A link between surgery and cognitive decline has long been observed, but without understanding its nature or how to control it. A new study suggests that inflammation following an operation could be the trigger that accelerates the pathology of the disease. If so, it will become even more important to identify people at risk for developing the disease, and to find ways of blocking the brain from launching this harmful inflammatory response.
In the sad mental decline that is the hallmark of Alzheimer’s disease, many patients are able to pinpoint the onset of their symptoms to a time when they underwent major surgery, such as hip replacement or colectomy. While everyone takes time to recover after an operation, some patients, perhaps those already at risk for Alzheimer’s disease (AD), experience a lasting cognitive decline, from which they never recover. Maryellen Eckenhoff, a neuroscientist in the Department of Anesthesiology and Critical Care at the Perelman School of Medicine at the University of Pennsylvania, confirms that many people are able to say “‘Grandma was never the same after she had that surgery.’ So our patients and their families are telling us that there’s something going on.”
A new study published online in the September issue of Annals of Surgery helps to clarify the connections between surgery, anesthesia and the pathology of Alzheimer’s disease. The findings suggest that the surgery itself, and the resulting inflammation, may be involved in accelerating the development of Alzheimer’s symptoms.
Where there’s anesthesia, there’s surgery
“We started with the idea that anesthesia alone might accelerate the pathology of Alzheimer’s disease,” says Rod Eckenhoff, Professor of Anesthesiology at the Perelman School of Medicine and co-author of the study, explaining the roots of this research. But the evidence was inconsistent. In animal studies of Alzheimer’s, anesthesia had the predicted effect on neurological pathology, but not on cognition. “So we started to ask ourselves, ‘What else is going on?’ The obvious answer is that we don’t give anesthesia without surgery.” Indeed, adding surgery to the experimental variables produced a large cognitive effect in animal models.
The connection has not been proven, but Dr. Eckenhoff suspects neuroinflammation might be the cause of accelerated AD pathology and cognitive decline following surgery. “It is well known that surgery causes systemic inflammation. This peripheral response might be sensed by the brain and trigger inflammation there.” A 2011 study from the same laboratory found that, following surgery, an increasing level of tau protein, a biomarker of AD, in patients’ cerebrospinal fluid (CSF) was accompanied by significant increases in several inflammatory biomarkers, “suggesting neuroinflammation as a possible mechanism.”
A “sudden bump” on the path toward Alzheimer’s
Inflammation has a long history in Alzheimer’s research, “but it’s a very mixed bag,” according to Rod Eckenhoff. In the 1980s, it was observed that rheumatoid arthritis patients, who had been on very long-term anti-inflammatory treatments, had lower rates of Alzheimer’s disease. Prospective studies tried to duplicate this phenomenon by using anti-inflammatories as a treatment for AD, but without effect. “The issue might be when you treat – if you enroll older patients who already have symptoms, it might be too late, whereas rheumatoid arthritis patients have been treating themselves for decades,” he says.
There is a major difference, though, between the autoimmune patients’ long-term inflammation, and the Eckenhoff’s work with Alzheimer’s pathology accelerated by surgery. “Our research involves a big, transient inflammatory event,” Rod Eckenhoff explains. “We’re proposing that with surgery, you have a sudden bump on a trajectory towards Alzheimer’s disease that puts the disease on a new path.” That is, for a vulnerable brain that was going to develop AD anyway, surgery might alter the course of the disease, accelerating the pathology and cognitive decline. A study published in March 2012 in Anesthesiology lends support to this idea, from a different angle. A team at NYU found a correlation between surgery and brain atrophy, 5 to 9 months after the operation, even in patients who were still cognitively normal or only mildly impaired.
The ultimate goal of research like the Eckenhoffs’ would be to block the jolt caused by postoperative inflammation. One question that needs answering is related to the timing of an eventual treatment. “We don’t know if we should start treating patients with anti-inflammatories a day or a week before the operation. Nor for how long after.” The researchers also don’t know how well their study in mice will translate to humans. Mouse models, however imperfect, have led to greater understanding of the disease, but it will be important to conduct prospective clinical trials.
“The next step for the whole field is to understand how to identify vulnerable people. The underlying neuropathology begins 10-20 years before cognitive dysfunction. Once cognitive symptoms appear, the brain has experienced considerable decline.” Rod Eckenhoff suspects that “this is probably why most Alzheimer’s therapy trials have failed: they enrolled people who already had cognitive symptoms.” The next step, and a big challenge, he says, will be to identify people who are likely to get the disease. Biomarkers, molecules indicative of the disease, present in the cerebrospinal fluid are one indicator; unfortunately, few patients are willing to undergo an invasive spinal tap for the test. The discovery of a biomarker that could be tested via a blood sample would be ideal. Brain imaging – PET, CT, MRI scans – although too expensive to deploy systematically before all surgery, is receiving the most attention now, says Rod Eckenhoff. Pathological hallmarks of Alzheimer’s disease, such as the accumulation of beta amyloid proteins and the shrinking of specific brain regions, are visible in these types of scans, and begin well before symptoms appear.
“People haven’t figured out how to cure Alzheimer’s, so effort is focused on how to delay it. We’re not trying to cure AD,” Rod Eckenhoff clarifies about his team’s own research, “but prevent it from being accelerated. Fifty or 60% of people have surgery at some point in their lives. If we, as anesthesiologists and surgeons, are already contributing to an acceleration of Alzheimer’s disease, we need to identify that. And if we can do something about it, we could have a large effect on the prevalence of Alzheimer’s.”
Find out more:
"Barcelona: Inflammation -- That Two-Faced Beast", Alzheimer's Research Forum news http://www.alzforum.org/new/detail.asp?id=2761 “
Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy”, a review, January 2010 http://alzres.com/content/2/1/1 Chronic inflammation may contribute to Alzheimer's in mice http://www.alzheimersresearchuk.org/news-detail/10495/Chronic-inflammation-may-contribute-to-Alzheimers/
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