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LEADING THE FEDERAL EFFORT ON AGING RESEARCH

Sophisticated Tools Help Investigators Learn More About Changes in the Brain


cross-sectional image of head and brainAs people get older, changes occur in all parts of the body, including the brain. In the brain:

  • Synapses become less efficient or are lost.
  • Some neurons shrink, especially large ones in areas important to learning, memory, planning, and other complex mental activities. This translates into some shrinkage of brain volume over the course of years, even in healthy older people.
  • Tangles develop inside certain neurons in particular brain regions and amyloid plaques develop in the spaces between some neurons.
  • Damage by free radicals increases.

The impact of these changes differs among people as they age. Healthy older people may notice only a modest reduction in their ability to learn new things, retrieve information from memory, and plan and make decisions. Other people, however, experience much greater declines in their memory and cognitive abilities as they grow older because they are developing a neurodegenerative disease and these changes are occurring to a much greater extent. Understanding the difference between changes that occur with healthy aging and a neurodegenerative process is an important key to unlocking the secrets of AD.

It is now clear that by the time the symptoms of amnestic MCI or AD become evident, the disease process is well underway—neurons have died, plaques and tangles have become abundant in different brain regions, and damage from inflammation and free radicals has greatly increased. Decades earlier, biological processes may have begun that predisposed the individual to develop AD or another neurodegenerative disease. As the previous sections of this report show, it is also increasingly clear that these biological processes are directed by a complex interaction of many factors, including genetic, lifestyle, and environmental influences.

If the disease process actually starts many years before it becomes evident, while a person still appears to be healthy, then it is imperative for researchers to learn as much as possible about its early stages so that they can identify those who may be at high risk and develop interventions to disrupt or prevent the disease. Advances in several key tools are helping scientists understand these early changes in the brain:

  • Neuroimaging. Increasingly sophisticated brain imaging techniques, especially MRI and positron emission tomography (PET) allow investigators not only to measure brain structure, volume, and activity but also to correlate changes in these measures with cognitive performance. These findings provide valuable insights into what happens in the brain as the disease progresses. For example, Massachusetts General Hospital researchers recently showed that people with MCI may compensate for the damage already done by the condition by activating a larger portion of particular brain regions when they are asked to do a cognitive task than do less impaired people (Dickerson et al., 2005). This increased activation may serve as a marker for impending clinical decline.

    The NIBIB supports a broad portfolio of neuroimaging research, some of which is particularly relevant to AD. For example, cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid in blood vessels in the brain, has been implicated as a common cause of hemorrhagic stroke and other forms of vascular disease. CAA also is frequently seen in AD. NIBIB-supported researchers at Massachusetts General Hospital are using low magnification imaging of brains from an AD mouse model to define the characteristics of CAA during disease progression and to develop a classification system correlating the severity of CAA deposition with the advancement of disease. This approach may enable clinicians to monitor the response to treatment more accurately (Domnitz et al., 2005).

  • Neuropsychological testing. These tests, which measure delayed recall, verbal fluency, reasoning and decision-making abilities, and many other aspects of memory and cognition, are highly accurate in distinguishing between cognitively healthy people and those with mild AD, so long as differences caused by education, life experience, and age are adequately accounted for. They also are able to track changes in memory and cognitive function over time. These changes are the best way to differentiate between slow age-related changes and more rapid declines that are characteristic of amnestic MCI or AD. These capabilities make neuropsychological testing an essential tool for various purposes, including ensuring accurate diagnosis, measuring disease progression, and measuring response to treatments. Tests that may be practical for use in a doctor’s office, such as the AD-8, a brief 8-item questionnaire for caregivers, are being developed to differentiate those with very early clinical symptoms of dementia from adults with healthy cognition (Galvin et al., 2005).

  • Biomarkers. Techniques to measure specific components of blood, urine, and cerebrospinal fluid (CSF) are increasingly being tested in the laboratory. Understanding these biological markers—how they function and how, when, and why their levels change—will help investigators answer questions about the causes and early development of AD. They also will help scientists track changes in the brain and cognitive function over time and monitor response to treatments.

  • Sensory studies also are adding to our knowledge of ways in which the body signals that a disease process may be unfolding. For example, problems with identifying smells occur early in the course of AD. Researchers at the New York State Psychiatric Institute and Columbia University have demonstrated that a short smell identification test was able to differentiate people with MCI and AD from those who were cognitively healthy (Tabert et al., 2005). Results also strongly predicted whether people with MCI would go on to develop AD. More recently, a research team at the University of Chicago has found that both visual and hearing impairment were associated with an increased risk of cognitive and functional decline over time in older women (Lin et al., 2004).

Putting the Tools Together

A New York University School of Medicine group recently conducted a longitudinal study of cognitively healthy people and those with MCI. This study, the first to combine data from memory testing, MRI scans, and CSF biomarkers, found that combining these different types of measures consistently improved diagnostic accuracy (de Léon et al., 2006). Compared to cognitively healthy people, those with MCI showed decreased memory performance, decreased hippocampal size, and increased CSF levels of tau and isoprostane, two substances known to be often abnormal in AD. Moreover, levels of isoprostane increased significantly over a 2-year time period. This elevation was associated with decreases in CSF beta-amyloid levels and decreased hippocampal volume, suggesting a progression of degeneration consistent with AD.

Looking Toward the Future

For the moment, these technologies are used primarily in experimental contexts but, some day, they could be used more widely in clinical settings as a diagnostic tool. The findings from the New York University School of Medicine study, for example, support the idea that an accurate, reliable, and possibly specific clinical diagnosis of AD in the MCI stage is a reasonable expectation. As these tools improve and become more widely available, they also could be used to predict and follow the course of AD and other neurodegenerative diseases as well as to explain similarities and differences among them. Another important application of these advances is in measuring response to treatments, which would be invaluable in clinical trials of new drugs. Some day, as the influence of diet, exercise, intellectual stimulation, and other lifestyle factors on AD risk is clarified, these tools may even be useful in tracking changes in risk that result from behavioral and lifestyle changes. (For more on how this might be done, see the Alzheimer’s Disease Neuroimaging Initiative described in "Major AD Research Initiatives".)

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Page last updated Nov 25, 2008

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