Peter M. Aupperle, MD, MPH, medical director, Geriatric Services, University Behavioral Healthcare; director of the Division of Geriatric Psychiatry and associate professor of psychiatry, UMDNJ-Robert Wood Johnson Medical School

UMDNJ’s COPSA (Comprehensive Services on Aging) Institute for Alzheimer’s Disease and Related Disorders has developed into one of the prominent dementia clinics and research facilities in New Jersey. In addition to providing dementia management services, this facility also participates in clinical research trials. In these clinical trials, we are looking to improve the cognitive benefit for patients by augmenting standard cognitive enhancers with new compounds with novel modes of action or by adding already approved medications utilized for other indications. There are also trials that focus on more effectively treating the behavioral complications of Alzheimer’s disease (AD) that so often cause caregiver stress.

The COPSA Institute for Alzheimer’s Disease and Related Disorders is part of UMDNJ-University Behavioral HealthCare and is New Jersey’s designated center for the treatment of AD. The Institute provides outpatient services consisting of diagnosis and comprehensive management for patients with dementia, as well as educational services for their caregivers. The Institute has developed into a highly successful clinical, research and educational center, which has quadrupled its research funding in the last five years. Our research team is currently engaged in active projects funded by the National Institutes of Mental Health (NIMH) and numerous pharmaceutical companies, either as investigator-initiated single site protocols or multi-center projects. The primary areas of focus include research on cognitive enhancers to improve global impairment of function and the behavioral complications of AD.

We have conducted numerous pharmaceutical-sponsored, multi-center clinical trials. Two of the many companies involved in this research are Novartis and Forest Pharmaceuticals, Inc. Several of these trials involve acetylcholinesterase (AchE) inhibitors. These compounds act by preventing the breakdown of acetylcholine in the intra-synaptic neuronal cleft. Three of these medications (donepezil, rivastigmine, and galantamine) have been approved by the FDA and now constitute the class of drugs that are approved for AD patients with mild to moderate cognition impairment. We also conducted three studies involving memantine, which has now been approved by the FDA for the treatment of moderate to severe Alzheimer’s disease and is marketed as Namenda. This compound modulates glutamatergic neurotransmission by selective antagonism of NMDA receptors.

Enlarge the image Sequential MRI scans are utilized to measure the size of the hippocampus, which typically shows significant degeneration in Alzheimer's disease. With new cognitive enhancers, we look for stabilization in this brain structure.

We are currently enrolling patients in a study sponsored by NIMH and conducted by the Alzheimer’s Disease Cooperative Study group which involves using a Chinese herb, huperzine A, which is a potent inhibitor of acetyl cholinesterase. Preclinical studies have shown that huperzine A may have advantages over the three AchE inhibitors currently used in the U.S. to treat AD, as it is also an antioxidant and neuroprotective agent. It is highly selective for AchE in vitro, has good brain penetration and is relatively free of cholinergic toxicity. There are no controlled clinical studies of huperzine A outside of China.

In addition to single agents, “combination treatments” are being explored to see if additional or perhaps even synergistic effects can be demonstrated. We have already conducted several investigator-initiated and multi-center trials. Abbot Pharmaceuticals and Janssen Pharmaceutica Products, L.P., are two of the major companies involved in our investigator-initiated trials. One of these trials will assess the efficacy of the “cocktail” memantine and galantamine (Reminyl) for treating patients with moderate to severe AD.

I recently completed an investigator-initiated protocol to test the ability of divalproex sodium (Depakote) to augment cognition in AD patients already on donepezil (Aricept). Depakote is currently used extensively for AD patients to stabilize behavioral complications (such as agitation), but recent research also points to a potential neuroprotective property of this medication. In addition to neuropsychological testing, patients received volumetric MRI scans before and after the study to assess stabilization in the degeneration of the hippocampus that is typically seen during the course of AD. Improvement was seen in both cognition and behavior and the results of this study have been presented at national and international conferences.

Another upcoming study uses MPC-7869, a compound of a non-steroidal anti-inflammatory drug (NSAID) flurbiprofen. Flurbiprofen has been marketed as Ansaid® and Froben for the treatment of pain and inflammation. MPC-7869 has been shown to selectively lower the concentration of neurotoxic fragments of the amyloid precursor protein, which leads to the degeneration of neurons involved in memory and cognition, in cultured human cells and transgenic mouse models of Alzheimer’s disease. An additional study which is enrolling participants involves using xaliproden, an investigational drug. Xaliproden is influential in the development and repair of neurons, and therefore would be useful in the prevention of human neurodegenerative disease.

Peter M. Aupperle, MD, MPH, is director of the Division of Geriatric Psychiatry and associate professor of psychiatry at RWJMS. Dr. Aupperle is also medical director of Geriatric Services and principal investigator of the Institute for Alzheimer’s Disease and Related Disorders at University Behavioral HealthCare. He received his MD and Master’s degree in public health from the College of Physicians and Surgeons of Columbia University. Dr. Aupperle completed his residency in general psychiatry and fellowship in geriatric psychiatry at Mt. Sinai Medical Center. He was an assistant professor of psychiatry at Albert Einstein College of Medicine, Hillside Hospital and Long Island Jewish Medical Center, before coming to RWJMS. §