• March 17, 2009

    Cognitive impairment in people with mild to moderate Alzheimer’s disease (AD) can diminish their capacity to provide informed consent for clinical trials, presenting ethical challenges for researchers. A semistructured interview can help determine which people are capable of giving their own informed consent, according to an NIA-supported study in the American Journal of Geriatric Psychiatry.

    The MacArthur Competency Assessment Tool for Clinical Research (MacCAT-CR), an interview tool that assesses 4 decision-making abilities—choice, understanding, appreciation, and reasoning—was administered to 59 people with mild to moderate AD, who were participating in a 13-site clinical trial. Researchers, led by Dr. Jason Karlawish of the University of Pennsylvania School of Medicine in Philadelphia, adapted the interview procedure by allowing individuals to keep a summary of the trial as they answered questions. Three psychiatrists independently reviewed the MacCAT-CR interviews and decided the strength of each subject’s capacity to give informed consent.

    The researchers found that MacCAT-CR scores, specifically the subscores for understanding, had the best ability to discriminate which subjects were able to provide informed consent. Nearly half of the study group (47 percent) was judged not capable of providing their own consent. However, the authors note, this proportion could vary depending on the risk of the study and the techniques interviewers use to administer the MacCAT-CR. They caution other investigators against using this tool alone to decide which people with AD are capable of providing informed consent, but to use its results “as evidence to guide what is ultimately an ethical judgment.”


    Karlawish, J., et al. Interpreting the clinical significance of capacity scores for informed consent in Alzheimer disease clinical trials. Am J Geriatr Psychiatry. 2008. 16(7):568-74. Epub 2008 June 12.

  • March 17, 2009

    Researchers at Princeton University in New Jersey and Stony Brook University in New York used a novel method to assess the percentage of people experiencing pain and its severity at randomly selected times in a representative sample of U.S. residents. According to results published in the May 3, 2008, Lancet, more than a quarter of American men and women report feeling pain at any point in time, and those with lower incomes and less education spent more time in pain and had higher than average pain.

    Collecting diary information through a community-based telephone survey, Drs. Alan Krueger and Arthur Stone found that 29 percent of men and 27 percent of women said they felt some pain at sampled times. People with lower incomes or less education spent a higher proportion of time in pain and reported feeling more severe pain than those with higher incomes or more education. The average pain rating increased with age, although it reached a temporary plateau between the ages of 45 and 75 before rising again above age 75. Information was not collected on the cause, location, treatment, or duration of the pain. Medical conditions that might have caused the pain were not identified.

    An important aspect of this NIA-funded study was the measurement of pain during specific random periods of time rather than the global assessment typically used in population studies. This approach allowed researchers to study how pain affected activities of daily living in particular segments of the sample population.


    Krueger, A.B., and Stone, A.A. Assessment of pain: a community-based diary survey in the USA. Lancet. 2008 May 3. 371:1519–25.

  • March 17, 2009

    Training clinical staff in fall-prevention practices and strategies can help reduce serious falls and the need for related medical care among elderly people, suggests a new study, funded in part by the NIA.

    Research has shown that falls—a common cause of injuries, hospitalization, and functional decline among older adults—can be prevented through multifaceted programs addressing multiple risk factors for falls. But known prevention strategies rarely transfer from academic study to clinical practice, and researchers from the Yale School of Medicine in New Haven, CT, looked at whether interventions educating a variety of clinicians about risk factors for falls would help reduce falls in people age 70 and older.

    Working with the Connecticut Collaboration for Fall Prevention, the research team led by Dr. Mary E. Tinetti encouraged clinicians (including primary-care doctors, physical therapists, and advanced practice nurses) and facilities (such as home health care agencies and hospitals) in the Hartford, CT, area to incorporate proven fall-prevention techniques into their practices, providing clinicians with training materials and teaching them how to educate seniors about fall prevention.

    After 2 years of evaluation, the researchers found the rate of serious fall-related injuries, such as hip fractures and head injuries, was 9 percent lower in the intervention area than in a demographically similar usual-care area in southern Connecticut. Similarly, the rate of fall-related use of medical services was 11 percent lower in the intervention area than in the usual-care area. Data came from a Connecticut Hospital Association database of information on all state residents who receive care in an emergency department or hospital.

    The authors could not say which particular intervention or which group of clinicians accounted for the differences between the two geographic areas. However, they suggest that much discomfort, disability, and health care spending due to falls by older people could be averted by disseminating information about fall prevention to clinicians and encouraging them to adopt changes in clinical practice.


    Tinnetti, M.E., et al. Effect of dissemination of evidence in reducing injuries from falls. N Engl J Med. 2008 July 17. 359:252-61.


  • May 12, 2009

    Researchers at the Pennington Biomedical Research Center in Baton Rouge, LA, have shown that when people significantly reduce their calorie intake, they undergo a metabolic adaptation that results in a slower metabolic rate. The slower metabolic rate results in a behavioral adaptation in which individuals become less physically active.

    The researchers examined data from 48 overweight people who followed 1 of 4 diet regimens for 6 months: a 25-percent calorie restriction (CR) diet, a low-calorie diet, a 12.5-percent CR diet plus 12.5-percent aerobic exercise program, or a normal diet. While the first three groups lost weight, after 6 months, the CR and low-calorie diet groups showed a reduction in their basal metabolic rate, accompanied by reduced physical activity. The CR plus physical activity group also lost weight but did not undergo a metabolic adaptation.

    This is the first study to measure metabolic rate and energy expenditure precisely through the use of doubly labeled water and indirect calorimetry. The study also shows that long-term calorie reduction without increased exercise can result in a lower metabolic rate. The researchers note that the data “suggest potential mechanisms by which CR causes large inter-individual variability in the rates of weight loss and how exercise may influence weight loss and weight loss maintenance.”


    Redman, L.M., et al. Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS ONE. 2009. 4(2):e4377.

  • May 12, 2009

    The protein Lrp5, long known to play a critical role in bone remodeling, appears to exert its effects through the gut, not directly through the bone, as previously thought, according to preclinical research published in Cell. The findings could suggest new therapeutic approaches to increase bone mass in older adults and others with osteoporosis.

    In bone remodeling, old bone is resorbed by specialized cells, called osteoclasts, and new bone is formed by other specialized cells, called osteoblasts. Lrp5 (low-density lipoprotein receptor-related protein 5) is an important regulator in the underlying molecular process. A decrease in its function can lead to osteoporosis, while overproduction results in high bone mass syndromes in humans.

    Scientists have long believed that Lrp5 controls bone mass through signaling in the Wnt pathway in bone osteoblasts. However, NIH-supported researchers at Columbia University found that Lrp5 works indirectly through the gut. In a study in mice, they found that Lrp5 inhibits expression of the gene Tph1, which encodes an enzyme that, in turn, helps synthesize serotonin in the duodenum. The resulting decrease in serotonin production was associated with increased bone mass in mice. Conversely, mice deficient in Lrp5 produced excess serotonin in the gut and developed low bone mass. Furthermore, turning off Lrp5 in the gut, but not bone, affected serotonin levels and, through serotonin, bone mass.


    Yadav, V.K., et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008 Nov 28. 135:825–37.

  • May 12, 2009

    NIA-funded researchers have found that happiness is not an isolated phenomenon, unique to an individual, but rather spreads through social networks. Using data from the Framingham Heart Study, Drs. Nicholas Christakis of Harvard Medical School and James Fowler of the University of California, San Diego examined how social ties influence individuals’ mood and sense of well-being. They found that people who are surrounded by happy people are more likely to be happy themselves.

    The researchers looked at the happiness of nearly 5,000 individuals in the Framingham cohort during a period of 20 years. They found that one person’s happiness triggers a chain reaction that benefits not only their friends, but their friends’ friends, and their friends’ friends’ friends, with the effect lasting for up to a year.

    The effects are limited by both time and space. The closer a friend lives to a person, the stronger the effect. As distance increases, the effect decreases. This explains why friends who are next-door neighbors have an effect, but those who live around the block do not. Interestingly, the effects did not apply to co-workers and were stronger between same-sex than between opposite-sex pairs.

    This is the third major network analysis by these researchers that shows how social context affects health. The two previous studies, published in the New England Journal of Medicine, described the social network effects in obesity and smoking cessation.


    Fowler, J.H., and Christakis, N.A. Dynamic spread of happiness in a large social network: longitudinal analysis over 20 years in the Framingham Heart Study. BMJ. 2008 Dec 4. 337:a2338.

  • May 12, 2009

    The threat of smallpox resulting from bioterrorism has prompted a reassessment of the current population’s level of immunity. A recent study by researchers in the NIA’s Intramural Research Program shows that older adults who either had smallpox as children or were vaccinated years ago remain immune to the disease and would be unlikely to benefit from new vaccinations.

    Given the limited supply of smallpox vaccine in the United States, it makes sense to immunize people most at risk in the event of smallpox exposure, researchers wrote in the American Journal of Medicine. That population includes individuals born after 1972—about the time when routine smallpox vaccination ended in the United States—but not many older adults, they concluded in a study of 246 participants from the Baltimore Longitudinal Study of Aging.

    Older adults who were vaccinated at least once appear to remain immune, according to an analysis of more than 800 serum samples that had been stored for 13 to 88 years after vaccination. The researchers, led by Drs. Dan Longo and Dennis Taub, determined that levels of vaccine-specific antibody titers and neutralizing antibodies remained high enough to indicate continued immunity in 209 individuals who had been vaccinated, based on the comparable levels of their antibodies and those of 8 participants who had had smallpox as children. It is known that survivors of smallpox have lifelong immunity to it. Multiple vaccinations conferred only marginally higher protection than a single one.


    Taub, D.D., et al. Immunity from smallpox vaccine persists for decades: a longitudinal study. Am J Med. 2008 Dec. 121:1058–64.

  • May 12, 2009

    The prevalence of meniscal tears in adults increases with age, but often they are not accompanied by knee pain or other symptoms, according to a recent study supported in part by the NIA. Researchers led by Dr. Martin Englund of the Boston University School of Medicine sought to determine the prevalence of damage to menisci, the tissue-filled disks between knee bones. A random sample of 991 adults ages 50–90 in Framingham, MA, filled out questionnaires about symptoms and underwent magnetic resonance imaging (MRI) of their right knees.

    The presence of meniscal damage detected by MRI averaged 35 percent overall and rose with age—from 19 percent in women and 32 percent in men between the ages of 50 and 59 to 51 percent in women and 56 percent in men between the ages of 70 and 90. Most participants with meniscal tears (61 percent) reported no pain, aching, or stiffness during the month before the study. In people with knee osteoarthritis, the prevalence of a meniscal tear was 63 percent among those with knee pain, aching, or stiffness on most days and 60 percent among those without these symptoms.

    These epidemiologic findings emphasize the difficulties in appropriately interpreting MRI findings of the knee and the relationship of meniscal damage to knee pain. As the researchers note, the study suggests that incidental meniscal findings detected on MRI are likely to be frequent in clinical practice. Clinicians who order MRI of the knee should take into account the high prevalence of incidental tears when interpreting the results and planning therapy.


    Englund, M., et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med. 2008 Sept 11. 359:1108-15.

  • May 12, 2009

    Scientists have found a mechanism involving the protein SIRT1 that links DNA damage with age-related changes in gene expression. The study in mice has striking parallels with findings from studies of a similar mechanism in yeast.

    Past research has shown that in yeast, the protein Sir2—known for its part in extending life—plays an important role in stabilizing gene function. When DNA damage occurs, Sir2 abandons this role to assist with DNA repair. Without Sir2’s control, genes become unstable and render the yeast sterile, a characteristic associated with aging.

    NIH-funded investigators led by Dr. David A. Sinclair of Harvard Medical School in Boston looked at a parallel process in mouse stem cells. They found that SIRT1, the mammalian equivalent of Sir2, helps control gene activity—except when DNA is damaged. In that case, it leaves its normal role to help repair DNA. The resulting changes in gene activity in stem cells are similar to those seen in the brains of aging mice.

    Researchers also found longer survival and a lower incidence of tumors in mice with overexpressed SIRT1 than in mice with normal SIRT1 levels. These results indicate that increasing SIRT1 activity or quantity can increase genomic stability and is associated with longer life.


    Oberdoerffer, P., et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell. 2008 Nov 28. 135:907-18.

  • May 12, 2009

    Two recent NIA-funded studies used novel imaging techniques to explore the possible connection between the buildup of beta-amyloid protein deposits in the brains in living people and the risk of developing Alzheimer’s disease (AD). Abnormal deposits of amyloid in the brain are hallmarks of Alzheimer’s and, until recently, could only be confirmed at autopsy. But as shown in these two studies, researchers are using techniques involving PET (positron emission tomography) scans and tracers to image amyloid deposits in people who are symptom free.

    One study found large numbers of beta-amyloid protein deposits in the brains of cognitively normal older adults, suggesting that the deposits alone may not be enough to disrupt cognitive function. The other study showed that known genetic markers for the disease did indeed correlate with greater deposits of amyloid, suggesting that the PET method might eventually result in better and earlier detection of the disease.

    In the first study, reported in the Archives of Neurology, researchers used PET with the tracer element Pittsburgh Compound B (PiB) to image the brains of 43 adults, 65 to 88 years old, who did not have clinical AD or mild cognitive impairment, a condition that often precedes AD. They found that the 9 participants with beta-amyloid deposits in at least one brain area performed as well on cognitive tests as the 29 amyloid-negative participants and the 5 participants with “intermediate” evidence of amyloid deposits.

    The finding that an older person with “significant amyloid burden” can be cognitively normal suggests a high level of cognitive reserve or that beta-amyloid deposition alone does not lead to AD, write the authors, led by Dr. William E. Klunk of the University of Pittsburgh School of Medicine. Alternatively, some of these individuals may go on to develop AD—in which case PET may be useful in finding signs of AD before clinical symptoms appear. The findings with PiB mirror those previously found in clinicopathological studies, where a proportion of clinically normal people were found to have significant amyloid deposits in their brains after death.

    In the second study, published in the Proceedings of the National Academy of Sciences, researchers, led by Dr. Eric Reiman of the Banner Alzheimer’s Institute in Phoenix, conducted PET scans using PiB in 28 cognitively normal older people and correlated the results with the presence of the apolipoprotein E (APOE) ε4 allele, a known risk factor for AD.

    The researchers found progressively higher levels of beta-amyloid deposits in carriers with one and two copies of the APOE ε4 than in the noncarriers. They concluded that their findings “support the possibility of using fibrillar beta-amyloid imaging, along with other biomarkers of beta-amyloid, tau, and neuronal pathology and other risk factors, in the preclinical detection and tracking of AD and the evaluation of promising prevention therapies.” Previous autopsy studies have shown that ApoE ε4 carriers have higher levels of amyloid pathology in their brains at  death.


    Aizenstein, H.J., et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008 Nov. 65(11):1509–17.

    Reiman, E.M, et al. Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA. 2009 Apr 21. 106(16):6820-25.