Does diabetes hamper cognitive function by lowering the brain’s cholesterol?

Leave a comment

Diabetes_cholesterol_brain

Diabetes_cholesterol

Low cholesterol is generally a good thing. But decreasing the amount of low-density lipoprotein—LDL, the “bad cholesterol”—is only one part of the body’s equation for a healthy balance of lipids. And although lowering cholesterol can be good for the heart, it’s not always great for the brain, which contains about a quarter of the body’s cholesterol.

Recent research has shown that drugs that lower cholesterol, such as statins, might put some individuals at risk for cognitive problems. And a new study suggests that diabetes, which affects cholesterol synthesis in the liver, might also be changing the rate these compounds are made in the brain.

Researchers found that diabetic mice had less of the crucial cholesterol in the membranes around their neural synapses. “This has broad implications for people with diabetes,” Ronald Kahn, of the Joslin Diabetes Center at Harvard Medical School and coauthor on the new study, said in a prepared statement. The results were published online November 30 in Cell Metabolism.

“Since cholesterol is required by neurons to form synapses with other cells, this decrease in cholesterol could affect how nerves function,” Kahn said. Affected systems could include “appetite regulation, behavior, memory and even pain and motor activity,” he said. They correlate with increased risk of diabetic patients for eating disorders, depression and memory trouble.

For the study, Kahn and his team created mice that lacked sufficient insulin—to mimic a diabetic condition. In particular, the scientists targeted a gene known as SREBP-2 (which controls cholesterol metabolism) and other brain-based genes, causing the mice to produce—and retain—less cholesterol in key structures in the brain.

“These effects occurred in both the neurons and supporting ‘glial’ cells that helped provide some nutrients to the neurons,” Kahn said. “Ultimately this affects the amount of cholesterol that can get into membranes of the neuron, which form the synapses and the synaptic vesicles.”

When the diabetic mice received insulin injections, their genes seemed to return to normal functioning. The researchers noted that longer-term insulin depletion might cause more permanent damage to the myelin sheaths, the fatty covering of nerves that contain more than two thirds of the central nervous system’s cholesterol and are crucial to neural communication.

“It is well known that insulin and diabetes play an important role in regulating cholesterol synthesis in the liver, where most of the cholesterol circulating in the body comes from,” Kahn said. “But nobody had ever suspected that insulin and diabetes would play an important role in cholesterol synthesis in the brain.”

Advertisements

Recommended Daily Vitamin D Intake Gets a Boost

Leave a comment

Recommended-daily-vitamin

Recommended-daily-vitamin

Vitamin D deficiency has become something of a health bugaboo in recent years, especially after a 2009 study that declared three quarters of U.S. adults and teenagers deficient. Low levels of the vitamin—which is manufactured by the body when sunlight hits the skin and can be found in some fatty fish and fortified food products—have been linked to disparate conditions, such as a sluggish immune system and psychosis.

But a new report from the Institutes of Medicine (IOM), released November 30, concludes that the evidence linking vitamin D and calcium deficiency to anything but poor bone health is inconclusive. It also determined that most people in the U.S. and Canada are getting ample amounts of the vitamin. Even so, the organization is raising the level of recommended daily intake.

The new assessment recommends a daily vitamin D dietary allowance of 600 milligrams for most healthy people 9 years and older (with an estimated average requirement of 400 International Units per day—and no more than 4,000 IU of vitamin D per day). People 71 years and older should take 800 mg of the vitamin per day, according to the report. (Children aged 4 to 8 years should not have more than 3,000 IU/day and those aged 1 to 3 years should not have more than 2,500 IU/day.)

The updated daily recommendations are not directly comparable to previous sets, which were established in 1997 and are based on “adequate intakes” rather than on the newer recommended dietary allowance and estimate average requirement. Catharine Ross, chair of the IOM’s review committee and a professor of nutrition at Pennsylvania State University, noted in a Tuesday press briefing that the two values are “like comparing apples to pears.” (The previous adequate intake recommendations were 200 IU per day for infants through age 50, 400 IU/day for ages 51 to 70, and 600 IU/day for those 71 and older.)

Adequate intake was more of “a guesstimate,” Patsy Brannon, a professor of nutritional sciences at Cornell University and member of the IOM review committee, said at the briefing. Those who did not meet the previous adequate intake levels were at a higher risk for deficiency, but “you cannot assume that individuals are deficient if they do not meet the adequate intake,” she explained.

That the IOM is “recognizing that their 1997 recommendations are too low” is substantial progress, says David Hanley, a professor in the departments of Medicine, Community Health Sciences and Oncology at the University of Calgary, who was not involved in the new report.

The antidepressant reboxetine: A headdesk moment in science

Leave a comment

The-antidepressant

The-antidepressant

Every so often there comes a truly “headdesk” moment in science. A moment where you sit there, stunned by a new finding, and thinking, blankly…”OK, now what?”

For psychiatry and behavioral pharmacology, one of those moments came a few weeks ago with the findings of a meta-analysis published in the British Medical Journal (Eyding et al., 2010). The meta-analysis showed that an antidepressant, reboxetine (marketed by Pfizer in Europe, but not in the U.S., under the names Edronax, Norebox, Prolift, Solvex, Davedax or Vestra) doesn’t work. Not only does it not work, it really doesn’t work, and it turns out that Pfizer hadn’t published data on the putative antidepressant from 74% of their patients. Some people have reported that the study found that reboxetine was even “possibly harmful,” but that’s not quite true. What the study did find is that reboxetine produced more side effects (noted as “adverse events”) than placebo (as might be expected), but with no positive effects at all. While many antidepressants on the market today are not great, most are effective in around 60% of patients; reboxetine turns out to be even worse than that.

It turns out that publication bias was rampant. Pfizer and Lundbeck, the two companies running the studies, didn’t publish a lot of their data, especially the data showing no effect and unfortunate side effects. A bit nefarious, that. But bad science will out.

While sales of reboxetine never compared to sales of more traditional antidepressants like citalopram and fluoxetine, the study still puts a major kink in the pharmacotherapies currently available for depression. Whereas drugs like citalopram and fluoxetine primarily target the neurotransmitter serotonin, reboxetine targets the neurotransmitter norepinephrine. So it was hoped when drugs like reboxetine came on to the market that the different chemical focus might prove more effective or change the side-effect profiles normally associated with antidepressants. But obviously the side effects got worse, and reboxetine turns out to not be so effective in patients after all.

And this is a rough moment for scientists studying depression. Why? Because reboxetine works beautifully in our animal models. It’s practically a poster-child antidepressant. It produces acute effects in tests such as forced-swim tests and tail-suspension tests (which use changes in struggle as a measure of antidepressant efficacy). It produces neurogenesis in the hippocampus, which is thought to be correlated with antidepressant effects. When behavioral pharmacologists are doing comparisons between older antidepressants and newer ones, reboxetine is often used as a positive control, a drug known to have an effect in the behavioral test of choice.

But it doesn’t work in patients. And patients are what matters. Now, scientists are stuck with a difficult question: What went wrong? This is more than just an issue with an antidepressant that didn’t work, it’s an issue with the tests we are using to study depression. How effective are they, really? Are we in fact modeling the right things? Do the tail-suspension test and forced-swim test detect antidepressant activity after all? And if they aren’t detecting antidepressant activity, what are they actually doing? What does this mean for both the neurochemical theory of depression and the neurogenesis theory? Reboxetine affects both but still has no clinical effect. Does this mean that both of these theories are wrong? Or does it mean that they are incomplete? And where, exactly, do we go from here?

We may need new models to study depression, or we may need to simply redefine and reexamine the ones that we have. But the latest findings on reboxetine raise more questions than those about pharma companies, scientific conduct and efficacy in patients. They raise questions about the way we study depression and what it is we need to measure to come up with the therapies that patients need. And it makes it more important than ever to study the possible mechanisms behind depression and other mental disorders, to understand how they work and what behaviors and changes we need to detect, to gain new insights into how to combat depression with more success and less…reboxetine.

A Healthy Brain Needs a Healthy Heart

Leave a comment

The-heart-brain-connection

The-heart-brain-connection

When the National Institutes of Health convened a panel of independent experts this past April on how to prevent Alzhei­mer’s disease, the conclusions were pretty grim. The panel determined that “no evidence of even moderate scientific quality” links anything—from herbal or nutritional supplements to prescription medications to social, economic or environmental conditions—with the slightest decrease in the risk of developing Alzheimer’s. Furthermore, the committee argued, there is little credible evidence that you can do anything to delay the kinds of memory problems that are often associated with aging. The researchers’ conclusions made headlines around the world and struck a blow at the many purveyors of “brain boosters,” “memory enhancers” and “cognitive-training software” that advertise their wares on the Web and on television. One of the panel experts later told reporters in a conference call that the group wanted to “dissuade folks from spending extraordinary amounts of money on stuff that doesn’t work.”

But did the panel overstate its case? Some memory and cognition researchers privately grumbled that the conclusions were too negative—particularly with respect to the potential benefits of not smoking, treating high blood pressure and engaging in physical activity. In late September the British Journal of Sports Medicine published a few of these criticisms. As a longtime science journalist, I suspected that this is the kind of instructive controversy with top-level people taking opposing positions that often occurs at the leading edge of research. As I spoke with various researchers, I realized that the disagreements signaled newly emerging views of how the brain ages. Investigators are exploring whether they need to look beyond the brain to the heart to understand what happens to nerve cells over the course of decades. In the process, they are uncovering new roles for the cardiovascular system, including ones that go beyond supplying the brain with plenty of oxygen-rich blood. The findings could suggest useful avenues for delaying dementia or less severe memory problems.

Dementia, of course, is a complex biological phenomenon. Although Alzheimer’s is the most common cause of dementia in older adults, it is not the only cause. Other conditions can contribute to dementia as well, says Eric B. Larson, executive director of the Group Health Research Institute in Seattle. For example, physicians have long known that suffering a stroke, in which blood flow to the brain has been interrupted by a clot or a hemorrhage, can lead to dementia. But research over the past few years has documented the importance of very tiny strokes—strokes so small they can be detected only under a microscope after death—as another possible cause for dementia. Studies at autopsy of people who had dementia have detected many of these so-called microvascular infarcts either by themselves or along with the plaques and tangles more typical of Alzheimer’s in the brains of people with dementia. These findings suggest that most dementias, even those caused by Alzheimer’s, are triggered by multiple pathological processes and will require more than one treatment.

Proving that cardiovascular treatment is one of those approaches will take some doing. Just because microinfarcts may make dementia worse does not mean that preventing them will delay the brain’s overall deterioration. Maybe severe dementia makes people more vulnerable to microinfarcts. And just because better control of high blood pressure and increased physical activity seem to decrease a person’s risk of stroke, that does not necessarily mean they are less likely to suffer microinfarcts. Correlation, after all, does not necessarily imply causation. That scientific truism was the problem that kept bothering the panel of outside experts put together by the NIH. Thus, the expert panel concluded, with one exception, that “all existing evidence suggests that antihypertensive treatment results in no cognitive benefit.” Data showing the benefits of boosting physical activity in folks with confirmed memory problems were “preliminary.”

Ultramarathoners Reveal “Safe” Injuries

Leave a comment

Ultramarathoners-Reveal

Ultramarathoners-Reveal

For some reason, every year a few dozen runners dash from southern Italy all the way to the North Cape of Norway, in what’s called the TransEurope-FootRace. It takes about two months to cover the almost 2,800 miles, about 45 miles a day.

In the 2009 edition, 44 of the 66 participants allowed themselves to be examined medically throughout. The findings were presented November 29th at the annual meeting of the Radiological Society of North America in Chicago. And some of the discoveries may be of use to the less ambitious among us.

Muscle volume of the legs actually went down 7 percent because of the incredible energy consumption of the daily distances. And some leg injuries were found to be safe to run through. It was okay to keep going with simple leg muscle inflammation, for example. But other overuse injuries, like joint inflammation, carried a greater risk of worsening. Runners lost 40 percent of their body fat in the first half of the race and 50 percent altogether. Beginning runners can likewise expect to see a rapid fat loss at first. And you get to stop before reaching Norway.

Cybertherapy, placebos and the Dodo effect: Why psychotherapies never get better

Leave a comment

11-29-Sigmund-Freud

11-29-Sigmund-Freud

When the media report on a new diet that supposedly helps people lose weight once and for all, I wonder, “Does anyone still believe these claims, given the dismal track record of diets?” I have the same reaction to new treatments for psychological disorders, such as “cybertherapy.”

In a long, lavishly illustrated article in The New York Times, Benedict Carey reported that psychotherapists are harnessing virtual reality for treating social anxiety disorder, alcoholism, agoraphobia, gambling addiction, post-traumatic stress disorder and a host of other mental ailments. Therapists can, in effect, place an alcoholic in a bar, an acrophobe in a rooftop party and someone who fears public speaking in front of a large, restless audience. They then can manipulate the virtual environment to test patients’ ability to cope with different situations.

Patients can also discuss their troubles with a virtual therapist, relying on voice recognition and artificial intelligence software to parse remarks and respond appropriately. The therapist can take any form—male, female, black, white, young, old. The virtual therapist is a souped-up version of Eliza, an automated therapist that was created at the Massachusetts Institute of Technology in the 1960s and communicated via typed messages.

The U.S. Army is spending $4 million a year on research into cybertherapy for traumatized veterans, according to the Times. In a program developed at the University of Southern California, veterans roll through a virtual Iraqi village in a Humvee, which is attacked by bullets and bombs. The Army’s interest in cybertherapy evokes a certain cognitive dissonance because the military also employs virtual reality to prepare soldiers—from ground troops to pilots—for combat.

Cybertherapy sounds fascinating, and fun, but does it work? The Times story addresses this crucial question in its 31st paragraph. Researchers at the University of Quebec compared patients who received conventional talk therapy with others who got cybertherapy. “Both groups showed improvement, faring much better than a comparison group put on a waiting list,” the Times reported.

So cybertherapy is about as effective—or ineffective—as more conventional talk therapy. This finding confirms the so-called Dodo effect, which was originally proposed by the psychologist Saul Rosenzweig in the 1930s, when psychoanalysis was spawning a host of variants. He speculated that all talking cures share certain common factors—such as a caring therapist who establishes a bond with the patient—that make them equally helpful.

“Dodo” refers to an episode in Lewis Carroll’s fable Alice’s Adventures in Wonderland in which Alice and other characters wash up onto an island. There they encounter a Dodo bird who persuades them to race around the island. The Dodo finally announces that the race is over and proclaims, “Everyone has won, and all must have prizes!”

Over the last few decades, the psychologist Lester Luborsky of the University of Pennsylvania tested the Dodo effect by comparing different psychotherapies, including psychoanalysis, cognitive-behavioral therapy and interpersonal therapy. His research confirmed that all methods are equally helpful to patients. Claims that one therapy is more effective than others, Luborsky showed, can usually be explained by the “allegiance effect,” the tendency of researchers to find evidence for the therapy that they practice or favor.

Ironically, Luborsky, who died in 2009, displayed the allegiance effect himself. He strongly defended the value of psychotherapy in general and psychodynamic therapy in particular; psychodynamic therapy is a watered-down form of psychoanalysis that Luborsky favored in his clinical practice.

Other prominent researchers—notably Jerome Frank, a psychiatrist at Johns Hopkins—realized that the Dodo effect undermined the validity of all psychotherapies. Frank’s own research corroborated the Dodo effect. In one study, he and colleagues provided depressed patients with three treatments: weekly individual therapy, weekly group therapy and minimal individual therapy, which consisted of just one half-hour session every two weeks. “To our astonishment and chagrin, patients in all three conditions showed the same average relief of symptoms,” Frank wrote in Persuasion and Healing: A Comparative Study of Psychotherapy, first published in 1961 by Johns Hopkins Press and reissued in 1993.

Frank asserted that “relief of anxiety and depression in psychiatric outpatients by psychotherapy closely resembles the placebo response, suggesting that the same factors may be involved.” The specific theoretical framework within which therapists work has little or nothing to do with their ability to “heal” patients, Frank contended. The most important factor is the therapist’s ability to persuade patients that they will improve.

Frank’s view should disturb anyone who thinks psychotherapy has a scientific basis. It doesn’t matter whether your therapist is a Jungian, cognitive behaviorist, witch doctor—or a cybertherapist that exists only in a computer. What matters is whether you believe you will get better.

If talk therapy is really just a form of faith healing, should we abandon it and rely only on psychopharmacology for treating disorders such as depression and anxiety? Not necessarily. As Sharon Begley, one of my favorite science writers, pointed out in Newsweek in January, the placebo effect—and allegiance effect—may also account for the reported benefits of antidepressants. All are losers, and none must have prizes.

Readers Respond to “When the Sea Saved Humanity” and Other Articles

Leave a comment

Letters-dec-10_1

Letters-dec-10_1

Blowing the Whistle
In “Danger in School Labs” [News Scan], Beryl Lieff Benderly lists four fatalities from lab accidents. She notes that the Protecting America’s Workers Act would expand the jurisdiction of the Occupational Safety and Health Act of 1970 to include state employees, in particular those of state colleges and universities. Whistleblower protections would also improve. Sadly, 5,000 Americans die every year from workplace hazards. Sadder still, although dead bodies usually get Congress to pass better protections, opposition from the U.S. Chamber of Commerce has mired the bill in committees.
Under the 1970 act, whistleblowers can file a complaint with the Occupational Safety and Health Administration, but if OSHA decides not to take any further action in the case, the whistleblower has no further rights to any hearing or appeal. This dependence on OSHA has been devastating for the vast majority of workers who face retaliation after raising safety concerns.

In certain facilities, such as nuclear power plants, strong whistleblower protections already give workers in environmentally sensitive jobs meaningful legal remedies when they face retaliation for raising safety and compliance concerns. The new act would establish similar protections for all the employees OSHA covers in both the public and private sectors. When whistleblowers speak truth to power, they could finally hold employers accountable when they choose to retaliate. Our legislators need to know that lives are more important than Chamber of Commerce opposition.
Richard R. Renner
Legal director
National Whistleblowers Center
Washington, D.C.

Older Entries