Dietary Salt--Not Just Hypertension--May Affect Brain

George Citroner

Disclosures

May 04, 2018

Increased Salt, Decreased Cognitive Function

High salt intake may have a dramatic impact on memory and cognitive functioning, independent of its effect on blood pressure, according to an animal study published in Nature Neuroscience.[1]

After only a few weeks, mice fed a sodium-rich diet experienced significantly reduced blood flow to regions of the brain associated with learning and memory. The mice had difficulty building a nest and struggled to find their way out of mazes, as decreased blood flow appeared to affect both cognition and spatial memory.

The researchers—a team from Weill Cornell Medicine in New York City—fed mice the equivalent of nearly 6000 mg of salt per day in a human diet. By comparison, the Centers for Disease Control and Prevention recommends that Americans limit salt intake to about 2300 mg per day as part of a healthy eating plan.[2] According to the US Food and Drug Administration, most of us eat almost 50% more than that.

Although hypertension, associated with high salt intake, can lead to an increased risk for stroke and development of dementia,[3] lead author, Costantino Iadecola, MD, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine, does not believe that this is what caused the cognitive decline observed in his study.

"That was the surprise," he said. "We found that feeding mice a diet with a high content of salt (8-16 times the normal diet), corresponding to the highest levels of salt consumption in humans, is what results in cognitive impairment. The damaging effects of salt on the brain are independent of elevations of blood pressure. Therefore, it's the high dietary salt intake alone which impaired brain function."

Iadecola added that there is evidence in the literature supporting the idea that these results also apply to humans.[4]

"Epidemiologic studies cited in our paper demonstrate a significant link between excess dietary salt intake and cerebrovascular disease, cognitive decline, and dementia," he said.

Immune Response and the Gut-Brain Axis

The researchers found that mice eating a high-salt diet developed an immune response in their guts that increased white blood cell levels. This had a negative impact on other immune cells while also boosting the protein interleukin-17 (IL-17), which reduces levels of a compound critical to healthy circulation, nitric oxide.[4]

"The effect is due to accumulation in the intestine of a special class of lymphocytes called TH17 cells, which produce high amounts of IL-17," Iadecola said. "It enters blood circulation and affects endothelial cells in the brain, which line the brain's blood vessels, and it suppresses the production of nitric oxide. Such loss of nitric oxide reduces blood supply to the brain and causes the neuron damage, which will lead to impaired cognition."

He added that gut bacteria may also play a role in this salt-mediated immune reaction, because an earlier human study had noted its direct effect on gut lymphocytes.[5]

Iadecola said that the gut-brain connection could also be affected by other factors, including saturated fat, sugar, and artificial sweeteners. "That is a possibility, but it remains to be determined whether these dietary factors are damaging by being absorbed in the gut, entering the circulation, and acting directly on the blood vessels of the brain, or by inducing an immune response that results in the damaging effects, as we found was definitely the case for dietary salt," he explains.

Inhibitor Reverses the Effect

To establish that salt-induced high IL-17 levels, rather than hypertension, caused the cognitive decline, Iadecola and his colleagues gave the mice who were eating the high-salt diet a drug called ROCK inhibitor Y27632. This drug reduced IL-17 levels, which returned the mice to near-normal behavior and cognition.

However promising this may be, there is an important distinction between applying this treatment in mice and in humans, according to Iadecola. "We don't know if there is irreversible damage in humans who have consumed high dietary salt their whole life, as opposed to only a few weeks in mice."

Too Little Salt Could Also Be a Problem

According to Michael Harrington, MB, ChB, director of neurosciences at Huntington Medical Research Institutes in Pasadena, California, "The Nowak group study[6] on older humans is from actual blood sodium measures, and although the results are skewed from what a normal population distribution would be, they show that too low or too high blood sodium is not good for cognitive function and also correlates with worsening cognitive function."

Harrington is fascinated by the study's findings, however. "Iadecola's group of mice have this intriguing gut-brain connection, wherein elevated dietary gut salt triggers immune-mediated damage to the brain's capillaries, resulting in cognitive deterioration. It's amazingly interesting how mechanistic physiology getting a little out of control can cause brain damage."

This bolsters research showing that diet is a powerful factor influencing cognitive health. "We do know that a healthy diet is essential for someone with dementia to maintain a good quality of life and also prevent body weight loss, a common side effect of dementia therapies as well as underlying neuropathologies," said Deborah R. Gustafson, MS, PhD, professor in the department of neurology at State University of New York.

Gustafson believes that moderating salt intake is advisable, if only to prevent hypertension-related cognitive decline. "Since high dietary salt intake is associated with hypertension, at least in salt-sensitive people, then higher salt intakes could be associated with cognitive problems. Observational data are very consistent for a risky association of midlife hypertension with dementia."

According to a 2010 article in the American Journal of Hypertension,[7] brain matter damage caused by long-term hypertension is associated with cognitive impairment.

Iadecola concludes that although the full role of salt in Alzheimer disease and cognitive decline is only just being uncovered, "specific diseases aside, I believe that moderating salt intake is a necessary practice to keep the brain healthy and stave off brain diseases, especially in populations at risk, like individuals with cardiovascular risk factors (diabetes, hypertension, etc), multiple sclerosis, and inflammatory bowel disease."

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