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New York’s Role in the Fight Against Alzheimer’s Disease |
Jonathan Westring |
6/23/2006 |
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New York’s Role in the Fight Against Alzheimer’s Disease
Alzheimer’s Disease (AD) is an irreversible and gradually progressive neurodegenerative disorder that is estimated to affect 4.5 million people in the United States. Subsequent to the first characterization of the condition in 1906, progress in its research as a clinical disease, distinct from mental illness, was slow for much of the 20th century. However, the breakthroughs in genetics and cell biology within the last several decades have allowed research into the biochemistry of AD’s causes and pathology to yield effective therapies, and provide verification of assessment criteria. New York City’s research hospitals have been among the cutting edge in the utilization of recent advances in biology for improving comprehension and treatment of the disease. New York is also the only city in the US with three medical centers funded by the National Institute on Aging as official Alzheimer’s Disease Centers; out of the three, Columbia University performs the most comprehensive work in cell biology while New York University has a niche in psychosocial research and cognitive assessment. Another New York institution, Mount Sinai Hospital, also studies the biochemistry of AD and conducts clinical trials.
Outward symptoms of the illness in early stages include mild loss of cognitive abilities and short-term memory while prominent symptoms in middle to late stages include delusional behavior and loss of motor function. Despite much research on the subject, the primary pathologic mechanism that causes AD is still unknown. Among the risk factors, age correlates the strongest with the probability of onset. Genetics is also important, particularly in the early-onset familial form, although it plays a lesser role in the typical form where patients begin developing symptoms only over the age of 60. It is important to note that the number of patients with the common form doubles in every consecutive five-year age group over the age 65. According to the National Institutes of Health, almost half of all seniors over the age 85 are believed to be at some stage of AD progression despite the difficulty in diagnosing the illness through thorough physical, cognitive and psychological examinations. The problem appears to be expanding since the proportion of elderly within the United States population is increasing with the aging “Baby Boomer” generation. Based on 2003 study, the National Institute of Aging estimates that the number of AD cases will reach an average of 5.7 million by the year 2020, assuming the current rate of population growth is maintained and no new advances in treatment are found. Clearly, the effect this could have on the US healthcare system is potentially major, and is one reason why research into AD pathology is so well funded.
One of the most distinguishing characteristics of the disease is observed in a post-mortem analysis of the brain. Abnormal aggregation of proteins, in particular, the neurotoxic protein, amyloid-beta, accumulates in the AD brain as plaque. The protein is created by the faulty metabolism of a transmembrane glycoprotein, and its accumulation causes injury and death of nerve cells leading to the severe dementia seen in final stages. Exactly how those processes work has not been completely determined, however, biologists like Dr. Shi Du Yan and Dr. Carol Troy at Columbia University have been conducting experiments that have brought doctors steps closer to the answers. In a paper published in 2001, Dr. Carol showed that the death of neurons from amyloid-beta required the activation of c-Jun N-terminal kinases (JNK), enzymes that are involved in apoptosis, or induced cell suicide. This paper was one step forward out of many such advances, which helped to clarify the unique physiology behind the disease as well as to potentially allow other researchers develop means to solve this underlying biochemical problem. Professor Carol and her research staff currently continue their work to clarify the mechanisms of apoptosis in nerve cells.
Dr. Yan’s research has focused on how the interaction of two proteins, RAGE and ABAD, with amyloid-beta lead to memory loss and spatial learning deficits; both prominent cognitive symptoms of AD. In 1996, Dr. Yan, along with Dr. David Stern, another Columbia Professor, discovered that RAGE, or receptor for advanced glycation end products, binds with the amyloid-beta protein, and helps transfer the molecule across the blood-brain barrier into the Central Nervous System where it accumulates as plaque. Dr. Stern later patented this discovery as a method to increase cerebral blood flow in amyloid angiopathy as a treatment for blood flow inhibition in the brain caused by the protein’s build-up along vessel walls. This discovery is a good example of how even just one step towards clarifying the biochemical process of a disease can create opportunities for the development of potential treatments. The importance of “translational research” is taken seriously by the AD Research Centers, including Mount Sinai Hospital, which carries out independent laboratory research in conjunction with their clinical studies program. Biotechnology and pharmaceutical companies build upon research from institutions like Columbia in order to translate breakthroughs, which clarify the understanding of an illness, into effective treatments.
In addition to peptides accumulating in the brain, a decline in levels of the neurotransmitter, acetylcholine, is a hallmark of AD. One of the first Alzheimer’s pharmaceuticals to be approved by the US Food and Drug Administration (FDA) in the 1990’s were acetylcholinesterase inhibitors, molecules designed to shutdown the enzymes responsible for clearing acetylcholine from the synapses in between neurons. Pfizer’s donepezil HCl, which is marketed as Aricept, was the second such drug to be approved by the FDA in 1996. However, unlike the promising treatments currently being evaluated by some biotechnology companies, these drugs only delay disease progression and are not a cure.
While Aricept is currently Pfizer’s only AD treatment that is marketed to the public, the company recognizes the need to build upon its already strong neuroscience research. In early April, Pfizer announced that it entered into an agreement to acquire Rinat Neuroscience, a South San Francisco biotech, for an undisclosed sum that according to NeuroInvestment was rumored to exceed $300 million. Within Rinat’s pipeline, is RN1219, an antibody to amyloid-beta peptides that has demonstrated success in pre-clinical trials. Moves like Pfizer’s acquisition are a trend seen with greater frequently in the life science industry. As pharmaceutical company patents expire, acquisition of individual research projects or entire biotech companies appear more attractive as a way to bolster internal research and development efforts. In addition, the large size of the rumored-sum underscores the growing attractiveness of novel AD treatments as the acetylcholinesterase inhibitor market is becoming more difficult in which to gain entry and the numbers of AD patients in the US continue to rise.
Some companies, however, see the continuing success of the inhibitors as a good bet for a new product; New York-based Axonyx, for example, is currently testing more effective forms of the drug. Other companies, such as Memory Pharmaceuticals located in Northern New Jersey, are developing novel treatments such as PDE 4 inhibitors, which are molecules similar in function to currently marketed drugs for treatment of non-related ailments, and nicotinic agonists, or functional mimics of particular neurotransmitters. While in early experimentation these drugs could prove to be more effective than the current enzyme inhibitors.
The biochemical problem underlying AD is not only a matter of lowered acetylcholine levels or amyloid-beta plaque build-up, it include many other signature abnormalities. For example, the disease is also characterized by an increased presence of free radicals, or oxidants, which have come into popular media focus as cancer causing agents and the target of antioxidants. In the mid-1990’s Dr. Carol and her colleagues at Columbia’s Taub Institute for Research on Alzheimer’s Disease demonstrated that the down regulation of a particular antioxidant, super oxide dismutase, leads to apoptosis in the PC12 cell line, a cell model developed by Dr. Lloyd Greene, also a Professor at Columbia. As the antioxidant-to-free radical ratio decreases the frequency of nerve cell death climbs; the radicals react with and damage both DNA and proteins destroying nerve cells and leading to further cognitive decline.
In the late 1970’s, geriatric psychiatrist Dr. Barry Reisberg and three of his colleagues at the New York University developed an outline for the progression of primary degenerative dementia, a family of disorders that include AD. The doctors began to use their criteria to assess the patients with whom they worked. Their guidelines were based upon patients’ observable level of cognitive function and memory loss; through the course of five years of use at NYU the model was tested and substantiated using behavioral, neuroanatomic and neurophysiologic measures. In 1982, what became known as the Global Deterioration Scale, later known as the Reisberg Scale, was published in The American Journal of Psychiatry, and has since then has become the most widely used criteria for the assessment of AD. While its detailed delineation of the progression seen in primary degenerative dementia has come under some criticism, the seven staged scale is still used as the basis for predicting outcomes for individual AD patients. As home of one the NIA’s Alzheimer’s Disease Centers, NYU Medical Center continues its world-class work to improve quality of life for AD patients and their families in good part through psychiatric research such as programs aimed to better understand the day-to-day challenges of people with cognitive disabilities and those who care for them. However, NYU is working to expand their current research to include a competency in genomics and proteomics with the intention to discover and clinically test new therapies; they also continue their aim towards developing novel strategies for early clinical diagnosis.
Researchers believe that new treatments are on the horizon as a result of an increasing knowledge-base in the biochemistry of Alzheimer’s. New York institutions like Columbia University continue their work to elucidate the causes of the disease and others like NYU intend to do the same while leveraging largely non-biological, past research.
Given these current conditions New York City is likely to remain a hub for AD research into the 21st century when research of the past decades may serve as the foundation for a cure.
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