FDA halts trials for novel neuro therapeutic. Plus, a commercially available drug for cognitive impairment, and a new diagnostic measure for dementia

We’ve got a gut feeling that the future of neurology has got a whole lot to do with the microbiome. Recent research has uncovered links between the gut microbiome and the nervous system, and in this edition of NeuroBrief, we learn that those links may teach us something new about multiple sclerosis. Here’s a sneak peek at what else we’ve “gut” lined up: new research identifying genes that help zero in on Lewy body dementia; a dietary supplement for dementia; new links between antipsychotic drugs, obesity, and diabetes; and more. But no more bad puns. Promise.

Neuro Flashback

The bright ideas that led to the discovery of neuroplasticity go back to the early 1890s, when the “father of modern neuroscience,” Santiago Ramón y Cajal, described “neuronal plasticity” after recognizing that brains can change even after a person has reached adulthood. The term “neuroplasticity,” however, wasn’t coined by Ramon y Cajal, but by Polish neuroscientist Jerzy Konorski, who, in 1948, used the phrase to describe observed changes in neuronal structure. The phrase didn’t gain wide adoption until the 1960s, when we discovered that neurons could “reorganize” after a traumatic event. Further research found that stress (anyone feeling any of that lately?) can change not only the functions but also the structure of the brain itself. In the late 1990s, researchers discovered that stress can actually kill brain cells—although these conclusions are still not confirmed, thank goodness.

In the News

Another clog in the Alzheimer’s therapy pipeline. Drug developer Cortexyme recently had to put the brakes on its trials for atuzaginstat, a small-molecule novel virulence factor inhibitor, which aims to treat Alzheimer’s disease. The FDA placed a partial clinical hold on trials after a review of the current data identified adverse hepatic events. 

Atuzaginstat targets gingipains, or toxic proteases, which are produced by the bacteria Porphyromonas gingivalis. Gingipains have been found in 90% of patients with Alzheimer’s, and the Gram-negative bacteria has been shown to produce neurodegeneration in animal models. According to Cortexyme, the adverse hepatic events are concerning, but the effects appear to be reversible and there seems to be no risk of any long-term adverse effects. The clinical hold has forced the company to halt enrollment of any new participants in the open-label extension phase of the firm’s Phase 2/3 trial. Cortexyme hopes to get its trial back on track by working with the FDA on atuzaginstat’s development program.

Women hide their pain from male testers during clinical studies. Pain reporting is a crucial part of various clinical trials and studies. But what if those feelings of pain are confounded by variables we haven’t considered? According to new research, we may have been overlooking the fact that women report feeling less pain when tested by men than when tested by other women.

In the study, published in De Gruyter, investigators assigned 60 participants to four experimental conditions: males tested by male experimenters, males tested by female experimenters, females tested by male experimenters, and females tested by female experimenters. Participants were required to complete the Pain Catastrophizing Scale, and were then tested for sensitivity to heat and blunt and sharp stimuli. Both the experimenter’s sex and the participant’s pain catastrophising score influenced self-reported pain levels, especially in females. Significantly higher pain catastrophizing scores were associated with greater temporal summation of pain to high-frequency electrical stimulation, and with lower pressure-pain thresholds in females who were tested by male experimenters. The findings indicate that researchers—and physicians—should pay attention to psychosocial factors when interpreting pain responses. 

Study points to gut microbiome as possible source of MS. Multiple sclerosis affects the central nervous system, which has long led researchers to hypothesize that inflammatory molecules in the brain are responsible for this autoimmune disease. But the results of a new study suggest that the primary culprit may be found a little further south: the gut microbiome. 

Published in Science Immunology, the study found that two types of interleukin-17 (IL-17) molecules that regulate gut bacteria appear to be critical drivers of MS. While the CD4+ T helper cells that produce IL-17A and IL-17F have long been implicated in the development of the disease, scientists were uncertain whether the inflammatory functions of the T cells or the two cytokines played a leading role. For the new study, researchers used a mouse model to isolate these elements and found that the cytokines play an essential role in maintaining gut microbial balance, which, when disrupted, may lead to CNS autoimmune disorders like MS.

Sweet dreams. Now please answer a few math problems. When we dream, it feels like we’re in a different realm—which makes the findings of a new study rather surprising. Researchers have discovered that people who are deep in REM sleep can not only perceive questions from those who are awake, but they can also answer the questions, raising important questions about cognition, sleep disorders, and memory processing.

The new research, published in Current Biology, used a cohort of 36 people who attempted to have lucid dreams, a phenomenon in which a person becomes aware they’re dreaming without waking up. Researchers found that, during these dreams, participants were able to follow instructions, do simple math, answer yes-or-no questions, and tell the difference between different sensory stimuli, by responding with eye movements or by contracting facial muscles. Based on these findings, the researchers will conduct follow-up experiments to learn more about sleep and memory-storing processes, and how dreams can affect cognition while awake and sleeping. 

Neuro Trivia

Question: How many calories does the brain use per day?

Answer: Roughly 300 kcal, or 20% of our resting metabolic rate. No word on whether thinking about exercising burns more calories, but it probably can’t hurt.

Novel Diagnostics

Cognitive-cortical dysfunction? You can tell by the way they use their walk. Gait changes are common in people with neurodegenerative disorders, but new research indicates that these changes may be an underused diagnostic marker. A recently published study in Alzheimer’s & Dementia showed that high gait variability is a sign of cognitive‐cortical dysfunction, which could help physicians diagnose Alzheimer’s disease.

The study analyzed the gaits of 500 older adults with various kinds of cognitive impairment and dementia, alongside some healthy controls. By examining the rhythm, pace, variability, and postural control of the participant’s walking—combined with cognitive performance—researchers found that high gait variability was associated with lower cognitive performance and accurately discriminated AD from other neurodegenerative and cognitive conditions. The findings suggest that gait analysis could become an important tool in neurologists’ diagnostic tool belts.

Changes to brain and spinal fluid may indicate Alzheimer’s. When it comes to diagnosing Alzheimer’s, earlier is always better. That’s why we’re pumped about newly published data in the Journal of Alzheimer’s Disease, which reveals that Alzheimer’s patients with a specific gene variant tend to exhibit changes in the fluid around their brain and spinal cord. These changes are detectable years before symptoms present.

Investigators analyzed the cerebrospinal fluid of Alzheimer’s Disease Neuroimaging Institute research participants. Prior research had already established that people with more than one variant of the APOE4 gene have a greater than 10-fold risk of developing Alzheimer’s disease when compared with those with no variants. In the new study, researchers found protein level variations in the cerebrospinal fluid from people with an increasing number of APOE4 gene variant copies; those with more APOE4 copies had lower levels of C-reactive protein circulating in their cerebrospinal fluid, even prior to developing cognitive impairment. The findings suggest that this protein may be involved in the kind of synapse damage which ultimately leads to Alzheimer’s.

Lewy body dementia may depend on five newly identified genes. Lewy body dementia is rough. Patients can experience hallucinations, mood swings, and problems with thinking, movements, and sleep. Their life expectancy typically falls within 8 years of diagnosis, and there are currently no effective treatments. But the outlook for patients with Lewy body dementia may be getting brighter, after a new study identified five genes that may play a critical role in determining whether a person will suffer from the condition.

The study, published in Nature Genetics, looked at the chromosomal DNA sequences of almost 3,000 Lewy body dementia patients and compared them to nearly 5,000 controls. Researchers found that sequences of five genes in the Lewy body patients were different from those in the control group: BIN1 and TMEM175 (which may also have ties to Alzheimer’s and Parkinson’s diseases), and SNCA, APOE, and GBA. Further analysis of one of the genes, GBA, revealed that its mutated variant may have a particularly strong influence on the disease. Researchers hope that the findings provide a step forward in our understanding of Lewy body disease and may even help in development of a first-of-its-kind treatment. 

Antibodies provide key to unlocking MS biomarkers. In patients with optic neuritis, inflammatory damage to the optic nerve sends visual signals to the brain, resulting in difficult symptoms like pain with eye movement and temporary vision loss. What’s worse, while not everyone with optic neuritis will develop multiple sclerosis, about one-fifth of MS patients experience optic neuritis as their first symptom. Now, according to a new study, researchers have found two biomarkers that appear to predict the development of MS in patients with optic neuritis.

In the study, published in EBioMedicine, investigators analyzed antibodies that are released by immune cells in patients with optic neuritis, resulting in myelin damage. Using a technology known as mimotope variation analysis, they found the molecular targets of these antibodies in several cohorts of patients with optic neuritis. Next, researchers were able to identify two epitope biomarkers, which can be used to distinguish those with optic neuritis from those with optic neuritis that will eventually lead to MS. While further research is required to validate the findings, these biomarkers could lead to earlier intervention for future MS patients. 

Novel Treatments

A dietary supplement to…prevent Alzheimer’s? While there are plenty of lifestyle changes we can all make to lower our risk of developing Alzheimer’s or cognitive impairment, effective treatments for the condition are all but impossible to find––because they don’t exist. But new research suggests that a dietary supplement may offer hope as a novel strategy for the treatment or prevention of cognitive impairment and neurodegenerative diseases such as Alzheimer’s disease.

The study, published in Neurochemistry International, used mouse models to demonstrate that the glutathione precursor γ-glutamylcysteine (γ-GC) can reduce oxidative stress, neuroinflammation, and amyloid pathology in the brain. γ-GC supplementation also appeared to result in significant cognitive improvements, which was tested using the Morris water maze. The findings suggest that γ-GC, which is commercially available, could be an effective glutathione-elevating strategy to prevent, or even treat, Alzheimer’s in humans.

Bringing the heat to treat Huntington’s disease. Huntington’s disease is characterized by a faulty protein that clusters in brain cells, eventually killing the cells. In theory, these clusters could be stopped with heat shock proteins, but the interactions between these two proteins is not well-understood in the real world. Recently published research, however, has produced new insight into the structures of heat shock proteins, bringing us a step closer to using them to treat Huntington’s disease.

Heat shock proteins are produced by cells exposed to stressful situations, and come in many classes. The research, published in Nature Communications, looked at the protein DnaJB8, which is in the class of Hsp40—a class of heat shock proteins that work to suppress protein aggregates like those present in Huntington’s disease. Using solid-state NMR spectroscopy, researchers were able to partially resolve the structure of this protein, which allows scientists to understand how its mechanisms work. DnaJB8 is typically found in the testes, but researchers may be able to find ways to enhance the activity of DnaJB6—a similar protein found in the brain—which could lead to effective treatments for Huntington’s disease.

Terazosin, doxazosin, and alfuzosin may help fight Parkinson’s. Parkinson’s disease affects an estimated 10 million people worldwide––and none of them have access to neuroprotective treatments that can help cure the disease, because none have been found to work in clinical trials. But good news could be looming: The findings of a new study indicate that the answer may be found in terazosin, doxazosin, and alfuzosin.

The study, published in JAMA Neurology, was based on the recent discovery that these drugs enhance glycolysis and appear to reduce Parkinson’s progression in animal models. Researchers used data from nationwide health registries in Denmark, which included patient data collected between 1996-2017. The cohort of more than 52,000 patients included men without Parkinson’s who had started terazosin, doxazosin, or alfuzosin therapy, as well as those who had started tamsulosin therapy, which is also used to treat benign prostatic hyperplasia or unspecified urinary problems, but does not enhance glycolysis. Researchers found that those taking terazosin/doxazosin/alfuzosin were at a far lower risk of developing Parkinson’s than those taking tamsulosin. While further work is needed to assess the association, the findings suggest that glycolysis-enhancing drugs could serve as a protective measure against Parkinson’s.

A big cash injection for neuroregenerative therapies. One of the characteristics of multiple sclerosis is the loss of myelin in the brain. As MS progresses, patients lose their remyelination capabilities, which results in disruptions to nerve signals and, ultimately, nerve damage and chronic disability. There are currently no available therapies that can restore myelin, but this may be about to change. Pipeline Therapeutics recently announced that it’s raised $80 million to pursue therapies that restore myelin.

According to a press release from the company, the money will be funneled into the research and development of several neuroregenerative product candidate therapies, three of which are aimed at promoting and restoring neuronal health. Among them is PIPE-307, a muscarinic receptor type 1 antagonist that the company hopes will help patients regrow myelin. The big idea? Researchers hypothesize that the drug will stimulate oligodendrocyte progenitor cells to grow into mature, myelin-producing oligodendrocyte cells. The firm recently launched a phase 1 clinical trial to assess PIPE-307’s safety and tolerability. The trial will involve 72 individuals and has not yet started recruitment. 

New in Patient Management

Epileptic seizures may not be as random as we thought. Up until recently, it’s been broadly held that epileptic seizures are entirely random events. But a growing body of research suggests that seizures may, in fact, be linked to cyclical patterns of brain activity. A newly published study has uncovered new evidence for this hypothesis by using long-term recordings of brain activity to establish patterns in seizure cycles over periods spanning from hours to years. 

The study, published in JAMA Neurology, analyzed data from 222 adults with medically refractory focal epilepsy. Each patient was implanted with a device to record their brain activity. Researchers found that the prevalence of circadian (24 hours) seizure cycles was 89%, the prevalence of multi-day (between a week and a month) seizure cycles was 60%, and the prevalence of circannual (yearly) seizure cycles was 12%. The findings suggest it could be possible to predict periods of particularly high risk for seizures, which could help doctors in monitoring, diagnosing, and treating epileptic patients. 

Study shows why antipsychotic drugs help pack on the pounds. Patients who take antipsychotic drugs to deal with conditions like schizophrenia or bipolar disorder tend to gain weight and are at a much higher risk of developing diabetes. For years, the reason for this has remained a mystery. Now, new research has found that these drugs don’t just block dopamine signaling in the brain, but also in the pancreas, which explains the high prevalence of obesity and diabetes in psychiatric patients. 

Antipsychotic medications (like clozapine, olanzapine and haloperidol) alleviate symptoms like hallucinations and delirium by blocking a subtype of dopaminergic receptors in the brain. The new research, published in Translational Psychiatry, found that alpha and beta cells in the pancreas can make their own dopamine, which controls the production of blood glucose-regulating hormones. The researchers concluded that antipsychotic drugs upset this balance, which leads to hyperinsulinemia, hyperglycemia and, over time, obesity and diabetes. The discovery could lead to the development of more effective drugs in the fields of neurology and psychiatry. 

Study illuminates links between headache and heartache. As if things weren’t bad enough for patients with migraine, new research has shed light on a troubling new association. The review found that patients with migraine may have higher total cholesterol and triglyceride concentrations than healthy patients with comparable BMI values, resulting in a higher risk of cardiovascular disease for migraineurs.

The review, published in Headache, looked at 17 studies involving both healthy controls and patients with migraine. All study participants reported levels of total cholesterol, triglyceride concentrations, serum low-density lipoprotein (LDL-C) or high-density lipoprotein cholesterol (HDL-C). Researchers found that patients with migraine had higher levels of total cholesterol across 14 of the studies, and significantly higher levels of triglyceride concentrations across 15 of the studies. They concluded that differences in cholesterol levels between those with migraine and healthy controls provide one explanation for the unfavorable cardiovascular profile of migraineurs. Further research is required to explore why migraine sufferers also have higher cholesterol levels.

Troubled heart leads to a troubled mind. At this point, we’re all aware of the importance of controlling cardiovascular risk factors to keep our hearts healthy for longer. But new research suggests that these same protective measures could be keeping our brains healthy too. According to a new study published in the Journal of the American College of Cardiology, links between cardiovascular disease and cognitive impairment begin years before initial clinical symptoms of either condition are observable, which suggests that early intervention could prevent dementia. 

In the study, researchers used advanced PET imaging to examine the brain metabolism of more than 500 participants with an average age of 50 years. These participants had no symptoms, but already had evidence of atherosclerosis. The findings showed that those with higher cardiovascular risk also tended to have lower brain metabolism in parietotemporal regions involved in spatial and semantic memory and various types of learning, which are the same areas affected with Alzheimer’s disease. Researchers concluded that atherosclerosis and cardiovascular risk factors are linked to increased risks of future development of dementia, and particularly Alzheimer’s disease. The key takeaway? A healthier lifestyle works wonders for hearts and minds.

Latest in Journal Summaries

Early predictors of 9-year disability in pediatric MS.

Elevated blood purine levels as a biomarker of seizures and epilepsy.

Apathy induced by subthalamic nucleus deep brain stimulation in Parkinson’s disease.

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Upcoming Medical Meetings

The following meeting is entirely virtual:

Headache Medicine & General Neurology Virtual CME Symposium. March 12-13, 2021.

The following meetings are scheduled to be entirely in-person:

2021 Congress of Neurological Surgeons (CNS) Annual Meeting. Austin, TX. October 16-20, 2021.

Neuroscience 2021: The Society for Neuroscience (SfN) Annual Meeting. Chicago, IL. November 13-17, 2021.

 

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