Also among the "Hot Topics" presentations on the last day of the conference, anti-viral drugs have benefited AIDS patients but they may increase a person's chances of developing Alzheimer's disease later in life, and scientists unveiled a rat model of tau protein "tangles," one of the pathological hallmarks of Alzheimer's.
"The diversity of research in this session is a wonderful indicator of the health and vigor of the Alzheimer research field," said William Thies, Ph.D., vice president, Medical & Scientific Affairs, Alzheimer's Association. "And we will move the field forward as fast as we are given money to move it with."
Quetiapine Evaluated For Agitation In People With Alzheimer's
Although Alzheimer's is best known for its effects on memory, as the disease progresses, individuals often experience severe agitation or symptoms of psychosis. Doctors often prescribe antipsychotic drugs to alleviate these symptoms. Quetiapine (Seroquel, AstraZeneca) is one of the newer choices, and two related AstraZeneca-funded studies presented at ICAD address questions about its effectiveness and safety. Earlier studies suggested that drugs similar to quetiapine might increase risk of stroke in older adults.
In a 10-week multicenter study, researchers assessed the effects of quetiapine in 333 elderly, institutionalized patients with severe Alzheimer's. Pierre Tariot, M.D., of the University of Rochester Medical Center, Rochester, NY, and colleagues reported significantly better scores on several indices of agitation among patients receiving quetiapine (200 mg/day) versus placebo. They reported no significant safety issues, especially strokes or transient ischemic attacks (TIAs, "mini-strokes"). This latter concern was addressed more directly in a separate analysis of data also presented at ICAD.
Led by Lon Schneider, MD, of the University of Southern California in Los Angeles, researchers pooled data from the above-referenced study and another 10-week study of quetiapine for agitation, looking for evidence of an increased risk of stroke or TIA associated with use of the drug. Both studies were conducted among institutionalized patients, and the average age was 83 years. Most of the 684 patients had Alzheimer's disease, though a minority had other types of dementia.
"Although the studies were not designed with the primary purpose of evaluating the incidence of these side-effects and the sample sizes were small, the data available so far are compatible with no increased risk for cerebrovascular adverse events with quetiapine in this population," said Schneider.
"Currently, there is broad use of antipsychotics in Alzheimer's disease for symptoms such as anxiety, sleep disturbances, delusions and hallucinations," said Sam Gandy, M.D., Ph.D., of the Alzheimer's Association's Medical & Scientific Advisory Council. "However, these drugs have not been extensively tested in people with Alzheimer's. So, questions remain about effectiveness and proper dosing levels, and clinicians need guidance. These studies are some of the first well-conducted studies of these drugs in people with Alzheimer's."
HIV Survivors Vulnerable To Alzheimer's?
AIDS patients are living longer thanks to anti-viral medicines, but those same medicines may increase their risk of Alzheimer's disease.
"The current adult HIV patient population in the USA stands a good chance of surviving the virus, which means they will become affected by many of the disorders associated with later stages in life," said Cristian L. Achim, M.D., Ph.D., of the University of Pittsburgh.
According to Achim and his collaborators, this includes neurodegenerative diseases such as Alzheimer's, which are characterized by abnormal – and possibly toxic – deposits of insoluble proteins in the nervous system. To complicate matters, the current generation of aggressive anti-viral drugs may accelerate the abnormal deposition of proteins. Achim's team examined the brains of 150 people who had died HIV positive. In two-thirds of the brains, they found deposits of beta-amyloid, one of the abnormal proteins associated with Alzheimer's disease. The deposits were found primarily inside brain cells, though in many cases beta-amyloid accumulated outside cells as well, consistent with the pathology of Alzheimer's disease.
"Although these results are preliminary, it is plausible to hypothesize that beta-amyloid brain deposits will only increase in the aging HIV population on prolonged anti-viral therapy. We intend to test this with new brain imaging techniques that can detect the accumulation of beta-amyloid," said Achim.
"Tangled" Rat Provides Landmark Experimental Model
A new animal model may allow the unraveling of one of the neuropathological mysteries of Alzheimer's – tau tangles. In addition to beta-amyloid deposits, Alzheimer's is characterized by "tangles," abnormal deposits of a protein called tau. The relationship between beta-amyloid and tau has not yet been worked out, but each protein is toxic to brain cells on its own.
Michal Novak, M.D., and colleagues at Axon Neuroscience in Vienna, Austria, created what they call "the first transgenic Alzheimer's rat showing massive, pathological neurofibrillary changes, memory impairment and decreased ability of the cells to use energy in the brain," by inserting human tau genetic material into rats. The rats then produce tau protein with the same structure as that found in people with Alzheimer's.
The abnormal tau was sufficient to generate many of the symptoms and pathological signs of Alzheimer's in the rats. Early on, there were mild memory deficits, followed by low levels of tau tangles. Later, the rats showed more severe memory deficits and more extensive tau tangles, as well as the death of brain cells.
Most previous attempts at tau animal models have not employed tau from humans with Alzheimer's. In addition, note the authors, earlier models were created with mice. "Rats are considered the animal of choice in memory and neurobehavioural testing, since they are more 'intelligent' than mice," said Novak. "The changes that we observed in the brains of our rats are much stronger, Alzheimer-like and earlier than previous mouse models."
"New animal models like this one are valuable in several ways. They allow scientists to examine how proteins like beta-amyloid and tau interact to cause Alzheimer's disease, and they can also be used to test future therapies that are developed," Gandy said.
The 9th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association, is the largest gathering of Alzheimer researchers in history. More than 4,500 scientists from around the world will present and discuss the findings of 2,000 studies showcasing the newest treatment advances in Alzheimer's disease and steps toward prevention. ICAD will be held July 17-22, 2004, at the Pennsylvania Convention Center in Philadelphia, Pennsylvania.
The Alzheimer's Association is the world leader in Alzheimer research and support. Having awarded more than $165 million to nearly 1,400 projects, the Alzheimer's Association is the largest private funder of Alzheimer research. To sustain the rapid progress, the Association calls for $1 billion in annual federal funding for Alzheimer research. For more information about Alzheimer's disease, visit www.alz.org or call 800-272-3900.
· Pierre Tariot – Quetiapine for the treatment of agitation in elderly institutionalized patients with dementia: a randomized, double-blind trial (S5-04, Thurs., 7/22, 10:30 am)
· Lon Schneider – Cerebrovascular adverse events and quetiapine: a pooled analysis in elderly patients with dementia (S5-04, Thurs., 7/22, 10:30 am)
- NOTE: The Tariot and Schneider abstracts will be combined for the oral presentation.
· Cristian L. Achim – AD Pathology in the HIV Brain (S5-04, Thurs., 7/22, 10:30 am)
· Michal Novak – Generation of a First Transgenic Rat Model for AD Neurofibrillary Degeneration (S5-04, Thurs., 7/22, 10:30 am)