Groundbreaking brain cancer treatments, historic milestone for Alzheimer’s, and a natural treatment for Parkinson’s?

In this time of national turmoil and anguish, we could all use a little good news. That’s why, this week, MDLinx is bringing you some of the most positive, noteworthy discoveries and innovations to recently come out of the field of neuroscience. Keep your spirits high and your mind informed by reading this week’s NeuroBrief.

Neuro Flashback

1981 was a big year for firsts in the United States: It saw the debuts of smash-hit video games Donkey Kong and Mario, blockbusters Raiders of the Lost Ark and Chariots of Fire, iconic chart-toppers like Journey’s “Don’t Stop Believin’” and Stevie Nicks’ “Edge of Seventeen,” the birth of the first test-tube baby, and the nomination and appointment of the first female US Supreme Court Justice. You know what else happened for the first time in 1981? Alexa Irene Canady, MD, became America’s first female black neurosurgeon. Think about that for a second: Not 1891. 1981! It’s crazy to think that such a stride was made only 40 years ago.

Interestingly, Dr. Canady almost never became a physician, owing to what she called a “crisis of confidence” as an undergraduate math major. But, after she regained her confidence, Dr. Canady went on to earn a scholarship to University of Michigan Medical School in 1975, where she graduated cum laude. Despite her inspiring journey, it wasn’t easy. She faced enormous prejudice along the way. During her surgical internship at Yale-New Haven Hospital in 1975, for instance, a hospital administrator called her an “equal-opportunity package.” Nevertheless, Dr. Canady persevered. Her fellow physicians at Children’s Hospital of Philadelphia would later vote her as one of the top residents of 1981-1982.

In the News

Groundbreaking pediatric brain cancer trial. Researchers from Australia are set to lead an international clinical trial of a new treatment for kids with low-grade gliomas. Gliomas are notoriously difficult to treat, and when a tumor can’t be surgically removed, the patient can suffer major morbidities and undergo years of treatment. When this happens, the only treatment options are cytotoxic chemotherapy and/or radiotherapy, which can both be harmful to the patient. So, it’s not hard to imagine why scientists have been searching for safer, more effective treatments to use in children. Luckily, they may have recently hit the jackpot. The new treatment to be tested is a targeted therapy designed to block the genetic driver behind low-grade gliomas. Because it’s made to target only cancer cells (leaving healthy cells alone), the therapy is associated with far fewer side effects than current alternatives, and it could significantly improve quality of life for survivors. Even better: It can be taken as a daily pill. If the drug checks all the boxes for safety, efficacy, and clinical activity, it could be a game changer for these patients, replacing chemotherapy as the standard treatment for low-grade glioma. The trial is due to launch later this year.

A cure for brain metastasis? Researchers have discovered that nicotine helps spread lung cancer to the brain…which may actually be a promising development. Now, we know what you’re thinking: Why is that good news? Turns out, the researchers may have figured out a way to reverse nicotine’s effects, opening up new possibilities for brain metastasis treatment and perhaps even prevention.

Scientists have known for a while that people with non-small cell lung cancer often develop metastatic brain tumors. But the reason behind this has always been unclear. So, researchers at Wake Forest Baptist Medical Center set out to find the truth. They looked at 281 patients with lung cancer and found that cigarette smokers had a much higher incidence of brain cancer. Using a murine model, the researchers found that nicotine promoted brain metastasis by crossing the blood-brain barrier to change the microglia from defending against tumor growth to supporting it. The researchers then searched for drugs that might be able to reverse nicotine’s adverse transformative effects and found a winner: parthenolide, a naturally occurring substance in feverfew. When given to mice, parthenolide was able to cross the blood-brain barrier—unlike traditional chemotherapy drugs—and stop nicotine-induced brain metastasis. Because feverfew has been used for centuries and is generally considered to be safe, the researchers believe that it may offer new approaches for fighting brain metastasis, especially in smokers and former smokers. The researchers are hoping to launch a clinical trial on parthenolide in the near future. Until then, you might want to advise your patients to quit smoking and avoid nicotine.

New brain cancer Tx on the horizon. Looks like brain cancers are are a major focus these days. For instance, the FDA has granted fast-track status to TVAX Biomedical’s vaccine-enhanced cell therapy (VACT) for glioblastoma. TVI-Brain-1 is an autologous VACT comprising a proprietary vaccine pretreatment to generate cancer-specific T cells and an activated antitumor T-cell treatment. Unlike other types of immunotherapy—which are only effective against a limited pool of cancer types—VACT is a unique, individualized T cell treatment that can effectively treat a wider range of cancers. The fast track designation was based on the positive results of phase 1 and phase 2 immunotherapy studies, particularly with respect to median survival time. The manufacturer is set to begin enrollment later this year for a phase 2B study of the treatment in patients with newly diagnosed glioblastoma multiforme.

Allergy meds for Huntington disease? That’d be nice, wouldn’t it? Stopping Huntington disease (HD) in its tracks with a bit of Claritin or Zyrtec? Unfortunately, science hasn’t gotten that far yet. The good news is that targeting the histamine H3 receptor, a known drug target for hay fever, could slow down HD—at least, according to a new study. Previously, researchers found that dopamine and histamine receptors, which are often found together, are responsible for controlling brain signaling. In HD, dopamine signaling has been shown to fade away, which can lead to neuronal death and problems with movement and memory. So, researchers theorized that targeting dopamine signaling via the histamine receptor would slow HD progression. To test this, they investigated whether these dopamine and histamine receptors are found together in mice with HD. The researchers discovered that younger healthy mice and those with HD had the dopamine D1 receptor (D1R)-H3R complex. But, when they looked at older mice, those with HD had lost the D1R-H3R complexes. The individual receptors were still there, but they were no longer acting together as partners.

To better understand the role of the D1R-H3R complex, the researchers tested the effects of thioperamide, an antihistamine, on movement, learning, and memory in mice with HD. Overall, the antihistamine-treated mice showed improvements in mobility and memory vs control mice. The researchers confirmed that thioperamide’s protective effects occur through the D1R-H3R complexes, which are needed for the drug to work. When the researchers looked at human brain tissue samples for the presence of D1R-H3R complexes, they found that these complexes were present only in the brains of those with early- but not late-stage disease. So, targeting D1R-H3R complexes in patients with early-stage HD could potentially slow disease progression. The researchers noted that, since there are several H3R compounds currently in clinical trials, there could be opportunities for drug repurposing for HD treatment.

Neuro Trivia

The first antiepileptic drug was discovered by accident in 1962. True or false?

We admit, this one was a trick question. Did we get ya? Phenobarbital was discovered by accident—but in 1912. (Valproate, another accidental discovery, came about in 1962.) Phenobarbital was originally formulated under the trade name Luminal for the treatment of insomnia. But, after German psychiatrist and neurologist Alfred Hauptmann began using phenobarbital for his patients with epilepsy, it replaced the de facto treatment of potassium bromide as the preferred therapy. Today, phenobarbital remains one of the primary treatments for epilepsy in the developing world.

Novel Diagnostics

Biomarker for concussion recovery. For survivors of concussion, the road to recovery can either be short and uneventful or long and challenging. Unfortunately, there’s been no real way to predict which patients will take which path—until now. Researchers have discovered that a biomarker called neurofilament light chain—a nerve protein that’s detected in the blood when nerve cells are injured or die—may help pinpoint which patients will take longer to recover. They looked at 195 military vets (mean age: 38 years; 85% male) with either no history of concussion (n = 45), a history of 1-2 concussions (n = 94), or a history of ≥ 3 concussions (n = 56). (For those with a history of concussion, it had been at least 7 years since the last concussion.) The military vets were also tested for symptoms of PTSD, depression, and post-concussive syndrome (ie, mood changes and memory problems), as well as headaches post-concussion. All participants provided blood samples to assess neurofilament light chain levels.

Overall, the researchers found that vets with multiple concussions (≥ 3) had much higher blood levels of neurofilament light chains (33% more)—even years after the last injury—than those with no history of concussion. High levels of the biomarker were also linked to chronic post-concussive syndrome, PTSD, and depressive symptoms. So, what’s the silver lining to all of this? By using a blood test to home in on this biomarker, clinicians may be able to intervene earlier to help reduce the overall effects of concussions over time, which could potentially help speed up recovery. Larger, more diverse studies are needed to confirm these findings, but the results are still very promising.

Predictive model for glioma classification. Love it or hate it, AI is here to stay. But, that doesn’t have to be a bad thing, especially when it comes to medical treatment. For instance, neuro-oncologists have been using radiomics—an approach that involves using AI-extracted MRI data to reconstruct 3D models of tumor tissue—to help improve patient diagnoses. The only problem is that its accuracy could be better. Enter innovation: Researchers have shown that a new machine learning tool could help clinicians tailor personalized treatments for patients with gliomas. It works by classifying the brain tumors into low or high grades, with nearly 98% accuracy. Because patient treatment and prognosis depend on the tumor’s aggressiveness, correct tumor classification is key, making this AI tool a godsend.

Using a dataset extracted from the MRI scans of 210 patients with high-grade gliomas and 75 patients with low-grade gliomas, researchers developed a computational decision support system for glioma classification using hybrid radiomics and stationary wavelet-based features—or CGHF, for short. They used certain algorithms for extracting features from some of the MRI scans and then used another predictive algorithm to process these data and classify the gliomas. Afterward, they tested their model on the remaining MRI scans to evaluate its accuracy. According to the researchers, their model “outperformed other state-of-the-art approaches for predicting glioma grades from brain MRI scans.” Pretty darn impressive, if you ask us. They anticipate it will be used for automatic or semi-automatic software that cancer specialists can use to tailor individualized treatment.

Historic milestone for Alzheimer disease. The FDA has approved manufacturer Lilly’s novel radioactive diagnostic agent Tauvid (flortaucipir F18) for PET imaging of the brain to assess the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adults with cognitive impairment who are being tested for Alzheimer disease (AD). The approval is based on the positive results of two clinical studies of Tauvid imaging efficacy and safety in patients with cognitive impairment being evaluated for AD. 

So, why is this a historic milestone? It’s the first and only diagnostic agent approved for imaging tau NFTs, one of the two neuropathological hallmarks of AD. (Until now, determining the distribution and density of tau NFTs in the brain was possible only at autopsy.) Lilly’s other radioactive diagnostic agent, Amyvid (florbetapir F 18), is currently available to demonstrate the presence of the other pathology, beta-amyloid plaques. Together, these two agents may help clinicians more accurately diagnose AD. Tauvid will initially be available in limited supply (30 mL and 50 mL multiple-dose vials), and will expand in response to commercial demand and payor reimbursement.

Novel Treatments

Natural treatment for Parkinson disease. Seems like dopamine is a key player in just about every major neuro disease. A new study shows that certain naturally occurring hormone-like compounds boost dopamine levels in the brain. Why is that big news? Because dopamine is sorely lacking in the brains of patients with Parkinson disease (PD), stimulating its production could help reverse PD progression. So, how did researchers come to this conclusion? Since the protein Nurr1 is vital for maintaining neuronal health and dopamine production, they speculated that reduced Nurr1 capability might lead to reduced dopamine levels that, in turn, spur the development of PD. Given this, the researchers theorized that small Nurr1-triggering molecules might be the key to treating PD. 

After identifying three FDA-approved drugs able to bind to and activate Nurr1, the researchers turned their attention to natural molecules with the same capabilities (but without any adverse effects). By studying mice, they identified two such endogenous molecules: prostaglandin A1 and E1. In a mouse model of PD, prostaglandin A1 or E1 treatment reduced disease symptoms, without side effects. When the researchers looked at the mice’s brains, they found that the treatment protected dopamine-producing neurons from death and promoted higher levels of dopamine production. Although this discovery may represent a turning point in PD research, the team cautioned that further studies are needed to find out whether these molecules can work in humans. Still, if this isn’t good news, we don’t know what is.

Life-changing Tx for Tourette syndrome. Everyone’s pretty familiar with Tourette syndrome (TS), often dubbed the “cursing disorder.” What may be less familiar are diagnosis and treatment options. In short, there’s no specific test that can help diagnose TS, and there’s no cure. But, there are some treatments that can help manage the disorder, with most focused on controlling tics that may interfere with daily activities of living. Still, these therapies are often lacking. As the National Institute of Neurological Disorders and Stroke (NINDS) put it: “Unfortunately, there is no one medication that is helpful to all people with TS, nor does any medication completely eliminate symptoms. In addition, all medications have side effects.” But, things may be turning around. Researchers believe they’ve found an answer to this treatment gap: stimulation.

Previous research has shown that tics are caused by changes in chemical signals within brain networks linked to the formation of habits and habitual movement. So, researchers wanted to find out whether rhythmic pulses of median nerve stimulation (MNS) could modify brain oscillations that influence the initiation of tics. To test this, researchers observed 19 participants with TS for random 1-minute periods, during which participants were given constant, rhythmic, electric pulses of the MNS to their right wrist. These same participants were also observed for 1-minute periods in which they received no stimulation. In all participants, stimulation reduced tic frequency, tic intensity, and the urge-to-tic. And this effect was most pronounced in participants with the most severe tics. Ultimately, the researchers’ work could lead to the development of a new safe, effective treatment for TS with no adverse effects. Their end goal is to create a wearable MNS stimulator (kind of like a Fitbit) that can be used by patients outside the clinic when they need to control their tics.

Stimulating pain relief. The vagus nerve is a major player in the body’s perception of pain. Previous research has focused on how the vagus nerve could be gently and effectively stimulated with special electrodes. Now, a team of biomedical engineers have accomplished this by creating a new device that delivers vagus nerve stimulation to help relieve chronic pain. In previous studies, chronic pain was treated by inserting tiny electrodes directly into the ear to deliver electric stimulation to the vagus nerve. The problem is that these electrodes have to be attached at an exact distance from the nerve without hitting any blood vessels. If the electrodes are too far away, the nerve won’t be stimulated, and if they’re too close, the impulses will overstimulate the nerve, suppressing it from sending signals to the brain.

So, for the first time, researchers carried out a microanatomical study of the spatial arrangements of the nerve fibers and blood vessels in the ear. Using hi-res photos of tissue samples, they created a 3D model to not only calculate the best stimulation of nerve branches, but also the best placement in the ear for the small needle-shaped electrodes. These results were then tested on patients. The researchers found that a triphasic stimulation pattern was particularly effective in patients with chronic pain. According to the senior author of the study: “Vagus nerve stimulation is a promising technique, the effect of which has been validated with our new findings and is now being further improved. Vagus nerve stimulation is often a lifesaving option, especially for people with chronic pain who have already been treated with other methods and do not respond to medication anymore.”

New in Patient Management

“Hot spot” brain circuit tied to pain. Can personal history influence pain sensitivity? A timely new brain imaging study shows that African Americans are actually more sensitive to pain than non-Hispanic white and Latinx individuals (contrary to long-held beliefs). But, the reason why may surprise you. Using functional MRI (fMRI), neuroscientists looked at the brain activities of 28 African American, 30 Latinx, and 30 non-Hispanic white individuals while participants experienced the exact same pain-inducing stimulus (a thermode heated to about 118 °F) at four spots on their left forearms. The researchers found that the neurologic pain signature, which reflects the most basic aspects of pain perception, responded the same way in all participants. Yet, African American participants reported higher pain scores than other participants. 

Looking into this a little deeper, researchers found that these higher pain ratings were facilitated by African American participants’ past negative life experiences, namely discrimination and hypervigilance. Turns out, the more discrimination participants reported enduring in their lives, the more intensely they felt pain. Equally intense were the activities in their frontostriatal regions, a newly discovered pain-related “hot spot” that interprets pain (ie, how long it will last and whether anything can be done to stop it). The upside to this revelation is that, just like how the “hot spot” can make pain feel worse, it can also help relieve pain. If these findings are replicated in other studies, they could have major implications for clinical pain care.

Stroke, spirituality, and quality of life. We previously reported on the powerful link between positive thinking and lower risk of stroke recurrence. Now, researchers have shown that higher spirituality among stroke survivors may be tied to better quality of life (QoL) and reduce symptoms of depression for them and their caregivers. They analyzed data from questionnaires completed by approximately 200 stroke survivors, with low-to-medium disabilities and no other major health issues, and their caregivers. Stroke survivors consisted of a sex-balanced cohort (mean age: 71 years), while women comprised the majority of caregivers (mean age: 52 years). Questionnaires measured respondents’ spirituality, depression, and QoL between 2016 and 2018. Overall, researchers found a strong association between the degree of spirituality and QoL—even if caregivers were depressed. 

Stroke survivors who scored above average on the spirituality questionnaire had higher psychological QoL even when their caregivers reported symptoms of depression. Likewise, caregivers with above-average spirituality scores had better physical and psychological QoL. Stroke survivors who scored below average on the spirituality questionnaire, on the other hand, demonstrated lower QoL, as did their caregivers with depression. So, what does all this mean? Basically, it boils down to this: Stroke survivors and their care partners are part of an interdependent unit. Feelings of depression in either party can affect the other. When caregivers feel depressed, stroke survivors’ degree of spirituality determined whether this was tied to better or worse quality of life. Greater stroke survivor spirituality was tied to greater QoL for both the survivor and the caregiver. The researchers cautioned that their study included only stroke survivors with low-to-medium disabilities and no other major health problems, so their findings may not apply to survivors with more severe disabilities or other underlying conditions. Still, the results provide strong evidence for spirituality’s protective role in health and wellness.

Mozart for epilepsy? Music has been shown to benefit health in a number of ways, from reduced pain and anxiety to improvements in cognitive function and sleep. So, is it really any surprise that music may also help people with epilepsy? A new clinical research study shows that a Mozart composition—“Sonata for Two Pianos in D Major, K. 448”—may reduce seizure frequency in people with epilepsy. 

Researchers enrolled 13 patients with epilepsy in a year-long trial. After 3 months of a baseline period, half of the patients listened to the first movement of this Mozart sonata every day for 3 months. Then, they switched to a scrambled version of the composition (control) for 3 months. The other half of the cohort followed the same protocol but in reverse. Patients kept “seizure diaries” in which they recorded their changes in seizure frequency during the trial. Their meds remained the same during the study. In all, the researchers found that daily listening to Mozart’s (unscrambled) sonata was associated with a reduction in seizure frequency in adults with epilepsy, suggesting that this may be an adjunctive therapy for seizure reduction in this patient population. Although the results are promising, the researchers acknowledged the need to validate these findings in larger, longer studies. Plus there’s the issue of having to listen to the same music on repeat… 

Latest in Journal Summaries

Long-term results after surgical resection of peritoneal metastasis from neuroendocrine tumors

Predictors of immediate remission after surgery in Cushing disease patients

Shift‐work‐related sleep disruption and the risk of decline in cognitive function

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Upcoming Medical Meetings

Please note that, in the interests of containing the current COVID-19 pandemic, the following meetings have been canceled. Please contact these organizations for details and specifics on refunds and rescheduling:

Evaluating and Treating Pain, to be held in Boston, MA, June 15-19, 2020.

NeuroRehabilitation 2020, to be held in Waltham, MA, June 18-20, 2020.

The following meeting has been changed to a virtual workshop:

22nd Annual Conference of the International Society for Bipolar Disorders (ISBD 2020), to be held in Chicago, IL, June 18-21, 2020.

The following meeting has been rescheduled:

19th International Symposium on Pediatric Neuro-Oncology (ISPNO2020), to be held in Karuizawa-machi, Japan, June 21-24, 2020, has been rescheduled for December 13-16, 2020, and will remain in Karuizawa-machi, Japan. Those who will not be able to attend in-person will be able to participate in the virtual meeting online.

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