6. Functional and Neurotransmitter-Toxic Neuronal Changes
Thus far, this report has highlighted several visible cellular changes in dementing diseases. However, there are functional changes that can remain invisible, but have dire consequences. Several pathophysiological mechanisms underlying alterations of neuronal function that may lead to neurodegenerative changes are under investigation. These functional changes can be appreciated on the electrophysiological, metabolic, and neurotransmitter levels; and they are introduced here briefly to show their relevance to dementia.
Learning and memory are central to AD and other dementing diseases.
Electrophysiological studies in the hippocampus have suggested that long-term potentiation may play an important role in these cognitive functions (Bliss and Collingridge 1993). Pharmacological experiments are beginning to provide a molecular understanding of these events. Glutamate receptors of the n-methyl-d-aspartate (NMDA) type appear to be required for long-term potentiation (e.g., Harris et al. 1984). Excitotoxins that activate the NMDA receptors also have been strongly implicated as initiators of neurodegeneration under conditions of compromised energy. This is relevant to dementia in that several laboratories have reported mitochondrial energy defects in AD patients. Energy impairment also can result in selective degeneration of NMDA receptor-bearing neurons, which eliminates NMDA receptors and renders the NMDA receptor system hypofunc-tional. NMDA receptor changes apparently can trigger widespread degeneration of neurons in corticolimbic distribution mirroring the neurodegenerative changes in AD (Bensimon et al. 1994).
Glutamate, another excitatory neurotransmitter, originally was shown to be toxic to central nervous system (CNS) neurons when administered subcutaneously or orally to immature animals. More recently, ingestion of shellfish containing an excitotoxin that activates glutamate receptors caused hippocampal neurodegenerative changes and memory impairment, especially in older people (Teitelbaum et al. 1990). Although such toxins are best detected in an acute overdose setting, it may be relevant to consider their destructive potentials in a more chronic setting. People may be exposed to such toxins incrementally at very low doses, making cumulative neuronal changes difficult to trace to the source. Because epidemiologic studies indicate environmental factors are important in AD (vide infra), it is regrettable that glutamate-like agents and other possible environmental toxins have not been better studied in the context of more common late-onset dementias.
Recent electrophysiological and pharmacological studies underscore the delicate balance needed for these excitatory neurotransmitter interactions to produce adaptive, rather than neurotoxic, effects. Excitatory neurotransmitters deserve more attention in AD, as they can influence the plasticity of interneuronal connections in the nervous system (Lipton and Kater 1989) and have been linked to chronic neurodegenerative states such as Huntington's disease. The mechanisms for damage (reviewed in Lipton and Rosenberg 1994) strongly suggest that chronic neurological diseases may be mediated, at least in part, by a final common pathway involving excessive stimulation of glutamate and similar excitatory receptors. Additionally, chronic changes in human dementia pugilistica (punch drunk) syndromes that develop years after repeated head trauma may be linked to an excitatory receptor-mediated cascade of damage. This suggests that preventive strategies to reduce head injury, including public education, if successful, could reduce cases of dementia.
One must consider the likelihood that multiple sources of damage to neurons are required to lead to AD. The sources probably vary from one AD patient group to another. It may well require the interaction of these multiple sources of damage to impair neuronal function and lead to loss of synapses (neuronal connections), neuronal atrophy, neurofibrillary change, and, ultimately, neuronal death.
There are a number of new NMDA antagonists and similar drugs that may interfere with excessive excitatory-receptor interactions. Several of these drugs are in clinical trials and appear to block or minimize the cascade of damage by this common pathway. Interestingly, one drug (Riluzole) that inhibits glutamate release has been reported in a preliminary study to slow the rate of neuronal dysfunction in the chronic neurodegenerative disease amyotrophic lateral sclerosis (Lou Gehrig's disease) (Bensimon et al. 1994). The possibility that slow neuronal degeneration in other conditions, including AD, might respond to such treatment deserves to be tested.
Several biotechnology companies are developing neurotrophic factors for commercial use. These naturally occurring proteins, some of which are made by glial cells, help keep neurons alive and healthy during development and adult life. They also may be required in small amounts during adulthood to prevent premature neuronal death. Many new neurotrophic factors, such as brain-derived neurotrophic factor, insulin-like growth factor, and ciliary neurotrophic growth factor, continue to be discovered and tested. These factors, like the transmitter-antagonists, appear to offer novel therapeutic ammunition. However, drug delivery to the brain, titration of levels to achieve a positive action without severe side effects, and long-term followup for efficacy will require substantial effort before these drugs can be used on a wide scale. In the meantime, the continued study of relevant animal models is most important. One study outlining the potential power of neurotrophic factors in treatment was published recently (Mitsumoto et al. 1994). Combined treatment with two neurotrophic factors was able to arrest disease progression for a time in mice with a genetic motor neuron degenerative disease, as measured by behavioral, physiological, and pathological criteria.
7. Free Radicals and the Nitric Oxide Cascade
The brain is extremely sensitive to oxygen deprivation. When oxygen is reduced, oxidative stress leads to the production of oxygen-free radicals, which can damage neurons (Reiter 1995). Several investigators have speculated, perhaps oversimplistically, that free radical changes may be the final link in several neurodegenerative disorders. Nitric oxide is generated when NMDA or other receptors are excessively stimulated (e.g., Dawson et al. 1991) and has been considered as a potential cause of AD (Coyle and Puttfarcken 1993). Some forms of nitric oxide can have a reverse or protective effect. Several scientists are investigating the nitric oxide cascade in AD. At the very least, nitric oxide appears to be a key molecule in the mechanism of synaptic plasticity and learning. The nitric oxide signaling pathways are extremely complex, but in the last few years, excitement and controversy have arisen over the ever-expanding list of functions of nitric oxide in the CNS (Dawson and Snyder 1994). Because excitatory amino acid neurotransmitters can generate massive numbers of free radicals, attempts to reduce free radical damage are logical. Anti-oxidants may be an important preventive strategy in AD (Reiter 1995). Insufficient nutritional intake of vitamins such as C and E may be a factor in the epidemiology of dementia, and vitamin supplementation can be done with little expense.
8. Epigenetic DNA Changes
Epigenetic changes are those that are superimposed on inherited DNA. Some changes can be fairly simple and due to damage, whereas others are often part of a natural host strategy to modulate gene expression. For example, calcium ions, important for normal neuronal functions, can activate nuclear enzymes with the capacity to cause DNA fragmentation. This action may be pertinent to chronic neurodegenerative disease. Intact DNA is required for the proper function of cells and is especially critical for the proper function of large neurons with enormous metabolic activity. In addition, free radicals (also elicited by calcium ion changes) can damage DNA directly. The brain is exposed to a plethora of environmental chemicals and other insults that may have detrimental effects similar to those of ultraviolet radiation.
The consequences of nuclear DNA changes in neurons have not been studied extensively in the nervous system. Because most neurons do not replicate their DNA, breaks within the DNA may be incompletely repaired. With time, these changes may be accentuated by a decreased capacity for repair in aging cells. These global DNA changes could be quite important in insidious diseases of the nervous system. Many environmental carcinogens can damage DNA, and some may promote the development of sporadic AD. Non-inherited DNA changes occurring after brain cells develop deserve attention, especially as recent data indicate the relevance of such changes for aging cells.
Epigenetic DNA and chromosomal studies in aging cells have just begun, and only a few basic model cell systems have been explored. The progressive shortening of DNA sequences at the ends of chromosomes (known as telomeres) has been linked to the onset of aging in yeast cells. Similar changes also have been observed in several human and mammalian cell lines studied sequentially in vitro (Harley et al. 1990). In addition, sperm have long telomeres, whereas aging skin cells have much shorter telomeres.
Investigating telomeric sequences in aging brain cells is both pertinent and feasible, as these sequences are well described in mammals. Other epigenetic changes in the chromosome, such as methylation (Surani 1993), have been defined in the context of development and in Huntington's disease and should be studied in other late-onset dementias. If epigenetic DNA damage accumulates in the nuclei of neurons during aging, one also would expect insidious and ultimately widespread functional cognitive problems.
Apoptosis, a rapid form of cell death, has been noted in the discussion of amyloid-induced toxicity. This avenue of research has far-reaching implications and has provided new tools and reagents for specific studies. Clumping of chromatin in the nucleus is a typical hallmark of apoptosis, and DNA fragmentation in a ladder pattern shows that specific types of breaks have been made. The discovery of "death-inducing" proteins by investigators working in developmental yeast genetics has made apoptosis an exciting new field. Researchers identified several genes that were required for a programmed or apoptotic cell death, as well as other genes that produced proteins with an opposite or savior effect (Barinaga 1994a). Both the destructor and savior apoptotic genes are conserved in evolution. Several human and murine homologs of these genes already have been cloned (Fang et al. 1994), and it has become increasingly apparent that these proteins (as well as the emerging death preventing proteins) might be involved in some forms of neuronal degeneration in adult dementias.
9. Persistent and Latent Viruses
As discussed above, AD now is accepted to be a complex, chronic disease that has both genetic and environmental causes. One environmental factor that may be incompletely appreciated is persistent viruses. Although it has yet to be demonstrated in AD, several scientists have suggested that a subset of dementia patients may have causal persistent and latent viral infections that do not induce typical lymphocytic reactions. Because many types of viruses are latent in the population, these unrecognized asymptomatic infections may contribute to dementing diseases (Manuelidis 1994a). Many persistent viruses can evade immune surveillance and slowly lead to a loss of specific functions, rather than the typical picture of an acute infection (Oldstone 1991). It has become increasingly apparent that a number of different viruses, such as HIV and the papovavirus that causes progressive multifocal leukoencephalopathy, can enter the brain and either live innocuously without producing symptoms or cause dementia in selected people. The cause of some of these dementias would certainly have been missed without specific viral markers. Persistent viruses such as human T-cell leukemia/lymphoma virus-I and Borna disease virus cause neurological consequences in only a few individuals, and symptoms may not be apparent for many years. The causal role of these viruses has been verified by experimental recreation of disease in animals or by careful epidemiologic analyses. Nonetheless, because some viruses apparently can be "innocuous" passengers, their specific role in diseases of the brain remains uncertain.
It has become increasingly clear that several common persistent viruses are lethal to only a few people. These viruses are more prevalent in specific geographic areas outside of the United States. However, with our modern cross-national contacts and exchanges of medical materials, infections with new and previously unknown viruses pose an increased risk for our population (Lederberg 1993; Manuelidis 1994b). Cognitive as well as personality changes can be caused by infections with the Borna disease virus, one only recently identified by recombinant techniques (Briese et al. 1992; VandeWoude et al. 1990). These are some of the reasons why viral causes of dementia should be pursued.
Why only certain people develop a disease in the face of a common infection has become much clearer with modern genetic approaches. Virological and molecular studies in animals have established the importance of heredity as a susceptibility factor for progressive infection. One infectious agent that shows this feature causes CJD, an infrequent late-onset dementia discussed previously in this report. Specific host gene polymorphisms have been linked to CJD. Remarkably, of the thousands of people who received CJD-contaminated growth hormone, only those with an inherited polymorphism in the PrP gene developed progressive disease after 8 to 25 years (Brown et al. 1992), suggesting an unusual genetic susceptibility to this infection. A recent epidemic of CJD (1,000 to 3,000 times the normal incidence) in 1 region of Slovakia is cautionary (Gajdusek 1994). Although the affected people have an inherited PrP polymorphism, they clearly have a transmissible disease that can be propagated in animals. This outbreak appeared after 1970, indicating that something in the victims' environment changed. Imported cows with a similar epidemic infection (known as mad cow disease or bovine spongiform encephalopathy (BSE) (Collee 1993)) may have been introduced. Alternatively, a change in medical practice could have introduced the infection. New ways to detect emerging slow or latent viruses in the environment and in medical materials injected into patients may lead to more effective preventive measures.
10. Other Environmental Factors that May Tip the Balance
The nutritional status of patients with dementia has not been studied adequately. However, it is well known that older people living alone, especially women on minimal pensions or other funds, may have inadequate nutritional intake over many years. Damage to DNA and membrane functions may be accentuated when critical scavenger pathways for free radical cleanup are at suboptimal levels due to poor nutrition. Other important metabolic and functional pathways also may be compromised, tipping the balance toward neurodegeneration. It may be appropriate to expose aging animals in a marginally adequate nutritional state to minimal doses of relevant toxic chemicals to discover whether aging changes in the brain, such as neuronal or synaptic loss, take place prematurely. Epidemiologic studies also could be informative, including early life and in utero nutrition conditions of humans. Supplementing diet with simple and inexpensive anti-oxidant vitamins to minimize free radical formation and its consequences also may have some value in retarding the onset of dementia.
11. Epidemiologic Studies
Studies of identical twins have been important in clarifying the contribution of the environment to the development of AD. In twins with identical genes, the age of onset of AD was not the same. One twin was prematurely stricken, while his sibling showed no clinical disease during a normal lifespan of over 75 years. A purely genetic or inherited cause of disease in the twins with AD is unlikely. Rather, epidemiologic data indicate one or more environmental factors may be essential for the development of AD. As noted above, such environmental factors could include toxins, nutritional states, and persistent unrecognized viruses. Because environmental factors may be more readily controlled than genetic factors, it is important to expand efforts to identify those that are critical and can affect the largest number of people.
Epidemiologic approaches to the study of dementia are being used to evaluate presumed environmental toxins as major causative factors in AD. For example, there has been concern that exposure to aluminum products could cause AD. This hypothesis has been evaluated by additional experimental and epidemiologic studies that have not substantiated a major role for aluminum. Without careful epidemiologic research and without support for investigators attempting to reproduce earlier observations concerning the effects of environmental exposure that may be identified in the brains of people with AD, major unnecessary lifestyle changes could have taken place. These self-critical studies also emphasize the importance of supporting multiple groups of investigators, rather than only single large laboratories.
Epidemiologic studies also have shown that AD affects more women than men, even if one allows for the higher proportion of women who survive into the higher age groups. The Panel considers it unfortunate that the women's health initiative does not include a major component on AD, as it disproportionately disables older women as patients and as caregivers.
One recent study indicates that post-menopausal women taking estrogen supplements may have a delayed onset or reduced incidence of AD (Larson et al. 1992; Larson 1993). A review of medical records of more than 2,000 women in southern California indicated that those on estrogen replacement therapy were less likely to develop AD than their untreated counterparts (Paganini-Hill and Henderson 1994), whereas another study failed to find this relationship (Brenner et al. 1994). Several small experimental research projects also have suggested that estrogen loss may be a factor in neurodegenerative disease (Okamura et al. 1994). Thus, preliminary studies raise the important possibility that estrogen supplements in women over 50 might delay or prevent the onset of AD. Studies of such supplements to prevent osteoporosis and other conditions are ongoing and will establish dosages and side effects. These studies could be expanded to include the effects of estrogens on dementia.
Several consortia have been established to bring greater efficiency to epidemiologic studies of dementia. The Consortium to Establish a Registry of Alzheimer's Disease (CERAD), funded by the NIA, established a U.S. and international database as well as consensus procedures to study the cognitive changes in AD (Morris et al. 1989). Researchers developed neuropsychological and neuropathological protocols (Mirra et al. 1991) and a protocol to measure behavioral disabilities (Larson et al. 1992; Larson 1993). CERAD has actively enrolled more than 1,300 people, including minorities, and has monitored them for over 7 years. Efforts have been expanded recently to include non-AD forms of dementia in the registry. CERAD has focused on developing and standardizing methods to be used in population-based studies, but has not pursued those studies itself. A consortium of the European community (EURODEM) has brought investigators from Europe and the United States together to enhance knowledge of risk factors in dementia (van Duijn and Hofman 1992). Epidemiologic studies also are being carried out in Canada and by the World Health Organization.
Domestic and international epidemiologic studies contribute important information for the development of public policy, including more accurate estimates of disease incidence and prevalence. They help define the magnitude and nature of specific problems in different regions of the country and among diverse ethnic groups, and also identify potential risk factors for disease. There now is reasonable agreement that the prevalence of dementia doubles with every 5-year increase in the age of subjects between 65 and 85 years old and appears to be present in more than 40 percent of people aged 85 and older (Larson et al. 1992; Larson 1993). Studies of this age group will be critical for health policy planning for the fastest growing component of our society–Americans over age 85.
Promising Areas of Research
The next important discoveries leading to better understanding of the causes or mechanisms of dementia and its effective therapy, postponement, or prevention cannot be predicted with confidence. However, of the many diverse and important scientific lines of inquiry in research cited earlier, some appear likely to produce tangible results in the near term. These include:
a. Pursuit of the cellular pathways specified by mutant genes in AD and other dementias
b. Identification of mechanisms of amyloid formation and neurotoxicity
c. Understanding the rules governing the steps between normal neuronal tauand NFT's
d. Continued development of cell culture and animal models of disease in which to test hypotheses and evaluate therapeutic agents
e. Use of ongoing searches for environmental risk factors, especially in cross-cultural settings, that use epidemiologic methods; and incorporation of recent advances in genetics (e.g., ApoE) to define interactions between genetics and environment in the more common late-onset AD.
Essential Research and Training Opportunities
Because the causes of dementia are heterogeneous, it would be unwise to prematurely exclude certain novel avenues or approaches. The entire research community should encourage investigator-initiated individual awards in addition to providing sustained and appropriate funding for established large center-collaborative projects that uniquely support in-depth studies of well-defined samples of patients. Together these assets can be used to identify the crucial causes of disease as well as appropriate treatments to halt disease progression. Individual investigator-initiated projects bring new minds and talents to work on solving the many riddles of dementia. The definition of extrinsic or environmental factors has the potential, at least in some instances, to point out a way to prevent or delay unnecessary disease. Ultimately, this approach could be a most cost-effective investment of health dollars. The expansion of initiatives and inclusion of more disciplines will invigorate the field, attract more top-ranking young scientists, and speed the progress of research.
Additional fellowship awards will encourage top scientists (both junior and senior) to enter this most important area of biomedical research. Because dementia studies require a long-term commitment, an initial award of 5 years is more appropriate than the usual 3 years. Encouraging more senior investigators with special resources, expertise, and willingness to train new independent investigators will facilitate interaction and further progress. Thus, there should be provision for more experienced investigators from various disciplines. If there is no mechanism to encourage talented people to enter this field, it may become prematurely narrow and inflexible. Investing in young scientists and giving them some latitude are essential for our own future, as well as for original and effective public health initiatives. Independent investigator initiatives such as immunological and neurotrophic therapeutic strategies to alleviate the progression of AD also should be supported further.
Summary and Recommendations
The impact of AD and other dementing disorders now is well recognized. The toll is exacted not only from the patients and their families, but also from the general population. The cost imposed on our society by these dementias now is estimated to be 100 billion dollars per year. This terrible drain on society and associated costs will continue to increase as the population ages. The Panel reemphasizes the unique advantages of a scientific solution to reduce the oppressive financial and human burden imposed by AD and other dementias.
Over the last 15 years, the Congress and the Executive Branches recognized the urgency of this problem and responded with significant increases in research funding. While this support has led to a major growth in knowledge with previously unsuspected and important findings, it is insufficient for addressing a problem of this magnitude. The biomedical community now is poised for rapid and relevant advances at all levels of investigation. This opportunity should not be lost (Khachaturian 1994). If the necessary infrastructure, already in place, is compromised by lack of funding, this biomedical research enterprise would require an enormous effort and expense to rebuild. The preceding report emphasizes fundamental advances that have given great impetus to the field. At the same time, the Panel emphasizes a realistic longer range perspective. This perspective is necessary to realize the fruits of past efforts and to combat the profound problem of dementia in our society. The broad range of opportunities predicts that further dramatic steps forward are possible. Increased stable funding is essential to reach these goals.
There currently are many underfunded biomedical research opportunities that are central to the understanding and treatment of dementia. These efforts deserve increased or new support. Even in this review of examples illustrating recent biomedical findings linked to dementia, one can glimpse the many convergent and complementary themes. Dementias are complex diseases, and each of these research themes deserves attention. Because many issues of causation remain unclear, it also is essential to support diversified initiatives and approaches, and encourage less traditional research directions with scientific merit and originality. One consequence of a limited budget is that there will be support only for safe, narrow, or well-publicized notions, which could be detrimental to progress in this area. In a time of budgetary stringency such as the present, this concern needs particular emphasis. The natural tendency to pursue only currently hot breakthroughs may squeeze out support for less popular, but often innovative lines of research. These avenues of research have the potential to lead to future conceptual and practical discoveries. The Panel emphasizes the need for support of additional independent grant awards to people and fellowships to bring the appropriate diversity of expert individuals into this field. This will speed up the development of therapeutic and preventive initiatives for the health of our population. The Panel does not intend that this endeavor should detract from the support of valuable research in the ADC's and other program project approaches.
The powerful techniques of molecular biology have been applied only to very limited problems in dementia. The progress in hereditary risk factors and amyloidogenic proteins has been extraordinary, but it is only the tip of the iceberg. If similar efforts were brought to bear on other themes mentioned above (such as NFT mechanisms, immunological responses, growth and hormonal factors, environmental toxins, animal models, persistent viruses, and pharmacological agents directed at specific pathways), we would be in a better position to prevent and treat these diseases. Given the increasing population subject to dementia, it would be shortsighted and ultimately more costly to ignore the current opportunities. Although one cannot predict which directions will be most fruitful, it is likely that several of these directions will lead to significant discoveries. Science is inherently unpredictable. However, recent advances demonstrate the need to avoid restricting research funds, an action that causes high risk, but ultimately high yield, projects to fall by the wayside.
The Panel wishes to emphasize in the strongest possible terms that, even in this age of cost limitations, underfunding of dementia research represents a serious disinvestment in America's future. The annual Federal biomedical research budget for AD comes to only 0.3 percent of the total costs of the disease. The Panel appreciates current fiscal restraints, as well as an immediate need to take care of current patients with dementia. However, an increase to 0.5 percent of total patient costs, or 500 million dollars annually, is not unreasonable given the magnitude, costs, and prevalence of these diseases. New approaches and treatments may allow people to function independently in preferred community settings. It is within the power of systematic science to identify sources of preventable disease, as well as ways to alleviate or delay mental deterioration. A long-term commitment to this multidisciplinary endeavor is the most likely way to succeed. It is reasonable to expect that a vigorous, diverse program of biomedical research during the next 10 years may lead to savings of billions of dollars by delaying the need for full-time care of AD patients at home or in long-term care institutions.
Source: Advisory Panel on Alzheimer’s Disease
Published in August 1995
DHHS Advisory Panel on Alzheimer's Disease
Leonard Berg, M.D.
Alzheimer's Disease Research Center
Washington University School of Medicine
St. Louis, Missouri
John P. Blass, M.D., Ph.D.
Director, Dementia Research Service
Burke Medical Research Institute
White Plains, New York
Christine Branche, M.A.
Cleveland Alzheimer's Association
Kathleen Coen Buckwalter, Ph.D., R.N.
Professor, College of Nursing
University of Iowa
Iowa City, Iowa
Past National Chairman
Gary Gottlieb, M.D., M.B.A.
Director and CEO
Lisa Gwyther, A.C.S.W.
Director, Family Support Program
Center for Aging
Duke University Medical Center
Durham, North Carolina
Robert L. Kane, M.D.
Minnesota Chair in Long-Term Care and Aging
School of Public Health
University of Minnesota
Eric B. Larson, M.D., M.P.H.
University of Washington Medical Center
Laura Manuelidis, M.D.
Professor and Head of Neuropathology
Yale University School of Medicine
New Haven, Connecticut
Donald L. Price, M.D.
Professor of Pathology, Neurology, and Neuroscience
Johns Hopkins University School of Medicine
Diane Rowland, Sc.D.
Senior Vice President
Henry J. Kaiser Family Foundation
Gregg A. Warshaw, M.D.
Associate Professor, Family Medicine
Director, Office of Geriatric Medicine
University of Cincinnati College of Medicine
Peter J. Whitehouse, M.D., Ph.D.
Director, Alzheimer's Center
University Hospitals of Cleveland
Jerome A. Yesavage, M.D.
Director, Aging Clinical Research Center
Veterans Administration Medical Center
Palo Alto, California
Ex Officio Members
The Honorable Philip R. Lee, M.D.
Assistant Secretary for Health
Department of Health and Human Services
Fernando M. Torres-Gil, Ph.D.
Assistant Secretary for Aging
Department of Health and Human Services
Clifton R. Gaus, Sc.D.
Agency for Health Care Policy and Research
Rex Cowdry, M.D.
National Institute of Mental Health
Richard J. Hodes, M.D.
National Institute on Aging
Samuel P. Korper, Ph.D.
Executive Secretary of Panel
National Institute on Aging
Office of the Director
National Institute on Aging
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