Alum SCORES KEY ACHIEVEMENTS in CLINICAL RESEARCH of ALZHEIMER'S DISEASE
Psychiatrist Barry Reisberg, M.D. '72, has pioneered the investigation for two decades. His latest study reveals the first effective treatment for later stages of the disease.
Marjorie Roberts
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ABOVE: Barry Reisberg, M.D. '72, clinical researcher in Alzheimer's disease. |
Alzheimer's disease, a rare entry in the medical literature until the 1980s, is now considered the most common form of dementia affecting people over 65. Not a part of normal aging, it is nonetheless estimated to strike half the elderly who live past 85. Although progress in treatment has been limited, research continues with all due speed at medical centers across the nation. Many of the most important studies published are rife with the name of School of Medicine alum Barry Reisberg, M.D. '72. Currently a professor of psychiatry in the School of Medicine at New York University and clinical director of its William and Sylvia Silberstein Aging and Dementia Research and Treatment Center, Dr. Reisberg is a leading investigator of the mind-robbing disease that is thought to afflict four million people in the U.S.
From NYMC to NYU
After his residency in psychiatry at affiliated Metropolitan Hospital Center in New York City, Dr. Reisberg spent nearly three years as a member of the College faculty-clinical instructor in the Department of Psychiatry in Valhalla, and staff psychiatrist at the College unit of the FDR Veterans Administration Medical Center in Montrose, N.Y. It was not until 1978 that he accepted his first appointment at NYU as a clinical assistant professor in the Neuropsychopharmacology Research Unit of the NYU Medical Center. "The dementia center was part of that unit," says Dr. Reisberg, "and I have been its director for more than 25 years." His associate all that time has been Steven H. Ferris, Ph.D., professor of psychiatry and of Alzheimer's disease.
On April 3, 2003, principal investigator Reisberg rejoiced when the results of a large multi-center clinical study were published in the New England Journal of Medicine. A total of 252 patients in the later stages of Alzheimer's disease were enrolled at 32 sites and randomly assigned to receive placebo or 20 mg of memantine daily for 28 weeks.
Compelling results
"Patients receiving memantine had a better outcome than those receiving placebo …Antiglutamatergic treatment reduced clinical deterioration in moderate-to-severe Alzheimer's disease, a phase associated with distress for patients and burden on caregivers, for which other treatments are not available," according to the New England Journal abstract. Here is Dr. Reisberg's view of the events:
"Those patients seem to be declining much less, about half as much as ordinarily expected, over a six-month period. Memantine slows down the otherwise inexorable progress of this disease, and it is remarkably free of side effects. These are very impressive results. Those who participated represent one of the most severely impaired groups ever enrolled in a rigorous, multi-center clinical trial of an anti-dementia drug. It looks like memantine really will have an impact on the disease."
The reason his group singled out the drug is "over-stimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate is implicated in neurodegenerative disorders," the abstract states. "So we decided to investigate memantine, which is an NMDA antagonist, to treat the disease. It blocks the activity of glutamate, a brain chemical that excites neurons. And we know that when neurons become over-stimulated because of an abundance of glutamate, the nerve cells can become damaged or die. This excitotoxicity has been linked to death of neurons in the brains of patients with Alzheimer's," says Dr. Reisberg. "And the nerve cells that respond to glutamate are involved in memory and learning. Memantine is a completely different chemical way of getting to the disease."
Will it have legs?
"We don't know if memantine can slow the disease for more than six months," he continues. "It may slow the progression for a longer time, and we have evidence it does, but that remains to be definitively determined." Available since January after approval by the FDA in 2003 on the basis of Dr. Reisberg's trial and other supportive data, memantine is made by Merz Pharmaceuticals, Frankfurt, Germany. Used there for more than a decade to treat neurologic conditions, it is sold in the U.S. under the proprietary name of Namenda by Forrest Pharmaceuticals, New York City.
This latest success for Dr. Reisberg places him on the top rung of the Alzheimer's ladder, a lifelong climb that he happily admits began at New York Medical College. If his thirst for research wasn't exactly quenched during his residency, it was certainly the training ground where he got his feet wet.
"I had been undecided between family practice and psychiatry. I knew I could do more with psychiatry, and so I interviewed widely for my internship. I picked New York Medical College because of the excellent psychiatry department chaired by Alfred Freedman," he says. "I was always interested in research. During my residency I worked with Michael Taylor, a faculty member, who was doing studies on symptoms of manic depression and schizophrenia at Metropolitan Hospital. Later, I published half a dozen papers with Turan Itil, who was a senior researcher and pioneer in brain EEG, at the Montrose VA when we were both on the College faculty," Dr. Reisberg says.
Seizes opportunity
"At NYU I was able to find my way and do what I wanted to do," he continues. He began with age-associated cognitive decline. "Here they called it geriatric psychopharmacology. I realized there was a whole world of opportunity in this field and that I would be investigating a disease that hadn't been described," he said. "I took it from there."
The landmark documents in which Dr. Reisberg provided seminal descriptions of many of the most important symptoms of Alzheimer's disease and its characteristic clinical course are the Global Deterioration Scale (GDS) and, subsequently, the Functional Assessment Staging Scale (FAST), which went on to describe the disease in terms of progressive changes in functioning in 16 stages and substages. (Dr. Reisberg says Medicare now mandates use of the FAST for certain evaluation purposes.) He quickly recognized that the FAST stages of Alzheimer's disease were a "precise reversal of the acquisition of capacities in normal development," a process he named "retrogenesis" in 1999. He also takes credit for having been first, beginning in the 1980s, to use the terminology Mild Cognitive Impairment.
Several years ago Dr. Reisberg moved his research in a direction that explains the role of the plaques and tangles characteristic of the Alzheimer's brain found on autopsy. He believes the toxic protein beta amyloid stimulates neurons to try to divide. "In neurons that cannot divide, this attempt at division is futile and results in tangles and cell death. The most viable neurons, which contain the most recently acquired information, are the most vulnerable," he says. "This explains the retrogenic clinical process that we have observed."
"I want to continue to develop drugs that will slow the process and otherwise treat the disease," he states. He points to Risperdal (risperidone), the leading antipsychotic medication approved by more than 30 nations for treating behavioral symptoms of dementia, which was developed for this purpose based on Reisberg's "Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD)." This scale was first published in the Journal of Clinical Psychiatry, May 1987, in the paper "Behavioral Symptoms in Alzheimer's Disease: Phenomenology and Treatment."
"I am using an anthropological-like technique of very systematic clinical observation in developing these scales. I continue to describe brain aging and Alzheimer's disease in greater and greater detail, and I've linked the clinical symptoms to the biomolecular and pathologic nature of the disease," says Dr. Reisberg. "Why shouldn't a clinician put this together rather than a molecular biologist?"