Thalidomide, a drug known for causing severe birth defects in the 1960s, may offer hope for people with Alzheimer’s Disease (AD) more than 30 years later.

The drug recently was approved by the Food and Drug Administration in the United States for the first time to treat a skin condition associated with leprosy. But, at UNMC, it will be achieving other firsts.

In the first collaborative study for AD patients through the Center for Neurovirology and Neurodegenerative Disorders (CNND), UNMC’s basic and clinical researchers will be the first to measure thalidomide as a novel treatment of AD.

Co-principal investigators of the study are William Burke, M.D., professor of psychiatry and director of the division of geriatric psychiatry; and Howard Gendelman, M.D., CNND director and professor, pathology/microbiology. Dr. Burke also is co-director, chief of clinical affairs and director of AD research for CNND.

"Thalidomide is a natural candidate for this study. It is a potent modifier of the immune system. It turns off the microglia, or cells in the brain that produce chemokines and cytokines.

"These are nasty chemicals that rip up the nerve cells," Dr. Burke said.

Ten patients will be enrolled in the six month open label study to test the efficacy, tolerability and safety of thalidomide.

Patients will be randomly assigned to receive either 100 or 200 mg. of thalidomide. Participants will be evaluated at an initial meeting, then again at six weeks, and three- and six-month follow-up visits.

The study is sponsored by Celgene, the company that produces thalidomide.

Inflammation appears to be a common pathway to brain degeneration in AD and AIDS-related dementia. More than 17 epidemiological studies that show that patients who take anti-inflammatory drugs may be at lower risk for AD. In a study of indomethacin, a non-steroidal anti-inflammatory agent, the rate of decline in patients with AD was reduced.

"While it’s not clear exactly which anti-inflammatory agents appear to reduce risk, it appears that these agents may have a role in disease modification and prevention," Dr. Burke said.

"This study will help us determine if thalidomide also effects the neuroinflammatory and neuroradiological sequelae and responses associated with AD- related neurodegeneration."

Participants in UNMC’s study will be diagnosed with AD and are still in the early stages of the disease, exhibiting mild to moderate impairment.

"These patients will have significant memory problems and will have begun to experience difficulty in functioning independently," he said.

Daily activities that are a problem for these participants include driving, shopping, keeping a checkbook and being oriented to their surroundings.

"We want to be able to measure an improvement in the patient’s functional activity and non-cognitive behaviors over a six-month time period," Dr. Burke said.

A third goal of the study is to determine if the sedative effect of thalidomide influences tolerability. (See sidebar below.)

Clinical and invasive and non-invasive laboratory tests will be used on all patients to measure the effectiveness of the drug.

A lumbar puncture, or spinal tap, will be used to measure inflammation in the ceberbal spinal fluid (CSF). Plasma and CSF will be analyzed for neurtrophins and neurotoxins, such as pro-inflammatory ctyokines, excitatory amino acids, arachidonic acid and its metabolites, and nitric oxide.

The non-invasive test may be the most promising for AD patients.

"The novel use of proton magnetic resonance spectroscopy (MRS) as a non-invasive test is perhaps one of the most exciting prospects of this study," Dr. Burke said. MRS measures in vivo brain metabolites.

James McConnell, M.D., associate professor, radiology, will conduct the MRS procedures.

The test will measure N-acetylaspartate, choline-containing compounds, creatine/phosphorcreatine, inositol, lactic acid and other metabolites in vivo in the temporoparietal lobes and hippocampus of the brain.

Previously, Dr. McConnell worked with Dr. Gendelman and Susan Swindels, M.B.B.S., associate professor and medical director of UNMC’s HIV clinic, to examine the pattern and extent of cerebral injury in HIV infection using MRS to monitor the metabolic response to therapies.

"MRS gives biochemical information about the brain that conventional methods of analysis cannot provide, and its clinical application has substantially extended the diagnostic capability of neuroimaging," Dr. McConnell said. The MRS test is done on the same scanner as the MR imaging examination.

The measurement techniques developed for the AIDS study will be adapted for the AD study.

The AIDS study has developed into a 10-university consortium through which brain images and spectroscopies of HIV-infected patients are collected and compared at Massachusetts General Hospital in Boston.

The objective of the consortium study is to standardize the MRS methodology and to accumulate substantial number of research results. The data from this will eventually impact treatment protocols.

"In the next 20 years, billion of dollars may be spent on neuro-brain imaging for dementia in the United States," Dr. McConnell said. "The added use of MRS may also can show us if newer treatments are working.

"That’s what this research is all about — improved treatment of patients with dementing diseases," he said.

Ideally, the non-invasive MRS test will replace the spinal tap, Dr. Burke said.