Health for life

New research that looked at whether two commonly prescribed statin medicines, used to lower low-density lipoprotein (LDL) or bad cholesterol levels in the blood, can adversely affect cognitive function has found that one of the drugs tested caused memory impairment in rats.

Between six and seven million people in the UK1 take statins daily and the findings follow anecdotal evidence of people reporting that they feel that their newly prescribed statin is affecting their memory. Last year, the US Food and Drug Administration (FDA) insisted that all manufacturers list in their side effects that statins might affect cognitive function.

The study, led by scientists at the University of Bristol and published in the journal PLOS ONE, tested pravastatin and atorvostatin (two commonly prescribed statins) in rat learning and memory models. The findings show that while no adverse cognitive effects were observed in rat performance for simple learning and memory tasks for atorvostatin, pravastatin impaired their performance.

Rats were treated daily with pravastatin (brand name - pravachol) or atorvostatin (brand name - Lipitor) for 18 days. The rodents were tested in a simple learning task before, during and after treatment, where they had to learn where to find a food reward. On the last day of treatment and following one week withdrawal, the rats were also tested in a task which measures their ability to recognise a previously encountered object (recognition memory).

The studys findings showed that pravastatin tended to impair learning over the last few days of treatment although this effect was fully reversed once treatment ceased. However, in the novel object discrimination task, pravastatin impaired object recognition memory. While no effects were observed for atorvostatin in either task.

The results suggest that chronic treatment with pravastatin impairs working and recognition memory in rodents. The reversibility of the effects on stopping treatment is similar to what has been observed in patients, but the lack of effect of atorvostatin suggests that some types of statin may be more likely to cause cognitive impairment than others.

Neil Marrion, Professor of Neuroscience at Bristols School of Physiology and Pharmacology and the studys lead author, said: "This finding is novel and likely lects both the anecdotal reports and FDA advice. What is most interesting is that it is not a feature of all statins. However, in order to better understand the relationship between statin treatment and cognitive function, further studies are needed."

Recent studies have linked caffeine consumption to a reduced risk of Alzheimers disease, and a new University of Illinois study may be able to explain how this happens.

"We have discovered a novel signal that activates the brain-based inflammation associated with neurodegenerative diseases, and caffeine appears to block its activity. This discovery may eventually lead to drugs that could reverse or inhibit mild cognitive impairment," said Gregory Freund, a professor in the U of Is College of Medicine and a member of the U of Is Division of Nutritional Sciences.

Freunds team examined the effects of caffeine on memory formation in two groups of mice—one group given caffeine, the other receiving none. The two groups were then exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow, and then allowed to recover.

The caffeine-treated mice recovered their ability to form a new memory 33 percent faster than the non-caffeine-treated mice. In fact, caffeine had the same anti-inflammatory effect as blocking IL-1 signaling. IL-1 is a critical player in the inflammation associated with many neurodegenerative diseases, he said.

"Its not surprising that the insult to the brain that the mice experienced would cause learning memory to be impaired. But how does that occur?" he wondered.

The scientists noted that the hypoxic episode triggered the release of adenosine by brain cells.

"Your cells are little powerhouses, and they run on a fuel called ATP thats made up of molecules of adenosine. When theres damage to a cell, adenosine is released," he said.

Just as gasoline leaking out of a tank poses a danger to everything around it, adenosine leaking out of a cell poses a danger to its environment, he noted.

The extracellular adenosine activates the enzyme caspase-1, which triggers production of the cytokine IL-1β, a critical player in inflammation, he said.

"But caffeine blocks all the activity of adenosine and inhibits caspase-1 and the inflammation that comes with it, limiting damage to the brain and protecting it from further injury," he added.

Caffeines ability to block adenosine receptors has been linked to cognitive improvement in certain neurodegenerative diseases and as a protectant against Alzheimers disease, he said.

"We feel that our foot is in the door now, and this research may lead to a way to reverse early cognitive impairment in the brain. We already have drugs that target certain adenosine receptors. Our work now is to determine which receptor is the most important and use a specific antagonist to that receptor," he said.

A new study from Australia finds that people with diabetes who take metformin suffer more cognitive problems than those who dont take the drug:

Increased Risk Of Cognitive Impairment In Patients With Diabetes Is Associated With Metformin, Diabetes Care, October 2013

"Participants with diabetes had worse cognitive performance than participants who did not have diabetes. ... Among participants with diabetes, worse cognitive performance was associated with metformin use."

Why does metformin affect cognitive performance? Its thought that the drug interferes with the absorption of vitamin B12, by interacting with a B12 receptor in the distal ileum, and B12 is necessary for a well-functioning nervous system. Indeed, in this study vitamin B12 and calcium supplementation was associated with better cognition.

Dr. Adriaan Kooy from the Bethesda Diabetes Research Center in the Netherlands says:

"The malabsorption of neurovitamins like B12 in metformin users may contribute to neuronal dysfunction — potentially being misinterpreted as diabetic neuropathy."

The link between metformin and vitamin B12 isnt new, but the affect on mental function is becoming more apparent. The studys lead author, Eileen Moore, PhD, told Medscape Medical News:

"Since the 1970s, clinicians and scientists have been aware that metformin is associated with lower vitamin-B12 levels. The hypothesis that this may increase the risk of cognitive impairment seemed sound."

Moore advises:

"Vitamin-B12 levels in patients using metformin should be monitored at least yearly."

Dr. Kooys group published evidence of the link between metformin and vitamin-B12 deficiency a few years ago:

Long Term Treatment With Metformin In Patients With Type 2 Diabetes And Risk Of Vitamin B-12 Deficiency: Randomised Placebo Controlled Trial, British Medical Journal, May 2010

They had the same advice:

"Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered."

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