2011;30:9–21. © 2010 SETACPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78481/1/373_ftp.pd

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Botulinumtoxin bei nichtneurogenen Blasenfunktionsstörungen

Die nichtneurogene überaktive Harnblase mit oder ohne Detrusorüberaktivität und/oder Inkontinenz ist ein belastendes Symptom für viele Menschen, das bis vor wenigen Jahren nur mit anticholinergen Medikamenten oder operativ behandelt werden konnte. Intradetrusorinjektionen mit Botulinumtoxin Typ A stellen eine minimal-invasive Alternative für Patienten dar, die auf Anticholinergika nicht ansprechen oder diese nicht vertragen. Dieser Übersichtsartikel fasst die relevanten Arbeiten der letzten 6 Jahre zu diesem Thema zusammen und gibt Auskunft über die Wirksamkeit, die Nebenwirkungen, die verwendeten Dosierungen und Injektionstechniken. Insgesamt zeigte sich eine gute initiale Wirksamkeit, die etwa ab dem 4. Tag nach Injektion beginnt und durchschnittlich bis zu 31 Wochen anhalten kann. Es ist allerdings je nach Dosis mit einer Erhöhung der Restharnmengen zu rechnen, die auch die Anwendung von intermittierendem Selbstkatheterismus notwendig machen können. Die Anwendung von Botulinumtoxin in der Harnblase ist noch immer keine offiziell zugelassene Therapie. = Nonneurogenic overactive bladder with or without detrusor overactivity and/or incontinence is a bothersome symptom for many people. Until a few years ago, it could be treated only with anticholinergic drugs or invasive surgery. Intradetrusor injection with botulinum toxin type A is a minimally invasive alternative therapy option for patients who do not respond to or tolerate anticholinergic treatment. This literature overview summarises the relevant articles on this topic over the last 6 years and provides information on the efficacy, adverse events, currently used dosages, and injection techniques. Overall, a favourable initial efficacy has been observed starting around day 4 after injection and can last up to approximately 31 weeks. Depending on the dose, however, elevated postvoid residual volumes should be anticipated and might require clean intermittent self-catheterisation. The use of botulinum toxin in the urinary bladder is still considered off-label

Perceptions of Brain donation and Medical Research Among African American Individuals: Implications for Recruitment and Retention into Alzheimer’s Research

Abstract Background African Americans (AAs) are twice as likely to have Alzheimer’s disease (AD) as their White counterparts; yet, this population is largely missing from brain donation research. According to the National Alzheimer’s Coordinating Center, merely 2% of brain donations are obtained from AAs. Medical mistrust among AAs has been well‐documented as a barrier to medical research participation. The purpose of this study was to expand our understanding of AA perceptions of medical research and brain donation. Method Using validated survey items, a 35‐item cross‐sectional survey was developed to understand attitudes and beliefs about medical research and brain donation among AAs. Surveys were administered via REDCap (Research Electronic Data Capture) and paper in Florida, New York, North Carolina and Ohio, United States from November 2021 to September 2022. Descriptive analysis of data on research participation and trust in medical research was conducted using SAS® software version 9.4. Result A total of 227 AAs participated in this study with about three‐quarters of participants being female. Approximately 90% of AAs reported being born in the US, and nearly half of the sample reported receiving some college education or higher. Only 10.6% of participants reported being very likely to donate their brain to research after death. Despite the low percentage of AAs willing to donate their brain to research, 77.1% had a positive view of medical research and 72.7% trusted researchers in general. In fact, participants perceived that it is “very important” to participate in medical research to help future generations (78.4%), to learn more about AD (66.5%), and receive medical information (56.8%). Conclusion Most AAs in this study reported strong trust in medical research and researchers. Medical mistrust may not be a significant barrier to participation in brain donation or AD research for AAs in this sample. Improved health literacy in AD research and brain donation procedures may facilitate engagement of AAs to participate in such research. Findings from this study will be used to inform the development of a culturally relevant health literacy program, with a focus on brain donation and AD research, to enhance opportunities for recruitment and retention of AAs

Outreach and recruitment of African Americans for Alzheimer’s disease studies during the COVID‐19 pandemic

Background Recruiting African Americans in AD studies remains a challenge, particularly during a pandemic, where major health disparities in this population are illuminated. The recruitment literature suggests myriad factors that contribute to the underrepresentation of AAs, including, but not limited to “mistrust” in researchers and their institutions. Maintaining a continuous presence in the AA community builds trust even when traditional outreach methods are not allowed. We continued to provide outreach and recruitment opportunities through COVID education and food for families as we educated them about AD, and opportunities for study participation. Method While our traditional outreach methods for recruiting AAs were interrupted, we continued to conduct AD outreach using virtual platforms, mobile phone calls, family conference calls and food distributions. We hosted nine webinars on COVID‐19 to maintain a presence in local and national AA communities and to remain connected to existing AD participants. We reached over 160,000 persons through webinars and social media. We established new relationship new faith leaders in the AA community who co‐hosted COVID‐19 webinars and also expressed interest in forming partnerships on AD education. In addition, we hosted food drives in AA communities that not only addressed food insecurity and COVID prevention, but also AD education and AD research opportunities. At the food drives we distributed bags with masks, hand sanitizers, AD brochures, booklets and study participation information. Result Between October and December of 2020, 64 AAs who attended food drives expressed interest in AD studies that required blood draws and cognitive testing. Fifteen enrolled in our genetic study, 15 requested additional follow‐up and 13 expressed interest in participating in more than one study. Conclusion Prior research suggests that recruiting AAs into AD studies requires continuous engagement. We used multiple strategies to maintain contact with the AA community and existing research participants, and successfully increased enrollment in the last quarter of the year. Maintaining consistent and continuous engagement facilitates trustworthiness with AAs and yields positive recruitment outcomes, even in a pandemic where traditional recruitment methods are limited