Innovative MS treatments, a common supplement for depression, and a nasty habit with a neuroprotective benefit?

It’s been a rough couple of years these last few months (or, at least, that’s what it feels like). From natural disasters and a once-in-a-lifetime plague to international tensions and civil unrest—it seems like 2020 has it out for us, doesn’t it? But, don’t get it twisted—it’s not all doom and gloom. Neuroscientists, for instance, have been crushing it this year with landmark innovations and discoveries. And, that’s pretty impressive, especially when you factor in the difficulties of scientific collaboration in this era of social distancing. So, what’s the latest buzz in the neuroscience community? Find out by reading this week’s NeuroBrief.

Neuro Flashback

Get ready for a timely dose of neuropsych history! Solomon Fuller, MD, was the nation’s first black psychiatrist recognized by the American Psychiatric Association. He earned his medical degree from The Boston University School of Medicine in 1897. During his career, Dr. Fuller played a key role in the development of psychiatry in the 1900s. He made significant contributions to the study of Alzheimer disease and other neurodegenerative diseases, such as schizophrenia and manic depression. He would later go on to become an emeritus professor of neurology at Boston University. The Dr. Solomon Carter Fuller Mental Health Center—a part of the Boston Medical Center, which is the primary teaching affiliate for The Boston University School of Medicine—is named after him.

In the News

Common supplement for depression. A new adult stem cell study shows that an easily accessible, natural product may help with depression: fish oil. This study adds to a growing body of evidence supporting the use of fish oil for the neuropsychiatric disorder. For their study, researchers used skin biopsies from two types of patients with clinically diagnosed depression: those who previously responded to antidepressant therapy and those who didn’t. Skin cells collected from these patients were then converted into stem cells, which were then directed to develop into nerve cells. When the researchers introduced fish oil to the cells, the models from both sets of patients responded positively. In fact, according to the researchers, the response was on par to that seen with prescription antidepressant treatment. But, interestingly enough, this response was produced through a different mechanism than expected. The fish oil acted, in part, on glial cells—not neurons—suggesting that glia may play a role in depression as well as antidepressant action.

This study is huge for a number of reasons. For one, the researchers showed that a stem cell model can be used to study treatment response. Secondly, the novel findings from the study could help researchers gain further insight into the inner workings of the brain and why some people respond to depression treatment while others don’t. Finally, it’s pretty exciting to find additional scientific evidence that a widely accessible, natural product like fish oil could be an effective treatment for depression (possibly eliminating the need for prescription depression drugs). Although more research is needed, these findings are still pretty impressive.

A nasty habit with a neuroprotective benefit? A new report on smoking is raising eyebrows in the neuroscience community. In a 65-year follow-up of male British doctors, researchers have found that those who smoked tobacco in 1951 had a significantly lower risk of death from Parkinson disease (PD) than never-smokers. Even more shocking: Doctors who continued smoking over the years had an even lower risk of PD mortality. The researchers caution that while their findings are not a promotion of smoking, the findings do warrant a closer look at the link between the protective effects of smoking on PD risk. Researchers first speculated on the link roughly 60 years ago, with supporting evidence accumulating over the years. But, because of the limitations of retrospective studies as well as insufficient case numbers or poor follow-up time in previous studies, the link remained unclear. So, investigators analyzed data on nearly 30,000 male British docs, excluding those with a pre-existing PD diagnosis. An initial questionnaire was given to registered doctors in 1951, and 6 resurveys were sent from 1958 to 1998, with response rates ranging from 94% to 98%. Cause-specific mortality was followed until December 2016.

Overall, 283 docs had PD listed as their underlying cause of death. Doctors with PD-related death died at a mean age of 82, but physicians who died of other causes died at a mean age of 77. Docs who smoked at baseline were found to have a 30% lower risk of death from PD vs docs who never smoked, and continuing smokers had a 40% lower risk vs never-smokers! Although the study did have some limitations—such as the small analytical sample and the fact that diagnosis for PD changed over time—the findings do support an inverse association between PD mortality and amount of tobacco smoked.

Schizophrenia tied to brain deficiency. Researchers have discovered a deficiency in the brains of people with schizophrenia that could lead to new therapies for the disease. Specifically, schizophrenia was linked to abnormally low levels of S1P—a sphingolipid (fatty molecule) found in the brain’s white matter. Preventing S1P degradation may be a new target for drug development in schizophrenia treatment. The drugs available for schizophrenia are mainly centered on dopamine. Unfortunately, these drugs are only effective in about two-thirds of this patient population. So, why aren’t other drug targets being explored? The problem is that scientists don’t have any other tangible idea about what causes schizophrenia. What scientists do know is that people with schizophrenia often have less white matter in their brains. Researchers have suggested that some stereotypical symptoms of schizophrenia, like hallucinations and the inability to distinguish reality from fantasy, may stem from white matter abnormalities that cause irregular communication between neurons.

With this in mind, researchers used mass spectrometry to take a closer look at the brains of patients with schizophrenia while paying close attention to sphingolipids, which are involved in white matter functioning. On postmortem analysis of the white matter tract that connects the left and right sides of the brain, they found a severe deficiency in S1P, a sphingolipid key to oligodendrocyte production. Additional testing showed that although normal amounts of S1P were generated, they were quickly (and abnormally) metabolized and degraded. The researchers then turned their attention to the brains of those with bipolar disorder and major depressive disorder. They found that S1P levels did not differ from those typically found in otherwise healthy brains, suggesting that the abnormality is schizophrenia-specific. The next step is to conduct animal studies to find out which S1P receptor-acting drugs are effective. They have their eyes on fingolimod, a drug for multiple sclerosis that works at the S1P receptor.

Brain blood vessel abnormality and gut bacteria. NIH-funded researchers have discovered a link between cavernous angiomas (CAs)—abnormal bundles of brittle blood vessels in the brain or spinal cord—and gut bacteria composition. CAs contain slow moving or stagnant blood that can cause hemorrhagic strokes, seizures, or headaches. Although previous studies have suggested a link between CA and gut bacteria, this is the first study to look at the role of the gut microbiome in a larger population of people with CAs.

Researchers used advanced genomic analysis techniques to compare stool samples from 122 people who had ≥ 1 CA as detected on brain scans with those from age- and sex-matched non-CA controls. They found that, on average, patients with CA had more gram-negative bacteria compared with controls, who had more gram-positive bacteria. Higher levels of three gut bacterial species were used to distinguish patients with CA from controls—regardless of their sex, geographic location, or genetic predisposition to the disease. Gut bacteria from patients with CA also seemed to produce more lipopolysaccharide molecules, which have been previously shown to trigger CA formation in mice. On further analysis, researchers discovered that some gut bacteria compositions could distinguish between aggressive and non-aggressive CA forms as well as those with recent symptomatic hemorrhages. Overall, the researchers posited that their results show evidence of a “permissive microbiome” linked to the formation of neurovascular lesions in the human brain. They also speculated that their study, which involved combining gut bacteria data with results from blood plasma tests, may serve as a model to help clinicians better diagnose the severity of a brain disorder.

Neuro Trivia

Which famous neurologist was the first person to describe amyotrophic lateral sclerosis?

We admit, this one might’ve been a little too easy for all you docs out there. If you guessed Jean-Martin Charcot, you’re right! Jean-Martin Charcot, often hailed as the father of modern neurology, first described amyotrophic lateral sclerosis in 1869. The neuro disorder was initially named Charcot disease, but it later became known as Lou Gehrig disease before taking on its current moniker of amyotrophic lateral sclerosis, or ALS.

Novel Diagnostics

New diagnostic signature for ALS. Scientists have identified a unique biomarker for amyotrophic lateral sclerosis (ALS)—a discovery that could lead to a simple blood test for improved diagnosis. This is big news, considering that clinical diagnosis of ALS can take up to a year, and patients with the disease live just 2-5 years, on average, after diagnosis. Researchers compared blood samples from a total of 245 patients with ALS and controls to analyze their patterns of non-coding ribonucleic acids (ncRNA). They found a biomarker signature for ALS consisting of seven ncRNAs. When these ncRNAs were expressed in a certain pattern, the researchers were able to distinguish ALS patients from controls. The researchers speculated that their findings may help other scientists to assess potential drug treatments for ALS by using ncRNA levels as a measure of efficacy. Their next step is to validate this biomarker signature in a larger sample of patients to find out why ncRNAs change in patients with ALS.

New MRI methods for better PD outcomes. A recent study describes three newly developed, precision MRI techniques that target a pea-sized brain region linked to Parkinson disease (PD) and essential tremor that may lead to improved outcomes—without the surgery and with less risk of adverse effects (like problems walking and slurred speech). The new techniques allow neuroradiologists to home in on a tiny area in the thalamus involved in movement. Using the MRI scans to guide them, physicians can then use high-intensity focused ultrasound (HIFU) to ablate any problem tissue. Basically, with this new procedure, clinicians can target the desired brain structures without hitting the wrong target, resulting in fewer adverse effects for the patient.

Although MRI-guided HIFU is currently approved for treatment of essential tremor and tremors in patients with PD, the three newly refined MRI techniques are better at delineating the target tissue: diffusion tractography, which creates precise brain images by accounting for the natural water movement within tissues; quantitative susceptibility mapping, which creates contrast in the image by picking up distortions in the magnetic field due to substances like iron or blood; and fast gray matter acquisition TI inversion recovery, which works like a kind of photo negative, turning the brain’s white matter dark and its gray matter white to give a better picture of the gray matter. The researchers, along with colleagues at the Mayo Clinic, plan to conduct a multicenter clinical trial to test the diffusion tractography method in patients.

Blood sample for FTLD prognosis. When neuronal damage occurs, neurofilament light chain (NfL), an intracellular structural protein, is released into the intercellular space and eventually ends up in the blood. Higher blood NfL levels have been observed in a range of neurodegenerative diseases and after brain injury. Traditionally, NfL levels have been measured in cerebrospinal fluid, since there’s a higher concentration of the proteins there vs in the blood. But new, extra-sensitive methods have made it possible to detect NfL levels in the blood, making blood NfL a minimally invasive biomarker for neurodegeneration. Now, a new study shows NfL measured from a blood sample can offer insight into the severity and duration of disease in patients with frontotemporal lobar degeneration (FTLD)—the second most common cause of degenerative and progressive dementing diseases in the working-age population.

Researchers found that patients with FTLD and high blood NfL levels had a shorter duration of disease and a faster rate of brain atrophy. High levels of blood NfL were especially pronounced in patients with FTD and motor neuron disease (FTD-MND) and primary progressive aphasia (PPA)—two sub-forms of FTLD. Carriers of the C9orf72 repeat expansion—a predisposing genetic mutation for FTLD—also had elevated blood NfL levels. Overall, the study findings suggest that blood NfL levels may help with both differential diagnosis and predicting disease outlook. The researchers suggested that this protein biomarker may also help to assess drug treatment response down the road.

Novel Treatments

New FDA-approved NMOSD drug. Neuromyelitis optica spectrum disorder (NMOSD) is a rare but severe neuroinflammatory autoimmune disease that can be fatal. Patients can experience vision loss, paralysis, bladder dysfunction, nerve pain, and respiratory failure, among other complications. There are an estimated 10,000 patients with NMOSD in the United States, and roughly 80% test positive for anti-aquaporin-4 (AQP4) antibodies. Less than a year after the FDA approved eculizumab (Soliris)—the first NMOSD drug—the agency has given the nod to inebilizumab (Uplizna) for treatment of the disease. It’s the first and only B cell-depleting antibody approved for NMOSD. Inebilizumab is indicated to reduce the risk of attacks in adults who are positive for anti-AQP4 antibodies. Unlike eculizumab, which is administered intravenously every 2 weeks, inebilizumab consists of a biannual maintenance regimen after two loading doses.

The approval comes after the positive results of a 230-participant, double-masked, multicenter trial, in which patients were randomized to 2 initial doses of 300-mg intravenous inebilizumab or placebo and were given an option to receive additional doses every 6 months. Overall, 89% of anti-AQP4 antibody–positive participants remained relapse-free 6 months after treatment vs 58% participants who received placebo. The monotherapy also reduced the number of NMOSD-related hospitalizations and had robust safety and tolerability profiles. The most common adverse events included urinary tract infection, nasopharyngitis, infusion reaction, arthralgia, and headache. With eculizumab’s notoriously expensive price tag (roughly $700,000 annually), inebilizumab could be the boon that patients have been hoping for. Manufacturer Viela Bio hasn’t released a list price yet, but some financial analysts anticipate a net price of around $175,000 per year. The drug is set to launch later this month.

Internal parasite for a neuro disease? The idea of treating multiple sclerosis (MS) and other autoimmune disorders with hookworms has been bounced around for years. But, there’s never been a clinical trial to test the potential benefits of hookworm therapy on MS—until now. Researchers conducted the first clinical trial of hookworm treatment for MS. Unfortunately, the results were mixed. Researchers recruited 71 patients with MS and randomized them to receive either hookworm therapy or placebo. In the intervention group, the researchers placed hookworm larvae on gauze pads that were then applied to patients’ arms for at least 30 minutes. Those in the placebo group received a gauze pad dampened with purified water.

After 9 months of follow-up to see if hookworms would delay MS brain scarring, the researchers found disappointing results: MRIs showed no significant differences between the brains of hookworm-treated patients and placebo-treated patients. The researchers suggested that the negative results could be due to the fact that the trial was too short, because the study sample was too small, or because the study patients had a milder form of disease. But, there was some good news. On further investigation, researchers found that hookworms helped calm MS patients’ immune response. Patients had increased levels of T regulatory cells—a sign that hookworms can trigger the kind of change needed to help delay or stop MS progression. While the beneficial effects of hookworm therapy may pale in comparison to currently available immune-modulating MS drugs, the researchers speculate that some people with milder disease who prefer this more “natural” approach may benefit. Still, it does seem pretty revolting if you ask us.

Brain cells hold promise for MS Tx. If you weren’t sold on creepy-crawlies as a treatment for multiple sclerosis (MS), try this on for size: A new study shows that human brain cells can repair damage from MS. Specifically, when researchers transplanted human glial cells into animal models of MS and other white matter disease, the cells were able to repair damage and restore function. This breakthrough research, which is more than 15 years in the making, has significant clinical implications and signifies a proof-of-concept for future clinical trials of MS and other neurodegenerative diseases, according to the researchers.

In MS, glial cells are lost during the disease course. So, for their study, researchers created techniques to manipulate the chemical signaling of embryonic and induced pluripotent stem cells to create glia, including glial progenitor cells. These progenitor cells help to create astrocytes and oligodendrocytes, which play key roles in the health and signaling function of neurons. The researchers found that when human glia progenitor cells were transplanted into adult mouse models of progressive MS, the cells traveled to where needed in the brain, made new oligodendrocytes, and replaced lost myelin. In mice, the process of remyelination actually restored motor function. The researchers believe this approach could also be applied to other neuro disorders like pediatric leukodystrophies—childhood hereditary diseases in which myelin fails to develop—and certain stroke types affecting the white matter in adults. Oscine Therapeutics’ experimental transplant therapy for MS and other glial diseases like Huntington disease, based on this research, is currently under early FDA review for clinical trials.

New in Patient Management

A font that boosts memory? Sans Forgetica is a font that was created to boost people’s memory for information written in that font (compared with reading information in a more commonly used font like Times New Roman). In a previous study of 400 students, researchers found that 57% remembered facts written in Sans Forgetica vs 50% who remembered facts written in Arial. Sadly, in a new study involving more than 800 people, scientists have found that Sans Forgetica does not enhance memory. In fact, it’s just plain hard to read.

The researchers conducted four peer-reviewed experiments that compared San Forgetica’s alleged memory-boosting capabilities with ordinary fonts, and they found that Sans Forgetica did not help. In the first experiment, researchers found that Sans Forgetica felt harder to read vs Arial. In the second experiment, they found that when people were shown pairs of words in Sans Forgetica or Arial, they recalled fewer Sans Forgetica pairs than Arial pairs. In the third experiment, researchers noted that when people were shown educational info in Sans Forgetica and Arial and were then tested on recall, there was no evidence that Sans Forgetica improved their performance. In the last experiment, they found that when testing people’s understanding of educational passages written in Sans Forgetica or Arial, people had equal understanding of information with either font—there was no proof that Sans Forgetica improved understanding.

Geographic inequities in stroke care. While more industrialized, population-dense parts of the United States are still struggling to combat COVID-19, it seems that rural America has not been spared of its own medical care challenges. On top of higher rates of chronic disease, poverty, and joblessness, rural America has another hardship to address: poor stroke care. A new study shows that people living in rural areas are less likely to receive the most advanced treatments for stroke and, not surprisingly, are more likely to die in the hospital than those treated for stroke at hospitals in urban areas. The study also shows that between 2012 and 2017, there were no improvements in rural/urban disparities in stroke treatment and outcomes.

Researchers looked at national data from more than 790,000 adults (most over age 64) who were hospitalized with stroke between 2012 and 2017. They found that stroke patients treated at rural hospitals were half as likely to receive clot-busting meds to treat clot-caused strokes when compared with stroke patients living in urban areas. But, that’s not all. About one-third of rural patients were less likely to undergo a procedure to remove a stroke-causing clot. Even worse, rural stroke patients were more likely to die of any type of stroke before leaving the hospital. So, what can be done? The researchers suggested that telehealth could go a long way in helping to address issues concerning lack of access to advanced therapies and specialists, which would, in turn, help to close the gap in urban-rural care disparities.

Vision problems linked to dementia. If an older patient is having trouble seeing, it could be a sign of a condition more insidious than plain old age—it could be dementia, according to a recent a study. Specifically in older women, objectively measured visual impairment was associated with up to a five-fold greater risk for dementia. Researchers compared the odds of dementia or mild cognitive impairment among women with and without baseline visual impairment. The study sample included 1,061 women aged 66-84 years. Of these, 183 had objective visual impairment that was diagnosed through questionnaires and visual acuity measurements with three threshold levels: 20/40 or worse, 20/80 or worse, and 20/100 or worse in at least one eye.

Overall, 42 women were classified as having probable dementia, and 28 were classified as having mild cognitive impairment that did not progress to dementia. The risk for dementia was highest in participants with a visual acuity measurement of 20/100 or worse, and the findings were similar for those classified with mild cognitive impairment. “In secondary analysis of a prospective longitudinal cohort study of older women with formal vision and cognitive function testing, objective visual impairment appears to be associated with an increased risk of incident dementia. However, incident cases of dementia and the proportion of those with visual impairment were low. Research is needed to evaluate the effect of specific ophthalmic interventions on dementia,” concluded the authors.

Latest in Journal Summaries

Altered awareness of motor symptoms in Parkinson disease and dementia with Lewy Bodies

Link between seizures and MRI in patients with anti‐NMDAR encephalitis

Prevalence of sleep-disordered breathing in opioid users with chronic pain

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Upcoming Medical Meetings

The following meeting has been changed to a virtual workshop:

2020 Peripheral Nerve Society (PNS) Annual Meeting, to be held in Miami, FL, June 27-30, 2020. Please check the website for up-to-the-minute information.

The following meeting has been rescheduled:

8th Annual Scientific Conference of the European Association of Psychosomatic Medicine (EAPM 2020), to be held in Vienna, Austria, June 24-27, 2020, has been rescheduled for June 2-5, 2021, and will remain in Vienna, Austria.

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