A ‘cocktail’ for Alzheimer’s, an asthma drug for a notorious neuro disorder, and your brain on migraines

Although the coronavirus has put the brakes on a number of clinical trials and life-changing drug launches, it still hasn’t stopped neuroscientists from gaining new understandings of the brain and its many disorders. For example, could a certain cocktail prevent Alzheimer disease? Could a common asthma drug help treat a notorious neurodegenerative disease? And could a dental analgesic be the key to fighting PTSD? Read this week’s NeuroBrief to discover the answers and other top stories.

Neuro Flashback

Parkinson disease (PD) is the most common neurodegenerative disease next to Alzheimer disease. Although the debilitating condition is named after London doctor James Parkinson—who first described it in a detailed medical essay in 1817—PD has been known since ancient times. In the Indian medical system of Ayurveda, it is referred to as Kampavata. And, in Western medical literature, it was described in 175 CE by the physician Galen as “shaking palsy.” Researchers aren’t sure what exactly causes PD, and there’s no definitive diagnostic test for it. While PD itself isn’t fatal, it can severely and negatively impact quality of life. Because there’s no cure for PD, clinicians and patients rely on a range of treatment options to manage symptoms, including medication, surgery, and lifestyle changes. But, scientific research into the neurological disorder has significantly advanced in recent years, offering new insights and possible therapeutic strategies that may one day help eliminate the disease.

In the News

Antioxidant cocktail for Alzheimer’s prevention. We previously reported on a study that showed that people who eat a diet rich in flavonols—a type of antioxidant found in nearly all fruits and vegetables, plus tea and wine—may be at lower risk for Alzheimer disease (AD) dementia. Now, a team of international researchers have discovered that a diet high in nutrients and antioxidants, along with an antioxidant combo cocktail, may be able to prevent or possibly reverse the effects of AD. They found that taking a combo of antioxidants at increasing doses had a greater beneficial effect on preventing AD than any other currently available treatment.

Why or how does this nutritional cocktail work? Previous studies have suggested that oxidative stress may be a major factor in AD development. Oxidative stress occurs as a result of an imbalance between free radicals and antioxidants in the body. The researchers suggested that antioxidants react with free radicals in the body to neutralize them. They looked at a broad range of antioxidants to figure out which ones were most effective for neuronal protection. In all, complex phenolic carotenoid, as well as antioxidants like vitamin C and vitamin E in high concentrations, were most effective at reducing AD risk. The researchers noted that while a nutrient-rich diet helped balance the pH levels in the body that caused oxidative stress, concurrent supplementation of an antioxidant combo cocktail, with tailored doses, was most effective at preventing and managing chronic disease. These findings highlight the clinical value of a holistic, personalized treatment approach to healthcare.

Brain malfunctions trigger migraine. Patients with migraine have shown increased cortical responses to sensory stimuli during the interictal period. But, the cellular mechanisms responsible for these changes have remained unknown. Luckily, a team of neuroscientists may have found the answer. They’ve discovered a new cellular mechanism involved in a form of migraine caused by genetic mutation. Specifically, they found that familial hemiplegic migraine type 2 (FHM2) causes a malfunction of astrocytes in the cingulate cortex— the brain region involved in feeling pain. Not only that, malfunction of the cingulate cortex was also found to affect migraine occurrence.

Using a murine model, the researchers showed that mice had increased sensitivity to head pain triggers. By manipulating astrocytes in the cingulate cortex, they were able to reverse their dysfunction, preventing increased head pain in mice with the genetic defect. Overall, the study findings show that astrocyte malfunction caused by genetic defects influence neuronal activity and sensitivity to head pain triggers. The research also sheds light on migraine pathophysiology and suggests that the cingulate cortex may be a key player in the disease. The neuroscientists speculated that the link between astrocyte dysfunction in the cingulate cortex and familial migraine could lead to new migraine treatment strategies.

Strange neuro condition could explain consciousness. The ability to see despite being completely blind sounds like something out of a comic book. But, it just so happens that the phenomenon, known as blindsight, is quite real. People with blindsight can’t physically see objects in front of them, but they have a subconscious “second sight” that allows them to safely maneuver around obstacles and identify items placed in front of them with a high degree of accuracy. The condition usually results from damage to the primary visual cortex—one of the brain regions responsible for vision. Damage to this area can result in either partial or total blindness. The prevailing theory is that the eyes receive light and then convert it into info that’s sent to the primary visual cortex. Because this area is damaged and can’t properly process info, it never makes it to conscious awareness. But, the info is still processed by other areas of the functional visual system, granting these folks their “second sight.” (Theoretically, at least. There’s still a lot of controversy on the mechanics of it all.)

For years, researchers have been baffled by blindsight and its connection to consciousness. Now, Henry Taylor, PhD, Department of Philosophy, University of Birmingham— whose research has so far focused on the intersection of philosophy of cognitive science, philosophy of mind, and metaphysics— is taking a deeper look at the science behind it all. His goal is to distinguish the vague concepts of “perception,” “consciousness,” and “sight,” to determine where in the brain consciousness begins and ends; and to define how consciousness differs in people with blindsight. Although Dr. Taylor’s research is still a work in progress, his insights could potentially lead to new tests for consciousness, as well as treatment strategies, down the road.

Four proteinopathies linked to neurodegeneration. Four common types of misfolded proteins—tau neurofibrillary tangles, amyloid-beta, alpha-synuclein, and transactive response DNA-binding protein 43 (TDP-43)—are often seen in the brains of older adults. But, few studies have looked at the phenotype of the coexistence of all four proteinopathies, dubbed “quadruple misfolded proteins” (QMP). Now, a new study shows that QMP is linked to dementia and impaired cognition in older adults. To better understand QMP, including the trajectories of global cognition, researchers used brain-autopsy data from 375 people who participated in a longitudinal community-based cohort study of aging and dementia. These individuals’ average age at death was 86.9 years, and most were women (61.9%) and white (96.8%).

The researchers found that 43.2% had two of the four misfolded proteins, 38.1% had three, and 12.3% had all four (the QMP group). The prevalence of dementia was highest in the QMP group (89.1%), followed by those with tau, amyloid-beta, and TDP-43 (81.7%); tau Braak stage V to VI and amyloid-beta (71.9%); and tau, amyloid-beta, and alpha-synuclein (61.1%). Interestingly, none of the 45 individuals with mild cognitive impairment had QMP. The average time spent in the MCI state was shortest in the QMP group, with researchers suggesting a more aggressive disease course for these people. Those in the QMP group also had the lowest final mean Mini-Mental State Examination score. The researchers noted that their findings may have significant clinical implications, as prevention and management strategies for Alzheimer disease dementia may be complicated by the unrecognized presence of multiple additional neuropathologies.

Brain connectivity in cannabis users. Regional brain activation and static connectivity in response to cannabis cravings have been previously studied in cannabis users, but fluctuations in brain network connectivity have not—until now. Researchers recently looked at the underlying brain networks in chronic cannabis users to determine patterns of brain connectivity when the users crave cannabis. Using functional MRI, they examined changes in dynamic connectivity in 54 adult cannabis users and 90 controls during a cannabis cue exposure task. Their study findings extend those from a 2009 study, led by the same senior author. That study shed light on the first evidence of underlying neural mechanisms during cravings of cannabis users. Specifically, the results showed that long-term users have increased neural response in reward-related brain regions when they have a cannabis craving, and the strength of the response is linked to the severity of cannabis-related problems.

The current study supports that brain regions don’t function in isolation. Instead, they perform through a chain of multiple brain networks that signal to each other depending on need and state. The researchers also found that brain connectivity during cannabis craving isn’t static. Rather, it has fluctuations in connection patterns between the central executive network and the nucleus accumbens—reward-related regions rich in dopamine. The new research also underscored the need to better understand the effect of these dynamic patterns in relation to cannabis use. Overall, the study shows that there are differences in large-scale brain network patterns in chronic cannabis users when there is craving. And these can be used as biomarkers of cannabis use disorder to help support the creation of better treatment strategies for cannabis dependence.

Neuro Trivia

The inheritance of what variation of the apolipoprotein E gene is the most prevalent genetic risk factor for Alzheimer disease?

If you read last week’s NeuroBrief, then the answer should be a piece of cake. It’s APOE4. According to the National Institute on Aging, APOE4 is the most common allele linked to increased Alzheimer disease (AD) risk and earlier age of disease onset. Here’s where it gets tricky, though: Because you inherit one APOE gene from your mom and one from your dad, you have two copies of the APOE gene. Having at least one APOE4 gene variant increases your risk of developing AD, and if you have two APOE4 genes, your risk is even higher. But, not everyone who has one or both gene variants develops the disease. In fact, the disease occurs in many people who don’t even have an APOE4 gene, meaning that the gene affects risk but not cause. Other genetic and environmental factors are likely involved in the development of AD.

Novel Diagnostics

Early clue to Alzheimer degeneration. Researchers may have gotten one step closer to pinpointing targets for brain degeneration that occur decades before symptoms of Alzheimer disease (AD) appear. They found that basal forebrain volume—specifically, cholinergic denervation—reliably predicts the cortical spread of AD degeneration. The discovery is generating quite the buzz, given that it could open the door to early treatment—the ultimate goal next to prevention.

In their study, researchers examined the basal forebrain, an area in the brain’s subcortical region that includes cholinergic neurons, which are often severely damaged as a result of AD. They used more than 835 samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to get indices of grey matter in the basal forebrain and entorhinal cortex—the brain region responsible for memory, navigation, and perception of time. They then measured the change in the entorhinal cortex over 2 years to determine if baseline volume in the basal forebrain predicted an entorhinal cortex change. To find out if the change was connected to biological AD, the researchers identified a group of individuals in the ADNI database with pTau and amyloid-β proteins. Using these biomarkers, they were able to confirm that the degeneration pattern from the basal forebrain to the entorhinal cortex was only linked to individuals who had abnormal pTau and amyloid-β proteins. Overall, findings showed that degeneratin in the basal forebrain can predict damage to other parts of the brain, specifically the entorhinal cortex. These findings could prove useful to clinicians in identifying early-stage AD. Looking at the bigger picture, the researchers speculated that cholinergic neurons could be new treatment targets for limiting the degeneration from the basal forebrain.

Novel system for multi-brain activity measurement. Using zebrafish, researchers have created a novel system for measuring multiple brain electrical signals concurrently, which could open the door to cheaper and faster drug testing for neuro disorders. Zebrafish share many disease-related genes with humans, so they’re great models for drug development. However, experimental methodologies using zebrafish have several shortcomings. For example, behavior monitoring can’t be used to accurately quantify zebrafish’s neurological responses. Techniques that can be used for more accurate quantification, like EEG, have been developed—but they can only be used in larval zebrafish or one adult fish at a time. So, to address this issue, researchers developed a system that makes it possible to take EEG measurements from multiple adult zebrafish concurrently. 

This system separates the drug delivery and fish holding units. Individual anesthetized fish are held in small plastic compartments, aka “fish fixers.” Drugs and water are sent directly into the mouth of the fish through small tubes at controlled rates. The electrical signals from the fish brains are recorded using flexible electrodes attached on the surface of the fish’s head. Because the drug delivery and fish fixing units are separate, no physical/environmental elements interfere with the EEG recording process and output. This makes it possible to produce simultaneous clear recordings of the biological effects of the drugs on all the fish in the fixing unit. The researchers tested their system by administering an epilepsy-inducing drug to fish that had and had not been given the anti-epileptic drug valproic acid beforehand. The EEG readings they received successfully mapped the changes in the fish’s brain signals during epileptic attacks, proving that their system could accurately measure valproic acid’s efficacy. They hope that their study will help accelerate the drug development process for currently intractable diseases.

Novel Treatments

An asthma drug for Alzheimer’s? A new, early-stage study shows that repurposing a common asthma drug, albuterol, may be a promising treatment for Alzheimer disease (AD). If validated in further clinical trials, the rapid-response drug could be a game-changer for AD patients everywhere. Researchers used a new automated “high throughput” screening approach to study the structure of the misfolding tau protein with an analytical technique called “Synchrotron Radiation Circular Dichroism.” With this technique, they were able to look at more than 80 existing compounds and drugs at the same time to determine their efficacy at preventing the formation of tau fibrils. They found that epinephrine was effective at stabilizing the tau proteins and preventing the formation of tau tangles. But, because epinephrine isn’t easily absorbed into the body and is rapidly metabolized, the researchers looked at a range of existing compounds with similar chemical structures. They found four possible drug candidates—ethamivan, fenoterol, dobutamine, and albuterol—with the winner being albuterol.

Albuterol was shown to inhibit tau aggregation in vitro. And tests where albuterol was added to solutions with tau resulted in significantly reduced density of fibrous tau structures responsible for the tau neurofibrillary tangles. The researchers speculated that albuterol interacts with an early stage of tau fibril formation and diminishes their ability to form an initial nucleus, which drives the aggregation process. But, there’s one catch to these promising findings: Because current asthma inhalers result in only a small amount of albuterol reaching the brain, a new delivery method would also need to be developed if further testing of albuterol for AD is successful. On the upside, because it’s easily ingested, absorbed into the brain, and remains in the body for a long time, albuterol makes for an attractive new treatment for AD. Plus, it also doesn’t hurt that it’s low-cost.

New Tx strategy for IDH-mutant gliomas. Gliomas with mutations in the isocitrate dehydrogenase (IDH) genes are the most common brain tumors in adults aged 18-45 years. Although these patients can benefit from aggressive surgery coupled with radiation and chemotherapy, the treatments are rarely curative. But, researchers have recently uncovered a promising new strategy to target these IDH-mutant gliomas and improve treatment. Previous research has shown that IDH-mutant gliomas have a metabolic weakness that makes them vulnerable to treatments that lower levels of NAD+, an important metabolic molecule commonly thought of as the “currency of metabolism” in cells.

Previous studies have also shown that chemo triggers an enzyme that stimulates NAD+ molecules to join together to make PAR, a key DNA damage signal, which is a known susceptibility in IDH-mutant gliomas. Activation of the enzyme by chemotherapy causes available NAD+ to be significantly depleted for the production of PAR in IDH-mutant glioma cells, but not normal cells. This suggests that maintaining high PAR levels and low NAD+ levels, along with chemo, may target IDH-mutant glioma cells. In light of these previous findings, researchers of the current study developed a new treatment strategy and tested it in tumor cells and animal models. They found combining temozolomide (the chemotherapy drug commonly used to treat patients with IDH-mutant gliomas) with a PAR glycohydrolase inhibitor (a drug that blocks PAR breakdown) to be most effective. Overall, this is the first study to show that PAR glycohydrolase inhibitors can be used to boost chemotherapy efficacy in tumors with metabolic weaknesses in the NAD+ pathway.

New drug for stroke-induced brain damage. Researchers from the University of Pittsburgh and the University of Arizona have created an experimental new drug that could help prevent brain damage after a stroke. Previously, researchers found that neurons can die because of potassium ions leaking out of a potassium channel called Kv2.1. This can be caused by interactions between the channel and a protein called syntaxin. The researchers found that they could prevent cell death by blocking that interaction with a compound called TAT-C1aB.

In this study, researchers discovered a potential way to use this finding to further reduce cell death after a stroke. They found that there are two types of Kv2.1 channels in the membrane of neurons. One of them helps extra Kv2.1 channels find their way into the cell. This, in turn, increases the amount of potassium lost and, as such, increases cell death. To combat this, the team created a small protein called TAT-DP-2, which keeps the new channels from passing into the cell, preventing potassium leaks and keeping the cells alive. In mice, the researchers found that the area of brain damage after a stroke was much smaller for animals that received TAT-DP-2 injections vs untreated mice. Treated mice also had better long-term neurological function. Further studies are needed to validate the drug’s viability and efficacy. Still, the study results are promising, and provide early evidence of drug targets that could help millions of patients in the future.

New in Patient Management

Opioid use among migraineurs. A troubling new study shows that more than one-third of patients with migraine are either current opioid users or keep opioids on hand to manage their migraines. Researchers looked at data from the Chronic Migraine Epidemiology and Outcomes study—a cross-sectional, longitudinal, Internet study—to compare the sociodemographics, clinical characteristics, and migraine burden/disability of opioid users with nonusers. Of the nearly 2,400 migraineurs who reported using prescription meds for acute treatment, 36.3% were either current opioid users or kept opioids on hand for headache treatment. Current opioid users had more comorbidities, greater headache-related burden, and worse quality of life compared with nonusers. Factors associated with opioid use included male sex, BMI, allodynia, increasing monthly headache frequency, Total Pain Index score (excluding head, face, neck/shoulder), anxiety, depression, at least one cardiovascular comorbidity, and emergency department/urgent care use for headache in the past 6 months. Physician-diagnosed migraine/chronic migraine was linked to significantly lower odds of opioid use. While this news certainly isn’t good, it is something to keep in mind when seeing your migraine patients.

Surprising short-term strategy for PTSD. Post-traumatic stress disorder (PTSD) is no laughing matter. Ironically, short-term relief for the disorder may come in the form of some very “funny” stuff: laughing gas. A new pilot study shows how one simple, inexpensive treatment involving nitrous oxide can quickly relieve symptoms of PTSD. If validated in further studies, nitrous oxide could lead to improved treatments for PTSD sufferers, particularly military vets.

Previous studies have suggested that laughing gas may be an effective therapy for treatment-resistant depression. In light of this, researchers wanted to test its effect on PTSD. For this small case series, three vets with PTSD were asked to inhale a single 1-hour dose of 50% nitrous oxide and 50% oxygen through a face mask. Within hours of doing so, two of the vets reported a significant improvement in their PTSD symptoms. This improvement lasted 1 week for one of the patients. The second patient’s symptoms gradually returned over the course of the week. The third patient reported an improvement 2 hours after his treatment but then began experiencing PTSD symptoms the next day. The researchers posited that, like other therapeutics, nitrous oxide may be effective for some patients but not for others, so further study of the treatment in a larger subset of patients is needed. But, still, the results are promising.

Use of alternative medicine in multiple sclerosis. Some interesting and useful new insight for clinicians: A new survey of more than 1,000 people with multiple sclerosis (MS) shows that the vast majority use complementary and alternative medicine (CAM), including cannabis. In 2001, researchers conducted a survey on the use of CAM in people with MS in Oregon and southwest Washington. In 2018, they sent out a revised survey in the same region to evaluate updated patterns of CAM use in patients with MS and to compare changes in the use, perceived benefit, and patterns of communication between participants and providers regarding CAM over the past 17 years.

They found that patients with MS surveyed in 2018 were nine times more likely to talk to their neurologist about CAM use, including cannabis, as treatment options than they were in 2001. Not only that, but 81% of MS patients reported using dietary supplements to help with disease management, 39% reported using mind-body therapies (like mindfulness and massages), 30% reported using marijuana for symptom treatment, and 81% used exercise to help manage symptoms. While it may be concerning that such a large proportion of MS patients are turning to CAM, it’s heartening to know that patients are more open to discussing their use of CAM with their clinicians—an important dialogue than can help prevent adverse interactions with conventional meds.

Latest in Journal Summaries

Ischemic stroke risk in patients with COVID-19 vs patients with influenza

Association between sedentary behavior and the risk of dementia

Correlations between COVID-19 and burden of dementia

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Upcoming Medical Meetings

The following meeting has been changed to a virtual workshop:

The Translational Neuroimmunology Conference: From Mechanisms to Therapeutics, Babson Park, MA, July 19-23, 2020

The following meeting has been rescheduled:

NeuroSafe 2020, to be held in Minneapolis, MN, July 23-24, 2020, has been rescheduled for July 29-30, 2021. Please check the website for up-to-the-minute information.

The following meeting has been rescheduled and changed to a virtual workshop:

Alzheimer’s Association International Conference (AAIC 2020), to be held in Amsterdam, Netherlands, July 26-30, 2020, has been rescheduled for July 27-31, 2020 and will now be held as a virtual forum. 

 

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