Targeting the CNS for COVID-19, breakthrough BBB-breaching drug delivery system, and an app for brain tumors
With practices slowly reopening across the nation, we imagine it’s been pretty hectic lately. But, don’t worry—we’ve got you covered when it comes to staying up to date on the latest and greatest neuroscience research. From new insights into the brain’s role in COVID-19 to breakthrough tech that could deliver life-saving treatments for a wide range of neuro diseases, stay in the know by reading this week’s NeuroBrief.
Everyone’s pretty much familiar with rabies—the rare but lethal viral encephalitis popularized by the likes of Cujo. And you’re probably also familiar with the treatment protocol: a series of fast-acting shots (rabies immune globulin) immediately upon exposure to prevent infection. What you may not know is that before modern medicine, a traditional European treatment for rabies was something called “St. Hubert’s Key.” The story goes that St. Peter gave Hubert (the first bishop of Liège in Belgium) a golden key and told him that God had given him special powers against evil spirits. Soon afterward, Hubert is said to have healed a man bitten by a rabid dog. After Hubert’s death, people would make pilgrimages to his shrine in hopes that he would protect them from rabies. Those who couldn’t make the pilgrimage were given pieces of iron known as the keys of St. Hubert. When a bite occurred, these “keys”—which were often shaped like nails, crosses, or cones—would be heated until they were red-hot and then placed directly on the trauma site. (Talk about the cure being worse than the disease. Yeesh.) This “treatment” was usually performed by priests, who also performed an operation called “cutting.” They would make a small incision on the affected person’s forehead and insert a thread said to have been taken from St. Hubert’s stole. The forehead would then be covered with a black bandage for 9 days. And this practiced carried on well until the start of the 20th century.
In the News
The brain’s role in COVID-19. When a patient has a pulmonary or respiratory infection, their immune system normally kicks in to fight it off. But, in some cases—like with COVID-19—the immune system’s defense response can go haywire, resulting in even more lung damage, aka acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Current treatment for patients with ALI or ARDS focuses on protecting and healing the lungs, supported by mechanical ventilation. But, a new study shows that clinicians may also need to tackle neuroinflammation to completely treat ALI and other lung diseases like COVID-19. Apparently, lung damage isn’t limited just to the lungs—it may also have far-reaching and lasting effects in the CNS’ respiratory control center. Luckily, researchers have found that targeting the parts of the brain that regulate breathing and blood flow might help patients with respiratory problems and speed up ventilatory weaning time.
To reach this conclusion, they looked at rats with lung injury and found that the parts of the brain that regulate breathing were also affected. Even after removing the rodents’ lungs, characteristics of the pathologic breathing pattern remained, highlightingindicating the residual impact that lung damage can have. The researchers also found evidence of inflammation in the brain region that produces the breathing pattern, suggesting that the lungs aren’t the only factors involved in breathing disorders related to lung injury. After injecting anti-inflammatory drugs directly into the CNS of conscious lung-injured rats, the researchers found that the drugs reduced neuroinflammation and mitigated the effects of lung injury. These findings suggest that brainstem circuits play an important role in the pathophysiology and recovery of the respiratory system after lung injury and ARDS. This new insight is incredibly important in light of the current pandemic, as some critically ill patients with COVID-19 can have trouble transitioning from mechanical ventilation to breathing on their own.
New trial platform for PD cure. Despite decades of research, no drugs have been found to successfully slow or stop the progression of Parkinson disease (PD). What makes things worse is that each potential PD cure has to go through three isolated clinical trial phases to test its clinical benefit, real-world efficacy, and safety—which can be an incredibly long, inefficient, and expensive process. So, researchers have come up with a new trial platform to help optimize and speed up the search for a PD cure. They describe the concept as a multi-arm, multi-stage (MAMS) trial platform that would allow several potential therapies to be investigated at once. Basically, the MAMS platform could test many potential therapies in parallel, smoothly transitioning through, say, a phase 2 safety and efficacy study to a phase 3 clinical trial. Plus, early analyses will permit ineffective treatment arms to be dropped and replaced by new ones, allowing for the continuous assessment of interventions.
Sounds ingenious, right? Well, you might be surprised to learn that MAMS trials are nothing new. They already exist in the United States for certain cancer types, and they’re being developed in the United Kingdom for neuro diseases like progressive multiple sclerosis and motor neuron disease. So, why hasn’t this platform been implemented earlier for PD? Simply put, a lot of important variables and challenges need to be addressed for the platform to work well over the long haul. One of the biggest hurdles involves having a pipeline in place to continuously identify and evaluate suitable drug candidates. Another hurdle is that selected outcome measures have to be sensitive enough to changes in disease progression throughout the interim stages and the full duration of the trial. Then again, similar challenges have been met in MAMS trials for other diseases. So, over the next year and a half, the researchers plan to work with leading PD organizations to fine-tune and establish the MAMS trial platform for PD.
Focused ultrasound vs the BBB. The blood-brain barrier (BBB) is one of the CNS’ greatest defense mechanisms. Unfortunately, it’s also one of the biggest painsgreatest challenges for delivering drugs to the CNS. But, that struggle may soon come to an end, thanks to new innovation from a team of biomedical engineers. They’re using MRI-guided focused ultrasound to circumvent the BBB so that doctors can finally deliver treatments directly into the brain to combat neurological diseases. Their novel approach involves breaching the BBB only where and when needed to deliver precision treatment. The breakthrough technique could revolutionize treatment for a wide range of neuro conditions—from Alzheimer disease and epilepsy to brain tumors and stroke.
MRI allows doctors to visualize a target—like a brain tumor—and select it for treatment. Focused ultrasound precisely directs sound waves inside the brain, allowing doctors to manipulate tissue without cutting into the skull. By marrying the two pieces of tech, doctors can pinpoint where they want to open the BBB, apply the focused ultrasound there, and deliver treatment—including gene therapy—with the BBB closing naturally within a few hours. The researchers are currently exploring the use of focused ultrasound to deliver gene therapy via deep-penetrating nanoparticles. To treat stroke, the engineers aim to help the brain heal itself by using focused ultrasound to put “homing molecules” inside damaged areas to attract neural stem cells to do repairs. Their technique could soon prove useful in cancer treatments, with a similar mechanism to recruit immune cells into a tumor. Although their work is still ongoing, the researchers predict their new techniques could change how major neuro diseases are treated in the near future.
Are antipsychotics harming the brain? If something’s too good to be true, it probably is. Enter: antipsychotics. These drugs are widely prescribed for a range of pediatric, adult, and geriatric neuropsych disorders. And, for many patients, the meds are a godsend. But, a new study suggests that antipsychotics could be harming the brain’s structure. For this study, the researchers compared the effects of olanzapine with placebo on brain structure in adult patients, all with psychotic depression. All participants were given olanzapine and sertraline for 12-20 weeks, which included 8 weeks of psychosis remission and remission/near remission of depression. Patients were then randomized to continue receiving this regimen or to receive placebo and sertraline for 36 weeks. All 72 patients included in the final analysis had an MRI scan at randomization and at the end of the 36-week period or at time of relapse.
The researchers found that continued use of olanzapine vs placebo was linked to a thinning of the cortex in the left and right hemispheres, over 36 weeks. But, no significant change was found with olanzapine vs placebo in subcortical volumes or surface area. Cortical thickness changes were even more pronounced in elderly patients. What’s even more interesting is that patients who suffered an illness relapse while on placebo also had a reduction in cortical thickness, indicating antipsychotics’ important role in treating disorders where psychosis is present. And, for patients who received olanzapine, those who sustained remission experienced significant decreases in cortical thickness compared with those who relapsed. Despite the value of these new insights, there were some limitations to the study. For instance, the researchers couldn’t address any potential effects of sertraline on brain structure since both groups received this medication. And there were differences in scanner models across sites, which could have resulted in detected MRI changes representing an epiphenomenon rather than actual brain alterations. Regardless, the researchers concluded that their findings could help clinicians build “a predictive model of which patients require long-term treatment with antipsychotics and which patients can safely discontinue them.”
It takes 30 seconds for nicotine to enter the brain after smoking a cigarette. True or false?
Bad news for cigarette smokers: The answer is “false.” Nicotine is one of the most heavily used addictive drugs in the United States, and it can reach max levels in the bloodstream and brain rapidly. In fact, it takes as little as 10 seconds for the nicotine in cigarette smoke to reach the brain. Because the acute effects of nicotine dissipate in a matter of minutes, smokers often feel the need to smoke repeatedly throughout the day to get their nicotine fix. Plus, the more nicotine you inhale, the more your brain changes in response, with those changes causing addiction.
New score predicts ICH. Because there aren’t much available data on predictors of symptomatic intracranial hemorrhage (ICH) in patients who’ve had mechanical thrombectomy, researchers carried out a study to identify such indicators. They found that high results from the novel TAG score were linked to higher risk for symptomatic ICH in this population. To determine this, the researchers collected data on patients treated with mechanical thrombectomy at a comprehensive stroke center and then compared characteristics between patients with and without symptomatic ICH to identify potential predictors. Independent predictors were combined to create a symptomatic ICH prediction score, which was then externally validated using data from the Blood Pressure After Endovascular Treatment multicenter prospective registry.
The researchers identified 578 patients who received thrombectomy for acute ischemic stroke. Of these, roughly 3.3% had symptomatic ICH. Thrombolysis in Cerebral Ischemic score, the Alberta Stroke Program Early Computed Tomography Score, and glucose level were all found to predict symptomatic ICH. Together, these three factors comprise the “TAG” score. The researchers used multivariate logistic regression to derive the weighted TAG score, which they found to be statistically significantly associated with symptomatic ICH in both the derivation and validation cohorts. They concluded that high TAG scores are linked to symptomatic ICH in patients receiving mechanical thrombectomy. But, they noted that larger clinical trials are needed to validate the scoring system, evaluate interventions and strategies to reduce symptomatic ICH risk, and make thrombectomy safer in patients with high TAG scores.
Biomarker for ventriculomegaly. Ventriculomegaly is an abnormal condition marked by fluid buildup in the brain ventricles that don’t drain properly, making them enlarged. In itself, ventricular enlargement within normal range isn’t considered a disease. The bad news is that, left unchecked, it can lead to ventriculomegaly and dementia. Researchers in Japan have found that natural age-related ventriculomegaly was linked to a lag in blood drainage from a specific deep area of the brain. The good news? The lag can be easily picked up with MRI, making it a potential biomarker for predicting ventriculomegaly and the aging brain, which can then be quickly treated.
In their study, the researchers found that ventriculomegaly was linked to changes in brain blood circulation. They used MRI to measure changes in blood flow and found that the time it takes for blood to drain through two different pathways—the deep pathway and the surface pathway—becomes out of sync as we age. The result is a time lag between the two pathways—a lag that increases with age. A diagnostic MRI that measures a patient’s lag between the two drainage pathways might be a good biomarker for the aging brain and a possible predictor of ventriculomegaly, the researchers concluded. Because dementia due to normal pressure hydrocephalus can be reversed by removing the fluid that builds up in the ventricles, early diagnosis is key. The researchers are already developing non-invasive applications of this technology.
App for meningioma. Can you screen a tumor with your smartphone? Looks that way, and yes, it’s as cool as it sounds. Researchers have now created an open-source smartphone app to help with the diagnosis and prognosis of meningiomas. To develop this, the researchers created AI algorithms to discover patterns of association between malignancy, survival, and a series of basic clinical variables like tumor size, tumor location, and surgical procedure. Their models were trained and validated in over 60,000 patients from the Surveillance, Epidemiology, and End Results database.
They found that their models could predict meaningful clinical outcomes for individual patients, with good generalizability. For the survival model, the researchers found that age at diagnosis affected survival and that increased tumor size was linked to worse survival. Malignant tumors predicted worse survival vs borderline malignant tumors, which predicted worse survival than benign tumors. Specific surgeries predicted the greatest improved survival compared with no surgery. The two most important features in the malignancy model were tumor size and age at diagnosis, which were the only features kept in the final model. But, the researchers noted that future model improvements and prospective replication are needed to prove true clinical utility.
CBD for deadly brain cancer. Sound too good to be true? Well, it’s not. A new study of human and canine brain cancer cells shows that cannabidiol (CBD)—the non-psychoactive chemical compound derived from marijuana—could be a useful treatment for glioblastoma. This is exciting news since survival rates for glioblastoma have not improved significantly in recent years, even with major advancements in treatment. For this study, the researchers looked at human and canine glioblastoma cells because the cancer is remarkably similar between the two species. They tested the effects of CBD isolate, which contains 100% CBD, and CBD extract, which also contains small amounts of other naturally occurring compounds like cannabigerol and tetrahydrocannabinol. They found that CBD slows cancer cell growth and is toxic to both canine and human glioblastoma cell lines. Pretty impressive, right? Interestingly, the differences in anti-cancer effects between CBD isolate and extract seemed to be negligible.
The researchers found that CBD‐induced cell death occurs via apoptosis, and a classically necroptotic protein, RIPK3, also appears to be involved. Their study showed that cells treated with CBD demonstrated significant reductions in mitochondrial activity. They believe that CBD’s anti-cancer actions target mitochondria by causing the mitochondria to dysfunction and release harmful reactive oxygen species. The researchers speculate that their findings could lead to new treatments that could help both people and dogs with glioblastoma. They plan to transition from cell cultures to animal models to test CBD’s effects on the cancer. If all goes well, the work could progress to clinical trials on dogs that are being treated for naturally occurring glioblastoma. Good for people and dogs? We can get behind this.
New compound for AD. Researchers have created a new compound that significantly reduced the number of amyloid plaques in the brain, brain inflammation, and other molecular markers of Alzheimer disease (AD). Recent studies have shown that aggregates of p-tau collect around amyloid plaques, increasing the neuroinflammation that is associated with AD. Because of this, many studies have focused on dissolving or disrupting the formation of the amyloid plaques, which are composed of a protein fragment called beta-amyloid peptide. Previous researchers have found that soluble beta-amyloid fragments are more harmful to brain health even before they aggregate into plaques. And studies have shown that they can cause memory loss and neuron cell death. So, plaque formation might be the brain’s way of trying to neutralize the threat. Metal ions like copper and iron also play a role in AD pathology. They form associations with the beta-amyloid peptide, stabilizing the more harmful, soluble beta-amyloid species. They also contribute to the damaging oxidative stress and brain inflammation seen in AD.
To address these different pathological aspects of Alzheimer’s disease, researchers created a compound called L1 that interacts with different regions of the beta-amyloid peptide, as well as with metal ions. When the compound was tested in mice genetically predisposed to develop AD-like pathologies, it was able to cross the blood-brain barrier, reduce neuroinflammation, and decrease the number of amyloid plaques and the p-tau aggregates associated with these plaques. The researchers’ findings suggest that drugs that interact with different parts of amyloid-beta protein fragments and other AD-associated peptides and metal ions could improve outcomes for people with AD.
New FDA-approved drug for MS. The FDA has granted final approval to Bafiertam (monomethyl fumarate, Banner Life Sciences) for the treatment of relapsing forms of multiple sclerosis (MS)—including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease—in adults. Bafiertam—(your guess is as good as ours on pronunciation how to pronounce that)— is a novel fumarate bioequivalent alternative to its prodrug dimethyl fumarate (Tecfidera). A lower dose of Bafiertam is equivalent to Tecfidera. Plus, it may lead to better gastrointestinal tolerability for patients, especially in the early treatment regimen. The exact mechanism of action for Bafiertam has not been established, but it has been shown to trigger the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. The FDA’s approval of Bafiertam was based on bioavailability studies comparing oral dimethyl fumarate delayed-release capsules to Bafiertam delayed-release capsules in healthy individuals. Because both dimethyl fumarate and diroximel fumarate are metabolized to monomethyl fumarate, concomitant use with Bafiertam is contraindicated. But, Bafiertam may be started the day following discontinuation of either of these drugs. Bafiertam will be available in 95-mg delayed-release capsules.
New in Patient Management
Yoga for migraine. Breathe in, breathe out. And repeat. A new study shows that yoga may help cut down on the number, length, and severity of headaches in people with migraine. Researchers looked at 114 adults with episodic migraine who had 4-14 headaches per month. They randomized participants to two groups: medication only or yoga plus medication. Those in the yoga group were taught a 1-hour yoga practice that included breathing and relaxation exercises and postures. They were supervised by a yoga instructor 3 days a week for a month. Afterward, they practiced yoga on their own at home for 5 days a week over the next 2 months. Both groups received the appropriate medications and counseling about lifestyle changes that may help with migraine, such as getting enough sleep, eating regular meals, and exercising. Participants recorded how long their headaches lasted, how severe they were, and what medications they took. The researchers found that people improved in both the medication-only and yoga groups. But, the benefit was higher in the yoga group in all areas—including headache frequency, pain severity, medication usage, and migraine’s interference with daily life.
In terms of headache frequency, the yoga group started with an average of 9.1 headaches per month and ended with just 4.7 headaches per month—a 48% reduction. The medication-only group reported an average of 7.7 headaches per month at the start of the study and ended with 6.8 per month at 3 months—a 12% decrease. The average number of pills people in the yoga group used decreased by 47% after 3 months, while the average number of pills the medication-only group used decreased by about 12%. A couple of things to keep in mind are that participant data were self-reported, so the results may not be consistent, and the study only lasted 3 months, so more research is needed to look at yoga’s benefits over the long term. But, it’s still pretty clear that something as simple as yoga could be a real game-changer, especially for people who struggle to afford their migraine medications.
Simple question improves pain treatment. They say that the best things in life are simple, and that’s never been truer when it comes to pain management. A new study shows that a simple question posed to patients, along with the traditional 0-10 numeric rating scale (NRS), could help doctors better understand whether pain treatments, including opioids, are actually needed. Researchers asked over 500 patients at nearly 160 primary care practices to rate their chronic pain using the 0-10 NRS and also respond yes or no to the question: “Is your pain tolerable?” In the moderate range of the NRS (scores of 4–6), only 40 of 211 patients (19.0%) said that their pain was intolerable. And, in the severe range (scores of 7–10), 72 of 137 patients (52.6%) considered their pain intolerable. These findings show that a substantial subgroup of patients with severe pain actually consider their symptoms to be tolerable. In fact, almost 4 of 5 patients in the primary care setting who rated their pain as “moderate” in intensity found it tolerable. And 30% to 40% of people who rated their pain as “severe” also described the pain as tolerable. The researchers say that knowing that a patient’s pain is tolerable could help physicians decide whether it’s necessary to prescribe a medication with serious risks or expose them to surgery. Plus, physicians could explore other avenues for pain control, such as mood, sleep, and curtailing certain activities.
CVD risk and epilepsy. Status epilepticus has been linked to a higher risk for sudden unexpected death in people with epilepsy. Even worse, researchers have now found that people with status epilepticus have a higher prevalence of cardiovascular risk factors and a higher risk of developing cardiovascular diseases compared with those who don’t have the neuro disorder. (Talk about bad luck.) In their study, researchers looked at adults with epilepsy or seizure disorders who either did or did not have status epilepticus. No participants had a history of cardiac arrest, ischemic heart disease, or cerebrovascular disease. A total of 337,570 participants had a diagnosis of epilepsy or seizure disorders. Of these, 12,310 had comorbid status epilepticus. In this cohort, patients with status epilepticus had a higher prevalence of cardiovascular risk factors (7.7% vs 4.0%), diabetes (13.2% vs 7.0%), and tobacco use (28.4% vs 14.5%) than those without it. Patients with status epilepticus were also found to be more likely to develop ventricular tachycardia, atrial fibrillation, heart failure, atrioventricular block, and cardiogenic shock. So, the researchers concluded that underlying cardiovascular disease might contribute to sudden unexpected death in patients with epilepsy who have status epilepticus, and that cardiovascular screenings in this patient population should be investigated.
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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:
Mid-Atlantic Neurocritical Care Symposium, in Baltimore, MD, May 21-22, 2020.
Case Based Tutorials in Neuroradiology: Head/Neck Radiology, Musculoskeletal Radiology, in Chatham, MA, May 22-24, 2020.
The following meeting has been changed to a virtual workshop:
American Society of Clinical Psychopharmacology (ASCP) 2020 Annual Meeting, in Miami Beach, FL, May 26-29, 2020, has been changed to a virtual workshop and will be hosted online.