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Neurology News

Follow our Neurology News blog for the latest news on neurologic diseases and research.

Friday, June 14, 2019

Scientists have identified abnormal levels of glutamate and glutamine in the limbic regions of the brain in people diagnosed with functional motor symptoms (FMS). The condition is thought to be psychogenic in nature and patients are often referred for psychiatric treatment. Results of the study, which was led by researchers at the Aldo Ravelli Research Center for Experimental Brain Therapeutics at the University of Milan Medical School in Italy, were published online in Neurology on June 5.

On a hunch that a biological basis underlies FMS disturbances, Alberto Priori, MD, PhD, professor of neurology and director of the neurology clinic at San Paulo Hospital in Milan, and colleagues recruited 10 FMS patients and an equal number of healthy controls. Using magnetic resonance spectroscopy, the researchers measured the brain chemicals N-acetylaspartate, myo-inositol, choline, glutamate, and glutamine in different areas of the brain, including the anterior cingulate cortex, medial prefrontal cortex, and occipital cortex, to see if there was a correlation between any neurochemical limbic activity and the severity of motor and psychiatric symptoms. They reported significant increases – four times the normal level – of glutamine and glutamate and creatine in the limbic regions of the 10 patients and none in the controls. The abnormal activity was not outside of the limbic system.

The patients also underwent extensive neuropsychological testing, including the Mini-Mental State Examination, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Toronto Alexithymia Scale, and the EuroQol 5D, a questionnaire that helps assess quality of life. The severity of their symptoms was linked to increasing levels of these metabolites.

Dr. Priori and his colleagues said these abnormal limbic increases could have a "crucial pathophysiological role in FMS," and could possibly trigger abnormal movements. If so, drugs that target these biochemicals could be useful in reducing symptoms. "The goal of our research is to understand the biological basis of neuropsychiatric disturbances frequently seen in clinical practice," said Dr. Priori. These syndromes "are very expensive for national health systems and difficult to manage." 

The researchers added that patients with FMS also have psychiatric symptoms, but the question is whether these chemical abnormalities could be causing a limbic imbalance that can drive depression and anxiety. Drugs that modulate glutamatergic activity such as memantine and ketamine might work in reducing symptoms in FMS patients. "Drugs acting on the glutaminergic system should be tested in a systematic controlled trial," said Dr. Priori. "At this point, we don't know whether the increase in glutamate is because its receptors are down-regulated or because its metabolism is primarily altered. We have experiments underway to clarify this issue."

It is important for patients to know that a biological abnormality could explain their symptoms, he said. "This abnormality may also reflect a psychopathological problem," he added.

They are now embarking on a study to see whether psychotherapy can lower these abnormal glutamate levels.

Link Up to More Information:

Demartini B, Gambini O, Uggetti C, et al. Limbic neurochemical changes in patients with functional motor symptomsNeurology 2019;93:1-7. Epub 2019 June 5.

Thursday, June 13, 2019

A mobile app for a behavioral therapy program reduced episodes of migraine, according to results of a  June 4, 2019, study in Digital Medicine, a journal published by the International Society of Digital Medicine. 

The researchers, led by Mia Minen, MD, chief of headache research at NYU Langone Health, reported that patients who used the progressive muscle relaxation technique at least two times a week had fewer episodes over the course of the study.

Dr. Minen and her colleagues designed the study to determine whether they could get more migraine patients using nonpharmacological treatments such as cognitive behavioral therapy, biofeedback, and progressive muscle relaxation. A growing body of research demonstrates the long-term benefits of these techniques, but studies also show that only about 50 percent of patients referred for these types of treatments (by a migraine specialist) follow through on them. Many primary care providers are not even aware of these effective treatments, said Dr. Minen.

The NYU team brought together headache specialists and migraine patients to create an app that could be used at home. Based on five- and 15-minute audio files, the app instructs patients on how to relax one muscle group at a time.

The researchers recruited 51 migraine patients through the NYU neurology clinic, most of whom continued to have frequent and severe migraines despite their treatments. On average, study participants had 13 headache days per month, ranging between four and 31. More than 60 percent self-reported severe symptoms and 75 percent were taking preventive medications. "This is a severely affected group," said Dr. Minen.

During the 90-day study, patients were asked to keep a daily log of their headaches as well as document the amount of time they listened to the audio files. Participants reported a mean amount of time spent on the audio files of 11 minutes and an average number of days engaging with the exercise of 22. Half the patients used the app once a week and a third used it two or more times a week. Those who used it two or more days a week had four fewer headache days during the second month compared to baseline. Patients who used it once a week had two fewer headache days over the next month of the study.

The researchers also assessed anxiety and depressive symptoms at baseline; at the end of the study they found that those who were anxious were more likely to use the app than those who were depressed.

"We may be able to use the anxiety and depression scales as a tool to see who would benefit from the app," said Dr. Minen. "The goal is not to listen to the audio files every day but to use the technique in everyday life." In other words, patients can listen to the audio tape once or twice to learn how to relax one muscle group at a time on their own.

Link Up for More Information:

Minen MT, Adhikari S, Seng EK, et al. Smartphone-based migraine behavioral therapy: a single-arm study with assessment of mental health predictors. NPJ Digit Med 2019; 46 (2019)

Wednesday, June 12, 2019

Low-level electrical currents that stimulate a network that runs through the left rostrolateral prefrontal cortex improves memory performance, according to a study published May 29 in the Journal of Cognitive Neuroscience. The rostrolateral prefrontal cortex is associated with high-level reasoning and is important in monitoring and integrating information. 

The research team, led by Jesse Rissman, PhD, an assistant professor of psychology and of psychiatry and biobehavioral sciences at University of California, Los Angeles, believe these techniques may one day be helpful in older people who have problems retrieving memories. "The findings suggest that electrical stimulation helps generate retrieval cues and boosts a person's ability to remember things," said Dr. Rissman, whose research has used functional magnetic resonance imaging (fMRI) scans to understand patterns in memory formation and retrieval and how people make decisions when asked to recall events.

The research team designed a simple two-day experiment to tap into memory judgment and reasoning—and to identify the volunteers' memory sources. On day one, the 72 volunteers, all college students, were shown 80 words one at a time and asked to imagine themselves doing something with the word (say a clock) or imagine someone else doing something with the word. On day two, they were shown words again—in sets of four—and asked whether each set contained a word they had seen on the previous day, and if so, whether they had imagined themselves or someone else interacting with that word.

In earlier studies, the research team used fMRI during these tasks to help identify the left rostrolateral prefrontal cortex as an important player in memory retrieval and analogical reasoning. (They measured reasoning in the volunteers by showing them sets of four words and asking them whether the top pair of words shared an analogous semantic relationship with the bottom pair of words, a task that requires deeper thinking.)                      

These earlier findings set the stage for the current study. What would happen if they targeted the area with electrical current? Researchers repeated the same study design but instead of scanning on the second day, they placed electrodes on the scalps of the volunteers over the target region and delivered a weak electrical current thought to decrease or increase the excitability of neurons.

All volunteers received 30 seconds of stimulation so they all felt a slight tingle. Then, some volunteers received no stimulation for 30 minutes and positive stimulation for the next 30 minutes over the left prefrontal region. (There was a negative charge sent to the right motor cortex as a control.) Another third received a positive charge over the right motor cortex and not the prefrontal cortex. And a third received a sham stimulation with no current during the 60-minute exercise.

The researchers reported a 15.4 percent improvement in those who had the positive electrical charge over the left rostrolateral region during the memory retrieval task on the second day. (Volunteers were more likely to recognize which word they saw the previous day and correctly identify the source of that memory.) "They are bringing back the details of that memory," said Dr. Rissman. He added that the electrical stimulation had no effect on the tasks designed to test reasoning.

In their next study, the researchers hope to repeat the experiment in older people.

Link Up for More Information:

Westphal AJ, Chow TE, Ngoy C, et al. Anodal transcranial direct current stimulation to the left rostrolateral prefrontal cortex selectively improves source memory retrievalJ Cogn Neurosci, 2019; Epub 2019 May 6.

Tuesday, June 11, 2019

A team of scientists at the Washington University School of Medicine in St. Louis has determined why some gliomas grow faster than others. They observed that cancer cells recruit immune cells, which in turn send out signals for the cancer cells to multiply. The more immune cells inside a glioma, the faster the cancer grows, according to the study published May 29 in the journal Neuro-Oncology.

The finding opens the door to novel therapies directed at the immune system, the researchers wrote.

The team, led by David H. Gutmann, MD, PhD, FAAN, the Donald O. Schnuck Family professor of neurology and director of the Neurofibromatosis Center, wanted to explore why tumors grow differently in patients with neurofibromatosis 1 (NF1). A genetic disorder of the nervous system, NF1 often causes tumors to grow on the nerves of the skin, brain, and other parts of the body. Some children may develop optic gliomas.

For the studies, Dr. Gutmann and colleagues used a collection of mouse models of NF1 engineered to develop optic gliomas, and set out to answer the following question: Are the cancer cells mainly responsible for how fast an optic glioma grows or do the non-cancerous cells in the tumors dictate tumor growth?

The scientists created five different mouse strains harboring different NF1 mutations or other genetic changes. Optic glioma growth in each of these five strains was variable, with some tumors developing at three months and others at six. In one strain, only 25 percent of the animals developed an optic glioma.

The study showed that the cancer cells grew at about the same speed in a laboratory dish, which means the genetic properties of these cells are not primarily responsible for tumor growth. When the investigators turned their attention to the lymphocytes and microglia—the non-cancerous cells in the tumor—they saw that the interactions between these cells best correlated with overall tumor growth.

The investigators observed that the cancer cells were secreting chemokines, attractants that lure microglia and T cells into the tumor cells. Once inside the glioma, the immune cells start producing growth factors. "These immune cells are driving how fast the tumors divide," said Dr. Gutmann, who now sees this as a viable way to slow or stop cancer growth. "We have to interrupt this choreographed dance between the immune cells and the tumor cells."

The researchers have been targeting T cells and microglia in mice and have had success slowing tumor growth. They hope to learn more before applying their findings to human trials. "We need to dissect this immune circuitry and learn more about how T cells are recruited and activated, as well as how microglia make growth factor that fuels tumor growth," Dr. Gutmann explained. "The findings from this study help us shift our focus from the cancer cell to the supportive environment that drives cancer cells."

Ultimately, the goal is to help people with NF1, who are at increased risk for tumors of the brain and nerves. "We need to understand who is at greatest risk for developing these tumors, and how best to treat them," Dr. Guttmann said. "Defining the role of immune cells in these tumors may offer new opportunities to predict and manage optic gliomas in children with NF1."

Link Up for More Information:

Guo X, Pan Y, and Gutmann DH. Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cell and microgliaNeuro-Oncol 2019; Epub 2019 May 3.

Thursday, May 23, 2019

Patients with relapsing multiple sclerosis (MS) who received evobrutinib, a Bruton's tyrosine kinase inhibitor (BTK), showed fewer T1 gadolinium-enhancing lesions in the brain, than those who received placebo, according to the results of a double-blind, randomized, phase 2 trial published online May 10 in the New England Journal of Medicine.

Evobrutinib is a dual action-mode oral investigational therapy that regulates the function of B cells and myeloid cells. It inhibits the protein BTK that transmits signals through a variety of receptors in B cells and myeloid cells. Activated B cells and innate immune cells play a role in the pathogenesis of MS, and BTK inhibition may alter these biological pathways.

Evobrutinib has previously been found effective in experimental autoimmune encephalomyelitis, an animal model of brain inflammation.

Currently, BTK inhibitors are being investigated in several types of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis.

In the current trial, patients who received 75 mg of evobrutinib once daily had significantly fewer gadolinium-enhancing lesions during weeks 12 to 24 than did those who received placebo (mean 1.69 vs 3.85).

The researchers, led by Xavier Montalban, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, and colleagues, reported no significant difference in those who took evobrutinib at 25 mg once daily or the 75-mg twice daily  compared with placebo. There were no significant changes in the annualized relapse rates or disability progression at any dose.

To investigate the effects of evobrutinib on patients with RRMS, the researchers enrolled and randomized 267 RRMS patients into five treatment groups: placebo, 25 mg once daily evobrutinib, 75 mg once daily evobrutinib, 75 mg twice daily evobrutinib, or open-label dimethyl fumarate as reference. All patients were white and had a mean age of 45 years old; 69 percent were women. A total of 261 patients were included in the modified intention-to-treat analysis, which consisted of those who had been randomized to a treatment arm and  had had an MRI at baseline and at least once after baseline.

The primary endpoint was the cumulative number of lesions identified by T1-weighted MRI at weeks 12, 16, 20, and 24.

The mean total number of gadolinium-enhancing lesions at weeks 12 to 24 was 3.85 in the placebo group, 4.06 in the evobrutinib 25 mg group, 1.69 in the evobrutinib 75-mg once daily group, 1.15 mg in the evobrutinib 75 mg twice daily group, and 4.78 in the dimethyl fumarate group.

Secondary outcomes included the annualized relapse rate and change from baseline in the Expanded Disability Status Scale (EDSS), a measurement of disability on a 0 (no disability) to 10 (death due to MS) scale in 0.5-unit increments.

Compared with placebo, the baseline adjusted rate ratios for the total number of lesions over time were 1.45 in the evobrutinib 25 mg group (p=0.32), 0.30 in the evobrutinib 75 mg once daily group (p=0.005), and 0.44 in the evobrutinib 75 mg twice daily group (p=0.06).

At week 24, the unadjusted annualized relapse rate was 0.37 in the placebo group, 0.57 in the evobrutinib 25 mg group, 0.13 in the evobrutinib 75 mg once daily group, 0.08 in the evobrutinib 75 mg twice daily group, and 0.20 in the dimethyl fumarate group. As compared with placebo, no significant effect on the annualized relapse rate was found in the evobrutinib groups.

Also, the investigators observed no significant effect  from baseline in the EDSS score. Patients had an average EDSS score of around 3.0 to 3.5 at baseline.

The highest rate of serious adverse events occurred in patients treated with evobrutinib 75 mg twice daily (7 percent). Grade 3 or 4 adverse events most common were among patients in the evobrutinib 75 mg once daily group (13 percent), the evobrutinib 75 mg twice daily group (15 percent), and the DMF group (13 percent).

Nasopharyngitis and increases in levels of alanine aminotransferase, aspartate amino-transferase, and lipase were commonly associated with evobrutinib, the researchers reported. Those with elevations in liver aminotransferase values were asymptomatic and the elevations were reversible.

Overall, "longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis," the researchers concluded.

Study limitations included an older MS patient population, longer disease duration, and fewer patients with relapses within two years before baseline, as compared with other MS trials. In addition, only white patients were included in the study, limiting the generalizability of the findings to other patient populations. Lastly, the trial focused on MRI disease activity as an outcome measure.

EMD Serono Research and Development Institute supported the study.

Dr. Montalban and co-authors disclosed relevant relationships with Merck Serono, Biogen, Novartis, Sanofi-Genzyme, Teva Pharmaceuticals, Roche, Celgene, Actelion, EXCEMED, the Multiple Sclerosis International Federation, and the National Multiple Sclerosis Society.

Link up for More Information:

Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med 2019; Epub 2019 May 10.