31 Oct 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

Comments

1. • Suzanne Tyas
     University of Waterloo
   • Posted: 31 Oct 2010
   • Paper: Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia.

   Evidence has accumulated that cigarette smoking not only increases the risk of developing Alzheimer’s disease, but also is associated with increased numbers of neocortical plaques and earlier death from the disease. These studies have demonstrated that smoking is not protective, as had been suggested by earlier reports that were affected by methodological limitations, such as survival bias and asymmetric reporting (smoking history obtained by self-reports for controls but by proxy reports for Alzheimer’s cases).

   This study by Rusanen et al. contributes to our understanding of this issue by confirming the association between smoking and increased risk of Alzheimer’s disease in a large, ethnically diverse sample. In addition, this study reports an association between smoking and vascular dementia after adjustment for potential confounders, including vascular factors.

   The authors cite limitations of reliance on medical records for dementia diagnosis, the potential for undiagnosed dementia, and limited smoking data. In addition, it is unfortunate that genetic data were not available, given that the association between smoking and Alzheimer’s disease has previously been shown to vary by apolipoprotein E status.

   Cigarette smoking has well-known links to adverse health conditions such as cancer and cardiovascular disease, yet some individuals continue to smoke. Studies such as that by Rusanen and colleagues may provide additional motivation for smoking cessation by showing the adverse consequences of smoking for Alzheimer’s disease, one of the most feared health conditions in later life.

   View all comments by Suzanne Tyas

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References

Paper Citations

1. Quartin AA, Schein RM, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA. 1997 Apr 2;277(13):1058-63. PubMed.
2. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE. Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med. 2010 May;38(5):1276-83. PubMed.
3. Yende S, Angus DC. Long-term outcomes from sepsis. Curr Infect Dis Rep. 2007 Sep;9(5):382-6. PubMed.
4. Fong TG, Jones RN, Shi P, Marcantonio ER, Yap L, Rudolph JL, Yang FM, Kiely DK, Inouye SK. Delirium accelerates cognitive decline in Alzheimer disease. Neurology. 2009 May 5;72(18):1570-5. PubMed.
5. Angus DC. The lingering consequences of sepsis: a hidden public health disaster?. JAMA. 2010 Oct 27;304(16):1833-4. PubMed.
6. Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, Spears L, Miller M, Franczyk M, Deprizio D, Schmidt GA, Bowman A, Barr R, McCallister KE, Hall JB, Kress JP. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009 May 30;373(9678):1874-82. PubMed.
7. Ott A, Slooter AJ, Hofman A, van Harskamp F, Witteman JC, Van Broeckhoven C, van Duijn CM, Breteler MM. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet. 1998 Jun 20;351(9119):1840-3. PubMed.
8. Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, Launer LJ. Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2003 Jul-Aug;24(4):589-96. PubMed.
9. Reitz C, den Heijer T, van Duijn C, Hofman A, Breteler MM. Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study. Neurology. 2007 Sep 4;69(10):998-1005. PubMed.
10. Salomon AR, Marcinowski KJ, Friedland RP, Zagorski MG. Nicotine inhibits amyloid formation by the beta-peptide. Biochemistry. 1996 Oct 22;35(42):13568-78. PubMed.
11. Dickerson TJ, Janda KD. Glycation of the amyloid beta-protein by a nicotine metabolite: a fortuitous chemical dynamic between smoking and Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8182-7. PubMed.
12. Wang CC, Lu TH, Liao WC, Yuan SC, Kuo PC, Chuang HL, Lee MC, Yen CH. Cigarette smoking and cognitive impairment: a 10-year cohort study in Taiwan. Arch Gerontol Geriatr. 2010 Sep-Oct;51(2):143-8. PubMed.
13. van Duijn CM, Hofman A. Risk factors for Alzheimer's disease: the EURODEM collaborative re-analysis of case-control studies. Neuroepidemiology. 1992;11 Suppl 1:106-13. PubMed.

External Citations

1. Health and Retirement Study
2. Phase 2 trial

Further Reading

Papers

1. Fong TG, Jones RN, Shi P, Marcantonio ER, Yap L, Rudolph JL, Yang FM, Kiely DK, Inouye SK. Delirium accelerates cognitive decline in Alzheimer disease. Neurology. 2009 May 5;72(18):1570-5. PubMed.
2. Dickerson TJ, Janda KD. Glycation of the amyloid beta-protein by a nicotine metabolite: a fortuitous chemical dynamic between smoking and Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8182-7. PubMed.
3. Rusanen M, Rovio S, Ngandu T, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. Midlife smoking, apolipoprotein E and risk of dementia and Alzheimer's disease: a population-based cardiovascular risk factors, aging and dementia study. Dement Geriatr Cogn Disord. 2010;30(3):277-84. PubMed.

News

1. Research Brief: Delirium Hastens Cognitive Decline in Alzheimer Disease 11 May 2009
2. Nicotine and β Amyloid—Smoking Guns? 20 Jun 2003