| Clinical Research Branch |
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| B. Gwen Windham, M.D., M.H.S., Staff Clinician Longitudinal Studies Section |
 Dr. B. Gwen Windham received her medical degree in 1996 from the University of Mississippi, where she also completed an internal medicine internship and residency. Dr. Windham completed fellowship training in geriatric medicine at Johns Hopkins Bayview Medical Center, a Masters of Health Science in the Epidemiology of Aging and a Certificate in Gerontology at Johns Hopkins Bloomberg School of Public Health in 2003 while supported by the Epidemiology and Biostatistics of Aging training grant (NIH T32 AG00247). She was a co-investigator on the Women's Health and Aging Study II, where she was primarily responsible for supervising vision and hearing assessments, medical adjudication of cardiovascular disease, and updating the medications database. She joined the National Institute on Aging, Clinical Research Branch in 2003 as a staff physician and a co-investigator for the Baltimore Longitudinal Study of Aging. Since joining the NIA, she has worked closely with Dr. Luigi Ferrucci and Dr. Shari Ling to create the current standardized physical examination used in the Baltimore Longitudinal Study of Aging. In addition, she implemented new protocols to assess autonomic function and visual fields in participants of the Baltimore Longitudinal Study of Aging. |
| 1. Autonomic Nervous System and Aging: The current paradigm being used for the new design of the Baltimore Longitudinal Study of Aging (BLSA) includes the longitudinal assessment of the physiologic subsystems that are important for mobility. This is consistent with one of the goals of the BLSA, which is to learn how multiple impairments interact with age in causing disability. The neurological system is hypothesized to be one of the critical subsystems of interest in this process. In particular, the autonomic nervous system continuously regulates the internal environment of the body to maintain homeostasis by monitoring and controlling blood flow, blood pressure, extracellular fluid volume and distribution, energy expenditure, and visceral smooth muscle and glands including the liver, pancreas, and adrenals. The autonomic nervous system (ANS) also regulates the immune system at regional, local, and systemic levels. Regionally, sympathetic nerves innervate immune organs, including the thymus, spleen and lymph nodes, releasing neurotransmitters such as norepinephrine. Neurotransmitters then act systemically on immune cells (e.g. lymphocytes); both norepinephrine and epinephrine inhibit proinflammatory cytokines, (IL-12, TNF-a, and interferon g) and stimulate anti-inflammatory cytokines (IL-10 and transforming growth factor b). The current design of the BLSA will allow the study of the interactions among the multiple systems regulated by the ANS. |
| The current accepted non-invasive measure of autonomic function is heart rate variability (HRV), which is a measure of the variability in the time between normal sinus beats rather than variability in the actual heart rate. In the BLSA, HRV is being assessed via 24-hour Holter monitors. We hypothesize that autonomic function will be an important factor in maintaining mobility and other components of physical function and metabolic functions such as glucose metabolism and inflammation. We will examine the potential mediating and modifying roles of inflammation, a strong independent predictor of physical function decline, on autonomic function and how this relates to the development of physical and cognitive decline. The connection between autonomic function and inflammation is also being investigated in a collaborative study established to investigate associations between autonomic function and rheumatoid arthritis, a prevalent and debilitating inflammatory disease of the joints. |
| Preliminary results from the BLSA demonstrate that lower HRV is associated with higher glucose levels in the latter part of the oral glucose tolerance test in persons without diabetes. Future research will explore whether autonomic function predicts persons at risk of developing glucose intolerance and will attempt to identify characteristics that contribute to maintenance of a healthy autonomic nervous system. |
| Other developing or ongoing collaborative placebo-controlled studies are evaluating whether the drug glucophage, a biguanide oral hypoglycemic medication used to treat diabetes, affects autonomic function in non-diabetics with metabolic syndrome and whether omega-3 fatty acid supplementation improves autonomic function in persons with kidney disease. |
| 2. Renal Function in Aging: Early studies from the BLSA demonstrated that, on average, renal function declines approximately 1ml/min in men after the age of 50. Such studies did not inlcude women. In addition, numerous formulas are now available to estimate the glomerular filtration rate (GFR). However, these formulas are notoriously variable and inaccurate in older adults. Serum creatinine, common to most of these formulas, performs poorly in persons as an indicator of renal function, especially when muscle mass, the major source of creatinine production, is low. This is often the case in frail, older adults. In the InCHIANTI study, grip strength, a surrogate of muscle mass, explained variance of calculated creatinine clearance from timed urine collections above that of the Cockcroft-Gault equation, although the additional clinical value of grip strength in estimating renal function is questionable. Cystatin C is a cysteine protease inhibitor produced by all human nucleated cells, filtered by the kidney, and degraded by the proximal tubule. It is therefore considered by many to be a reliable indicator of GFR and can be measured in blood. To better understand aging-associated changes in renal function, we are investigating cystatin C as a marker of renal function and its role in the aging process independent of kidney function. Ongoing analyses are investigating longitudinal changes in renal function in women with plans to include assessments of cystatin C in stored samples of men and women participants. This will allow comparisons of cystatin C, creatinine clearance from timed urine collections, estimating equations, and in the near future, a true measure of GFR using iohexol clearance. |
| Cystatin C has also been shown to be predictive of cardiovascular events, all-cause mortality, cardiovascular-related mortality, incident myocardial infarctions and strokes in persons 65 years and older independent of renal function, and predicted incident peripheral arterial disease better than creatinine or the MDRD equation. It has been demonstrated that higher levels of inflammation are associated with downregulation of cystatin C production by macrophages. There is also some evidence that cystatin C may be a negative biomarker of inflammation. However, cystatin C has been associated with higher levels of C-reactive protein and fibrinogen in the Cardiovascular Health Study, a community-dwelling population of older adults. These reports suggest that the utility of cystatin C extends beyond assessing renal function and perhaps is indicative of other underlying pathophysiologic processes. Additional studies that allow a more complete examination of these relationships is warranted, especially in older persons. Using data collected in the BLSA, we will explore the role of cystatin C in understanding renal function changes with aging, how cystatin C can be used clinically as a measure of renal function in older persons, and attempt to clarify the role of cystatin C in the development of cardiovascular and inflammatory-related diseases. |
| 3. Vision and Aging: Contrast sensitivity, visual acuity, visual fields, and to a lesser extent, stereopsis, have all been shown to be related to various mobility measures and activities that contribute to independent living. Longitudinal data are currently available on contrast sensitivity, visual acuity, and stereopsis in the BLSA. Visual field screening tests were implemented in 2006 in the BLSA and are ongoing. We will examine the contributions of these vision domains to mobility and gait function in the BLSA, how these relationships change with age, and how vision interacts with other systems that are important for maintaining mobility. |
| Contact Information: Clinical Research Branch Harbor Hospital 3001 Hanover Street Baltimore, MD 21225 Phone 410-350-7338 E mail windhamgw@grc.nia.nih.gov For more information about the Branch: http://www.grc.nia.nih.gov/branches/crb/crb.htm |
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