Alison C. Burggren - US grants

DESCRIPTION (provided by applicant): Marijuana (Cannabis sativa) is the most widely used illicit drug worldwide, with 17.4 million Americans reporting past month use in 2010 and 4.6 million meeting criteria for dependence, underscoring the public health importance of understanding the biological implications of use. How heavy cannabis use affects brain structure and cognitive performance in late life is unknown. The ongoing maturation in the adolescent brain, including the developmental circuitry underlying memory performance and executive control puts the adolescent brain at high risk for detrimental effects of heavy cannabis use. With the aging of the 'baby boomer' generation, many people who used cannabis heavily as adolescents are now entering their senior years when age-related cognitive decline may begin. Cannabis use doubled in less than a decade during the 1970's when 38% of those surveyed in the U.S. Survey on Drug Abuse reported using cannabis and 12% of those users reported using cannabis more than 20 times a month. Understanding how heavy, early cannabis use may affect neurobiological and cognitive outcomes is of high importance for this aging population, which is already at risk for memory and cognitive deficits in aging. Because cannabis use appears to have a primary effect within the hippocampus, the main structure for memory and the structure affected most by age-related memory impairments and pre-clinical Alzheimer's disease, we expect that the effects of chronic cannabis use may be greatest during aging. To our knowledge, no study has investigated the long-term effects of adolescent cannabis use on hippocampal morphology and cognitive performance in an aging population. We will investigate hippocampal integrity and cognitive performance using high-resolution magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and neuropsychological testing in an aging population of subjects (55-70 years old) who used cannabis more than 20 times a month for at least a year during adolescence. Of the 30 subjects we propose to enroll in this heavy use category, we have already identified 9 subjects, and collected MRI, DTI and cognitive testing data for these subjects. We will compare data collected from heavy cannabis users to subjects who did not use cannabis but are matched for age, gender, education, light tobacco and light alcohol use. Finally, because family history and genetic risk are known to accelerate hippocampal morphology and memory decline in aging, we will investigate whether possession of the APOE ¿4 variant in heavy cannabis users is synergistically related to thinner hippocampal cortex and white matter deficits. This project advances the Candidate's training by building on the strengths of her previous research in neuroimaging of the aging brain while providing new training and mentorship in addiction research. The training program combines formal coursework, one-on-one mentoring with Dr. Edythe London, an established investigator in addiction research, and a series of meeting and workshops to foster the Candidate's growth in addiction research.

ABSTRACT Age-related changes in hormone levels occur in both men and women but are more pronounced in women approaching menopause, typically between the ages of 45 to 52 years old 1. Despite prior data addressing brain-aging differences in women and men, how hormone changes in midlife affect brain structure and cognition in women remains unclear. Women appear to be more vulnerable to cognitive decline during this peri-menopausal period 2, and there is general agreement that women experience memory deficits during this timeframe 3?6. Estrogen-depletion is widely regarded as a likely cause of cognitive impairment in peri-menopausal women 7 but the mechanistic understanding of how declining estrogen rates affect cognitive decline and brain changes is relatively poorly understood. In animal models, estrogen receptors are found throughout the brain, but predominate in limbic-related areas that play a crucial role in cognitive function 8. Specifically, these animal studies show hippocampal subfields Cornu Ammonis 1, 2, and 3 as densely populated regions of estrogen-receptors; activation of these estrogen-receptors has been shown to mediate estrogen's beneficial effect on synaptic plasticity as well as play a role in preventing neurodegeneration in hippocampal neurons 9,10. We propose here investigating the impact of declining estrogen levels on hippocampal structure and function in peri-menopausal women as part of our collaboration with the Human Connectome Project- Aging (HCP-A). This project makes use of the rigorously structured data collection pipeline HCP-A is using to objectively stage menopause data points. Although the data detailed here are being collected as part of the HCP-A project, with 103 subjects currently available and an additional 107 anticipated to be recruited over the coming 2 years, no support for subsequent investigations is included as part of the HCP-A; investigations proposing to answer scientific questions using the dataset must be funded with separate research support. Specifically, we will analyze high-field magnetic resonance imaging (MRI) data of the hippocampus in order to assess memory structures and function in fine detail and determine whether lower estrogen levels predict poorer memory performance in peri-menopausal women. We will also investigate whether hormone replacement therapy has a beneficial effect at mediating the effect of changes in estrogen levels in midlife women. We expect results from this project to shed light on the complex relationship between changes in hormone levels and subsequent effects on hippocampal structure and memory function in midlife.