1993 — 2002 |
Bliwise, Donald L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sundown Syndrome in a Skilled Nursing Facility
This is a revised competitive renewal investigating how the circadian timing system is altered in dementia. In a previous version of the application, we sought to study this problem by correlating antemortem descriptions of agitated behavior over the 24-hour day with postmortem neuroanatomic findings from regions hypothesized to control those behaviors. In the present study, we will rely on physiologic assessments of the circadian timing system in living geriatric patients with known disease to index integrity and functional status of the circadian timing system. Nocturnal disruptive behavior, sometimes called "sundowning,' represents a major problem in the care of elderly patients. Many, but not all, patients with dementia show dramatic upheaval of their sleep/wake cycle, a condition often characterized as "day/night reversal." For individuals not yet institutionalized, such agitated behavior at night represents a major cause of nursing home placement and is a severe stressor for family members. Within the nursing home environment, such behaviors cause upheaval among staff and other patients, and often lead to unsuccessful treatment with neuroleptic medications. While some researchers have focused on environmental factors underlying such disruptive behavior, our emphasis has been on neurobiologic causes for such "sundowning." One possible substrate for such behavior involves the brain region known to control the timing of sleep/wakefulness, rest/activity and the 24-hour periodicity of nearly all physiologic functions, including the diurnal body temperature cycle. This area, an extremely small region called the suprachiasmatic nucleus (SCN) located in the anterior portion of the hypothalamus, is known to undergo marked changes with normal aging. Additionally, there is some evidence to suggest that certain forms of dementia may be associated with even greater deterioration in this region. The proposed study will assess the output of this brain region by examining the 24-hour body temperature cycle and sleep/wakefulness in elderly patients with Alzheimer's Disease (AD), Parkinson's Disease (PD), Vascular Dementia (VasD) and aged matched controls. Individuals will be studied in the sleep laboratory over a period of 3 1/2 days during which they will undergo frequent body temperature measurements and polysomnography on an altered sleep/awake schedule alternately allowing 30 minutes for sleep and 60 minutes of wakefulness. Based on existing behavioral, neuroanatomical and physiological evidence, we expect the greatest disruption of circadian physiology to occur in VasD, the least disruption in controls, and an intermediate level of disruption in AD and PD. These results will provide information on the mechanistic basis for sundowning in aged patients with dementing disorders.
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1996 — 1998 |
Bliwise, Donald L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
State-Dependent Motor Control in Neurologic Disease
DESCRIPTION: (Applicant's Abstract): Neurologists treating patients with movement disorders often encounter considerable heterogeneity of symptoms. While considerable progress has been made in the understanding of the pathophysiology and treatments of disorders such as Parkinson's Disease (PD), the varied presentations of this disease (e.g., tremor versus rigidity/bradykinesia) and how those clinical presentations are modulated by state of arousal remain poorly understood. The present proposal investigates the hypothesis that manifestations of movement disorders occurring at night reflect state-dependent alterations in the identical neural substrates also responsible for such clinical heterogeneity. The Parkinsonian condition provides an ideal opportunity to investigate this hypothesis since: 1) varying levels of cortically defined arousal in PD patients are commonly punctuated by specific forms of skeletomuscle activity; 2) neuronal output of the internal segment of the globus pallidus (GPi), whose dysfunction is central to models that account for manifestations of PD, target brainstem regions known to be important modulators of level of arousal; 3) the MPTP-primate model of Parkinsonism affords the unique opportunity to define the role of the GPi in electrophysiologically defined stares of activation. Ongoing human and animal protocols at Emory allow elucidation of the mechanisms underlying state-dependent motor control which we postulate to occur in PD. In humans, a recently initiate clinical trial assessing the efficacy of pallidotomy in affecting clinical features of Parkinson's Disease, such as tremor, rigidity, bradykinesia and dementia, presents a singularly unique opportunity to further understand nocturnal exacerbation of this disease. similarly, availability of primates subjected to experimentally-induced Parkinsonism through MPTP-injections will allow neurophysiologic, pharmacologic, and neuroanatomic understanding of how arousal state may modulate motor output form the GPi at the cellular level. The overall goal of this study is the elucidation of state-dependent motor control in neurologic illness via a coordinated effort of both clinical research and basic science.
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2000 — 2006 |
Bliwise, Donald L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Polysomnographic Assessment of Alternative Treatment
Patients with Parkinson's Disease have exceptionally poor sleep. Even relative to other neurodegenerative diseases such as Alzheimer's Disease, the sleep of the PD patient is fragmented and disturbed. Most notably, sleep in PD is characterized by excessive activity in surface electomyographic (EMG) recordings from many different muscle groups. Despite the sleep disturbance, approximately 50 percent of PD patients note that, on nights when they are able to achieve sleep, they experience a transient (1 to 3 hour) reduction in waking motor symptoms upon arising in the morning. This effect has been termed Sleep Benefit. To date there are no double-blind placebo-controlled studies treating sleep disturbance using PD using any (conventional or alternative) medical treatments. In this randomized, double- blind, parallel-groups, placebo-controlled polysomnographic clinical trial we will compare two alternative medical treatments (valerian, melatonin) and two conventional medical treatments (diphenhydramine, zolpidem) for the disturbed sleep of PD patients. Compelling basic science and clinical rationales exist for use of each of these substances (including valerian and melatonin) for treatment of sleep disturbance in PD. The proposed study will be conducted for six consecutive nights (3 Baseline, 3 Drug) using state-of the-art digitized ambulatory polysomnography in each patient's home. Outcomes will include both measures of nocturnal sleep and waking motor function. Polysomnographic measurements will include customary variables such as total sleep time, sleep efficiency and sleep latency, as well as EMG measures of periodic and isolated muscle activity during sleep. Assessments of motor function will be made the morning immediately, following the third Baseline night and third Drug night in order to test for improvement related to improved sleep. Data will be analyzed with Analysis of Covariance examining Condition (Baseline, Drug), (valerian, melatonin, diphenhydramine, zolpidem, placebo), and characteristic Sleep Benefit (positive, negative) main effects, as well as their interactions, after adjusting for Baseline values. The results would represent the first data applying rigorous clinical trial methodology to the study of disturbance sleep in PD patients and would critically examine the efficacy of two substances currently seeing widespread use as over-the counter hypnotics for which little polysomnographic data currently exist.
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2003 — 2005 |
Bliwise, Donald L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biomarkers of Aging in the Bay Area Sleep Cohort
DESCRIPTION (provided by investigator): Sleep Disordered Breathing (SDB) is a common condition in the elderly population but its relationship to health in old age remains uncertain and its natural history is virtually unknown. The proposed longitudinal study will continue a previously initiated follow-up of a cohort of elderly subjects studied with physiologic sleep recordings (polysomnography). This unique group of 256 individuals, initially recruited and evaluated with in-lab polysomnography between 1974 and 1985 and followed prospectively since that time, is referred to as the Bay Area Sleep Cohort (BASC). A substantial number of BASC subjects already have undergone two occasions of polysomnographic measurement (n = 173), whereas as a smaller subgroup has been studied previously on three occasions (n = 76). Surviving BASC subjects (n = 137, X age = 81.2) will be re-recorded in a joint effort between investigators at Emory University in Atlanta, Georgia and SRI International of Menlo Park, California. These two institutions, and the Principal Investigator and Co-Principal Investigator, respectively, have a ten-year history of working on field studies of SDB in elderly populations in different geographic regions in the United States. The application requests funds to locate all surviving members of BASC as well as to: follow-up these individuals using current state-of-the-art ambulatory polysomnographic technology; perform comprehensive evaluations of health, including measures of neurobehavioral, pulmonary, and cardiovascular function among those surviving members; archive and summarize existing polysomnographic recordings; and to analyze data longitudinally by calculating each individual's rate of change in their characteristic levels of SDB. Individual differences in rates of change will be related to changes in neurobehavioral, pulmonary, and cardiovascular function over time. "Families" of regression lines will compare stage-specific rates to examine how changes in sleep architecture parallel development of SDB at follow-up. These results will allow elucidation of SDB as a potentially sensitive aging biomarker as well as characterizing how this index of physiologic age relates to other better recognized biomarkers of aging. The early establishment of this cohort and the absolute scarcity of information on population-based data on the progression of SDB present a unique opportunity to discover how human sleep may reflect fundamental alterations in aging processes.
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2005 — 2009 |
Bliwise, Donald L. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Clinical Core
The Clinical Core of the Emory Alzheimer's Disease Center (ADC) provides state-of-the-art diagnostic assessment of AD and other dementias, with a special emphasis on comorbid conditions that contribute to impaired cognition. The primary mission of the Core is to afford access to well-characterized patient pools with which to conduct innovative clinical and basic research projects. The Emory ADC has many unique features, including a large, ethnically diverse patient population and investigators with expertise in clinical and basic science related to a broad range of dementing illnesses. In addition, there is active involvement of established investigators with expertise in other conditions known to impair cognition in the aged population. An implicit component of the Clinical Core is the broadening notion of Mild Cognitive Impairment (MCI). A major challenge is to identify features that will predict which cases of MCI will progress to AD, or other dementing disorders, including dementia with Lewy bodies, vascular dementia, and Parkinson's disease. In addition, a substantial body of literature indicates that conditions, such as depression, cardiac disease, diabetes, hypertension, and sleep apnea, which are highly prevalent in the geriatric population, exert strong independent influences on cognitive function, and they can accelerate the progression of degenerative neurologic diseases. Through the activities of the Clinical Core and its interactions with other components of the Emory ADC, we will achieve three specific aims: 1) to evaluate cases of MCI, AD, and other dementias by systematic collection and evaluation of neurological and neuropsychological measures and examination of medical comorbidities;2) to enhance the care of patients and families through comprehensive clinical services, education, and access to promising clinical trials and other research activities;and 3) to support and promote research studies by sharing carefully and systematically collected data from registry participants, including clinical evaluations, family histories, DMA, and other biological materials.
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2006 — 2010 |
Bliwise, Donald L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sleep/Wake Contiuum in Lewy Body Disease
DESCRIPTION (provided by applicant): Dementia with Lewy Bodies (DLB) represents the second most common cause of dementia. The sleep/wake continuum plays an integral, though seldom explicitly recognized role in characterizing DLB, with both fluctuations in alertness and hallucinatory experiences (often accompanied by dream-enactment behaviors) considered core features of the condition. In this study, we will compare patients meeting clinical criteria for DLB (n=50), idiopathic Parkinson's Disease (IPD) (n=50) and elderly controls (n=20) to examine potential pathophysiologic mechanisms underlying these observations. Patients and controls will be studied at entry in an intensive, 72-hour laboratory protocol with polysomnographic and neurobehavioral measurements and followed-up 3 years later neurobehaviorally. Our Specific Aims are: 1) to compare polysomnographically excessive daytime sleepiness (EDS) and nocturnal sleep in DLB, IPD and controls;2) to test whether fluctuation in mental status in DLB is related to EDS;3) to predict whether declining cognition over 3 years is predicted by polysomnographic and neurobehavioral markers at entry. The results of this study will inform basic sleep/wake science by investigating potential substrates underlying the observed pathophysiology seen in DLB and IPD. The proposed work will also provide important clinical insights into disease correlates and disease course across the broad spectrum of Parkinsonism.
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2009 — 2012 |
Bliwise, Donald L. Rahbari-Oskoui, Frederic Farid |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Melatonin and Nighttime Blood Pressure in African Americans
DESCRIPTION (provided by applicant): Elevated nighttime blood pressure (BP) is an important risk factor for cardiovascular disease (CVD). Indeed, recent data suggest that elevated nighttime BP may be a stronger risk factor for CVD than elevated daytime BP. African Americans are more likely than other racial/ethnic groups to suffer from elevated nighttime BP, which may partially explain why African Americans are at higher risk of mortality from coronary heart disease and stroke, and have a higher incidence of renal disease, than other racial/ethnic groups in the United States. Thus, investigating methods of reducing nighttime BP in African Americans should be considered an important public health goal. Evidence suggests that melatonin supplementation may help lower nighttime BP. However, randomized studies of melatonin supplementation and nighttime BP in African Americans have not been conducted. The long term goal of this proposal is to examine whether melatonin supplementation helps reduce nighttime BP in African Americans with elevated nighttime BP, and to explore potential mechanisms by which this BP lowering effect might occur. We plan to conduct a pilot randomized, double blind, placebo- controlled, crossover clinical trial (n = 40) examining the effect of melatonin supplementation on nighttime BP in African Americans. The specific aims of the pilot trial are as follows: (i) obtain preliminary data on the efficacy of 4 weeks of nightly melatonin supplementation on nighttime BP in African-American subjects suffering from elevated nighttime BP; (ii) explore sleep factors, sympathetic drive, and vasorelaxation as potential mechanisms by which melatonin may lower nighttime BP; (iii) determine the feasibility of recruiting and randomizing African American subjects with elevated nighttime BP for a melatonin supplementation trial; and (iv) estimate whether melatonin supplementation has any adverse side effects when taken nightly for four weeks in African-American adults with elevated nighttime BP. Results from the proposed trial should help provide important preliminary data that could be used to guide a larger, more definitive trial. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it will help shed light on whether melatonin supplementation can lower nighttime blood pressure in African Americans who suffer from elevated nighttime blood pressure.
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