David J. Moser - US grants

molecular biology; diabetes mellitus; biomedical facility; recombinant DNA; information dissemination; genetic library; nucleic acid chemical synthesis; training; nucleic acid sequence; computer assisted sequence analysis;

genetic regulation; hormone regulation /control mechanism

The degree to which individuals with schizophrenia are able to provide informed consent to participate in research is an important and highly controversial issue. Recent studies (including our own pilot investigation) suggest that individuals with schizophrenia, on average, may have relatively impaired decision-making ability, but that many are able to provide informed consent. Nonetheless, the issue remains complex and becomes even more so within the context of medication free schizophrenia research. There is clearly a need for scientifically rigorous and ethical medication-free schizophrenia research, but there exists the valid concern that individuals may be able to provide consent at the beginning of a given study that requires a medication taper and subsequently "lose" this capacity following discontinuation of medication. The proposed research will directly measure the degree to which informed consent capacity changes following discontinuation of antipsychotic medication and whether this change is related to worsening psychiatric symptoms, increasing cognitive impairment, or both. It will also be determined whether reduced informed consent capacity can be remediated. At the time of enrollment, subjects will already be scheduled to undergo a medication-free period on an inpatient schizophrenia research unit with 24-hour supervision, and all decisions regarding discontinuation and reinstatement of medication will be made independently of the proposed research project. Assessment of informed consent capacity (using a hypothetical drug study scenario), neuropsychological functioning and psychiatric symptoms will be administered before and at the end of a 14-day medication free period. Subjects who demonstrate significantly reduced decisional capacity at the end of the medication-free interval will participate in an educational intervention focused on remediating this capacity and will then be reassessed. We are unaware of any investigation that has directly addressed this important scientific and ethical question in the manner that we propose. Our findings will have significant implications for the continued development of ethical guidelines that provide adequate subject protection without placing undue restrictions on important scientific advance, and will also lay the foundation for larger studies of informed consent capacity in vulnerable populations.

DESCRIPTION (provided by applicant): This proposal is submitted in response to PAR-03-056: NIA Pilot Research Grant Program, Research Objective #2: Cardiovascular and Cerebrovascular Aging: Behavioral, clinical, social, cellular, and molecular studies of cardiovascular and cerebrovascular aging. The PI (David J. Moser, Ph.D.) is in his first year of a career development award from NIA (1 K23 AG020649-01A1; "Aging, Vascular Disease and Cognition") and is conducting a longitudinal study on forearm blood vessel function and cognition in elderly patients with atherosclerosis. That ongoing study is based on preliminary data showing a strong relationship between forearm blood vessel function and cognition in these patients. For reasons discussed in detail in the body of this proposal, it is surmised that blood vessel function may serve as an indicator of total atherosclerotic risk factor burden and, because it is significantly associated with level of cognitive function, it is hypothesized that it will also be found to be associated with subsequent vascular-related cognitive decline. With additional research, this could eventually lead to the use of blood vessel function measures in the early identification of those individuals at greatest risk for vascular cognitive decline and dementia. What is lacking in the Prs current K23 project is a mechanism by which the relationship between forearm blood vessel function and cerebrovascular function can be explored. It is assumed that the relationship between forearm blood vessel function and cognition demonstrated by the preliminary data is the result of compromised cerebrovascular function but this has never been studied. If funded, the proposed pilot study will enable our research team to conduct PET imaging on 20 elderly subjects enrolled in the Prs K23 project, allowing for an unprecedented examination of the relationships among forearm blood flow, cerebral blood flow, cerebrovascular reserve, and cognition in the elderly. The proposed research is expected to yield publishable results and will also provide valuable pilot data for larger scale (e.g. R01) grant applications.

clinical depression; psychophysiology; vascular endothelium; cerebrovascular disorders; cardiovascular function; human old age (65+); cognition; clinical research; human subject;

DESCRIPTION (provided by applicant): This is the third submission of an R01 requesting five years of funding to support research on vascular disease, cognition, and brain structure in individuals with atherosclerotic vascular disease (AVD) and healthy comparison participants. AVD is the leading cause of morbidity and mortality in industrialized nations and is a primary or contributing factor in well over half of all cases of dementia. Despite this, there are relatively few longitudinal studies of AVD-related cognitive decline and the factors that are most predictive of this process. The early identification of individuals who are at greatest risk for such decline will have important implications for the development of interventions aimed at preventing or attenuating this important health problem. Our research team is using an innovative physiological measure (forearm vascular function - the degree to which forearm vessels dilate in response to vasoactive agents) as an indicator of vascular health to be examined in relation to cognition and brain structure. We have published cross-sectional findings in Stroke and in Arteriosclerosis, Thrombosis, and Vascular Biology showing that this measure of vascular function is significantly related to cognition in patients with AVD, and we have obtained pilot data that suggest that this measure is also related to frontal/temporal grey and white matter volumes. The proposed research will significantly expand upon our current findings by allowing us to achieve the following goals: 1) Determine whether the relationship between vascular function and cognition is unique to AVD or is also present in the general elderly population, as part of the normal aging process;2) Determine whether vascular function measured at baseline, and change in vascular function across time, are associated with cognitive decline across time;3) Determine the relationships among oxidative stress-mediated suppression of vascular function, neurohumoral mediators of vasoconstriction (endothelin levels, indicators of renin-angiotensin- aldosterone system and sympathetic nervous system activation), vascular function, and cognition;4) Determine the relationship between vascular function and specific MRI-based brain measures (both cross- sectionally and longitudinally) in patients with AVD;5) Conduct a pilot study on vascular function and MRI- based brain measures in healthy comparison participants. We will study healthy elderly participants (N = 100) as well as those with AVD (N = 135, 85 of whom are already enrolled in our ongoing research). This will allow us to conduct baseline and three-year follow-up assessments on those participants who are newly enrolled, and six-year follow-up assessments on those who are already participating in our research. The proposed research will allow us to make significant strides toward our long-term goals of elucidating the mechanisms by which vascular disease contributes to cognitive decline, finding better ways to identify those individuals who are at greatest risk for vascular-related cognitive decline, and developing more effective treatments to prevent or attenuate this process. Atherosclerotic vascular disease is a major contributing factor to cognitive decline and dementia in the elderly. This study is designed to help clarify the mechanisms by which vascular disease causes cognitive decline and to develop better ways to identify those individuals who are at greatest risk for vascular-related cognitive changes. PUBLIC HEALTH RELEVANCE: The randomized clinical trial will support the notion that targeted infection control interventions can reduce the burden of infections and antimicrobial resistance in these frail elderly in the NH setting. Molecular epidemiologic methods will trace the origin of resistant strains in NHs and further characterize newer hyper-virulent strains of MRSA emerging in this often neglected setting.