Technological advances in cellular and molecular biology, brain imaging, and genetics have yielded an understanding of many of the fundamental neurobiological processes that are essential to the function of the normal brain. This has led to the hope that these insights will provide improved treatments for brain diseases that prevent or degrade normal brain function. Thus, great optimism has arisen that neurobiological progress at the molecular level will lead to effective treatments for patients. The widely used phrase 'going from the bench to the bedside' encapsulates this hope for the future.
The range of research in memory disorders at Johns Hopkins is an outstanding example how this translation of knowledge is occurring. Projects range from efforts to understand the basic mechanisms of memory at the cellular level to clinical trials aimed at delaying the onset of Alzheimer's disease. Most importantly, researchers at each of these levels of expertise interact regularly with one another, with the goal of speeding the transition of basic discovery in model systems to effective treatments in man.
The Johns Hopkins Alzheimer's Disease Research Center, which has been supported since 1984 by the National Institute on Aging, is one the longest standing centers of its kind in the United States. It facilitates the integration of memory research through cross-department and cross-campus activities that include students and faculty all levels. The following are examples of the outstanding work that is underway in the area of aging and Alzheimer's disease (AD), which is currently the major focus in the area of memory disorders at Johns Hopkins.
Expertise in the Development and Evaluation of AD Mouse Models
The hallmark of AD is the accumulation of changes in the brain known as 'plaques' and 'tangles'. During the last two decades, through studies of families with AD, it has been demonstrated that a small group of genetic mutations can cause a rare form of AD among younger individuals (generally seen at 40-50 years of age). These genetic mutations have been studied in great detail. It is now known that they lead to the accumulation of a substance known as beta-amyloid, which is found in plaques, and appears to be toxic to cells. This has led to efforts by pharmaceutical companies to develop medications that alter the way in which beta-amyloid is produced or cleared from the brain.
One of the methods for understanding the nature of these genetic mutations and how they produce the pathology associated with AD has been the use of animal models. Particularly important have been the mouse models that have been genetically engineered to carry one or more of these AD mutations. These mouse models develop a progressive memory impairment (much like that of AD patients) and, when their brains are examined, large numbers of plaques are found throughout. Dr. Donald Price and his colleague Dr. Philip Wong have developed a range of mouse models for AD. They can manipulate the models to vary the age at which the memory impairment appears, and the severity of the pathology observed. Currently, this outstanding group of investigators is developing methods for 'turning on' and 'turning off' the pathological features of AD at varying ages.
Expertise in the Evaluation and Examination of Rat Models
Dr. Michela Gallagher and her colleagues have developed a rat model of aging. Cognitive impairment, which occurs in approximately 60% of the aged population in this model, is associated with abnormalities in the synapses (i.e., the connections between nerve cells) at sites where AD is first detected. Moreover, gene expression profiles in this model also demonstrate changes in regions that are affected earliest in AD. Dr. Gallagher and her colleagues have now begun a series of studies to examine whether the brain changes associated with cognitive impairment in these aged rats confers a selective vulnerability to the expression of AD pathology by using gene transfer methods. Dr. Richard O'Brien uses similar animal models to determine how nerve cells change in response to injury and with experience. These rat models may provide important clues to the evolution of AD.
Expertise in Evaluation and Characterization of Patients with Memory Disorders
Dr. Marilyn Albert and Dr. Constantine Lyketsos have considerable expertise in the evaluation and characterization of AD patients. Both have also led large longitudinal studies related to the evaluation of cognitive decline over time. In recent years, Dr. Albert has focused her efforts on studying the evolution of cognitive problems among individuals with memory problems who do not meet criteria for dementia. Dr. Lyketsos has focused primarily on characterizing the behavioral difficulties that such individuals demonstrate. Dr. Argye Hillis and Dr. Chiadi Onyike have considerable expertise in the evaluation and characterization of patients with Frontotemporal Dementia (FTD). Dr. Hillis is primarily interested in the language disturbance experienced by some patients with FTD patients and understanding how it evolves over time. Dr. Onyike is focused on the behavioral disturbance of the patients, with the hope that it can be treated more effectively than is currently the case. Dr. Paul Dash has a particular interest in improving ways in which the practicing clinician can accurately diagnose patients with mild cognitive symptoms. The overall goal of this research is to identify individuals in whom AD is developing but do not have the full blown dementia syndrome. When medications are found that delay progression of disease, these will be the individuals one would want to target for early treatment.
Expertise in Understanding how Vascular Factors Influence Change in Mental Ability
Dr. Guy McKhann and his colleague Rebecca Gottesman have been following patients with vascular disease for many years in order to understand the influence of vascular risk factors on cognitive decline. Through their work, it is increasingly clear that vascular risk factors, such as high blood pressure, diabetes and high cholesterol, increase the likelihood that individuals will experience cognitive decline. Moreover, vascular factors increase the severity of symptoms in patients with other brain disorders, such as AD. This is a particularly important area of research because a lot is known about medications and life style changes that can reduce vascular risk. The next step is to determine whether reduction in vascular risk alters the likelihood of cognitive decline.
Expertise in Brain Imaging
Dr. Peter vanZijl (Director of the Kirby Imaging Center) oversees a state-of-the-art magnetic resonance imaging (MRI) center at Johns Hopkins. He and his colleagues, Drs. Susumu Mori and James Pekar have developed a number of novel approaches to imaging (including Diffusion Tensor Imaging) and have considerable expertise in standard imaging applications as well. Dr. Dean Wong (Director of Research in the Department of Radiology) oversees a state-of-the-art positron emission tomography (PET) imaging facility at Johns Hopkins. He and his colleagues have developed novel PET ligands and routinely implement the most promising PET methods for use by Hopkins investigators. Both imaging groups have formed collaborations with many of the investigators listed above, and are in the process of conducting several longitudinal imaging studies related to AD. Most of this work is being conducted in humans, but imaging in animal models of AD has begun as well.
Taken as a whole, this work will provide: (1) insights into the basic mechanisms involved in the death of brain cells and possible strategies for blocking or reversing those changes; (2) early detection of disease so that therapies under development can be applied before the disease is full blown; and, (3) the ultimate goal, truly effective treatments for patients.