Emerging pandemic linked to neuro diseases, breakthrough therapy for cognitive decline, and…the end of pain meds?
Are we closer to a vaccine or cure for COVID-19? Will the economy bounce back? Is social-distancing here to stay? Life as we know it seems to be one giant question mark at the moment. But one thing’s for certain: The wheels of neuroscience research keep on turning. Just recently, for instance, researchers discovered that not one—but two—neurodegenerative diseases are linked to air pollution. The silver lining? A newly developed blood test could help catch one of them early. Plus, could the answer to chronic pain come in the form of a widely accessible and legal—albeit taboo—cannabis plant derivative? Get the full details on these studies and more by reading this week’s NeuroBrief.
Some experts will argue that amputation is the earliest known medical operation. But a wealth of scientific evidence actually supports trepanation as the oldest documented surgical procedure performed by man. Since the New Stone Age, people around the world have practiced trepanation—a surgical procedure that involves boring one or more holes into a person’s skull (ie, burr holes). Experts believe that ancient civilizations performed trepanation to not only exorcise malevolent spirits from an individual, but also to treat certain health conditions like convulsions, headaches, and infections. Today, neurosurgeons still use trepanation. (Though, thankfully, not for expelling demons.) It’s primarily used for treating epidural and subdural hematomas. In fact, according to some researchers, trepanation may actually be a safer, more effective alternative procedure for the treatment of acute and chronic subdural hematomas compared with modern-day craniotomy, which is associated with a high mortality rate. Trepanation is also used for surgical access to help relieve intracranial pressure.
In the News
New insights: ALS and the gut-brain link. More and more, we’re learning about the gut’s unique relationship with the brain. Just recently, researchers showed that unique sensor molecules in the gut may be responsible for the brain’s sugar cravings. Now, scientists have discovered a new gut-brain link in amyotrophic lateral sclerosis (ALS). Their new study shows that altering the gut microbiome using antibiotics or fecal transplants could positively affect ALS outcomes. But how is this finding different from other ALS discoveries over the years, you ask? Well, it’s big news because it could explain why only some carriers of the most common ALS gene mutation go on to develop the disease. Plus, the research could lead to a new therapeutic approach based on the gut microbiome.
Using a specific mouse model at different lab facilities but with identical genetics, scientists studied the most commonly mutated gene in patients with ALS. In the first lab, the mice developed overactive immune responses, including neural inflammation, which led to premature death. But, in the other lab, the mice had the same genetic mutation but did not have neural inflammation, resulting in longer life. These striking differences were a real head-scratcher, considering that both models had the same genetic makeup and lab conditions, which led the scientists to take a closer look at contributing factors in both environments. In the end, they traced the different outcomes to the gut microbiome. Using DNA sequencing to identify gut bacteria, they found that certain microbes were present in the mice from the first location but not in the second. The scientists then tested different ways to change the microbiome to improve outcomes for the mice in the first lab. Ultimately, they found that treating mice with antibiotics or fecal transplants lowered neural inflammation and, consequently, increased longevity. The scientists’ research on the gut microbiome may explain why only some mutation carriers go on to develop ALS, as well as shed light on a potential target for ALS therapy in the future.
Psoriasis = Alzheimer disease? More than just a cosmetic health problem, psoriasis is a chronic autoimmune skin disease that can be painful and negatively impact quality of life. There are many different types of psoriasis, but the most common signs and symptoms include scaly plaques, dry or cracked skin that might bleed, itching and burning, soreness, and painful joints. And if that wasn’t bad enough, it turns out that the skin disease may be linked to another horrible illness: Alzheimer disease. A recent Korean study shows that the incidence of AD is strikingly higher in patients with vs without psoriasis. Previous studies have shown that neuroinflammation plays a role in AD development. Since psoriasis is a chronic inflammatory disease that genetically overlaps with AD, researchers investigated the risk of AD in patients with psoriasis.
They analyzed data from over 500,000 people with psoriasis and more than 2 million age- and sex-matched controls without psoriasis. All individuals had at least 3 health exams between 2008 and 2014, and AD risk was assessed in both groups. During follow-up (median: 3.35 years), 1.87% of controls developed AD vs 2.11% of patients with psoriasis. And, in adjusted models, patients with psoriasis showed significantly higher risk for AD vs controls. Notably, AD risk among patients with psoriasis was much higher in those not receiving systemic therapy vs those receiving systemic therapy. In other words, systemic treatment for psoriasis was associated with a reduced risk of AD. The authors speculated that “systemic anti-inflammatory drugs reduce the inflammation of neuronal cells, lowering overall inflammation in the body, which has a preventive effect on AD.” More studies are needed to find out what’s driving the increased AD risk in patients with psoriasis and whether the type of systemic treatment plays a role. But, it’s a good idea to keep this newly discovered psoriasis-AD link in mind when seeing patients who have this skin disease.
Diesel and Parkinson disease. Do you know what pandemic is causing more premature deaths than smoking, HIV/AIDS, parasitic and vector-borne diseases, wars, and other forms of violence? Hint: It’s not COVID-19. You might be surprised to learn that it’s air pollution. You know what else air pollution causes? Apparently, Parkinson disease (PD). A new UCLA study in zebrafish shows that air pollution damages brain cells, potentially contributing to PD onset. Previous researchers have shown that people living in places with high levels of air pollution tend to have higher rates of PD. To understand why that is and how it affects the brain, researchers tested the effects of diesel exhaust on zebrafish. (They chose zebrafish as test subjects since their neurons interact similarly to those in humans. Plus, since the fish are transparent, researchers can observe the biological processes in their brains without killing the animals.)
The researchers added diesel exhaust chemicals to the water the zebrafish were being kept in. These chemicals caused exposed fish to behave strangely, which researchers found was due to neuronal death. They looked at the activities in several brain pathways associated with PD to find out exactly how pollutant particles were causing cell death. Seems that diesel exposure had disrupted the autophagy disposal process in the brain, leading to a toxic buildup of alpha-synuclein proteins, which can kill neurons and interfere with proper brain functioning. This, of course, can result in symptoms characteristic of PD: tremors and muscle rigidity. To verify that this disruption in autophagic flux was the reason behind neuronal death, the researchers treated fish with nilotinib, an autophagy-inducing drug. And this was shown to save cells from death after diesel exposure. To confirm the effects of diesel in humans, the researchers replicated the zebrafish experiment using cultured human cells. Not surprisingly, diesel exhaust exposure had similar effects on human cells. These findings not only give further insight into the pollution-neurodegeneration link, but also open up the possibility for new therapies focused on mitigating environmental exposures to promote neuroprotection.
City living = higher MS risk? In more pollution news, a recent study done in Italy and presented at the 6th Congress of the European Academy of Neurology shows that air pollution could be a risk factor for the development of multiple sclerosis (MS). In fact, researchers found that MS risk was about 30% higher for people living in cities. On the flip side, people living in rural areas, where air pollution is lower, were found to have reduced MS risk. (Another reason to move to the countryside, it seems.)
The study included more than 900 patients with MS in the Lombardy region of Italy, where MS rates were found to have increased 10-fold in the last 50 years. And, it was done in winter, when pollutant concentrations are at their highest in this region. The researchers compared three different areas in the region based on “urbanization” level. In two areas, air pollution levels were higher than the European Commission’s threshold. People living in these areas had a 29% higher risk for MS onset. The researchers are now conducting specific analytical studies in the higher risk areas to pinpoint the exact environmental factors that may explain the uptick in MS risk. While environmental factors like vitamin D and smoking habits have been thoroughly studied in relation to MS, few studies have focused on air pollution’s link to the disease. Since the number of people living with MS globally is growing, this ongoing research could provide valuable insight into new therapeutic approaches.
What bizarre neurological condition is characterized by the involuntary actions of a rogue limb?
Anyone else think of “Thing,” the disembodied hand from The Addams Family? Well, we don’t blame you, considering that the answer is alien hand syndrome (AHS). In people with AHS, the affected limb—usually the hand (but sometimes the leg)—feels foreign. It’s not under the control of the mind and will act of its own free will, deliberately moving to perform unintentional tasks. The most common causes of AHS include anterior cerebral artery strokes, midline tumors, and neurodegenerative illnesses. There’s no cure for AHS, but successful management strategies include botulinum toxin injections, clonazepam, cognitive behavioral therapy, distracting the affected hand, and visuospatial coaching techniques.
Look to your pearly whites for ALS. We touched on the gut microbiome’s link to amyotrophic lateral sclerosis (ALS). Now, let’s turn our attention to diagnosis—specifically, how to catch it early. Mount Sinai scientists have discovered an interesting biomarker for ALS—the teeth! Researchers have known that too much or too little essential elements (like zinc and copper) and toxins (such as lead and tin) are implicated in ALS development, but they haven’t known the age when metal dysregulation occurs. So, to find out whether metal uptake is dysregulated during childhood in ALS, the researchers turned to teeth. They carried out a study using teeth from autopsies or dental extractions from 36 patients with ALS and 31 controls.
Using lasers to map growth rings that form daily in teeth, the scientists found that patients with ALS do indeed metabolize metals differently than those without ALS during childhood and adolescence. Metal levels were higher in those with ALS vs controls: 1.49 times for chromium (at 15 years), 1.82 times for manganese (at birth), 1.65 times for nickel (at 8 years), 2.46 times for tin (at 2 years), and 2.46 times for zinc (at 6 years). Similar findings were confirmed in tooth biomarkers of an ALS mouse model. This is the first study to show a clear ALS signature in early life—decades before clinical signs and symptoms of ALS manifest, which usually occurs in people’s 50s and 60s. Since there’s no test to predict ALS onset, these findings can be a game changer. The researchers’ long-term goal—after validating the results in larger studies, of course—is to look at biological pathways that could be modified with drug development.
Blood test for progressive MS. Researchers have created a new, noninvasive blood test that could help predict which patients with multiple sclerosis (MS) will get worse over the following year. The blood test homes in on the biomarker neurofilament light chain—a nerve protein that can be easily picked up when nerve cells die. To do this, the researchers carried out a study in nearly 4,400 people with MS and over 1,000 age- and sex-matched controls. Neurofilament light chain blood biomarker levels were tested in all participants, who were followed for MS progression over the following year and for increased disability over a total of 5 years. They also looked at which patients developed secondary progressive MS.
Overall, people with MS had, on average, about 52% more pg/mL of the nerve protein in their blood vs controls. Those with the disease and high levels of neurofilament light chain were also 40% to 70% more likely to have worsening disability during the following year vs those with lower protein levels. And these findings were adjusted for confounding factors. But, it’s important to note that high protein levels were not consistently linked to greater risk for more significant disability, which was defined as needing a cane or crutch to walk 100 m, or with the risk of secondary progressive MS onset. Regardless, elevated neurofilament light chain blood biomarker levels caught early in the disease course could help clinicians predict how MS will develop and monitor treatment efficacy. And with such an unpredictable disease like MS, this could be extremely valuable and make all the difference in terms of quality of life and survival outcomes. More research is needed for validation before a blood test becomes available for routine clinical use, but the findings are promising.
MRI-glucose measure for AD. Sugar on the brain is never a good thing. But what about sugar in the brain? Researchers have created a new, noninvasive molecular imaging technique using MRI to dynamically measure glucose level changes in the brain’s lymphatic system—aka the glymphatic system. The findings from their preclinical study may help in the early identification and treatment of Alzheimer disease (AD). Previous studies have shown that abnormal glucose uptake and clearance in the glymphatic system are key features of early AD. This system allows CSF to flow through brain tissue and clear glucose and protein waste from the brain. Glucose uptake and metabolism can be assessed using PET scans, but they’re usually costly and invasive. Plus, patients can’t be scanned too often due to radioactive tracers. So, researchers began looking for a better alternative. In doing so, they created a new imaging approach based on Chemical Exchange Saturation Transfer MRI (CEST MRI), which has been used to diagnose brain tumors in the past.
They injected glucose into genetically modified mice with AD and healthy age-matched mice (6 and 16 months). Then, they used their modified CEST MRI approach to noninvasively and simultaneously measure the dynamic response of glucose, both in the CSF and brain parenchyma, in the mice’s glymphatic system—the first time that the imaging technique has been used in such a way. They found that mice with AD had significantly slower CSF clearance rates than age-matched control mice—a finding consistent with previous neuropathological studies. Six-month-old mice with AD also had much higher glucose uptake in the brain parenchyma than age-matched controls. And 16-month-old mice with AD had much lower glucose uptake in the brain parenchyma and CSF vs age-matched controls—findings that are also in line with previous research. The researchers say that these findings, in which glucose is used as a “tracer,” may serve as defining features to distinguish AD from normal aging. Even better, since glucose is natural, biodegradable, and commonly used in hospitals, it makes for a safe, noninvasive, and relatively inexpensive MRI contrasting agent.
Ultrasound for brain disorders. A new study is making “waves” in the neuroscience community. Biomedical engineers have discovered that ultrasound treatment may be an effective alternative to prescription drugs and even surgery for a range of neuro disorders—including depression, anxiety, epilepsy, and chronic pain. What makes this so appealing is that the precision therapy is noninvasive, targeted, and patient-tailored. Plus, it could eliminate the need for drug “cocktails” for some individuals. It might sound too good to be true, but we assure you that the treatment is very real. The ultrasound treatment involves emitting pulses of sound at high but inaudible frequency into a patient’s brain using an ultrasonic transducer, which is like a wand used for ultrasound scans. The sound pulses home in on neural brain circuits and cause neuronal membranes to oscillate—triggering neurons and affecting the behavior those neurons are responsible for. The best part? There’s no pain or discomfort, and no surgery is required.
To test the therapy, the engineers emitted ultrasonic waves into the brains of monkeys. With the proper frequencies and neuronal targeting, the engineers were able to control whether the monkeys looked left or right. One of the main takeaways from the experiment was just how powerful ultrasound can be—up to the point of controlling behavior, which is exactly what the researchers were hoping for. Think about how this might help reduce tremors in patients with Parkinson disease or seizures in those with epilepsy. The possibilities are endless. The engineers have built a prototype device for ultrasound therapy, with plans to begin clinical trials in humans with major depression in the next few years.
New hope for dementia. A new study shows that the lowest dose of hydromethylthionine (8 mg/d)—(your guess is as good as ours on pronunciation)—could slow clinical decline and brain atrophy in behavioral variant fronto-temporal dementia (bvFTD) and Alzheimer disease (AD). It’s the first report of a drug that has pharmacological activity against clinical decline and brain atrophy in bvFTD. Hydromethylthionine blocks pathological aggregation of tau and TDP-43 proteins. The drug is in development for AD but has also shown remarkable therapeutic value for bvFTD, setting it as a potentially important new avenue for the treatment of neurodegenerative diseases. Researchers performed a 52-week, global, phase 3 study in 200 patients with bvFTD who had clinically confirmed evidence of brain atrophy. Patients were randomized to receive either 200-mg/d or 8 -mg/d hydromethylthionine. The principal endpoints were change on the Addenbrookes Cognitive Examination – Revised, the Functional Activities Questionnaire, and whole brain volume. Using a discriminatory plasma assay, the researchers also undertook a population pharmacokinetic exposure-response analysis in 175 of the patients with available blood samples and outcome data.
Surprisingly, the results showed no significant differences between the high and low doses. Hydromethylthionine 8 mg/d had statistically significant concentration-dependent effects on clinical decline and brain atrophy similar to those reported in a recent trial of the drug in AD. In the pharmacokinetic analysis, the researchers found that the effects of the 8-mg daily dose of hydromethylthionine were determined by the blood level. And most patients had high enough blood levels of the drug even at this low dose to reduce clinical decline and brain atrophy by about 50% over a year vs those with minimal blood levels. The 200-mg/d dose offered no additional benefit. Based on these findings, the researchers suggested that a dose of about 30 mg/day would be optimal for treating bvFTD and could further reduce the rate of disease progression. A confirmatory placebo-controlled trial is now in the works.
Neurostimulation device for OSA. Good news for your patients with obstructive sleep apnea (OSA): The FDA has approved an expanded age range for Inspire therapy to include patients aged 18-21 years with moderate to severe OSA who can’t use continuous positive airway pressure (CPAP). Inspire therapy was previously only approved for patients aged 22 years and older. It’s a fully implanted neurostimulation device—comprised of a small generator, sensing lead, and stimulation lead—that’s placed under the skin of the neck and chest during a same-day outpatient procedure. The device monitors breathing patterns and opens the patient’s airway so that they can breathe normally during sleep. Inspire therapy received FDA approval in 2014 based on the positive results from a phase 3 trial of efficacy and safety in 126 people with OSA. Using the device, patients showed a 68% reduction in apnea events, a 70% reduction in oxygen desaturation events, significant reductions in daytime sleepiness, and significant improvements in daytime functioning. Manufacturer Inspire Medical Systems plans to continue conducting research on specific OSA characteristics in children, including adolescents with Down syndrome.
New in Patient Management
The power of positivity. Are you a glass-half-full or glass-half-empty kind of person? Turns out, your state of mind could make all the difference when it comes to your health, including stroke. A new study shows that having positive health beliefs—particularly the belief that you can protect yourself from another stroke—is linked to lower blood pressure among stroke survivors, namely women. Researchers analyzed data from a randomized, controlled trial that included 552 stroke patients. They looked at the link between positive health beliefs and blood pressure reduction 1 year post-stroke. Before hospital discharge, stroke survivors were asked whether they agreed with the following statement: “I can protect myself against having a stroke.” More than 75% of participants agreed.
Following up with participants 1 year after discharge, the researchers found that those who believed they could protect themselves from having another stroke had a 5.6 mmHg greater reduction in blood pressure than those who did not—a clinically significant difference. On additional analysis, the researchers also found the female stroke survivors who held positive health beliefs were especially likely to have lower blood pressure a year later. But, this finding was not statistically significant in male patients. On average, female patients who didn’t believe they could protect themselves from another stroke had a slight increase in blood pressure. The study findings underscore the link between positive psychological states and better health outcomes. Plus, since a lot of adults have trouble controlling their blood pressure—even with lifestyle changes and medication—this research could help open up avenues for improvement strategies among stroke survivors.
Plant derivative for chronic pain. Researchers have shown that a legal but somewhat controversial plant derivative may be effective for treating chronic neuropathic pain. Can you guess what it is? If you said Cannabis hemp oil, kudos to you. What’s exciting is that this is the first study to assess the therapeutic value of legal hemp oil with low tetrahydrocannabinol (THC) levels (< 0.3%), making it an attractive, easily accessible, and relatively safe treatment for pain. Using a mouse model, researchers studied the efficacy of taking hemp oil extract from the whole Cannabis plant. In mice that were exposed to chronic postoperative neuropathic pain—equivalent to several years of chronic pain in humans—the hemp oil extract reduced mechanical pain sensitivity 10-fold. Best of all: This effect lasted for several hours. The authors acknowledged that some psychedelic episodes may occur even in Cannabis plants with low THC, and more research is needed to determine the effects of long-term hemp oil use. But, the study findings are still very promising.
The heart of chronic pain. Not to bring you down from the high (pun intended) of the last story, but it’s not all good news when it comes to chronic pain research. Case in point: A new study links chronic pain to major cardiac and cerebrovascular events (MACCEs). Researchers in Taiwan carried out a nationwide, population-based cohort study in over 17,000 adults with chronic pain and over 35,000 age- and sex-matched controls. They compared MACCEs occurring between the two groups via follow-up from 2001 until 2015. They found that participants with chronic pain had a higher prevalence of hypertension, diabetes, renal disease, and depression. After adjusting for these underlying comorbidities, the researchers noted that patients with chronic pain had a higher risk for MACCE than those without chronic pain, regardless of sex. But, those aged < 20 years had a greater risk for MACCEs. Participants taking opioids also had a higher risk for MACCEs than those who did not take opioids. The researchers suggested that patients with chronic pain may be at higher risk for MACCE due to included “reduced activity, disability, sleep disturbance, fatigue, and mood alterations such as anxiety and depression.” Because MACCE risk was higher in those aged < 20 years, early detection and intervention in this age group are key.
COVID-19: New neuro ethical guidelines. The American Academy of Neurology (AAN) has issued new ethical guidance for neuro specialists caring for patients during the COVID-19 pandemic. The AAN recommends that patients with chronic neurological illness requiring a doctor’s appointment in non-medical emergency situations be offered telehealth appointments to limit the spread of COVID-19. The AAN also noted that some neuro medications can weaken a person’s immune system, putting them at even greater risk of the infectious disease. Also, to prepare for the possibility of limited resources in the future, the AAN recommends that neurologists work with their patients to complete advance care planning documents. This will allow patients more control over the treatments they receive. The AAN’s position statement goes on to list criteria that should be considered when determining resource allocation in the event of a scarcity, emphasizing that decisions should be made based on need, benefit, and best medical evidence, while keeping in mind personal freedoms and the interest of the entire community. Ultimately, the main goal should be to maximize the number of lives saved, which could require some very tough decision-making.
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Upcoming Medical Meetings
Please note that, in the interests of containing the current COVID-19 pandemic, the following meeting has been canceled. Please contact this organization for details and specifics on refunds and rescheduling:
Innovations in Cerebrovascular Care 2020, in Cleveland, OH, June 4-5, 2020.
The following meeting has been changed to a virtual workshop:
American Headache Society (AHS) 62nd Annual Scientific Meeting, to be held in San Diego, CA, June 4-7, 2020, has been canceled and will be offered, in part, as a virtual platform on June 15. Please check the website for up-to-the-minute information.
The following meetings have been rescheduled:
Psychiatry 2020 Conference, to be held in Boston, MA, June 4-6, 2020, has been rescheduled for September 24-26, 2020, and will remain in Boston, MA.
Current Psychiatry/American Academy of Clinical Psychiatrists (AACP) 2020 Focus on Neuropsychiatry, to be held in Arlington, VA, June 5-6, 2020, has been rescheduled for August 12-14, 2020, and will be held in Washington, DC.