Dangerous neuro effects of COVID-19, a bioengineered virus for brain tumors, and statins for stroke prevention
This week, there’s probably a lot of COVID-19 on your mind, and it’s about to get worse: looks like lung issues are just the tip of the iceberg, as researchers explore possible neurological effects. But there’s a lot going on in neuro, too. A ketogenic, low-carb diet, for instance, may help your brain reverse age-related deterioration. And researchers have succeeded in printing a 3D working glioblastoma model, complete with vasculature through which to channel and test therapeutic agents. Finally, statins may be the key to preventing recurrent events in patients with history of stroke or transient ischemic attack (TIA). Read on to find out the details of all these and more research happenings in this week’s NeuroBrief!
A ‘rose-y’ year for neurons. Only 2 years ago, researchers at the Allen Institute, Seattle, WA, discovered a completely new type of neuron—the rosehip neuron—in humans. These neurons contain dense bundles of processes surrounding the center of the cell that—are you ready?—look like a rose does after it sheds its petals. Found only in the human brain, these neurons have never been seen in mice or other lab animals. Are they specific to humans? It’s still early in the game, so researchers really don’t know yet. Some have postulated that rosehip neurons—and the lack thereof in laboratory animals—may be why animal studies do not often translate to humans. Rosehip neurons comprise almost 15% of all neurons in the outmost layer of the brain that supports high-level cognitive function. Why these neurons are so rare, what they do, and whether they’re linked to neuropsychiatric disorders remains to be seen.
In the News
Neurological effects of COVID-19. If you think coronavirus disease 2019 (COVID-19) damages only the lungs, think again. In an article in Neurology Today, experts detail some of the possible neurological effects of coronavirus disease 2019 (COVID-19). The article pointed to a report from three COVID-19–designated hospitals in Wuhan, China, where over 33% of patients with COVID-19 had neurological symptoms, including altered consciousness, evidence of skeletal muscle damage, and acute cerebrovascular disease. And these symptoms were more common with severe disease. What is unknown is whether these complications were caused by direct viral injury or secondary infections.
Neurologists are called upon to remain vigilant, especially with patients with severe disease and those in high-risk categories, including those aged 60 years and older and with underlying medical conditions (eg, heart disease, lung disease, and diabetes). What’s more, patients with neurological diseases may be at high risk for severe COVID-19, including those with multiple sclerosis, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis (ALS), and myasthenia gravis. Early reports show that some COVID-19 patients may have headaches, stiff necks, and muscle aches—symptoms that may all suggest viral meningitis. But, since pulmonary symptoms often overwhelm these patients and lead to death, brainstem involvement is hard to discern. For now, those with ALS and other condition that affect respiration should be counselled to stick to CDC recommendations for high-risk groups. Neurologists, be alert.
Should you put your brain on a diet? Maybe, according to researchers who have found that a low-carb diet may be just what your brain needs to reverse age-related brain deterioration. Unfortunately, they also discovered that many of the brain’s pathways start to erode in your late 40’s, much earlier than previously believed. Yikes. Good thing they also saw that these pathways can be repaired via dietary changes—ie, exchanging glucose for ketones as the fuel for neurons. Enter the ketogenic—or low-carb—diet.
To reach this conclusion, researchers from Stony Brook University, Stony Brook, NY, studied functional MRIs from nearly 1,000 participants aged 18 to 88 years. They found that damage to the neural pathways increased depending on what energy source the brain was using. Here’s how: Glucose decreased the stability of the brain’s networks, while ketones made them more stable. The hypothesis behind this is that, with age, the brain may lose its ability to metabolize glucose efficiency, similar to what happens in the rest of the body. This may cause neuronal starvation as well as destabilization of brain networks.
The ketogenic diet is high in fats and proteins and low in carbs, and it’s been successfully used to treat some forms of pediatric epilepsy. But, dieters beware: This diet has also been shown to have bad effects on cardiovascular health. Seems like nothing comes without a cost.
Hit RECORD! We may be a few steps closer to learning how the brain “records” and “replays” memories. Preclinical studies have suggested that the brain may store memories in unique neuronal firing sequences. So, researchers from the National Institutes of Health decided to test this hypothesis in humans. They analyzed the firing patterns of neurons in the anterior temporal lobe, the language center of the brain, in patients with epilepsy. Patients were asked to learn word pairs, and researchers recorded electrical currents generated by neurons in their brains.
Unique firing patterns of individual neurons were associated with learning each new word pair. When patients were asked to later repeat the word pairs and were shown the first word in the pair, a similar firing pattern was replayed milliseconds before they remembered the second word. What’s more, memory recall caused the brain to replay these neuronal firing patterns in several other areas. Researchers hope their results will help further the understanding of how people form and retrieve memories, and that this, in turn, will tell us more about how neuronal circuits can break down in memory disorders. In the meantime, how about a nice card game of “Memory”?
Catching the bad guy. Inflammation may be more of a culprit in several forms of dementia than previously thought, according to researchers from the University of Cambridge. Neuroinflammation has been recognized and associated with many disorders, including depression, psychosis, multiple sclerosis, and, more recently, Alzheimer disease (AD).
Researchers studied 31 patients with three different types of frontotemporal dementia (FTD): behavioral variant, semantic variant, non-fluent variant. Using PET, they scanned patients’ brains to detect inflammation and abnormal “junk” proteins. In all three types, scans revealed that the more inflammation was present, the more harmful junk proteins had built up. What’s more, microscopic exams of 12 postmortem brains confirmed these results. They hypothesized that this may be part of a “vicious circle”–with cell damage triggering inflammation, triggering further cell damage, and so on, and so on. The bottom line: inflammation may play a role in other neurodegenerative diseases besides AD, such as Parkinson and Huntington diseases. But, here’s the silver lining: Their discovery could lead to new and better treatments!
3D printed tumors? You bet. Using a combination of bioprinting and imaging of glioblastoma cells, researchers have been able to more accurately model what happens inside the human body when a glioblastoma occurs. To construct a 3D glioblastoma tumor cell model, they made bioinks from patient-derived tumor cells and printed them along with blood vessels, which allowed the printed tissue to live and mature. (Mind. Blown.) This way, they could study the “printed” tumors for months. Another plus? The bioprinted blood vessels were actually channels that therapeutics could travel through.
Here, researchers used temozolomide to study how to better get it past that blood-brain barrier. They said bioprinting is uniquely positioned to help them better see what would happen in vivo with different treatments. And, to better understand what was happening, researchers developed a specialized technique to “take pictures” of the bioprinted tissue at the cellular level. They say it allows for better images than even fluorescence microscopy, allowing them to see if the cells are growing and if they respond to temozolomide. In the future, this technique could help determine the efficacy of several drugs against glioblastomas. All kinds of thinking out of the box going on here!
What is the blood-brain barrier most permeable to?
The brain-blood barrier is a dynamic interface between the peripheral circulation and the CNS, and is most permeable to glucose and oxygen. It consists of tight junctions between endothelial cells that form the capillary wall. These tight junctions work to restrict blood-borne substances from entering the brain.
Virtual halls, virtual falls. Virtual reality (VR) could be much more than fun and games. In fact, in patients with multiple sclerosis (MS), a VR system may be a reliable and early test for balance impairment. Patients with MS are often at increased risk for falling, and even those with minimal or no disabilities are more than twice as likely to fall as healthy individuals. Many of these falls happen while they’re walking. So, to find a more effective way to test walking balance deficits in these patients, researchers used a VR system.
Fourteen patients with MS and 14 age-matched controls were tested while walking on a treadmill. They were shown a virtual hallway and then optical flow perturbations were generated to mimic falling. In MS patients, all was normal during normal walking. But, when the disruptions were generated, they didn’t do so well. In fact, these patients had higher step-width variations, sacrum position, and margins of stability compared with controls. Their standing sensory organization tests were also worse. The hope is to further develop a VR-based test and make it portable and widely available to neurology clinics to help clinicians and patients with MS detect undetected balance impairments.
It’s all in the ‘where’ and the ‘how.’ 7T MRI can lead to incredibly detailed images of the human body, and for neuroscientists, that’s good news. In a recent study, Dutch researchers used this new, high-powered MRI to identify the top three risk factors associated with intracranial vessel wall lesions that lead to ischemic stroke. Diabetes, hypertension, and increasing age, in that specific order, correlated in a higher number of vessel wall lesions in those with ischemic stroke or transient ischemic attacks. What’s more, their results contradict those from three previous studies of what these risk factors are and how they contribute to intracranial atherosclerosis and stroke. Could it be in the imaging? The location? Both?
Previous studies used lumenography and reported that the top three risk factors leading to ischemic stroke as smoking, dyslipidemia, and male sex. The current researchers went beyond this, finding that diabetes, hypertension, and increasing age contributed most significantly to atherosclerotic lesions and stroke with anterior circulation vessel wall lesions. 7T MRI beats CT, MR angiography, and digital subtraction angiography any day, and has the capability of evaluating vessel wall lesions that occur in the most advanced stages of intracranial atherosclerosis. We’ll take their word for it!
Right up the nose. Dantrolene is a muscle relaxer used to treat muscle spasticity caused by conditions such as spinal cord injuries, stroke, cerebral palsy, and multiple sclerosis. But, what if it could help in the treatment of neurodegenerative diseases? The catch is, it may have to be delivered not orally but nasally! Yes, researchers have found that delivering dantrolene through the nose, rather than the mouth, helps it penetrate the brain more effectively, possibly maximizing its therapeutic benefits for neurodegenerative diseases such as Alzheimer disease.
At the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, researchers performed a preclinical study—the first of its kind—to study the effects of nasal vs oral dantrolene. Mice given the nasal formulation had higher concentrations of dantrolene in their brains for longer than those who received the oral form. At 180 minutes, nasal dantrolene was still present in the brain, whereas at 120 minutes, no traces of the oral dantrolene were found. More research is needed, especially on toxicity and side effects, but this could lead to a much needed new therapeutic for neurodegenerative diseases.
New hope for a rare disorder. Researchers from the National Cancer Institute’s Center for Cancer Research are closer to finding a treatment that improves outcomes for kids with neurofibromatosis type 1 (NF1). In a phase 2 clinical trial, selumetinib—a MEK 1/2 inhibitor—shrank the plexiform neurofibromas that form in children with NF1. The kids also had less pain as well as improved function and quality of life.
So, why’s this important? There are currently no effective medical therapies for NF1. These neurofibromas are difficult to treat, grow quickly, and can be quite large—up to 20% of the child’s body weight! Surgery is often not an option because the tumors can intertwine with healthy nerves and tissues. Even tumors that have been surgically and partially removed tend to grow back.
Getting back to the study—researchers included 50 kids, aged 3 to 17 years, with NF1-related plexiform neurofibromas. Common symptoms caused by the tumors were disfigurement, strength and range of motion limitations, and pain. The children took selumetinib twice daily for 28-day cycles, continuously, and were assessed at least every 4 cycles. So far, 70% had a confirmed partial response, with tumors shrinking 20% or more. Most of them maintained this response for over 1 year. Both kids and parents reported lower pain and less interference of pain on their daily function, overall quality of life, strength, and range of motion. What really surprised researchers was selumetinib’s impact on pain. Even kids living with chronic debilitating pain didn’t need pain meds anymore. Pretty fantastic!
Viruses deliver a one-two punch for cancer? Could an engineered cold sore virus destroy brain tumors from the inside out? Researchers at UTHealth sure think so. They found that cancerous cells treated with an engineered herpes virus signaled their neighboring cells (how friendly of them!) and made them respond to gamma secretase inhibitors (investigational agents) that could then finish off the tumor. The cellular nitty gritty of this is that the cold sore viruses express microRNA, which then activates the NOTCH signaling pathway to start cellular cross-talk. These virus-encoded microRNA, say researchers, essentially “ring the doorbell” on adjacent uninfected tumor cells, and tell them to stop resisting the investigational NOTCH-pathway blocking cancer drugs. In murine models, this one-two punch of virus and cancer drugs significantly improved the ability to kill brain tumors, and increased survival. Virotherapy plus gamma secretase inhibitors for cancer treatment are getting a closer look, thanks to these results.
New in Patient Management
Seeing clearly with PD. Be on the look-out for vision problems (no pun intended!) in your patients with Parkinson disease (PD). According to new research, vision and eye problems—such as blurry vision, dry eyes, trouble with depth perception, and problems adjusting to rapid changes in light—are more common in people with PD and affect them daily. Researchers from Radboud University Medical Centre, Nijmegen, The Netherlands, compared 848 people with PD with 250 healthy controls. Those with PD had symptoms for an average of 7 years, and the mean age in both groups was 70 years. All completed a questionnaire about eye and vision problems they may have been experiencing.
Here’s what researchers found: 82% of those with PD reported one or more eye problems, compared with only 48% of healthy controls. What’s more, 68% of PD patients reported that eye problems interfered with their daily lives, compared with only 35% of those without PD. Problems with vision can be especially debilitating for those with PD, and results showed that over 50% of patients with PD had problems with reading, and 33% had problems that interfered with driving. Based on their results, researchers are recommending visual screening in PD patients, as well as referral to vision specialists for those who report eye problems. Keep your eyes on the eyes.
Worse than a punch in the nose. Damage to the lining of the nasal cavity could increase the risk of invasion of the brain by Burkholderia pseudomallei, according to researchers from Queensland’s Griffith University. These invading bacteria could sneak into the brain through the nerves and cause some nasty long-term health issues, including melioidosis, a disease endemic to northern Australia and Southeast Asia that has a high mortality rate and can affect the central nervous system. The researchers had previously shown that B. pseudomallei can enter the CNS within 24 hours through peripheral nerves that extend between the nasal cavity and the brain, fully bypassing the ever-vigilante blood-brain barrier.
In their new study, they found that prior injury to the nasal epithelium—like that caused by trauma, colds, and even allergies—can increase bacterial invasion of the olfactory nerve, which runs in a straight line from the nasal cavity into the brain. What’s worse is that infection of the olfactory nerve increases the risks for CNS infection. And researchers went as far as to postulate that the neuroinflammation from bacteria and viruses may even contribute to neurodegenerative disorders like Alzheimer and Parkinson diseases. So, from now on, take good care of your nose. Your brain will thank you!
Statins to the rescue, again! In patients with a history of stroke or transient ischemic attack (TIA), atorvastatin was associated with a 32% reduction in total vascular events. Results were even better in atorvastatin-treated patients with diabetes, who experienced a 50% lower risk. How’s that for positive results!
In the aptly named SPARCL trial, researchers found that treatment with atorvastatin (80 mg) prevented more than twice the number of total events than first events compared with placebo. Among the 4,731 patients with recent stroke or TIA (1-6 months before the study) and no known coronary heart disease, researchers found 390 fewer total vascular events, including 177 fewer cerebrovascular, 170 fewer coronary, and 43 fewer peripheral events. Over 6 years, this further translated into the avoidance of 20 vascular events per 100 patients with atorvastatin treatment. Is there nothing statins can’t do?
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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 cancelled. Please contact these organizations for details and specifics on refunds and rescheduling:
The 2020 Lennox-Lombroso Pediatric Epilepsy Conference, in Boston, MA, March 20-21, 2020.
World of Neurosurgery: American Association of Neurological Surgeons (AANS) 2020 Annual Scientific Meeting, in Boston, MA, April 25-29, 2020.
American Academy of Neurology 71st Annual Meeting (AAN 2020), in Toronto, ON, Canada, April 25-May 1, 2020.