31 October 2010. Two large, prospective studies published this week solidify claims that midlife habits and acute predicaments can take a serious toll on brain health years down the road. As reported in the October 27 issue of the Journal of the American Medical Association, seniors hospitalized for severe sepsis faced tripled odds of cognitive impairment during the study’s eight-year follow-up. “We were able to measure their physical functioning and cognitive disability and show they had enduring deficits, not just one-hit deficits,” said lead investigator Theodore (Jack) Iwashyna of the University of Michigan in Ann Arbor. By putting firmer numbers on this suspected phenomenon, the findings should inspire greater vigilance in preventing and treating sepsis, suggested the authors.
Meanwhile, a study published online October 25 in the Archives of Internal Medicine establishes heavy smoking in midlife as a risk factor for Alzheimer’s disease and vascular dementia, dousing the flames of earlier controversial reports suggesting that smoking could be protective. Analyzing an ethnically diverse sample of more than 21,000 people, Rachel Whitmer of Kaiser Permanente Division of Research in Oakland, California, and colleagues report that lighting up can double one’s risk for dementia two to three decades later. “Even if they’re lucky enough to not get cardiovascular disease, [midlife smokers] may be putting their brains at greater risk,” Whitmer told ARF.
For severe cases of sepsis, in which the body’s vigorous response to infection causes vital organs to malfunction, just coming through hospitalization alive is a feat in and of itself. Beyond that, sepsis survivors are twice as likely to die in the next five years, compared to hospitalized controls (Quartin et al., 1997), and face increased odds for a variety of health problems. While past research showed this to be true up to two years post-sepsis (see reviews by Winters et al., 2010 and Yende and Angus, 2007), the current paper widens the timeframe considerably—to about eight years before and after hospitalization. Unlike studies that asked, How were you doing two weeks ago?, Iwashyna said, the current study followed participants for years, so “we had a good sense of people’s trajectory before they developed sepsis. We could compare how someone was doing afterward to how the same person was doing beforehand.”
Among the study’s strengths are its prospective design and nationally representative cohort, said David Knopman of Mayo Clinic, Rochester, Minnesota, who was not involved in this study. “It strengthens the conclusion of previous studies.”
Drawing from the ongoing longitudinal Health and Retirement Study involving some 22,000 Americans, Iwashyna’s team analyzed 1,194 elderly who were hospitalized for severe sepsis between 1998 and 2005, as determined by information on Medicare claims. More than 40 percent of those patients died within 90 days. Among the 516 participants who survived sepsis and had at least one follow-up two years later, 6.1 percent had moderate to severe cognitive impairment when surveyed just prior to sepsis. The prevalence of mental decline two years afterward jumped nearly threefold, to 16.7 percent. Sepsis afflicts more than 750,000 people in the U.S. annually. Based on the new data, it may give rise to some 20,000 new cases of moderate to severe cognitive impairment each year.
In addition to assessing cognition, the researchers also scored, every two years, the participants’ functionality in 11 areas—six daily skills, such as walking and dressing, and five harder tasks like preparing meals and managing finances. Patients with three or fewer deficiencies prior to severe sepsis developed, on average, about 1.5 additional limitations after being hospitalized. For participants who were already severely impaired (i.e., with four or more deficiencies) at baseline, “it did not look like severe sepsis actually changed the trajectory much,” Iwashyna said, noting this was probably due to ceiling effects.
“The work is really novel, and really important,” noted Tamara Fong of Harvard Medical School in Boston, whose recent study showed that delirium, a comorbidity of sepsis, hastens cognitive decline in AD patients (Fong et al., 2009). “When people become critically ill, the focus is generally on survival, but considering functional and cognitive long-term outcomes may change the way we take care of our patients.”
There are currently no therapies for reducing post-sepsis morbidity. Iwashyna hopes the new data help define sepsis “as a real enough thing” to enable potential therapies to be tested in clinical trials with long-term follow-up. Many studies evaluating sepsis therapies have used day 28 all-cause mortality as their primary endpoint, as detailed assessments of physical and cognitive function are “challenging and costly in the multicenter trial environment,” Derek Angus, University of Pittsburgh School of Medicine, Pennsylvania, noted in an accompanying editorial (Angus, 2010). “However, the larger cost may be from failure to measure these outcomes and miss important benefits or harms of therapies in the lingering consequences of sepsis,” he wrote. For instance, in a small trial of ICU patients who had been on mechanical ventilation, starting physical therapy on day 1 instead of day 7 led to a dramatic drop in rates of discharge to nursing homes (Schweickert et al., 2009). This is one example of a “huge, potentially easy win” that needs validation in larger, longer trials, Iwashyna said.
Smoking Goes Down in Flames
In the second paper, researchers led by Whitmer and first author Minna Rusanen of Kuopio University Hospital, Finland, measured the impact of midlife smoking on future development of AD and vascular dementia. Previous data from the Rotterdam and Honolulu-Asia Aging studies demonstrated that smoking increases dementia risk (e.g., Ott et al., 1998; Tyas et al., 2003; Reitz et al., 2007), but those studies tended to be small and/or have short follow-up (i.e., seven years or less). Meanwhile, some basic science studies suggested the opposite, by showing that nicotine can slow amyloid deposition (Salomon et al., 1996; Dickerson et al., 2003). Furthermore, there is epidemiological data that seem to support a protective effect of smoking on dementia (Wang et al., 2010; Van Duijn and Hofman, 1992 review), though some of the earlier studies suffer from survival bias and other methodological limitations, Whitmer said.
The current investigation clears the fog by confirming the association between smoking and increased AD risk in a large, ethnically diverse population. The researchers analyzed prospective data from 21,123 northern California Kaiser Permanente HMO members who were 50 to 60 years old when surveyed between 1978 and 1985 on their health and medical history, including whether they smoked, and then assessed for dementia in 2008. “We were looking at long-term dementia,” Whitmer said. “We also looked at smoking amount—not just ‘do you smoke, yes or no?’ but how much you smoked.”
Participants who were smoking more than two packs a day when they were surveyed went on to develop AD and vascular dementia 20 to 30 years later about twice as often as those who said they never lit up. Those who reported smoking one half to two packs a day had a 34 to 37 percent greater risk of dementia, relative to never smokers. Former smokers and those who smoked less than a half pack each day fared the same as those who had never smoked.
The study “sends a clear message that heavy smoking is going to increase your chances to develop AD and vascular dementia,” said Kim Janda of Scripps Research Institute in La Jolla, California. The link between smoking and AD has gained some traction in the pharma sector. Pfizer is collecting final data for its Phase 2 trial of varenicline, a nicotinic receptor partial agonist that is sold under trade name Chantix as a smoking cessation patch.—Esther Landhuis.
Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27;304(16):1787-94. Abstract
Rusanen M, Kivipelto M, Quesenberry CP Jr, Zhou J, Whitmer RA. Heavy Smoking in Midlife and Long-term Risk of Alzheimer Disease and Vascular Dementia. Arch Intern Med. 2010 Oct 25. Abstract
Angus DC. The lingering consequences of sepsis. A hidden public health disaster? JAMA. 2010 Oct 27;304(16):1833-1834. Abstract