Peter J. Whitehouse, MD, PhD - US grants

Although considerable work has been performed recently on the clinical and biological features of the cognitive impairment of AD, little attention has been paid to the psychiatric symptoms. In the proposed University Hospitals of Cleveland/Case Western Reserve University (UHC/CWRU) Alzheimer Clinical Research Center (ACRC), we will characterize cognitive and psychiatric symptoms of a population of AD patients, follow them longitudinally, and explore the relationships between alterations in adrenergic and serotonergic markers in life and in death with the clinical features. The goal of this ACRC is to contribute to a better understanding of the biological basis of the cognitive and behavioral manifestations of AD, which will lead to better diagnostic and therapeutic approaches. This goal will be accomplished through six cores: Clinical, Clinical Pharmacology Neuroimaging, Neuropathology, Data Management and Analysis, and Administrative. The cores will serve as a resource for investigators in the ACRC, as well as other investigators at UHC/CWRU. A comprehensive diagnostic and therapeutic approach to the cognitive and psychiatric manifestations of AD obviously requires both biological and behavioral aspects. Five specific research projects are included in the proposal: 1) biochemical assessment of serotonergic and noradrenergic markers in blood platelets, 2) the role of adrenergic and serotonergic systems in the regulation of cortisol secretion and glucocorticoid receptor number, 3) post mortem alterations in cortical, adrenergic, and serotonergic binding sites, 4) description of the pathology of the locus coeruleus and raphe nucleii, and 5) studies of the neural control of blood-brain barrier regulation. In addition, mechanisms are specifically included in the ACRC to evaluate new research proposals generated by UHC/CWRU investigators.

The proposed Alzheimer's Disease Research center (ADRC) will be built on existing individual expertise and institutional commitment to the study of Alzheimer's disease (AD), clinical care of patients, and the dissemination of knowledge concerning this devastating disorder. University Hospitals of Cleveland (UHC) and Case Western Reserve University (CWRU) support an Alzheimer Center that coordinates research, clinical care, and educational programs in AD. Our proposed ADRC will examine the functional importance abnormalities occurring in AD ranging from molecular biology to activities of daily living. Emphasis will be placed on understanding inter-relationships between different levels of scientific inquiry, i.e. how do changes in messenger RNA relate to cell dysfunction; how does cell dysfunction relate to cognitive impairment; and how does cognitive impairment convert to functional disability? The proposed ADRC will be organized around five cores: 1) Administrative, 2) Clinical (including a patient registry and a data management and analysis component), 3) Research Training and Information Transfer Core (Education Core), 4) Imaging Core, and 5) Neuropathology Core. Three research projects will be added to the already existing research program: 1) Vessels of the Brain Aging and AD (Harik/Kalaria), 2) Characterization of Amyloid in AD (Younkin), 3) Functional Communication Decline in AD (Ripich). In addition, we propose several pilot research projects which will be built on our already existing pilot grant research program. Studies proposed for year one include: Immunostain Fingerprints of the Neural Tissue (Caplan), PHF Binding Proteins (Perry), and Socially Desirable Response Tendency and Caregiver Burden (Smyth). Second year proposal include: Physicians' Attitudes and Practices toward AD Patients (Kahana), ADL skills and Cognitive Status in AD (Martin), Higher Visual Functions in AD (Mendez), and Black and White Caregivers of Elders with Dementia (Wykle/Segall). The proposed ADRC will permit an already cohesive, nationally recognized group of investigators to continue making major contributions to understanding this disorder, converting this understanding into improved clinical care, and educating lay groups, professionals, and policy makers--both locally and nationally--concerning this devastating disease.

The enormous international scope of the problem of dementia combined with exciting discoveries in neurosciences is leading to new hope and urgency in the treatment of Alzheimer's disease and related conditions. Little discussion in either the lay or the academic literature has focused on the practical or conceptual issues surrounding the establishment of therapeutic goals in these disorders. New efforts based in the principal of discourse ethics have begun to explore the kinds of ethical issues and value conflicts faced by patients with dementia, caregivers, and professionals. These approaches have led us to recognize the complexities that are faced in the actual caregiving situation. National and international efforts are underway to design therapies to improve both the cognitive and behavioral symptoms as well as to slow the progression of disease. In this proposal, we will use a variety of methods to explore the establishment of therapeutic goals in dementia. We will expand on our national recognized work to develop focus groups of affected persons, their caregivers, and health care professionals. These focus groups will be complemented by surveys designed to collect data about the attitudes of broader populations of caregivers and patients. In our initial focus groups, improvement of quality of life has consistently emerged as a key concept yet there has been little work done to assess quality of life in intervention studies. We will further develop two instruments designed by Meryl Brod and Rebecca Logsdon and colleagues to assess quality of life. We will examine the relationship between performance on these quality of life instruments and other neuropsychological abilities, including memory, language, executive function and insight. Finally, we will compare methods of establishing utility weights in both patients and caregivers, including time tradeoff, standard gamble and rating scales. The integrating theme behind these efforts is that further exploration of therapeutic goals in dementia is required and that a variety of techniques may allow us to understand better the needs and desires of those families affected by these conditions. In the final years of the proposal we will develop interventions based on the knowledge accumulated during the initial periods of the grant to enhance the decision- making of other caregiving units.