New Perspectives In Translational Neuroscience Of Late Life Mental Disorders
The Geriatrics Research Branch of the Division of Adult Translational Research and Treatment Development of NIMH recently undertook a review and analysis of its Translational Neuroscience program to identify strengths and gaps in the funded science, and to identify promising new research targets and strategies for fostering portfolio growth. Previously, extramural experts in the fields of imaging, genetics, and clinical research, recognizing the descriptive nature of work in this area, had promoted more mechanism-oriented research that included more biological theories of aging into the study of late life mental disorders.
As part of this process, the extramural panel of consultants suggested that the branch hold a workshop to identify new research directions that can most productively be pursued in light of the new Strategic Plan of the NIMH. In the resulting workshop, convened in February 2009, the branch aimed to bring together basic and clinical researchers interested in topics of aging and mental health to identify key research questions relative to discovering the causes of mental disorders, and to chart mental illness trajectories to determine when, where and how to intervene. Another major goal of this workshop was to discuss critical infrastructure issues relevant to nurturing the next generation of researchers who would be able to carry out this multidisciplinary and translational research effort.
Presentations explored several research topics and covered a wide range of novel findings and ideas under four major themes, including: (1) neuropathological mechanisms and late life mental disorders; (2) biology of aging and the pathophysiology of late life mental disorders; (3) late life mental illnesses as developmental disorders with an emphasis on biological parameters; and, (4) infrastructure barriers to the advancement of geriatric translational neuroscience at NIMH.
Neuropathological mechanisms and late life disorders
Workshop participants identified several research areas needed to advance understanding of basic mechanisms of disease, as well as biological models of aging that could inform the science of late life mental disorders. Specifically, epigenetic studies of DNA methylation, as well as an examination of both hormonal and other biological mechanisms of aging were seen as opportunity areas for the field. A gap area exists between basic animal work and clinical correlates of disease across the lifespan. To this end, workshop participants suggested conducting more research to explore the phenotype or models of aging systems in both animal and human research. Furthermore, animal models that examine the role of accelerated aging may provide some insights into the effects of psychiatric disturbances on decreasing mortality and what mechanisms may be contributing to this increased morbidity and mortality.
Participants encouraged more research on how the epigenetic mechanisms identified in younger adults may be understood as a function of chronicity of disease or age. Moreover, several participants identified the need to gather biological information from older adults to add to ongoing repository efforts relevant to psychiatry. Specifically, obtaining samples from older adults with late life schizophrenia and bipolar disorder and establishing brain banks for these samples would provide data concerning the neuropathological mechanisms responsible for the development of these disorders late in life. These samples would also provide evidence for possible new study targets for samples from younger patients, thereby providing data on relapse prevention.
Biology of aging and the pathophysiology of late life mental disorders
Participants also commented that the field needs a better understanding of how model systems of biological aging could be combined to examine how chronic disease or aging itself influence risk and protective factors in the maintenance and etiology of illness in late life. Another research gap identified by participants centered on examining vulnerable periods of risk, to determine appropriate mechanisms of response that could lead to the development of new interventions. A specific example was raised with regard to the study of menopausal transitions as a vulnerable period for the development of late life psychotic disorders. Another area in need of better understanding in late life is the pathophysiology of major mental disorders due to the greater degree of homogeneity seen in older adult populations.
Late life mental illnesses as developmental disorders
Another promising area of study is the further analysis of broader models of aging and disease and how these may interact with the expression of psychiatric disturbances later in life. For example, studies of vascular disease as a process that may lead to depression and other co-morbid illness in late life could be conducted with middle-aged or young adults. An examination of white matter disease earlier in life may identify new targets for prevention. Work done with elders may offer insights into mechanisms of disease progression and/or maintenance that would be useful for younger adult populations. These types of studies have the potential to lead to the discovery of new targets for intervention research. In turn, new targets may lead to the development of new compounds that target symptom expression or relapse. These new medications would be useful across the lifespan, but especially beneficial among elders due to changes in both pharmacokinetics and pharmaco-dynamics with age.
Infrastructure barriers to the advancement of geriatric translational neuroscience at NIMH
Participants cited several barriers to advancement in this area. Most notable were a lack of aged animals available to investigators for the study of chronic disease models. In addition, participants noted that few investigators examining pathophysiology were pursuing questions related to the course of chronic illness. Other barriers included a lack of integration between clinical and basic research that would aid in these crosswalks between fields. In terms of resources, there is a lack of investigators who are conversant in conducting translational neuroscience work in the field of geriatric mental health. New training paradigms and career development opportunities to move the field in this direction may be needed.
Participants identified several important questions, strengths, and gap areas relevant to research on the aspects of translational neuroscience research that may be applicable to late life mental disorders. The rich dialogue between clinical and basic scientists created tangible new research directions and identified promising strategies for expanding basic, translational, and clinical studies on late life mental disorders to help bridge the gaps between genes, circuits and behavior. Meeting participants agreed that future neurobiological studies should focus on mechanisms of action and should incorporate more factors suggested by molecular, cellular, and other biological theories of aging so that variables from those areas of research could be investigated for their potential relevance to late-life psychopathology. Discussion highlighted new directions that appear to offer the greatest promise for future studies, and also helped to identify ways to bring more basic scientists into collaborative work in the geriatric mental health research field. The goals and the products of this workshop address the NIMH’s Strategic Plan, Objective 1 to promote discovery in the brain and behavioral sciences to fuel research on the causes of mental disorders, and Objective 2 to chart mental illness trajectories to determine when, where, and how to intervene.