Multiple sclerosis pathogenesis: association between amount of leaked hemoglobin and severity of brain shrinkage

A leak of a protein called hemoglobin from damaged red blood cells may be associated with brain shrinkage in multiple sclerosis. This is the conclusion of a team from Imperial College London, whose early-stage findings suggest treatments that lower levels of hemoglobin could slow progression of the disease. Haemoglobin carries iron and oxygen around the body in red blood cells.

The research, which involved 140 patients with an advanced form of the disease, called secondary progressive multiple sclerosis, has just passed peer review on a new publishing platform, Wellcome Open Research.

Professor Charles Bangham, the lead author of the study from the Department of Medicine at Imperial, said: “These are exciting but early results. If further studies confirm them, they may suggest new avenues of treatment and hopefully more options to offer patients in the future.”

Multiple sclerosis (MS) affects around 100,000 people in the UK. The lifelong condition affects the brain and spinal cord, and results in nerves being destroyed. The symptoms and the severity of the illness vary widely from person to person but often include fatigue, vision problems, muscle spasms and impaired mobility. At first, patients tend to experience repeated episodes of the condition, but symptoms improve between each period of illness. However around 65 percent of patients eventually develop a more severe form of the disease, called secondary progressive multiple sclerosis. In this phase, which generally starts around 15 years after the initial MS diagnosis, the symptoms become steadily worse, with no periods of improvement.

The condition also causes brain cells to die, and on average the brain shrinks by about 0.3 per cent a year in secondary progressive MS. Previous research has found high amounts of iron deposited around blood vessels in the brain. Although the mineral is crucial for our bodies to function, it is toxic at high levels – and scientists have suggested this may trigger the death of brain cells in MS. In the new study, the team suggests that hemoglobin, which carries iron and oxygen around the body may cause these high iron levels.

Haemoglobin is usually contained within the red blood cells. However, previous research suggests red blood cells in MS patients are, for unknown reasons, more fragile than normal and break apart easily.

When red blood cells break down they release hemoglobin into the bloodstream. Normally, the protein would then be prevented from entering the brain by a ‘checkpoint’ between the bloodstream and the brain. However, in MS patients this checkpoint – called the blood-brain barrier – is weakened, allowing hemoglobin to sail through.

The team suggests that once hemoglobin enters the brain it is broken down by an enzyme called haem oxygenase I, which has been found at high levels in the brains of MS patients. The destruction of hemoglobin causes iron to be released into the brain.

Professor Bangham explained: “The iron escapes from the hemoglobin, and may then result in the cell damage and brain shrinkage we see in secondary progressive MS.”

The researchers stress that there are no dietary methods for reducing hemoglobin levels, and people should not remove iron from their diet. “Iron eaten in foods has no effect on the levels of iron that accumulate in the brain. It is the hemoglobin levels, rather than iron that needs to be tackled. Iron is vital for the body, and should not be reduced in the diet,” said Professor Bangham.

In the study, the team found that the MS patients had high levels of a compound called serum lactate dehydrogenase, which is released when red blood cells disintegrate. In the research, the scientists analyzed blood samples of 140 patients with secondary progressive MS, taken over a two-year period, and looked for any proteins raised above normal levels. The team also analyzed brain scans of the patients, as well as blood samples from 20 healthy controls, and 40 patients with other medical conditions apart from MS. They found that blood levels of “free” hemoglobin – hemoglobin that has escaped from the red blood cells – were significantly higher in MS patients with the greatest amount of brain shrinkage. The researchers calculated that a 30 percent increase in free hemoglobin levels resulted in an increased rate of brain shrinkage by 0.1 per cent. This could make a significant difference to a patient’s symptoms.

Professor Bangham explained that the findings were unexpected: “We were amazed by the results, and we were surprised by the size of the apparent effect of hemoglobin on brain shrinkage. Over a number of years, it could significantly impact a patient’s symptoms.” He added that high hemoglobin levels are not the only factor leading to brain shrinkage, but could be a significant contributor.

Existing trials are testing potential MS treatments that mop up excess iron. Professor Bangham questions whether this is the best approach. “It may be more effective to look at ways of removing excess hemoglobin from the blood, rather than iron. There are a number of drugs that do this, although none have been used for multiple sclerosis.”

Furthermore, testing hemoglobin in the blood would not be helpful. This would only show that brain shrinkage is occurring – which would already be detectable on a scan.

The study was performed on patients who had been taking part in a clinical trial, examining the effect of statins on secondary progressive MS. The trial showed statins may have a beneficial effect on brain shrinkage, although this doesn’t seem to be linked to hemoglobin levels said Professor Bangham. “We are still unsure how the statins work, but it seems to be completely separate from the way hemoglobin triggers brain shrinkage.”

The team is now working on further studies to confirm the findings and explore what treatments may tackle high levels of hemoglobin in the blood.

Citation: Alex Lewin, Shea Hamilton, Aviva Witkover, Paul Langford, Richard Nicholas, Jeremy Chataway, Charles R.M. Bangham.  “Free serum hemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis”. Wellcome Open Research 2016 vol: 1 pp: 10.
DOI: 10.12688/wellcomeopenres.9967.1
Research funding: Wellcome trust, Medical Research Council
Adapted from press release by Imperial College London.

Research shows Statins lower the risk of Alzheimer’s disease

The new study shows that, based on a sample of 399,979 Medicare beneficiaries, men and women who took statins two years or more lowered their risk of Alzheimer’s disease in the period spanning from 2009 to 2013. The incidence of Alzheimer’s disease was reduced for beneficiaries frequently prescribed statins (high users), compared to low users, USC and University of Arizona researchers found. Among women who were high users, the incidence rate was 15 percent lower. Among men, the rate was 12 percent lower.

Researchers found the risk of Alzheimer’s disease was reduced for Medicare beneficaries who were frequently prescribed statins. The risk reduction, measured by the hazard rate, varied by statin. Rates below 1 are statistically significant. Credit: USC Schaeffer Center and JAMA Neurology

Researchers noted that black men were the only group that did not show a statistically significant reduction in risk, likely due to sample size. “We may not need to wait for a cure to make a difference for patients currently at risk of the disease. Existing drugs, alone or in combination, may affect Alzheimer’s risk,” said lead and corresponding author Julie Zissimopoulos, associate director of the USC Leonard D. Schaeffer Center for Health Policy and Economics and assistant professor at USC Price School of Public Policy.

Prior studies have shown a link between cholesterol and the hallmark of Alzheimer’s disease: the beta-amyloid plaques that interfere with memory and other brain functions. “We looked to statins as a candidate because they are widely used and have resulted in the reduction of cholesterol,” she said. The findings were published in JAMA Neurology.

Although much is known about Alzheimer’s, scientists have been unsuccessful so far in developing effective treatments to prevent and slow the memory-erasing disease that affects more than 5 million Americans. Hopes were high for the experimental drug, solanezumab, by Eli Lilly that was designed to attack the amyloid plaques. The drug failed for patients with mild dementia in a recent large clinical trial.

In a previous study, Zissimopoulos found that if medical advances could delay the disease’s onset by a year, more than 2 million Americans would be spared from developing Alzheimer’s. This also would result in a $220 billion savings in health and caregiving costs by 2050. Zissimopoulos cautioned that a silver tsunami of aging baby boomers will increase the number of Alzheimer’s patients 70 and older to 9.1 million by 2050. Annual health care costs will surge to $1.5 trillion.

The research team divided the patients into two groups: high-use beneficiaries those who took statins for two years or more between 2006 and 2008 and low-use beneficiaries who took them less frequently or who started taking statins after 2008. Both sets of beneficiaries were in similar health and had no diagnosis of Alzheimer’s disease. The researchers studied records dating from 2009 to 2013 to track the onset of Alzheimer’s disease.

The estimated 400,000 Medicare beneficiaries who became the focus of the study were 65 and older as of January 2006 and were continuously enrolled in Medicare fee-for-service and Part D prescription drug coverage. The study sought results on four of the most commonly prescribed statins: simvastatin, atorvastatin, pravastatin and rosuvastatin.

The researchers also found a reduction in risk for certain demographic groups who were frequently prescribed statins for two years or more. The greatest drop in incidence of Alzheimer’s disease 29 percent was among Hispanic men. Among white men, high users of statins had an 11-percent lower risk of incidence of the disease. A similar reduction in risk  12-percent was found among Hispanic women.

The risk of Alzheimer’s disease was also lower for white women who were high users (15 percent lower than women who took statins less frequently). Simvastatin was linked to a reduced risk of Alzheimer’s for white women, Hispanic women and black women, as well as for white men and Hispanic men. Atrovastatin was associated with a reduced risk of Alzheimer’s for white women, Hispanic women, black women and Hispanic men. Pravastatin and rosuvastatin results showed a statistically significant reduction of Alzheimer’s risk for only white women.

Some scientists believe that certain statins such as atorvastatin and simvastatin, known as lipophilics, would be most effective as an Alzheimer’s preventive treatment because they cross the blood-brain barrier, a protective layer of cells that restricts the types of substances that can pass to the brain. “We generally found that they’re all associated with reduced risk,” Zissimopoulos said.

The researchers plan to study combinations of other existing drugs to measure their effects on the risk of Alzheimer’s disease.

Citation: Julie M. Zissimopoulos, Douglas Barthold, Roberta Diaz Brinton, Geoffrey Joyce. “Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease”. JAMA Neurology 2016 vol: 111 (5) pp: 390-400.
DOI: 10.1001/jamaneurol.2016.3783
Research funding: NIH/National Institute on Aging, USC Zumberge Research Fund.