Cognitive Enhancers: The New Frontier in Treating Aging and Dementia

Reported by Nadia Halim original source

While memory disorder means Alzheimer's disease to most, only 50% of all dementias are of the Alzheimer's type and dementias represent only the more severe of all learning/memory disorders stemming from heredity, disease, injury, or age. Perhaps as many as 30 million Americans suffer some type of clinically recognized memory disorder.

Cognitive impairment represents a broad spectrum, from normal, age-associated memory decline, to mild cognitive impairment (MCI), to Alzheimer's disease (AD). MCI is defined as memory loss without any significant functional impairment, with the majority of MCI patients eventually developing AD.

6 million Americans may have Alzheimer's disease by 2020.

In the United States alone, there are currently about 4.5 million people suffering from Alzheimer's disease, and this number is expected to grow to 6 million by 2020. MCI affects another 4.5 million people.

Hope is on the horizon, however, in the form of recent advances such as the completion of the Human Genome Project, modern molecular biology, and new brain-imaging technologies. Researchers have an unprecedented view into the workings of the brain, which has in turn helped define the chemistry of the brain and suggested gene targets for the discovery of cognitive enhancers, drugs that sharpen mental faculties.

CREB: The memory switch?

The brain is a complex network of neurons that communicate with each other through chemical signals. This process can trigger the synthesis of proteins, which is necessary in memory formation. But when this process is blocked, as in the brains of Alzheimer's patients, the effect on memory is disastrous.

Much of the research in the development of cognitive enhancers is focused on the activity of cyclic-AMP response element binding protein (CREB) in the hippocampus of the brain. CREB is a transcription factor thought to be important in memory and learning in organisms as diverse as Aplasia (a type of sea slug), Drosophila, and humans.

CREB is involved in the capacity for long-term memory through a phenomenon called long-term potentiation (LTP), which is thought to be important in learning and memory. LTP occurs when a large amount of neurotransmitter is released from one neuron to another, triggering a biochemical cascade that strengthens the connection (called a synapse) between the two neurons.

Evidence supports a model that the CREB pathway regulates memory by controlling the expression of proteins that promote synaptic plasticity. Plasticity is the ability of the brain to change the structure and function of synapses in response to cell signaling.

Drugs targeting this pathway may offer an effective way to reverse memory impairment in normal, age-related neurodegeneration, as well as in disease. The benefit of such treatments may be a wider therapeutic window and more general use since they target basic mechanisms in memory formation and are not limited to a specific pathology.

While many researchers are focusing on the hippocampus, others emphasize the fact that the brain is a heterogeneous structure with many parts involved in memory. The prefrontal cortex (PFC), for instance, is important in working memory such as intelligent thought, planning, and organization. The chemical needs of different parts of the brain are different, so drugs that may improve fixed memory for long-term storage in the hippocampus, may at the same time impair dynamic updating of working memory in the prefrontal cortex.

The development of successful cognitive enhancers will have to consider the full complexity of the brain. In the mean time, an alliance of academic researchers is working on animal models to facilitate finding better gene targets in the search for memory enhancing drugs.

The future

At least 40 potential cognitive enhancers are currently in clinical development. Many of the new compounds being scrutinized seek to improve the way recent memories are stored, transformed into long-term memories, and brought back into consciousness when needed.

Cognitive enhancers offer hope for millions whose current treatment options are bleak. On November 14, 2004, four scientists involved in research on cognitive enhancers met with the Neurodegerative Diseases Discussion Group to discuss the feasibility of such drugs and the various strategies being pursued in their labs.

Tim Tully's lab at Cold Spring Harbor Laboratory has defined a biochemical pathway in fly neurons that is activated in the learning process. Although Drosophila evolutionarily separated from humans 60 million years ago, researchers have shown that mechanisms of memory formation in flies and humans have basic similarities. Thus, Tully is using the information gained from flies to develop memory-enhancing drugs that may someday help counteract the normal decline of memory and also the pathological causes implicated in such diseases as Alzheimer's.

Ottavio Arancio from Columbia University is working to identify mechanisms of synaptic dysfunction that may underlie neurodegenerative diseases. Alterations in the synapses between neurons of Alzheimer's patients are highly correlated with the severity of dementia. Currently only a handful of drugs to treat Alzheimer's disease are approved in the United States, but they offer only symptomatic benefit at best. Patients usually succumb to the disease within a relatively short time. His lab suggests that therapeutic approaches aimed to increase the activity of the transcription factor CREB might effectively revert memory impairment in AD.

Brian Ramos's research in Amy Arnsten's lab at Yale University is showing that the chemical needs of different parts of the brain are very different, and often oppose one another. He emphasizes the importance of this fact in developing cognitive enhancers. For instance, though many portions of the brain control memory function, memory-enhancing drugs primarily target the hippocampus, the known site of long-term memory consolidation. Another portion of the brain, the prefrontal cortex, is important in working memory such as intelligent thought, planning, and organization. Ramos's research has shown that drugs with a beneficial effect on long-term memory may have deleterious effects on working memory and the prefrontal cortex.

Steven Ferris from the New York University School of Medicine discussed the current status of treatment strategies for aging and dementia. Researchers are tackling this problem with two distinct approaches. One is to treat a particular pathology, which causes a neurodegenerative disease such as Alzheimer's. The other is to develop compounds that target not a specific pathology, but a basic mechanism in the brain that declines with age, resulting in a more general cognitive enhancer.