6
Needs, Opportunities, and Next Steps

Sex differences in neurological disorders have been observed in disease susceptibility, disease incidence, time to onset of symptoms, manifestation of illness, prognosis, and drug response, including pharmacokinetics, phamacodynamics, efficacy, adverse events, and treatment outcomes. The differences may be a result of sex hormone activation of genes and circuits, developmental pathways, sex chromosome effects, or a combination of these factors. Breakthroughs in molecular biology and noninvasive brain imaging have redefined the goals and promise of neuroscience research, and knowledge about sex differences must now be incorporated into basic and translational research strategies.

Over the course of the workshop, participants provided numerous examples of when and how researchers are studying these differences across the spectrum of neurological diseases. We now know that some tissues have huge sex differences in gene expression. The challenge is how to utilize our current knowledge to inform the practice of the variety of stakeholders involved in central nervous system (CNS) drug development enterprises (e.g., preclinical researchers, funding agencies, Food and Drug Administration [FDA], journals, industry, patient advocacy groups).

In the keynote address, Morgan Sheng highlighted the challenge of determining when limited resources should be invested in studying sex differences. For some diseases, investments in basic science research of nervous system disorders may be more appropriate even if there are known sex differences.

In the closing session, Workshop Chairs Stevin Zorn and Rae Silver reviewed the barriers impeding sex differences research that were identified



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6 Needs, Opportunities, and Next Steps Sex differences in neurological disorders have been observed in disease susceptibility, disease incidence, time to onset of symptoms, manifesta- tion of illness, prognosis, and drug response, including pharmacokinetics, phamacodynamics, efficacy, adverse events, and treatment outcomes. The differences may be a result of sex hormone activation of genes and circuits, developmental pathways, sex chromosome effects, or a combination of these factors. Breakthroughs in molecular biology and noninvasive brain imaging have redefined the goals and promise of neuroscience research, and knowledge about sex differences must now be incorporated into basic and translational research strategies. Over the course of the workshop, participants provided numerous ex- amples of when and how researchers are studying these differences across the spectrum of neurological diseases. We now know that some tissues have huge sex differences in gene expression. The challenge is how to utilize our current knowledge to inform the practice of the variety of stakeholders in- volved in central nervous system (CNS) drug development enterprises (e.g., preclinical researchers, funding agencies, Food and Drug Administration [FDA], journals, industry, patient advocacy groups). In the keynote address, Morgan Sheng highlighted the challenge of determining when limited resources should be invested in studying sex differences. For some diseases, investments in basic science research of nervous system disorders may be more appropriate even if there are known sex differences. In the closing session, Workshop Chairs Stevin Zorn and Rae Silver reviewed the barriers impeding sex differences research that were identified 

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 SEX DIFFERENCES AND IMPLICATIONS during the panel discussions. They challenged participants to identify the next steps necessary to overcome these challenges, other factors that could ease the successful translation of sex differences from preclinical to clinical studies, and additional priority areas for research. Much of the workshop discussion focused on females because they often bear the greater burden across many parameters in the neurological disorders discussed. However, sex difference research offers the opportunity to determine why one sex may be more predisposed to certain diseases, or have worse outcomes, while the other sex is protected. Therefore, the results from sex differences research will have a significant impact on the public health of both sexes. BARRIERS Over the course of the workshop, a variety of barriers to conducting more appropriate, extensive, or prioritized sex-based research in diseases of the nervous system were identified (Box 6-1). Participants broadly acknowl- edged that sex differences are important in neurological disorders, but that current knowledge of underlying biology is insufficient, both in health and disease. Participants were very concerned that almost no attention is paid to the importance of personalized medicine (age, race, ethnicity, sex, genetics) in health science education curriculums. Participants identified a lack of expertise by study section reviewers in recognizing the importance of sex differences research in funding ap- plications. Another difficulty is that no study section or special emphasis panel exists that specifically funds research on sex differences. For example, locating funding to develop a mouse model for estrogen receptor action in the brain would be difficult. The study of sex differences transcends tis- sues, diseases, and the Institutes at the National Institutes of Health (NIH). The traditional way that the NIH has been organized does not allow for a concentrated interest in sex differences; they must be studied in the context of something else. The absence of animal models of human neurological conditions was also highlighted by participants as a barrier, as was the fact that many stud- ies predominantly use male animals. The absence of reliable animal models is a tremendous barrier to CNS drug development. As animal models are developed, strategies will need to be established that take into account potential sex differences. Dissemination of information on sex differences was also a topic of interest. Even when studies include male and female animals, results are often not reported by sex. Journals generally have no standard policy about including information on the sex of subjects studied or cell lines used, or the

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 NEEDS, OPPORTuNITIES, AND NEXT STEPS BOX 6-1 Barriers to Sex-Based Research in Diseases of the Nervous System • General lack of recognition of the importance of sex differences in health and disease. • Lack of implementation of policies by large influential organizations, such as neuroscience professional societies, to require attention to sex differences. • Inadequate focus on sex differences in graduate and medical education curriculums. • Financial, resource, and time constraints associated with studying both sexes. • Lack of expertise in sex differences in study sections and program review staff. • Difficulty of securing funding to study sex differences in general (as grants generally fund studies only in the context of a particular disease). • Limitations of animal models of nervous system disorders. • Basic studies are largely conducted in male animals; concerns and confusion about variability in female animals due to estrous cycles. • Institutional review boards face an ethical dilemma in approving the conduct of studies in humans in which the researchers do not have a strong basis in animal or preclinical work. • Clinical studies may include both male and female participants, but are often not designed to allow for analysis of sex differences. • Sex-specific data are often not reported in the medical literature, especially if no difference was observed. • Difficulty of engaging commercial sponsors in investing in late-phase develop- ment to repurpose drugs that are already available generically (e.g., estriol). reporting and analyzing of data by sex. Private-sector sharing of preclinical data was also discussed. Industry participants pointed out that little animal research done in industry goes unpublished. In some cases, however, the information may not published until compounds involved are patented. Some participants acknowledged that communication between basic and clinical researchers is lacking, and facilitating collaborations among the NIH, the FDA, and industry can be a challenge. They also pointed out that workshops, studies, and reports over the past 30 years have drawn attention to the need to address sex differences in health, but few recom- mendations have been implemented. Contributing to this general disregard for sex differences is the fact the large and influential bodies, such as neuroscience professional societies and journal publishers, have acknowledged sex differences, but have not implemented policies that require researchers to address them.

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 SEX DIFFERENCES AND IMPLICATIONS ADDITIONAL PRIORITy AREAS FOR SEx DIFFERENCES RESEARCH Four specific neurological disease areas were reviewed during the work- shop, including depression, pain and pain perception, sleep medicine, and multiple sclerosis and neuroinflammation. Other conditions were raised as examples during the discussions. At Zorn’s request, participants offered additional suggestions of priority areas for sex differences research. Researchers should be looking for possible sex differences during the time in life at which vulnerability to adult problems arise, a participant said. For example, studies suggest that vulnerability to depression and drug abuse in adults may be associated with prenatal stress in males, but early childhood stress in females. Differences in when early stressors produce vulnerabilities may also impact cardiovascular disease and pain. Multiple- syndrome liability and the times during the lifespan when these vulner- abilities are established may be a worthwhile commitment of resources and effort in studying sex differences. Stuttering was suggested as another example of a dramatic sex differ- ence in which there is also a differential sex recovery. Stuttering occurs in 1 percent of the general population, with a 4–5:1 male-to-female ratio. Interestingly, at the onset of symptom occurrence in early childhood, the sex ratio is closer to 2:1, female to male, but there is a differential recovery among females. Many more girls recover within years of stuttering onset, leaving many more boys who stutter by adolescence and adulthood. Re- search in this area is still in the early stages, but preliminary data show exaggerated deficits in structural and functional connectivity among left hemisphere speech-related regions of the brain in persistently stuttering females compared to persistent males. One function that is clearly sexually differentiated is reproduction, a participant pointed out. Yet there is still little understanding of the brain mechanisms associated with reproduction, especially at the cellular and molecular levels. This would seem to be an obvious priority when looking at cellular mechanisms of sexually differentiated function. NExT STEPS In introducing the workshop, Silver said the mission was to “look back- ward at what we already know and race forward to do something about it.” Over the course of the workshop, participants discussed practical next steps that could be taken to facilitate a better understanding of sex differences in neurological health and disease, and translation of that knowledge into effective treatments for both sexes (summarized in Box 6-2). Those who fund, regulate, perform, or report research all have important roles to play,

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 NEEDS, OPPORTuNITIES, AND NEXT STEPS BOX 6-2 Possible Next Steps Recommended by Individual Workshop Participants Government Funders • Fund basic and clinical integrative, interdisciplinary research to establish the scientific basis for sex differences in health and neurological disease, build predictive and translatable models of human neurological disease and identify potential biomarkers. • Establish mechanisms to fund sex difference (i.e., not necessarily in the con- text of a specific disease). • Set standards for reporting of sex-related clinical data. Regulators • Require that studies be sufficiently designed to allow for analysis by sex. Industry • Establish precompetitive, public–private partnerships with academia and gov- ernment to understand the biological basis for sex differences as they relate to disorders of the nervous system. • Apply this knowledge to generate hypothesis testing studies, with the goal of es- tablishing evidence-based therapeutic approaches for personalized medicine. Academia • Incorporate information about sex differences into the curriculums of graduate and medical education programs to raise awareness of the pervasiveness of sex differences, highlight the opportunities for medical advances related to them. • Design clinical trials around evidentiary needs. • Develop action steps and set disease priorities for mining of existing data sets for sex differences. • Conduct studies or mine existing data to answer questions regarding female variability due to estrous cycle. Journal Publishers • Develop and institute guidelines for the inclusion of sex-related subject infor- mation in all publications, including sex of origin of tissues, cell lines, etc. • Establish guidelines to encourage authors to analyze data by sex and to report sex differences, or the lack thereof: requiring reporting of means and standard deviations by sex would help facilitate systematic reviews. • Develop checklists for authors and reviewers to consult when preparing and reviewing manuscripts to ensure inclusion of sex-related information.

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 SEX DIFFERENCES AND IMPLICATIONS from the bench to the bedside, in acquiring and applying knowledge about sex differences in neurological disorders. Facilitating Sex Differences Research: Funding and Collaboration Many workshop participants recognized that mandating research on sex differences was not appropriate. But rather, and especially given the limited resources, beginning to establish a comprehensive plan is important. The plan should review available data sources and develop a process to prioritize sex differences research. Existing databases provide a rich source of available data that could be analyzed. Analysis of available databases and development of new databases for analysis of materials that have been overlooked could serve as a valuable starting point. A variety of funding models were suggested, from government grants specifically for the study of sex differences to public–private partnerships. One opportunity that resonated with the workshop participants was the need to establish multisector partnerships that can share risk and stimulate research and development for CNS drugs, a participant said. An example is the Alzheimer’s Disease Neuroimaging Initiative, a $60 million, multisec- tor, public–private partnership among the NIH, the FDA, and 12 industry and other partners. They are conducting longitudinal studies at sites across the United States to attempt to map the cause of Alzheimer’s disease and identify biomarkers that could be used in clinical trials. No single company, university, or NIH Institute could fund a study this large, but in partnership it is possible, and high-quality data are already emerging. With regard to government funding through grant programs, efforts should be made to increase the expertise of reviewers on study sections so they recognize the importance of sex differences. Another suggestion by some workshop participants was to issue Requests for Applications for general neuroscience research, outside the context of a particular disease, where a significant sex difference has been identified. Within the NIH the “Blueprint for Neuroscience Research” is a cooperative effort across NIH Institutes and Centers that supports neuroscience research and is aimed at pooling resources and expertise to advance basic and clinical research. Another approach to studying sex differences would be as an initiative of the NIH Roadmap. Education Some participants stressed the need to incorporate the importance of sex differences into health science education curriculums at all levels. In the developing age of personalized medicine, graduate and medical students should be learning about the impacts of not just sex, but also age, race,

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 NEEDS, OPPORTuNITIES, AND NEXT STEPS ethnicity, and genetics. Not enough is known about sex differences in health and disease, or how to apply what is known to healthcare practice. Building this area of study into the core medical education curriculum will better prepare the next generation of scientists and clinicians to advance under- standing of sex differences and better translate that knowledge to improve patient lives. These scientists would then be better equipped to consider sex differences if they serve on study sections. With regard to raising general awareness of sex differences, a partici- pant suggested mining the power of the Internet. Websites such as Google and Wikipedia are very popular, yet information on sex differences is lacking on these sites. These public information venues present another opportunity to increase understanding of sex differences as they relate to health care. Disseminating Information About Sex Differences: The Roles of Journal Publishers and Professional Societies Suggestions for how journals could foster dissemination of data on sex differences included developing checklists for authors and reviewers to consult when preparing and reviewing manuscripts, and requiring authors to state the potential implications of studying only one sex. A participant suggested that manuscripts that include both sexes should be required to report means and standard deviations by sex because this would facilitate systematic reviews. Authors often simply report that there were, for example, five males and five females and no statistically significant was difference observed, and do not include numerical data. But there may be a direction or a trend that could be found if the data could be included in a meta-analysis. Sex Is Always There, So Always Look at Sex Sex differences can be studied in multiple, one participant said. Studies of sex differences that are hypothesis driven should be sufficiently powered to test the hypothesis and analyze the results by sex. But in studies in which a sex-based hypothesis is not being tested, researchers should be encour- aged to explore sex differences in whatever phenomenon they are studying, even though it might not be sufficiently powered, and convey those results in publications.

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