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Alzheimer's, Dementia & Mental Health
IVIg Headlines Alzheimer's Treatments at International Conference
Therapies show promise, address multiple aspects of the disease
July 19, 2006 – In April of last year, SeniorJournal.com published a story, " IVIg Therapy May Improve Cognitive Function in Alzheimer's Patients," that became one of the most read stories the Website had ever published .Yesterday, IVIg was a hot topic again at a conference in Madrid sponsored by the Alzheimer's Association. It was, however, among several drugs showing promise in the battle against Alzheimer's that were discussed at the conference.
“The world’s population is growing rapidly larger and older, and Alzheimer’s diagnoses will sharply increase,” said Steven Ferris, Ph.D., a member of the Alzheimer’s Association’s Medical & Scientific Advisory Council. “We desperately need major breakthroughs in new therapies to reduce disability and suffering, and control costs. Therefore, it is very important that we have a diverse drug pipeline and investigate all viable options that might slow progression or prevent the disease.”
Ferris is Friedman Professor in the Department of Psychiatry at New York University (NYU) School of Medicine, and Director of the Alzheimers Disease Center at NYU's Silberstein Institute.
Following are summaries of some of the presentations on Alzheimer's treatments presented at the 10th International Conference on Alzheimer's Disease and Related Disorders (ICAD).
● IVIg may promote removal of beta amyloid - Antibodies provide lasting benefits in Alzheimer’s
Intravenous immunoglobulin (IVIg) is a purified mixture of human antibodies that has proven effective in several immune system disorders. It also may promote removal of beta amyloid from the body.
Beta amyloid is an abnormal protein that collects in the brain and is considered central to the progression of Alzheimer’s.
In a previous study, IVIg treatment for six months improved or stabilized cognitive test results of eight patients with mild to moderate Alzheimer’s (mean age 75). When therapy was stopped, the IVIg treated patients rapidly declined.
Norman R. Relkin, M.D., Ph.D., from Weill Cornell Medical College, New York City, and colleagues resumed their IVIg trial as a low dose, open label study for an additional nine months with the eight previously-treated patients. Participants received IVIg at a dose of 1g/kg/2 weeks for 3 months followed by 0.4g/kg/2 weeks for 6 months. Subjects were maintained on stable doses of their regular Alzheimer’s drugs during the study. Mental status was assessed every three months.
The researchers found that participants’ cognitive status remained stable throughout the first three months of follow-up treatment and trended upward in the majority of cases (six out of eight) during the remaining six months.
This is the first study to demonstrate that IVIg can have lasting benefits in Alzheimer’s when administered over a year or more.
“This study suggests that IVIg can exert long-term benefits for the treatment of cognitive decline in Alzheimer’s,” Relkin said. “In our eight participants, we observed that spinal fluid beta amyloid levels were reduced by more than a third over 18 months. This is consistent with the movement of amyloid out of the central nervous system and into the blood stream where it can be cleared from the body. That is a very positive sign.”
● Anti-inflammatory drug may be effective in Alzheimer’s
Research has uncovered signs of inflammation in brain regions affected by Alzheimer's, and observational studies have shown that groups of people who take large doses of nonsteroidal anti-inflammatory drugs (NSAIDs) have a reduced likelihood of developing Alzheimer's. However, clinical trials of anti-inflammatory compounds in Alzheimer’s have so far been unsuccessful.
Triflusal, a medication used as an antiplatelet agent in prevention of cerebral and myocardial infarction, also has been shown to have potent anti-inflammatory effects in the central nervous system. Teresa Gomez-Isla, M.D., from Hospital Santa Creu i Sant Pau, Barcelona, Spain, and colleagues have completed preliminary research demonstrating that triflusal lowered the probability of progression to Alzheimer’s in a group of people with amnestic mild cognitive impairment (MCI). Amnestic MCI means memory impairment but not dementia, and having it increases the risk of progression to Alzheimer’s.
A total of 257 study subjects (129=triflusal, 128=placebo) were randomized to receive placebo or triflusal (900 mg per day) for 18 months. A very slow rate of recruitment forced a premature cessation of the study after an average follow-up of 13 months. Over the course of this time, 41 participants developed dementia (16=triflusal, 25=placebo), a rate of 16% per year. Triflusal therapy was well tolerated.
The researchers found that the probability of progression to dementia was significantly lower in the treated group than in the placebo group (hazard ratio, 2.10; 95 percent confidence interval, 1.10 to 4.01; p=0.024; adjusted analysis by baseline ADAS-cog and geographical zone).
“MCI represents a critical point for early intervention in Alzheimer’s disease,” said Gomez-Isla. “However, because this trial was prematurely halted, these results should be interpreted with great caution. Nonetheless, the effect of Triflusal in this study is a hopeful signal to continue this research.”
● Lithium may have therapeutic role in Alzheimer’s
Lithium is believed to inhibit GSK-3, a common enzyme that is involved in producing tau tangles, which are hallmark lesions in the brains of people with Alzheimer’s.
Peter Annas, Ph.D., from AstraZeneca R&D Sodertalje, Sweden, and colleagues conducted a 10-week placebo-controlled study of 71 Alzheimer patients (33 treatment, 38 placebo) to investigate whether lithium could inhibit GSK-3 in humans and improve the cognitive symptoms of Alzheimer’s. The effect of lithium on the tangle producing process was measured assessing levels of key enzymes and various forms of tau in blood and cerebrospinal fluid. The effect on the Alzheimer’s symptoms was measured through three well established tests of thinking and memory (ADAS-cog, MMSE and NPI).
Though not statistically significant, initial results showed a 30 percent improvement (defined as a reduction of 4 points or more on the ADAS-Cog scale) in the lithium group as compared to a 10 percent improvement in the placebo group. Other results are forthcoming.
“A 10-week study is quite short when compared to conventional Alzheimer studies,” said Annas. “Our preliminary results warrant additional studies with more potent GSK3 inhibitors.”
● Memantine may reduce Alzheimer’s tau tangles
Memantine, a moderate affinity N-methyl-D-aspartate receptor antagonist, is approved for treatment of moderate to severe Alzheimer’s. It appears to work by regulating the activity of glutamate, one of the brain’s specialized messenger chemicals involved in information processing, storage, and retrieval. In studies using rat brains, memantine has been shown to inhibit and reverse the formation of tau tangles.
To investigate if this is also true in people, Malin Degerman Gunnarsson, M.D., and colleagues from the Department of Public Health/Geriatrics, Uppsala, Sweden, evaluated several chemical markers in cerebrospinal fluid (CSF) in 11 Alzheimer’s patients taking memantine therapy. Nine of the subjects also were taking cholinesterase inhibitors, which are approved for treatment of mild to moderate Alzheimer’s.
After one year, the researchers found a statistically significant reduction of p-tau, the abnormally phosphorylated tau associated with Alzheimer’s tangles, in CSF. No statistically significant difference of total tau or ß-amyloid was found.
“The results may reflect the effects of memantine on a key abnormality in the Alzheimer’s brain,” concluded Gunnarsson. “However, studies in larger number of patients are needed.”
“The diversity of therapies in the pipeline for Alzheimer’s, as represented by the wide variety of studies reported at ICAD this year, is very exciting,” said Khalid Iqbal, Ph.D., co-founder of ICAD and co-chair of the Scientific Program Committee. “While the ‘amyloid cascade’ may be the most popular theory of the Alzheimer’s and deserves significant attention, it is extremely important that we pursue a wide variety of avenues to treat and prevent this devastating disease.”
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