Abstract
Emerging importance of computerized cognitive testing — new therapies for dementia
Boston, MA – Computerized cognitive testing is increasingly playing a key role in therapy development for dementia and Alzheimer's disease. This week at the Alzheimer's Association International Conference, Keith Wesnes Ph.D., Practice Leader of Bracket and founder of the CDR System™, discussed new data for novel therapies at two poster presentations at the Alzheimer's Association International Conference.
Poster Title: Cognitive evidence in Alzheimer's disease patients that compromised hippocampal neurogenesis is related both to APOE4 status and CSF Abeta42
This presentation provides the first behavioural data in Alzheimer's patients which associates genetic and biomarker activity to dysfunction in a major brain area involved both in memory and the production of new nerve cells (neurogenesis), This exciting finding obtained in collaboration with a group including Kaj Blennow, University of Gothenburg, found that patients with two APOE ∊4 alleles (which confer a 10 to 30 fold increased risk of developing Alzheimer's disease) showed a selective decline in a computerised cognitive test measure associated with activity in the hippocampal dentate gyrus. Furthermore, in all patients studied, this test measure was more closely associated with the levels of the Aβ42 biomarker for the disease than a number of other memory measures associated with different hippocampal regions.
As interest in Alzheimer's research is shifting to begin treating the disease at its earliest stages, these findings identify a potential genetic and biomarker strategy for selecting individuals for early treatment with therapies which may promote hippocampal neurogenesis.
Poster Title: Memantine improves attention and verbal episodic memory in Parkinson's disease dementia and dementia with Lewy bodies: a double-blind placebo-controlled multicentre trial
A second presentation provides the first data that performance on objective tests of attention and memory can be improved by memantine in two other major forms of dementia - Parkinson's disease dementia and dementia with Lewy Bodies. The improvements detected were highly statistically reliable and of clinically relevant effect sizes; indicating that memantine can produce cognitive benefits in patients with these dementias which match those seen previously with anticholinesterases.
Both studies utilised the CDR System™, an automated cognitive test system, making a strong case for benefits for the increased sensitivity and specificity that such procedures bring to dementia research, when compared with the traditional tests which have been historically employed.
Another recent Alzheimer's trial conducted by Orion Corporation demonstrated proof of concept of a new drug with a novel mode of action. The phase II clinical trial tested ORM-12741 — the first drug to target a specific subtype of adrenergic receptors (alpha-2c) in the brain, which are believed to be involved in modulation of brain functions under stressful conditions. The trial of 100 patients showed significant positive effects on episodic memory in patients with moderate Alzheimer's disease. Efficacy was assessed using the CDR System™. (Source: EurekAlert! A service of AAAS and Bracket Global).
Weill Cornell presents updated results from Phase 3 trial of IVIG for Alzheimer's disease
NEW YORK (July 16, 2013) — Weill Cornell Medical College neurologist Dr. Norman Relkin reported new findings today from the Phase 3 clinical trial of IVIG (intravenous immunoglobulin) in mild to moderate Alzheimer's disease at the Alzheimer's Association International Conference (AAIC) in Boston, Mass. While the primary study outcomes were negative, observations from the subgroup analyses include whether there may be a dose-dependent reduction of beta amyloid in the blood and brain of IVIG-treated Alzheimer's patients who have the ApoE4 genotype.
IVIG is a mixture of antibodies derived from the blood of healthy donors. Given its ability to control infection and inflammation, IVIG has been used to treat disease for more than 30 years. It has been approved for use in treating several disorders, ranging from pediatric immune disorders to a blood cancer and Kawasaki disease, but is not approved for Alzheimer's disease.
The Gammaglobulin Alzheimer's Partnership (GAP) Study was a Phase 3, randomized, double-blind, placebo-controlled clinical trial in 390 people with mild to moderate Alzheimer's disease, conducted at 45 centers in the U.S. and Canada. Two different doses of IVIG were tested versus placebo as add-ons to approved Alzheimer's medications. The drug was administered every two weeks for 18 months. Primary study endpoints were changes on two well-established tests of cognition and daily functioning — the ADAS-Cog and ADCS-ADL.
In a topline announcement in May, the GAP researchers reported negative results on the GAP study's primary outcomes — the ADAS-Cog and ADCS-ADL. At the same time, preliminary observations were reported on favorable changes on another cognitive test, the Modified Minimental State Examination (3MS) in two subgroups: people with Alzheimer's who carried the APOE-e4 Alzheimer's risk gene, and those who were moderately impaired. The study was not powered to show statistical significance in these pre-planned subgroup analyses.
Today at the AAIC meeting, Dr. Relkin reported for the first time on additional cognitive and biomarker tests that shed further light on the study's outcomes. The researchers found that study participants in the APOE-e4 carrier subgroup receiving IVIG 400mg/kg/2wk (n = 87) had numerically superior results at 18 months relative to placebo on the Modified Mini-Mental State (3MS) Examination (n = 66) and the Trails B test (n = 77), two out of several measures of thinking ability made in the study. “Though 3MS and Trails B were not the primary outcome measures in the study, they are well-established cognitive measures.” Dr. Relkin says.
Biomarker analyses demonstrated that antibodies from the treatment reached the central nervous system. Among the findings that Dr. Relkin reported:
A statistically significant, dose dependent reduction in plasma beta-amyloid 42 levels (but not beta-amyloid 40) was observed in IVIG treated patients relative to placebo.
Statistically significant, dose dependent increases in anti-oligomer and anti-fibril antibodies in the CSF or plasma occurred in IVIG-treated patients relative to placebo.
A reduction in brain fibrillar amyloid (as measured by PET scan using florbetapir) was seen in patients who received IVIG at the 400mg/kg/2wk dose, particularly those who were APOE-e4 carriers.
No effect in tau and phosphorylated tau levels in spinal fluid.
“It is important to say that the GAP study results do not provide grounds for prescribing IVIG in Alzheimer's disease, even with this positive signal in the APOE-e4 carriers,” Dr. Relkin says. “Further confirmatory studies and regulatory approval would be needed before clinical use could be recommended.”
“The primary clinical outcomes are unequivocally negative, but there are intriguing signals in the clinical and biological markers,” he adds “With the understanding that we cannot draw conclusions about IVIG's effectiveness in these subgroups from these results alone, the effects of IVIG on beta-amyloid and antibody levels in the blood and brain are noteworthy. These results support that IVIG can target beta amyloid and that the antibodies it contains can reach the brains of people with Alzheimer's when administered through the bloodstream.”
Despite the negative results of the Phase 3 IVIG trial, and because of the successes of IVIG in animal models of Alzheimer's and early stage trials in people, researchers continue to pursue how IVIG may work in the brain to inform ongoing Alzheimer's therapy research.
“The favorable data in subjects who carry the APOE-e4 gene also underscores the need for further research and emphasis on a precision medicine approach to Alzheimer's,” Dr. Relkin says. “The APOE-e4 carrier group is easily identified by genetic testing. It may be important to more specifically target our next generation of Alzheimer's therapies with an eye towards treating identifiable subgroups of patients such as APOE-e4 carriers.”
Earlier Phase Studies at Weill Cornell Showed Promise of IVIG
Dr. Relkin is associate professor of clinical neurology at Weill Cornell Medical College and study leader of the Gammaglobulin Alzheimer's Partnership (GAP) trial, conducted by Baxter International and the Alzheimer's Disease Cooperative Study (ADCS), a clinical trial consortium supported by the United States National Institute on Aging in the National Institutes of Health.
Dr. Relkin, who is also director of the Memory Disorders Program at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and a researcher in Weill Cornell's Feil Family Brain and Mind Research Institute, became interested in IVIG when he and Weill Cornell colleagues Dr. Mark Weksler and Dr. Paul Szabo found evidence in 2003 of decreased levels of free antibodies against beta amyloid in the blood of patients with Alzheimer's disease. Following a report by German investigator Dr. Richard Dodel that IVIG contained increased levels of anti-amyloid antibodies, they began testing IVIG as a potential anti-amyloid immunotherapy for Alzheimer's disease.
For example, Dr. Relkin reported in 2006 that a pilot study found IVIG stabilized or improved cognitive function in Alzheimer's patients when administered over a period of a year or more. When the treatment stopped, cognitive abilities began to decline, and then stabilized once more when the treatment was offered again.
A 2007 laboratory analysis by Dr. Relkin and his colleagues demonstrated that antibodies in IVIG could not only recognize and scoop up toxic beta amyloid proteins, but also other proteins that accumulate in a wide variety of neurodegenerative diseases.
Phase 2 GAP results demonstrated that patients who responded best to IVIG did not measurably decline in cognitive abilities over 18 months and had an average rate of brain shrinkage similar to elderly individuals who did not have the disease. Dr. Relkin presented these findings in April 2010 at the annual meeting of the American Academy of Neurology.
Dr. Relkin proposed the GAP trial after the earliest phase studies he carried out showed the promise of IVIG in slowing dementia-related decline. The Phase 1 and Phase 2 trials he performed involved relatively small numbers of patients, however, making the generalizability of the findings uncertain. He proposed the GAP study as a means of assessing IVIG's safety and effectiveness in a larger number of Alzheimer's patients.
“The Phase 3 GAP study was conducted at a very high standard, setting goals that have not yet been reached by any medication for Alzheimer's disease that is approved or under investigation,” Dr. Relkin says. “What we stand to learn from this research cannot be overstated. The data reinforces some of the findings from the earlier phases of the GAP study, and we need now to delve deeper into the data to help move forward toward improving the treatment of Alzheimer's disease.” (Source: EurekAlert! A service of AAAS and Weill Cornell Medical College).
A second amyloid may play a role in Alzheimer's disease, UC Davis researchers find
A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta αβ plaques that are associated with Alzheimer's disease, a study by researchers with the UC Davis Alzheimer's Disease Center has found.
The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease, as well as combined deposits of amylin and plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer's.
“We've known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now,” said UC Davis Alzheimer's Disease Center Director Charles DeCarli.
“This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer's disease,” DeCarli said. “In fact, the amylin looks like the amyloid beta protein, and they both interact. That's why we're calling it the second amyloid of Alzheimer's disease.”
“Amylin deposition in the brain: A second amyloid in Alzheimer's disease?” is published online in the Annals of Neurology.
Type 2 diabetes is a chronic metabolic disorder that increases the risk for cerebrovascular disease and dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese and insulin resistant.
Amylin, or islet amyloid polypeptide, is a hormone produced by the pancreas that circulates in the bloodstream with insulin and plays a critical role in glycemic regulation by slowing gastric emptying, promoting satiety and preventing post-prandial spikes in blood glucose levels. Its deposition in the pancreas is a hallmark of type 2 diabetes.
When over-secreted, some proteins have a higher propensity to stick to one another, forming small aggregates, called oligomers, fibrils and amyloids. These types of proteins are called amyloidogenic and include amylin and αβ. There are about 28 amyloidogenic proteins, each of which is associated with diseases.
The study was conducted by examining brain tissue from individuals who fell into three groups: those who had both diabetes and dementia from cerebrovascular or Alzheimer's disease; those with Alzheimer's disease without diabetes; and age-matched healthy individuals who served as controls.
The research found numerous amylin deposits in the gray matter of the diabetic patients with dementia, as well as in the walls of the blood vessels in their brains, suggesting amylin influx from blood circulation. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer's who had not been diagnosed with diabetes; they postulate that these individuals may have had undiagnosed insulin resistance. They did not find amylin deposits in the brains of the healthy control subjects.
“We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the αβ, which is the suspected cause of Alzheimer's disease,” said Florin Despa, assistant professor-in-residence in the UC Davis Department of Pharmacology. “It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels.
“It is accumulating in the brain and we found signs that amylin is killing neurons similar to αβ,” he continued. “And that might be the answer to the question of ‘What makes obese and type 2 diabetes patients more prone to developing dementia?'”
The researchers undertook the investigation after Despa and his colleagues found that amylin accumulates in the blood vessels and muscle of the heart. From this evidence, he hypothesized that the same thing might be happening in the brain. To test the hypothesis he received a pilot research grant through the Alzheimer's Disease Center.
The research was conducted using tissue from the brains of individuals over 65 donated to the UC Davis Alzheimer's Disease Center: 15 patients with Alzheimer's disease and type 2 diabetes; 14 Alzheimer's disease patients without diabetes; and 13 healthy controls. A series of tests, including Western blot, immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to test amylin accumulation in specimens from the temporal cortex.
In contrast with the healthy brains, the brain tissue infiltrated with amylin showed increased interstitial spaces, cavities within the tissue, sponginess, and blood vessels bent around amylin accumulation sites.
Despa said that the finding may offer a therapeutic target for drug development, either by increasing the rate of amylin elimination through the kidneys, or by decreasing its rate of oligomerization and deposition in diabetic patients.
“If we're smart about the treatment of pre-diabetes, a condition that promotes increased amylin secretion, we might be able to reduce the risk of complications, including Alzheimer's and dementia,” Despa said.
(Source: EurekAlert! A service of AAAS and the University of California - Davis Health System).