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Institute of Medicine (US) Forum on Neuroscience and Nervous System Disorders. From Molecules to Minds: Challenges for the 21st Century: Workshop Summary. Washington (DC): National Academies Press (US); 2008.
If the percentage of the population facing neurological disease is large, the percentage facing the impacts of aging is total, that is, the aging body and brain impact everyone as they get older. There is no question that the brain changes naturally as it ages—just ask any 50-year-old how often they forget where their car keys are—but there is little understanding of how and why aging causes the brain to change. Understanding the physical changes that occur as the brain ages would be an important place to start in efforts to slow down, eliminate, or reverse the unwanted parts of this process in the future, suggested Volkow.
Questions such as “How does the brain work?” and “How does the interplay of biology and experience shape our brains and make us who we are?” are phenomenally interesting, and have many practical corollaries. But workshop participants, including Timothy Coetzee, executive director of Fast Forward of the National Multiple Sclerosis Society, also recognized that their research aims to have an immediate impact on easing the suffering of those facing neurological disease. It comes down to understanding questions such as: How do we keep our nervous system healthy as we age? Are there ways to protect, restore or enhance the function of our brains with aging?
The Question of Aging
A great deal of neuroscience research is played out against the backdrop of the time bomb of disease, said Blakemore. According to the World Health Organization (WHO), neurological and mental health disorders have a tremendous impact on individuals throughout their lifespan. It is estimated that 10 to 20 percent of children suffer from mental or behavioral problems and one in every four people develops a neurological disorder at some stage in life (WHO, 2001). Therefore, the time lost and economic impact caused by mental and neurological illness is tremendous.
Not only is the scale of the problem enormous, but it is growing as the population ages, and neither the public nor the scientific community is content to wait on basic discovery before we start investigating cures. “Society [has a] hunger for interventions long before we have a deep, fundamental knowledge” of how the neurological system works, said Hyman.
For many aging people, the question of how and why their brains age is much deeper than small forgetfulness; it goes down right to the core of personality. “People are obviously interested in how ‘me’ is developed,” said Marcelle Morrison-Bogorad, director of the Division of Neuroscience at the National Institute on Aging. “But they are also very interested in how ‘me’ is retained and how to retain ‘me’ in the presence of aging-related changes which take ‘me’ away.”
Theories do exist. Many have noted a rise in inflammatory markers in the aging brain, and guessed about ischemic effects that build up over time. There are signs of decreases of protein transcription and protein expression in the brain, signal-transduction alterations that likely lead to the morphological changes that are observed, including decreased numbers of neurons and connections between neurons Some believe that a lifetime of toxic exposures play a role, although we have not yet conducted the kind of epidemiological studies that would provide this information.
Starting at Square One
For many neurological disorders, we are really at square one in understanding how a particular disease works, and what avenues we should explore for treatment, let alone having a better understanding of what life style adjustments could be made to avoid or minimize the onset of aging-related complications. Many participants, including Greenberg and Steven Dekosky, chair of the Department of Neurology at the University of Pittsburgh, expressed a desire for a better core understanding of the physical morphology of neurological disease, as well as the physical morphology of aging. The ability to diagnose presymptomatic disease by either looking for biomarkers or, better yet, studying the genetic makeup, genetic expression, and neurological makeup of individual patients would be one good proxy for gaining an understanding of how diseases arise. This kind of research was not possible a few years ago, before the advent of high-throughput genetic sequencing and high-resolution neuroimaging, but it is becoming increasingly possible every day.
The Complicated Role of Genetics
A popular presumption is that many diseases are driven by a single genetic mutation, and that a magic switch in the body is either on or off—and as a result, you either have a disorder such as autism or Parkinson’s or you do not.
Increasingly, however, research suggests that these are disorders of complex genetics, where multiple genes and varying levels of expression are combined to create the impact of the disease. Understanding the etiology of a disorder is further compounded by the influence of the environment on genetic expression. Greenberg explained research showing how parts of the genome are involved in the process of synapse development, synaptic pruning, and the balance between exciting and inhibiting individual synapses.
Another emerging idea is that it is not just a genetic mutation that knocks out function, but subtle mutations that affect the level of expression of the genes and greatly impact disease and normal function. Perhaps this may give us some insight into the processes that lead to “graded” neurological spectrum disorders, such as autism spectrum disorders. As Takahashi highlighted, the use of applications made through advances in genetic tools will allow for a much more integrated understanding of our behaviors. Consequently, an improved understanding of the role of genetics and the environment will almost certainly improve our understanding of how best to protect, restore, or enhance the function of our brains and nervous systems.
The Trouble with Current Treatments
Without a core understanding of how the brain works, the current generation of neurological treatments and preventions is imprecise. In diseases like depression, our best current therapies are to expose the entire brain with a neuromodulator like serotonin, producing only a partial therapeutic response along with unwanted side effects. As Montague observed during the workshop, “We wiggle the knobs down here at the molecular end in a way . . . and we get some sort of behavioral endpoint out there. . . . In between there is nothing.”
With depression there is not even a real scientific definition of the focus of the disease—”mood”—and no accurate way to measure how it changes, nor is there a core understanding of how serotonin impacts the brain as a whole to alter mood, explained Coyle.
Similarly, Montague described how there is very limited understanding of the widespread “placebo effect,” both in neurological diseases and in other physical diseases. What is the physical morphology of the placebo effect, and how does the body use that to treat and cure itself? The impact is not small; huge efforts are undertaken to account for it in clinical trials. While it appears that the neurotransmitter dopamine has a role in the process, we still do not know how the total process works.
Marder also highlighted deep brain stimulation (DBS), in which electrodes are implanted into the brain to treat Parkinson’s disease, depression, and other maladies. Although the process of DBS is based on some understanding of what areas of the brain are impacted by disease, there is no depth to our understanding of the physical process by which DBS works. DBS is a perfect example of where a fundamental understanding of the structure and function of the brain could drive tremendous benefits. New neuroimaging techniques and new neuronal mapping techniques make it easy to imagine mapping out the structure and functional map of the brain in such a way that we could precisely target an intervention like DBS to create a desired treatment effect, for example as has been done to treat individuals suffering from Parkinson’s disease.
However, as Volkow described, at the end of the day the brain not only gives rise to some disorders of the nervous system, but it is also where emergent behaviors originate. Consequently, the brain is very likely to be driving the likelihood of optimizing health, through determining our behaviors, which then affects our lifestyles and our health.