Posts tagged neurology

A new study suggests that targeting B cells, which are a type of white blood cell in the immune system, may be associated with reduced disease activity for people with multiple sclerosis (MS). The study is released today and will be presented at the American Academy of Neurology’s 66th Annual Meeting in Philadelphia, April 26 to May 3, 2014.

For the study, 231 people with relapsing-remitting MS received either a placebo or one of several low dosages of the drug ofatumumab, which is an anti-B cell antibody, for 24 weeks, with the first 12 weeks making up the placebo-controlled period. The main objective was to determine the effects of ofatumumab dosing regimens compared to placebo on the total number of new brain lesions assessed every four weeks over a 12-week period.

All dose groups including placebo showed lesion activity in the first four weeks with lesion suppression in all ofatumumab dose groups from weeks four to12. Researchers measured the amount of B cells in participants and compared that to the total number of new brain lesions that appeared on brain scans, which is a marker of disease activity.

The researchers found that when B cells were reduced to below a threshold of 64 cells per microliter, disease activity, as measured by appearance of new brain lesions, was significantly reduced. On average, participants had an annualized rate of less than one new brain lesion per year when B cells were maintained below a threshold of 32 to 64 cells per microliter, compared with 16 lesions without treatment.

The most common side effects, defined as those occurring in at least five percent of participants and at a rate twice that of placebo for weeks zero to12, were injection-related reaction, dizziness, anxiety, fever, respiratory tract infection and nerve pain.

Study author Daren Austin, PhD, of GlaxoSmithKline in Uxbridge, United Kingdom, and a member of the American Academy of Neurology, said the study results also suggest that peripheral, rather than central, B cells may be the most relevant target for anti-B cell therapy.

“These results need to be validated, of course, but the findings are interesting,” Austin said. “They provide new insight into the mechanism of B cells in MS and present a possible new target threshold for exploring the potential benefit of anti-B cell therapy.” Ofatumumab is not approved anywhere in the world for use in the treatment of multiple sclerosis.

Researchers may have identified key genes linked to why some people have a higher tolerance for pain than others, according to a study released today that will be presented at the American Academy of Neurology’s 66th Annual Meeting in Philadelphia, April 26 to May 3, 2014.

“Our study is quite significant because it provides an objective way to understand pain and why different individuals have different pain tolerance levels,” said study author Tobore Onojjighofia, MD, MPH, with Proove Biosciences and a member of the American Academy of Neurology. “Identifying whether a person has these four genes could help doctors better understand a patient’s perception of pain.”

Researchers evaluated 2,721 people diagnosed with chronic pain for certain genes. Participants were taking prescription opioid pain medications. The genes involved were COMT, DRD2, DRD1 and OPRK1. The participants also rated their perception of pain on a scale from zero to 10. People who rated their pain as zero were not included in the study. Low pain perception was defined as a score of one, two or three; moderate pain perception was a score of four, five or six; and high pain perception was a score of seven, eight, nine or 10.

Nine percent of the participants had low pain perception, 46 percent had moderate pain perception and 45 percent had high pain perception.

The researchers found that the DRD1 gene variant was 33 percent more prevalent in the low pain group than in the high pain group. Among people with a moderate pain perception, the COMT and OPRK variants were 25 percent and 19 percent more often found than in those with a high pain perception. The DRD2 variant was 25 percent more common among those with a high pain perception compared to people with moderate pain.

“Chronic pain can affect every other part of life,” said Onojjighofia. “Finding genes that may be play a role in pain perception could provide a target for developing new therapies and help physicians better understand their patients’ perceptions of pain.”

(Source: newswise.com)

Similarities found between HIV-associated brain damage and impairment from genetic fat-storage disease

Johns Hopkins scientists have found that levels of certain fats found in cerebral spinal fluid can predict which patients with HIV are more likely to become intellectually impaired.

The researchers believe that these fat markers reflect disease-associated changes in how the brain metabolizes these fat molecules. These changes disrupt the brain cells’ ability to regulate the activity of cells’ “garbage disposals” meant to degrade and flush the brain of molecular debris. In this case, too much cholesterol and a fat known as sphingomyelin build up in the lysosomes — the garbage disposals — backing up waste and leading to often debilitating cognitive declines. 

As many as half of patients infected with HIV will develop some form of cognitive impairment, ranging from mild (trouble counting change or driving a car) to frank dementia (an inability to manage activities of every day life), but no tests have been available to predict which people were more likely to suffer cognitive losses.

 “Every researcher of neurodegenerative disease is chasing biomarkers for the same reason: It’s better to identify problems before they strike,” says Norman J. Haughey, Ph.D., an associate professor in the departments of neurology and psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. He led the current study described online in the journal Neurology.

“It’s very hard to reverse brain damage after it starts,” he says. “Instead, we want to figure out who is likely to lose cognitive function and stop the damage before it happens.”

Haughey and his team analyzed 321 cerebral spinal fluid samples collected from seven test sites across the continental United States, Hawaii and Puerto Rico. The samples came from 291 HIV-positive participants and 30 HIV-negative subjects. The investigators found that early accumulations of a small number of these fat molecules could predict the probability of cognitive decline. As cognitive function declined in these patients, the number of different types of fat molecules that accumulated increased. The types of accumulating fat molecules in HIV were very similar to those that accumulate in inherited forms of a class of diseases called lysosomal storage disorders. This suggests that in some HIV-infected patients, the brain is retaining more of these fats, and this may disrupt the function of lysosomes.

Haughey says he believes some of these impairments in the metabolism of these fats found in people with HIV stems from the infection itself, while others may be linked to the lifesaving antiretroviral therapy taken by most people with HIV. The medications have been associated with elevated blood cholesterol and triglycerides, along with a host of other side effects. Those with HIV are now taking these drugs for decades and the complications from long-term use have not been well studied, he says.

The similarities between the metabolic disturbances in HIV-infected individuals and those apparent in lysosomal storage disorders are enabling Haughey and his team to collaborate with researchers who study genetic lysosomal storage diseases, and who are developing experimental treatments to clear the fat buildup. They are currently exploring dietary and pharmacological interventions designed to restore balance that could potentially restore brain metabolism in HIV-infected individuals, and in doing so could promote good brain health by ensuring the lysosomes function properly.

(Source: hopkinsmedicine.org)

People with severe encephalitis — inflammation of the brain — are much more likely to die if they develop severe swelling in the brain, intractable seizures or low blood platelet counts, regardless of the cause of their illness, according to new Johns Hopkins research.

The Johns Hopkins investigators say the findings suggest that if physicians are on the lookout for these potentially reversible conditions and treat them aggressively at the first sign of trouble, patients are more likely to survive.

“The factors most associated with death in these patients are things that we know how to treat,” says Arun Venkatesan, M.D., Ph.D., an assistant professor of neurology at the Johns Hopkins University School of Medicine and leader of the study published in the Aug. 27 issue of the journal Neurology.

Experts consider encephalitis something of a mystery, and its origins and progress unpredictable. While encephalitis may be caused by a virus, bacteria or autoimmune disease, a precise cause remains unknown in 50 percent of cases. Symptoms range from fever, headache and confusion in some, to seizures, severe weakness or language disability in others. The most complex cases can land patients in intensive care units, on ventilators, for months. Drugs like the antiviral acyclovir are available for herpes encephalitis, which occurs in up to 15 percent of cases, but for most cases, doctors have only steroids and immunosuppressant drugs, which carry serious side effects.

“Encephalitis is really a syndrome with many potential causes, rather than a single disease, making it difficult to study,” says Venkatesan, director of the Johns Hopkins Encephalitis Center.

In an effort to better predict outcomes for his patients, Venkatesan and his colleagues reviewed records of all 487 patients with acute encephalitis admitted to The Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center between January 1997 and July 2011. They focused further attention on patients who spent at least 48 hours in the ICU during their hospital stays and who were over the age of 16. Of those 103 patients, 19 died. Patients who had severe swelling in the brain were 18 times more likely to die, while those with continuous seizures were eight times more likely to die. Those with low counts in blood platelets, the cells responsible for clotting, were more than six times more likely to die than those without this condition.

The findings can help physicians know which conditions should be closely monitored and when the most aggressive treatments — some of which can come with serious side effects — should be tried, the researchers say. For example, it may be wise to more frequently image the brains of these patients to check for increased brain swelling and the pressure buildup that accompanies it.

Venkatesan says patients with cerebral edema may do better if intracranial pressure is monitored continuously and treated aggressively. He cautioned that although his research suggests such a course, further studies are needed to determine if it leads to better outcomes for patients.

Similarly, he says research has yet to determine whether aggressively treating seizures and low platelet counts also decrease mortality.

Venkatesan and his colleagues are also developing better guidelines for diagnosing encephalitis more quickly so as to minimize brain damage. Depending on where in the brain the inflammation is, he says, the illness can mimic other diseases, making diagnosis more difficult.

Another of the study’s co-authors, Romergryko G. Geocadin, M.D., an associate professor of neurology who co-directs the encephalitis center and specializes in neurocritical care, says encephalitis patients in the ICU are “the sickest of the sick,” and he fears that sometimes doctors give up on the possibility of them getting better.

“This research should give families — and physicians — hope that, despite how bad it is, it may be reversible,” he says.

(Source: newswise.com)

Copper appears to be one of the main environmental factors that trigger the onset  and enhance the progression of Alzheimer’s disease by preventing the clearance and accelerating the accumulation of toxic proteins in the brain. That is the conclusion of a study appearing today in the journal Proceedings of the National Academy of Sciences. 

“It is clear that, over time, copper’s cumulative effect is to impair the systems by which amyloid beta is removed from the brain,” said Rashid Deane, Ph.D., a research professor in the University of Rochester Medical Center (URMC) Department of Neurosurgery, member of the Center for Translational Neuromedicine, and the lead author of the study. “This impairment is one of the key factors that cause the protein to accumulate in the brain and form the plaques that are the hallmark of Alzheimer’s disease.” 

Copper’s presence in the food supply is ubiquitous. It is found in drinking water carried by copper pipes, nutritional supplements, and in certain foods such as red meats, shellfish, nuts, and many fruits and vegetables. The mineral plays an important and beneficial role in nerve conduction, bone growth, the formation of connective tissue, and hormone secretion. 

However, the new study shows that copper can also accumulate in the brain and cause the blood brain barrier – the system that controls what enters and exits the brain – to break down, resulting in the toxic accumulation of the protein amyloid beta, a by-product of cellular activity.  Using both mice and human brain cells Deane and his colleagues conducted a series of experiments that have pinpointed the molecular mechanisms by which copper accelerates the pathology of Alzheimer’s disease.  

Under normal circumstances, amyloid beta is removed from the brain by a protein called lipoprotein receptor-related protein 1 (LRP1). These proteins – which line the capillaries that supply the brain with blood – bind with the amyloid beta found in the brain tissue and escort them into the blood vessels where they are removed from the brain. 

The research team“dosed” normal mice with copper over a three month period. The exposure consisted of trace amounts of the metal in drinking water and was one-tenth of the water quality standards for copper established by the Environmental Protection Agency. 

“These are very low levels of copper, equivalent to what people would consume in a normal diet.” said Deane.

The researchers found that the copper made its way into the blood system and accumulated in the vessels that feed blood to the brain, specifically in the cellular “walls” of the capillaries. These cells are a critical part of the brain’s defense system and help regulate the passage of molecules to and from brain tissue. In this instance, the capillary cells prevent the copper from entering the brain. However, over time the metal can accumulate in these cells with toxic effect. 

The researchers observed that the copper disrupted the function of LRP1 through a process called oxidation which, in turn, inhibited the removal of amyloid beta from the brain. They observed this phenomenon in both mouse and human brain cells.

The researchers then looked at the impact of copper exposure on mouse models of Alzheimer’s disease. In these mice, the cells that form the blood brain barrier have broken down and become “leaky” – a likely combination of aging and the cumulative effect of toxic assaults – allowing elements such as copper to pass unimpeded into the brain tissue. They observed that the copper stimulated activity in neurons that increased the production of amyloid beta. The copper also interacted with amyloid beta in a manner that caused the proteins to bind together in larger complexes creating logjams of the protein that the brain’s waste disposal system cannot clear. 

This one-two punch, inhibiting the clearance and stimulating the production of amyloid beta, provides strong evidence that copper is a key player in Alzheimer’s disease. In addition, the researchers observed that copper provoked inflammation of brain tissue which may further promote the breakdown of the blood brain barrier and the accumulation of Alzheimer’s-related toxins.  

However, because metal is essential to so many other functions in the body, the researchers say that these results must be interpreted with caution.

“Copper is an essential metal and it is clear that these effects are due to exposure over a long period of time,” said Deane. “The key will be striking the right balance between too little and too much copper consumption. Right now we cannot say what the right level will be, but diet may ultimately play an important role in regulating this process.”

(Source: urmc.rochester.edu)