National Institute on Aging
National Institutes of Health
|Brain Aging and Behavior Section|
Susan M. Resnick, Ph.D., Senior Investigator
Dr. Resnick received her Ph.D. in Differential Psychology and Behavioral Genetics from the University of Minnesota and completed a postdoctoral fellowship in Neuropsychology and Neuroimaging at the University of Pennsylvania. She was Research Assistant Professor of Psychology in Psychiatry at the University of Pennsylvania prior to joining the Laboratory of Personality and Cognition (Now the Laboratory of Behavioral Neuroscience), NIA in 1992.
She studies brain-behavior associations in health and disease and is currently the principal investigator of the brain imaging component of the Baltimore Longitudinal Study of Aging (BLSA). This longitudinal neuroimaging study focuses on early structural and physiological brain changes that may be predictors of memory and cognitive change in older individuals. Through this study and others in the BLSA, she has also been examining the hormonal modulation of age-associated cognitive and brain changes. Based on findings from these studies, she initiated the Women's Health Initiative Study of Cognitive Aging (WHISCA), an ancillary study to the Women's Health Initiative Memory Study (WHIMS) and the WHI randomized trials of the effects of hormone therapy.
Brain Changes as Predictors of Cognitive and Memory Decline: The goal of our research program is to identify brain changes which may predict declines in memory and other cognitive functions in older individuals. We use magnetic resonance imaging (MRI) to measure the structure of the brain and positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) during the performance of memory tasks and over time. A variety of risk and protective factors for cognitive impairment and dementia are examined.
Early Markers of Alzheimer's Disease - Brain Changes in the Baltimore Longitudinal Study of Aging (BLSA): We are performing a longitudinal neuroimaging study involving annual MRI and PET scans and neuropsychological evaluations in selected BLSA participants aged 55 and older. This longitudinal design provides a sensitive to way to investigate the relationship between changes in brain structure and physiology and decline in memory and cognition. Furthermore, using the wealth of prior psychological and medical information available for BLSA participants, we are able to examine trajectories of cognitive aging in relation to individual differences in the brain years later. To date, approximately 155 individuals (90 men, 65 women) have enrolled in the brain imaging study and most have completed as many as 10 annual assessments.
The specific goals of this study are: to determine the rate of brain changes with age, including increases in brain atrophy and ischemic/demyelinating white matter abnormalities; to determine the association between trajectories of memory and cognitive change and changes in brain structure and function; and to determine whether risk and protective factors, such as genetic susceptibility factors, hormone replacement therapy, use of non-steroidal anti-inflammatory agents, and vitamins, modulate these relationships. An understanding of the associations between brain and neuropsychological changes, as well as early detection of these changes, will be critical in identifying individuals likely to benefit from new interventions in preventing and treating Alzheimer's disease and other memory problems in the elderly.
MRI data from the first 5 years of our longitudinal brain imaging study have been published. A great deal of effort in our laboratory has focused on the development and validation of an image processing approach that provides sufficient accuracy for longitudinal studies. Quantitative analysis of MRI volumes, including separate estimates of gray and white tissue volumes and cerebrospinal fluid (CSF), revealed cross-sectional age and sex differences in brain and ventricular volumes. The cross-sectional findings from the Year 1 MRI scans indicate less gray and white matter volume and more ventricular CSF in older compared with younger participants; the magnitude of these findings is different across frontal, parietal, temporal and occipital brain regions. There were no detectable changes in lobar brain volumes over a one-year period, but there was a small but significant increase in the volume of the ventricles. In contrast to findings over one-year, four-year follow-up data revealed significant tissue loss in both gray and white matter volumes, even in a subgroup of very healthy elderly. Annual rates of tissue loss were 5.4 + 0.3, 2.4 + 0.4, and 3.1 + 0.4 cm3 per year for total brain, gray, and white volumes, respectively, and ventricles increased by 1.4 + 0.1 cm3 per year (3.7, 1.3, 2.4, and 1.2 cm3 in very healthy). Investigation of age effects on tissue characteristics was performed through quantification of changes in MR signal intensities. We found a significant negative association between age and gray-white contrast at initial evaluation (r = -.49, p < 0.0001) and longitudinal decline in gray-white contrast over the four-year interval. These longitudinal changes in tissue contrast are unrelated to changes in gray and white matter volumes, indicating that each provides unique information. We will investigate whether these measures of qualitative changes in tissue characteristics enhance our ability to detect cognitive impairment.
We have also examined the effect of Apolipoprotein E genotype on hippocampal volumes and rates of longitudinal hippocampal volume loss. Neuroimaging study participants without dementia who carry the e4 allele (e4+) did not differ from those negative for the e4 allele (e4-) at initial evaluation. In contrast, e4+ individuals showed a faster rate of hippocampal volume loss than age, sex and education matched e4- individuals. Because both the presence of the e4 allele and hippocampal volume loss are risk factors for Alzheimer's disease (AD), our findings suggest one mechanism by which e4 genotype may confer an increased risk for AD.
In addition to morphologic predictors of cognitive impairment and AD, we are investigating the utility of early blood flow changes as predictors of cognitive and memory change. PET-rCBF studies are performed annually as part of our BLSA neuroimaging study. These scans are obtained under three conditions: during rest and the performance of verbal and figural delayed recognition tasks. This procedure is conceptualized as a cognitive stress test to examine age-associated changes in rCBF during increased demand. Our memory tasks produce robust patterns of CBF activation, with increased blood flow in prefrontal cortex (right > left), bilateral insula and visual association areas during memory recall. In addition, voxel-based maps of the associations between age and resting rCBF (normalized for global CBF) demonstrate significant negative correlations between age and CBF in the insular and superior temporal regions, and in visual association cortex (Areas 18 and 19) bilaterally for both men and women. To our knowledge, this sample represents the largest study of associations between age and regional CBF studied with PET and provides a detailed map of age differences in blood flow during a period of accelerating cognitive and memory decline. Complementary to our PET studies, we perform cross-sectional studies of age differences in brain activation using functional MR (fMR) and behavioral probes targeted to specific brain regions. Because our volumetric fMR studies and behavioral studies suggest specific vulnerability of orbital frontal cortex and mesial temporal regions to age changes, we have conducted fMR studies of aging using a delayed-match-sample paradigm to investigate orbital frontal regions and a virtual navigation task to investigate age effects on parahippocampal activation.
Postmenopausal Hormone Therapy: A major focus of our research program is the investigation of the potential modulatory role of hormone replacement therapy on risk for Alzheimer's Disease and cognitive and memory decline in older women. We have shown that women in the BLSA who had ever used estrogen replacement therapy had a reduced risk of developing Alzheimer's Disease in comparison with women who had never used hormone therapy. We have also shown that nondemented women in the BLSA who were using estrogen replacement therapy performed better on a test of short-term memory for designs compared with never-users. In a small subgroup of women with memory assessments prior to and following initiation of hormone treatment, the estrogen therapy appeared to protect against age-associated decline in memory. We have also compared ERT users and nonusers who participate in our longitudinal imaging study. ERT users and nonusers showed significant differences in the patterns of brain activation during the performance of memory tasks. Most recently, we reported that ERT users compared with nonusers showed greater relative increases over a 2 year period in CBF in the hippocampus, entorhinal cortex, posterior parahippocampal gyrus, and portions of the temporal lobe. Interestingly, these regions overlap substantially with those showing physiologic abnormalities in early AD and in individuals at increased genetic risk for AD.
These findings, suggesting possible beneficial effects of hormone therapy in maintaining cognitive function, are challenged by the recent report from the Women's Health Initiative Memory Study (WHIMS) showing that daily doses of combination estrogen plus progestin doubled the risk for dementia in women randomized to receive hormone treatment after age 65. However, WHIMS did not address the effects of hormone treatment on specific cognitive functions. To address this question, we initiated an ancillary study to the WHIMS and WHI in collaboration with the WHIMS investigators. This study, the Women's Health Initiative Study of Cognitive Aging (WHISCA), examines the effects of hormone treatment (combination estrogen plus progestin in women with a uterus and estrogen only in women without a uterus) on longitudinal change in memory and other cognitive functions within the context of the large randomized intervention trial.
DHEA and Cognition: Dehydroepiandrosterone (DHEA) is a widely available hormone marketed as an anti-aging dietary supplement beneficial for physical and cognitive health. We have examined the associations of plasma concentrations of DHEA sulfate (DHEAS) and longitudinal changes in DHEAS with cognitive changes in older men in the BLSA. In this large sample, there were no associations between DHEAS concentrations or longitudinal changes in DHEAS and multiple measures of cognitive change. These data offer no support for the hypothesized relationship between endogenous DHEA levels and cognitive health.
Testosterone and Cognition: In contrast to the lack of associations between endogenous DHEA concentrations and cognition, we found that an index of endogenous free testosterone was associated with performance on specific cognitive tasks in older men. Higher free testosterone index (FTI) was associated with better performance on tests of verbal and figural memory and attention, even after adjusting for age and medical conditions that influence endogenous testosterone levels. Interestingly, these associations with specific aspects of cognition were not found for total testosterone and were specific to the FTI, which is more closely related to bioavailable testosterone and the fraction that may actually reach the brain to influence central nervous system functioning.
Future Directions: Our future work will emphasize continuation of the longitudinal neuroimaging study, including continued acquisition of annual evaluations, further analyses of existing imaging and neuropsychological data, development of new approaches for longitudinal analyses of functional images, and examination of modulating factors on the relationship between brain and neuropsychological changes. The data collected over the first 5 years of the study indicate substantial changes in brain volumes and ventricular CSF, but little overall cognitive change. It will be critical to continue repeated evaluations to examine the relation between brain and cognitive changes as the number of individuals with cognitive decline increases over the duration of the study.
Another important area of future research, which has only recently received attention in the brain imaging literature, is the role of modulatory factors on brain morphology and function. We are examining suggested risk and protective factors in relation to brain changes, neuropsychological changes and their association. For example, data on family history for Alzheimer's disease, apolipoprotein E genotype, head trauma, history of hypertension, use of hormone therapy, and circulating hormones (DHEA, testosterone, cortisol) are being investigated as potential modulators of the relationship between brain and neuropsychological changes. The neuroimaging study will be expanded to younger adults to determine whether our observations of sex differences in the brain reflect group differences or differential aging for men and women. Ongoing and future work will include intervention studies to examine suggested protective agents, such as estrogen and testosterone, on brain structure and function. Through WHISCA, we will continue to investigate the effects of postmenopausal hormone treatment on specific cognitive function.
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