Challenges Barriers to Program Development

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In 1978, task of launching a national initiative on neurobiology of aging and Alzheimer research faced a number of daunting hurdles. The process of program development involved the interaction of several variables and required inertia [work] to overcome impediments; the relationship of the key components is very similar to that in a chemical reaction. The raison d'ĂȘtre of NIA's efforts to mobilize the scientific enterprise was the acquisition of new "knowledge" to solve a looming public health problem. The ultimate "product" of the program was the discovery of a "cure" for Alzheimer's disease. However, the start of the process required "Energy" in form of massive funds to support research. Any large-scale national enterprise of discovery could not be initiated, maintained or, expected to make progress without the appropriate level of resources. Certainly the funding of any particular project alone could not assure discovery of "a cure", however inadequate funds was, and still is, a virtual certainty for failure. The second essential component for the process of building-up a program for the discovering a cure required "Substrates" in the forms of: 1) rich reservoir of fundamental knowledge about the disease, 2) critical numbers of talented/skilled investigators and, 3) adequate research infrastructure. The final crucial requirement of the process is the " Catalyst(s)" in the form of an advocate, facilitator or mentor. Throughout the process of program development a number of different actors played the important role of catalyst. Just to mention a few, these included prominent scientist, such as Lew Thomas, James Watson, Robert Katzman, Robert Terry & many others mentioned elsewhere in this article; Alzheimer Association, key legislators, foundations, individual patrons and science writers in the press.

Building a Budget The availability of funds determines whether a new program or an initiative can be launched. The struggle for additional funds is a chronic universal problem for all programs at NIH. However, increasing the budget for a new program at a new institute was particularly challenging. The first problem was that in the late 1970s the generic field of'neurobiology of aging', and NIA's 'neuroscience program' in particular, did not have any semblance of credibility or a track record of success stories e.g., reports of'major discoveries' or the 'promise of a cure.' The second dilemma for program development was the lack of effective grassroots advocacy by either an outside interest group or within the Congressional appropriation committees. These relationships with outside advocates and key congressional staff (or members of Congress) had to be established and cultivated. The third challenge was to erase the negative image of aging research and to remove the stigma of 'senility,' which impeded the progress of research on the disease. Members of Congress and their staffs, who were not well-informed about the clinical problem and the long-range public health implications had to be educated. The public attitude of a negative view of Alzheimer as a mental disorder had to be changed.

Stigma of Aging One of the most serious problems for program development stemmed from the lack of clear distinctions between the concept of "disease" and the construct of "aging". There was confusion about these two entities; and often were assume to be causally linked. From the initial identification of AD, there was no consensus on the nomenclature of "senility." "Senile dementia of Alzheimer's Type" or "pre-senile dementia" were commonly used, and interchangeable terms. The expression "senility" often implied dementia and generally described the de facto cause of the disease without any experimental proof. A prevailing misconception regarded AD as a hopeless and untreatable mental condition, an inevitable consequence of aging. As a result, very little clinical or research interest was generated, and focus on brain diseases in late life was generally deemed a career-killer in academic medicine and science.

The extremely poor reputation of "aging research" was a major handicap for program development. Aging research was regarded as 'low-grade science' and had two unique and negative consequences for NIA. One was the unfavorable attitude or scientific bias against aging research proposals reflected in the discussions of study sections. Proposals on aging or Alzheimer's invariably received substantially poorer merit ratings than those assigned to other institutes. The other outcome ofthe image problem of the field was the difficulty in attracting new competent scientific talent. Only a handful of investigators worldwide explored the unknown area of dementing disorders.

The important challenge for NIA was to change not only the public opinion, but also the attitudes of scientists and clinicians towards aging and aging research. Specifically, the concept of "senility" required replacement with the fact that AD is a brain disease. The promotion of this goal focused on the idea that despite a consistent correlation between "age" and incidence of dementia, there is no evidence for a causal relationship between the biological process "aging" and AD. The maxim that dementia is not an inevitable consequence of aging was adopted as the prime scientific principle for program development. This was critical for the goal of shifting the focus of research away from descriptive studies toward the search for the underlying neurobiology.

Credibility of the Science During the earlyphases [circa 1978-1985] of building the neuroscience program one of the major impediments was the lack of promising leads that might catapult the research career of a prospective investigator. The strategy to surmount this hurdle was to "program" or cultivate new project/proposals by proactively seek out prospective investigators. The goal was to actively recruit the best potential investigators into the fold of aging and Alzheimer's research and to recruit scientists with special expertise or technical skills. Such programming involved presentations of challenging scientific problems or unresolved questions and providing potential investigators assistance in identifying research opportunities in neurobiology of aging/Alzheimer's disease or help in planning, organizing and preparing. The strategy of "priming the pump" by actively seeking out investigators from related fields and promoting multidisciplinary research teams began to payoff by the mid-1980s. Such efforts to actively recruit talented investigators were one of the essential steps in establishing the "credibility" of aging/dementia research. Confidence in the quality of the science was crucial for changing attitudes towards aging research in the scientific community, congressional staff, legislators and the press Thus, the early foci of program development were to: a) prepare a compelling scientific story to justify targeted budget increases for AD research, and b) cultivate advocates, within the scientific community, Congress, and Alzheimer's Association.

Some of these almost insurmountable obstacles began to crumble by 1981 when NIA's budget request to Congress started to include an ever more compelling case for Alzheimer disease research funds. One of the first breakthrough findings in this regard was of the cholinergic deficits, by Peter Davies; the cholinergic hypothesis of

Alzheimer's provided the basis for such a story; later the amyloid and tau stories were promoted. As the science advanced, more 'stories' could be told to justify further funding increases, such as Carl Cotman's discovery of the retention of synaptogen-esis in the aging brain and Fred Gage's demonstration of neurite outgrowth of fetal transplants in old brains. The presentations to Congress began to emphasize the importation of modern neurobiology and cutting edge science into AD research, and presented Alzheimer's disease as a legitimate, specific neurodegenerative disease to combat the stigma of senility. Gradually research on brain aging and Alzheimer began to gain momentum leading to its current status as a vibrant and prominent field of research.

Catalysts The unique functions of catalyst in general, but especially the role NIH program staff as facilitators and mentors to prospective investigators, is very pertinent to the story of the trials and tribulations in program development. The accomplishments of the NIA program staff over the past 30 years, underscores the important role they have played in promoting, guiding, supporting and catalyzing Alzheimer's research. The Public Information Office of NIA and media in general became important allies of NIA program staff in getting the 'story' out to inform the public (Congress) and to increase the awareness of the problem. The task of "selling" research on brain aging and AD became substantially easier by the mid-1980's because: a) the NIA grant portfolio had grown and was much stronger b) the Alzheimer's Association became more active in public policy; c) Dominic Ruscio, the Association's lobbyist, was a highly effective ally, and d) the program began to cultivate and acquire a number articulate champions within the scientific community, grass roots organizations and the Congress. In this period other advocates for the cause appeared. Among these, the most notable NIA allies were: a) the Alzheimer's Association which began to fund peer-review research projects, b) the John Douglas French Foundation, which also funded new investigators through fellowships, c) MetLife Foundation began an awards program to recognize significant scientific contributions, and d) IPSEN Foundation in Paris, under the able leadership of Yves Christen began to organize seminal symposia and publish critical reviews.

Capacity & Team Building Contrary to the prevailing bias for individual investigator initiated projects (RO1s) at NIH, the NIA began to promote interdisciplinary research and multidisciplinary teams. The solution to enormously complex clinical problems required a systems approach involving the expertise of many specialties, subspecial-ties, and disciplines. Although the interdisciplinary approach strategy was believed to be effective for multifaceted problems the approach require extensive: 1) funding, 2) infrastructure, 3) organization, and 4) coordination. To address these challenges, the NIA organized a series of research planning workshops to develop strategies for team building and collaboration, creating clinical research infrastructure, and promoting standardize diagnostic procedures. After twenty years the benefits of "team science" are reflected in the sharing of data and samples fostered by the Alzheimer's Disease Centers network, Alzheimer Disease Cooperative Study and the National Alzheimer Disease Coordinating Center and the productivity of these groups.

Infrastructure for Clinical Studies In the early years the critical rate-limiting factors that impeding systematic clinical trials (therapy development) were the lack of:

1) promising therapeutic targets, 2) viable lead compounds, 3) well characterized postmortem brain tissue for molecular studies, 4) infrastructure to support longitudinal clinical studies, 5) consensus on diagnostic criteria, 6) standardized assessment instruments, and 7) expertise in clinical trials.

In the late 1970s, it was difficult to conduct clinical studies because one could not find AD patients at teaching hospitals, the usual site for clinical research. Most of the AD patients were in nursing homes which were not research friendly environments. To address the long-term strategic goal of developing treatments, it was necessary for NIA to build a) mechanisms for promoting collaborative research, b) the capability of the field to conduct longitudinal clinical research and clinical trials and c) infrastructure for clinical research. The NIA began to create the necessary national research infrastructure. The Alzheimer's Disease Research Centers (ADRCs), established in 1984, and the Alzheimer's Disease Core Centers (ADCCs), established in 1990, were central components of the research and capability infrastructure. These programs, referred to as the Alzheimer's Disease Centers or ADCs, provide the infrastructure for integrating clinical and basic science research and allowed the augmentation of a wide range of studies on the etiology and pathogenesis of AD. In 1991 the 'Satellite Clinics' program was established to fund outreach to underserved or rural patient groups. Now Satellites are an integral part of many ADCs. The Leadership and Excellence in Alzheimer's disease (LEAD) award was created in the late 1980's as a mechanism to: a) elevate the profile of AD research [will one million dollars per award] and, b) expand the field by create a formal mentorship between established senior investigators and new promising younger investigators.

Other strategies were required to address issues in the development of diagnostic criteria, standardization of assessment tools and the methodologies of clinical trials. The 'Alzheimer's Disease Patient Registry' Program (ADPR) was launched in 1986 to address the goal of developing standardized diagnostic assessments. This program includedtheConsortiumtoEstablishaRegistryfor AD (CERAD) ledbyAlHeymanand Gerda Fillenbarum, the Mayo Clinic Registry led by Len Kurland and Ron Peterson, the Seattle site led by Eric Larson, the Mon valley project with Lu Kuller and Mary Ganguli, and Denis Evans's group in East Boston. The CERAD project was successful in establishing uniform methods for the diagnosis and assessment of AD because of the dedicated and effective leadership provided by Al Heyman and the cooperation of clinicians and investigators nation and worldwide. The ADPR program overall was instrumental in the development of assessment instruments and procedures but also in filling gaps the epidemiology of AD.

In the late 1980s and early 1990s, there were no effective treatments and the drug industry had little or no interest in drug development. To stimulate targeted therapy development activities, the NIA launched two related programs: 1) Drug Discovery Groups, in 1991(as program projects), to facilitate pre-clinical drug discoveries and

2) the AD Cooperative Study (ADCS) program in 1991, led by Leon Thal, to promote clinical studies of new treatments (particularly for drugs developed in academia or small biotechnology companies) as well as to design, test and evaluate new instruments or methods in clinical trials. In the intervening ten years, the NIA has launched additional infrastructure building and or cooperative research programs, including the National Cell Repository for Alzheimer's Disease (NCRAD), National Alzheimer's

Coordinating Center (NACC), Imaging, and Genetics initiatives (with the Alzheimer's Association).

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