Smokers Burnt by Alzheimer's Risk Later in Life

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: October 25, 2010

Heavy smoking in middle age may more than double the risk of Alzheimer's disease later in life, according to a large population-based study.

The prospective cohort study of more than 21,000 people found that those who smoked more than two packs a day developed dementia of any kind twice as often as nonsmokers, Rachel A. Whitmer, PhD, of Kaiser Permanente in Oakland, Calif., and colleagues reported.

The brain might not see the most immediate impact of smoking -- but isn't immune to its long-term effects, Whitmer and co-authors cautioned online in the Archives of Internal Medicine.
Action Points 

    * Point out that as smoking data were collected only at midlife, the study cannot determine whether subsequent smoking cessation will reduce the dementia risk.

Smokers are more likely to die of other causes but shouldn't think they've gotten off scot-free if they don't have a heart attack or get lung cancer or emphysema, Whitmer noted in an interview monitored by a Kaiser Permanente media relations employee.

"If they've made it to late life and don't have respiratory disease or vascular disease, they need to know that their brain is also at risk," Whitmer told MedPage Today. "They need to know that there are long-term consequences."

The negative public health impact of smoking has the potential to become even greater as the population worldwide ages and dementia prevalence increases, she and her colleagues warned in their paper.

Tobacco's link with neurodegenerative or cognitive damage has been somewhat controversial, with some studies even suggesting a lower risk for smokers, Whitmer's group noted.

To get a handle on potential links between smoking and Alzheimer's disease (given its long preclinical phase), the researchers analyzed data from a multiethnic cohort of 21,123 individuals insured by Kaiser Permanente and surveyed as part of routine medical care between 1978 and 1985, when they were ages 50 to 60.

Over the next two to three decades (mean 23 years of follow-up), 25.4% of the study cohort received a diagnosis of dementia -- including 1,136 cases of Alzheimer's disease and 416 cases of vascular dementia.

Light or moderate smoking in middle age didn't appear to increase dementia risk in a direct linear fashion.

Rather, the risk of dementia jumped substantially to an age-adjusted 786.42 per 10,000 person-years once smoking topped two packs a day in mid-life -- producing a 2.14 fold higher risk (95% CI 1.65 to 2.78) than for nonsmokers in the fully-adjusted model.

The same was true for Alzheimer's disease risk, with a fully-adjusted risk 2.57 times higher for those who smoked more than two packs per day compared with nonsmokers (95% CI 1.63 to 4.03). The risk for vascular dementia was similar -- a 2.72-fold higher risk (95% CI 1.20 to 6.18) among heavy smokers.

The adjusted hazard ratio for dementia at lower levels of tobacco use when compared with nonsmokers was:

    * 1.44 for one to two packs per day (95% CI 1.26 to 1.64)
    * 1.37 for half to one pack per day (95% CI 1.23 to 1.52)
    * A nonsignificant 1.04 for less than half a pack a day (95% CI 0.91 to 1.20)
    * Not elevated for former smokers (HR 1.00, 95% CI 0.94 to 1.07)

None of those with less intense smoking habits or former smokers appeared to be at significantly increased risk of Alzheimer's disease or vascular dementia later in life -- but smoking less or quitting didn't seem to be protective either.

The researchers noted that the evaluation of smoking in middle age likely helped to reduce bias from falsely-recalled information or from the effect of subclinical dementia that might have been more of a concern in an elderly population.

But the study was limited by its use of medical records to determine dementia diagnoses and possible undiagnosed dementia in the cohort, Whitmer and colleagues cautioned. Moreover, the assessment of smoking only in middle age left it unclear whether quitting reduced dementia risk, they added.

Heavy smoking could have its impact on the brain via oxidative stress and inflammation -- both believed to be important in development of Alzheimer's disease -- or through vascular and neurodegenerative pathways, the investigators suggested.

However, the exact mechanism whereby smoking may lead to dementia still needs to be clarified, Whitmer's group concluded.

The study was supported by the National Graduate School of Clinical Investigation and by grants from Kuopio University Hospital, the Juho Vainio Foundation, Maire Taponen Foundation, a Kaiser Permanente Community Benefits, and National Institute of Health and Academy of Finland.

One of the authors reported having received honoraria for serving on the scientific advisory board of Elan and Pfizer and serving as a speaker on scientific meetings organized by Janssen, Novartis, and Pfizer.

Primary source: Archives of Internal Medicine
Source reference: Rusanen M, et al "Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia" Arch Intern Med 2010; DOI:10.1001/archinternmed.2010.393.

Reviewed by Zalman S. Agus, MD; Emeritus Professor, University of Pennsylvania School of Medicine and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Sleep Makes the Body Leaner

By Cole Petrochko, Staff Writer, MedPage Today
Published: October 07, 2010


Diet and exercise are important factors in a healthy lifestyle, but a third factor -- sleep -- may be the real key to eliminating fat, according to a small study.

Middle-age, overweight patients who slept 8.5 hours burned more fat than those who slept just 5.5 hours, according to Plamen D. Penev, MD, PhD, of the University of Chicago, and colleagues, who reported their findings in the Oct. 5 issue of the Annals of Internal Medicine.

By contrast, those who were sleep deprived burned more lean muscle mass.
Action Points 

    * Explain to interested patients that middle-aged, overweight patients who slept 8.5 hours burned more fat than those who slept just 5.5 hours.


    * Note that the study also found that participants in the sleep deprivation group were hungrier and expended less energy to compensate for reduced sleep.

They also found participants in the sleep deprivation group were hungrier and expended less energy to compensate for reduced sleep.

Researchers concluded that sleep loss while dieting, "amplifies the pattern of ghrelin-associated changes in human hunger, glucose and fat utilization, and energy metabolism."

The study measured fat and fat-free body mass loss, as well as secondary endpoint measures of caloric use, energy expenditure, hunger, and 24-hour metabolic hormone concentrations in 12 sedentary nonsmokers. The average age was 41 and at baseline the participants slept an average of 7.7 hours each night. Body mass indices ranged from 25 kg/m2to 35 kg/m2 .

Only 10 of the 12 volunteers completed the study (seven men).

Patients were randomly assigned to sleep for either 8.5 or 5.5 hours each night over 14 days and then crossed over for a second 14-day period at least three months later. Sleep was recorded nightly and patients were not allowed daytime naps.

Those in the study were given the same diet with calorie counts based on 90% of resting metabolic rate. Actual consumption was measured by weighing food before and after each meal.

Patients' energy expenditure, hunger scores, respiratory quotients, body water changes, and body composition were measured. Additionally, the researchers measured metabolic hormone levels, including acylated ghrelin, which acts as a switch to control energy expenditure, hunger, and fat retention, as well as regulate glucose production in the liver.

Regardless of sleep duration, patients lost about 3 kg, but the weight loss came from mostly lean mass in the sleep deprivation group -- 2.4 kg versus 1.5 in those who slept for 8.5 hours. Conversely, those who slept for more than 8 hours lost an average of 1.4 kg versus just 0.4 kg of fat loss in the sleep deprivation arm.

Also, patients in the sleep deprivation group were hungrier and 24-hour acylated ghrelin levels increased from an average 73 ng/L pretreatment to 84 ng/L group versus a decline in acylated ghrelin levels (81 ng/L to 75 ng/L) in the normal sleep group, which was statistically significant (P=0.04).

Alternately, resting metabolic rates were significantly higher in the better rested arm and 24-hour plasma epinephrine concentrations were lower, (P=0.005 for both).

There were no significant differences in the measures of the fractional thermic effect of food and 24-hour norepinephrine, cortisol, growth hormone, and thyroid hormone concentrations at the end of study between conditions.

The study was limited by its small sample size and short duration. The authors suggested, however, that the findings supported a larger trial with longer follow-up to examine long-term effects of reduced sleep on body composition, and energy metabolism.

The study was funded by a grant from the National Institutes of Health.
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Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Primary source: Annals of Internal Medicine
Source reference:  Nedeltcheva, AV. "Insufficient Sleep Undermines Dietary Efforts to Reduce Adiposity" Ann Intern Med 2010; 153: 435-441.

Stress Before Cancer Therapy Could Help Deadly Cells Survive Treatment, Lead to Disease Recurrence

ScienceDaily (Sep. 22, 2010)

Patients who experience physical or psychological stress -- including rigorous exercise -- one or two days before a cancer treatment might be unknowingly sabotaging their therapy, new research suggests.

Stress in the body -- even physical stress caused by intense exercise -- activates a stress-sensitive protein that can spark a series of events that allow cancer cells to survive such treatments as chemotherapy and radiation, according to the research.

Though the study involved a series of experiments in breast cancer cell cultures, the researchers say the findings are a clear indication that cancer cells have found a way to adapt and resist treatment with the help of this stress-inducible protein.

This cancer cell survival can be traced to the presence of heat shock factor-1, which previous research has linked to stress. Ohio State University researchers first noticed that this common protein can help heart tissue survive in a toxic environment, leading the scientists to suspect that in cancer, this phenomenon could have serious consequences.

A series of experiments using breast cancer cells showed that a protein activated by the presence of heat shock factor-1 could block the process that kills cancer cells even after the cells' DNA was damaged by radiation. The same was true when the cells were subjected to a common chemotherapy drug.

The researchers hope to develop a drug that could suppress heat shock factor-1 as a supplement to cancer therapy, but in the meantime, they recommend that patients avoid both psychological and physical stress in the days leading up to a cancer treatment.

"One of the known inducers of this factor is exercise. I am not against exercise, but the timing is critical. It looks like any intense or prolonged physical activity a couple of days before the start of cancer therapy is highly risky, and has potential to reduce the benefits of the treatment," said Govindasamy Ilangovan, lead author of the study and associate professor of internal medicine at Ohio State.

The study appears online in the journal Molecular Cancer Research.

Ilangovan, an investigator in Ohio State's Davis Heart and Lung Research Institute, specializes in cardiovascular medicine. But when he observed in previous research that this stress-inducible protein could salvage heart cells that otherwise were doomed to die, he collaborated with radiology specialists to test the protein's effects in cancer.

While he used breast cancer cells for this study, he suspects that the widespread presence of heat shock factor-1 in the body means the protein could have this same effect on any kind of adenocarcinoma, a class of cancer cells that originate in a gland.

Heat shock factor-1 activates a specific protein, known as Hsp27, that ends up helping the cancer cells survive, Ilangovan said.

The researchers conducted numerous experiments to observe how Hsp27 behaves in cancer cells after they undergo ultraviolet-C radiation. The radiation is used as a model for treatments designed to kill cancer cells by damaging their DNA. In this study, the stress of the UV radiation itself also induced the heat shock factor and, subsequently, Hsp27, which reduced the cell death.

In every experiment, a heightened presence of the Hsp27 protein was associated with lower levels of other proteins that participate in the process of cell death. When the researchers introduced siRNA, a molecule that interferes with Hsp27's function, the cell death mechanism was restored.

When the breast cancer cells were treated with doxorubicin, a common chemotherapy drug, the experiment produced similar results. When the Hsp27 protein was silenced, more of the cancer cells died.

"We clearly showed that a reduction in the level of the Hsp27 protein made the cancer cells more susceptible to both treatments," Ilangovan said.

This finding suggested to the scientists that a drug with the same effects as the interference molecule could stop Hsp27 from preventing cancer cell death. No such drug currently exists, and the siRNA molecule isn't suitable for use in patients, Ilangovan said.

But the interfering molecule had a significant effect, in one experiment leading to the death of at least 60 percent of the cancer cells that had undergone UV radiation.

Among the key reactions the researchers observed was Hsp27's relationship to a protein called p21, which allows cells to pause, repair themselves and continue dividing, leading to their survival. Damage to the DNA in cancer cells should disable this step in cell division, but the research showed that the Hsp27 caused p21 to change positions in a way that allowed for cell survival.

"It looks like a compensatory act. We are doing something to kill the cell, but cells have their own compensatory action to oppose that," Ilangovan said.

After irradiation, the levels of Hsp27 reached their height within 48 hours, suggesting that the protein is highly active in the two days following any stressful event that activates heat shock factor-1.

"The process that sets these activities in motion takes a couple of days," Ilangovan said. "It is not proven in a clinical setting, but our hypothesis leads us to strongly caution cancer patients about avoiding stress because that stress might trigger recurrence of cancer cell growth."

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Grants from the National Institutes of Health and the American Heart Association supported this research.

Co-authors of the study are Ragu Kanagasabai, Karthikeyan Krishnamurthy and Kaushik Vedam of the Department of Internal Medicine, and Qien Wang and Qianzheng Zhu of the Department of Radiology, all at Ohio State.