Common genetic disorder linked to debilitating neuro condition, new tech sees beyond brain disease, and cannabis for Parkinson’s

This week we bring positive research findings—a prostate enlargement drug that may be effective for Parkinson’s disease, another medication’s efficacy in children with relapsing-remitting multiple sclerosis, and a survey indicating that Parkinson’s patients are yearning to learn more about the therapeutic properties of a widely illegal drug. In this edition, you’ll also find new research on why men’s and women’s bodies react differently to the same neurological diseases, a new biomarker for Parkinson’s disease, and more.

Neuro Flashback

Today, nanotechnology occupies the frontier of neurological treatment development. In recent years, for example, neuroscientists have begun to explore the therapeutic applications of nanoparticles as drug-carriers due to their ability to cross the blood-brain barrier. But the ideas behind this have been a long time coming and can be initially traced back to a lecture that occurred more than 6 decades ago. The talk was given by physicist Richard Feynman a full decade before the term “nanotechnology” was coined by Professor Norio Taniguchi in his work exploring ultraprecision machining. And it wasn’t until 1981 that the development of the scanning tunneling microscope allowed scientists to look at individual atoms, which marks the true beginning of modern nanotech. Thank goodness for these giants, whose shoulders we stand upon today.

In the News

One step closer to telepathy. Sort of. Brain injuries and brain disease can leave a patient unable to communicate, but researchers at Washington University School of Medicine in St. Louis may have found a way to circumvent this disastrous outcome. According to a new study, LED light can be used to detect activity in the area of the brain responsible for visual processing. By decoding these brain signals, it’s possible to determine what the person is seeing

The study, published in NeuroImage, involved high-density diffuse optical tomography (HD-DOT)—a noninvasive, wearable, light-based brain imaging technology. When neuronal activity increases, that region of the brain is flooded with oxygenated blood. HD-DOT beamed light inside the head to detect these rushes of blood. Researchers then decoded the resulting data using a detailed map previously created by neuroscientists of the visual part of the brain. The findings, though limited, show that HD-DOT is sensitive and precise enough to be potentially useful in situations where other imaging methods are less applicable—like facilitating communication for people who struggle to express themselves because of cerebral palsy, stroke, or other conditions that result in locked-in syndrome.

Hormones play a key role in brain health. A mounting body of evidence illustrates the countless ways that men’s and women’s bodies react differently to the same diseases, but researchers are only beginning to understand why this is the case. Now, new research has found that hormones are one of the keys to understanding brain health differences between men and women.

The studies, which were led by Lisa Mosconi, PhD, director of the Women’s Brain Initiative at Weill Cornell Medicine in New York, sought to examine why women are more likely to be diagnosed with the likes of dementia and depression, as well as stroke and autoimmune disorders such as multiple sclerosis. Researchers found that hormones—testosterone in men and estrogen in women—play a key role in brain health. For example, one of the studies, published in Brain Communications, found that women who experienced menopause later in life were better protected against progressive forms of multiple sclerosis. The study’s findings also suggest that the more pregnancies a woman has, the less her disease progressed, suggesting that the flood of estrogen during pregnancy increased protection. While Mosconi noted that findings like these don’t mean that hormones are the only factor at play, the studies suggest that they play a significant role. 

Why we ought to pay attention to defective mitochondria. While studies have identified hundreds of mutations associated with autism spectrum disorder, it’s still unclear how these genetic changes actually lead to the condition. Recent research conducted at Children’s Hospital of Philadelphia, however, has demonstrated that the disorder may be caused by defects in the mitochondria of brain cells. 

The study, published in the Proceedings of the National Academy of Sciences, began with the hypothesis that if defects in the mitochondria predispose patients to autism, then a mouse model with relevant mtDNA mutations should exhibit autism endophenotypes. For this model, these traits included behavioral, neurophysiological, and biochemical features. Researchers found that the mouse indeed demonstrated impaired social interactions, increased repetitive behaviors, and anxiety, all of which are common behavioral features associated with autism spectrum disorder. They also found that the mouse had more seizures and other brain-region specific defects on mitochondrial function, but there was no obvious change in brain anatomy. The findings suggest that analyzing mitochondrial function could be a better way to diagnose and treat autism.

How do you solve a problem like football concussions? There may be no bigger concern in the world of professional football than the long-term neurologic health problems from repetitive head impact exposure (HIE) and concussion. In looking at this issue, a recent study arrived at a surprising finding: Concussion incidence and HIE among college football players are disproportionately higher in the preseason than in the regular season, and most concussions and HIE occur during football practices, not games. This, the researchers hope, may provide an opportunity to decrease concussion rates in the sport. 

The study, published in JAMA Neurology, followed 658 collegiate football players between 2015-2019 who were monitored using the Head Impact Telemetry (HIT) System. During five seasons, 528,684 head impacts were recorded across the cohort, with 68 players sustaining a diagnosed concussion. Researchers found that 48.5% of these concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Over five seasons, 72% of concussions and 66.9% of HIE were found to have occurred during practice. The researchers concluded that these findings point to areas where public policy, education, and other prevention strategies could be implemented to protect the health and safety of collegiate football players. When it comes to concussion and HIE, practice makes less than perfect.

Neuro Trivia

Has there ever been a brain heist?

Yes! In 2014, a 21-year-old man in Indiana was arrested after stealing 60 jars of human tissue, including brain tissue, from the Indiana Medical History Museum. The thief sold the brains to an intermediary, who then put them up for sale on eBay.

Novel Diagnostics

Likelihood of dementia in men linked to world’s most common genetic disorder. Hemochromatosis, known as the “Celtic curse,” is a genetic disorder that causes a build-up of iron in the body. It’s the world’s most common genetic disorder—an estimated 175,000 males of European ancestry in the United Kingdom have the two faulty genes that cause it. While the disorder is easy to treat, past research has shown that the condition is associated with an increased likelihood of developing liver cancer, arthritis, and frailty. And now, new research has found that men who have haemochromatosis may be more likely to develop dementia compared with those who don’t have the faulty genes.

The new study, published in the Journal of Alzheimer’s Disease, looked at 2,890 men and women, aged 40-70 years, with two faulty hemochromatosis genes—called HFE C282Y homozygous—using data from the UK Biobank. The researchers found that 25 of the 1,294 men with the two faulty genes went on to develop dementia—83% more than the group without the faulty genes. In addition, the analysis using MRI scans showed that a build-up of iron in key areas of the brain was linked to dementia in a subset of men with the faulty genes. Researchers hope that the findings will encourage more screenings for haemochromatosis.

For Parkinson’s, round up the usual genetic suspects. Genome studies on patients with Parkinson’s disease have led to the discovery of certain genetic areas associated with increased risk of disease, but the underlying genes and mechanisms at play have yet to be established. A new study published in JAMA Neurology has taken a step in that direction by using genome-wide association data and brain-derived gene regulation data collected from complementary bioinformatic tools to identify 11 candidate genes with evidence of disease-associated regulatory changes.

Researchers used two bioinformatic analysis tools—Coloc, and transcriptome-wide association studies (GWAS)—to integrate Parkinson’s case-control GWAS data published in 2017. Expression data came from multiple sources, and methylation data came from UK Parkinson’s brain samples. Researchers were able to uncover putative gene expression and splicing mechanisms associated with Parkinson’s genome-wide association study signals. These candidate genes were then further characterized using cell-type specificity, weighted gene co-expression networks, and weighted protein–protein interaction networks. The findings suggest some good news: Gene regulation data may be used to identify more candidate genes and pathways involved in sporadic Parkinson’s disease, leading us to better diagnosis and treatment.

Could genetic changes be responsible for cerebral palsy? It’s long been established that certain neurological disorders are caused by genetic changes. Recently, researchers discovered a strong link between those changes and cerebral palsy.

The study, published in JAMA Network, looked at the DNA sequence of 1,526 children and adults with cerebral palsy. Researchers found disease-causing changes in 229 genes, several of which were previously identified in patients with both cerebral palsy and other neurodevelopmental disorders. These changes were found in 32.7% of a primarily pediatric cohort of patients from one investigator, GeneDx Inc., and in 10.5% of a primarily adult cohort from Geisinger. The findings of the study build on other recent studies indicating that birth asphyxia accounts for less than 10% of cases of cerebral palsy, correcting an oft-cited attribution for the disorder. Researchers believe the findings reaffirm that DNA sequencing should be a first-tier clinical diagnostic tool for patients with neurodevelopmental disorders, which are known to co-occur with cerebral palsy.

For signs of cognitive decline, look to the gut. As new data continues to emerge, it appears that our guts and brains are quite the friendly pair. Recent research has shown that chronic constipation is often among the earliest signs of Parkinson’s disease, and that hepatitis C increases the risk of Parkinson’s as well. A new study has found a possible new concern to add to the list. According to a recently published analysis, changes in the gut microbiome may alter bile acid production by favoring synthesis of toxic forms of the acids, which appears to be a viable biomarker for diagnosing Parkinson’s early and tracking its progression.

The study, published in Metabolites, sought to determine whether the appendix microbiome is altered in Parkinson’s patients and to examine the biological consequences of these alterations. Researchers found an increase in hydrophobic and secondary bile acids, deoxycholic acid, and lithocholic acid in patients with Parkinson’s vs the control group. The findings not only suggest that bile acids could be a biomarker for Parkinson’s, but also point to possible new therapies that impede Parkinson’s-related changes in the gut to slow or even stop disease onset and progression. That’s why you should always trust your gut. 

Novel Treatments

For RRMS, a new drug contender emerges. Multiple sclerosis impacts an estimated 10,000 children worldwide, and most of those patients have relapsing-remitting multiple sclerosis (RRMS). But a new study brings hope for these kids. According to 2.5 years of data from the FOCUS phase 2 trial and an extension study, long-term treatment with dimethyl fumarate can safely and effectively reduce the frequency of relapses in children with RRMS.

The findings, published in Frontiers in Neurology, addressed a data gap on disease-modifying therapies for the pediatric population, which has resulted in a shortage of approved MS-specific treatment options for children. Researchers focused on dimethyl fumarate, an oral DMT approved to treat relapsing MS, which works by lowering inflammation and oxidative stress. They tested the drug’s safety, pharmacokinetics, and effectiveness in 22 pediatric RRMS patients aged 13 to 17 years. The study found that 20 participants who completed the 6-month treatment exhibited a significantly reduced number of new or enlarging brain lesions. Its safety and pharmacokinetics profiles were also consistent with those observed in adult patients. An ongoing phase 3 trial is looking to expand on this by studying the safety and effectiveness of dimethyl fumarate in 156 MS patients, aged 10 to 17 years. Stay tuned for results.

FDA gives OK to peginterferon beta-1a injections for MS. Peginterferon beta-1a, a disease-modifying drug for RRMS, was approved in its original subcutaneous formulation in the United States and Europe in 2014, and it is currently marketed in more than 60 countries. Now, both the FDA and the European Commission have approved an injection formulation of the drug that can be injected directly into muscle, much like a flu shot. 

The drug’s active component—Interferon beta-1a—is a signaling molecule that acts to regulate the activity of the immune system. It works by modulating immune activity, which reduces the inflammation that causes nervous system damage. Biogen, the drug’s developer, has stated that treatment via intramuscular injection is just as effective as the currently subcutaneous injection formulation, and that it lowers the likelihood of injection site reactions by roughly half. According to the drug’s prescribing information, the intramuscular formulation will be available as an injection delivered by a single-dose prefilled syringe. An injection is still an injection, but an intramuscular injection is certainly the lesser of the evils.

Mental disorders treated while you wait. Roughly one-third of patients with major depression don’t respond to any kind of treatment, and the same can be said for many millions who live with conditions like addiction and chronic pain. But soon-to-be-published research has found a possible route to new therapies for a whole host of neurological and mental disorders: personalized deep brain stimulation.

The research, which will be published in Nature Biomedical Engineering, focused on finding a way to predict what effect electrical stimulation will have on an individual’s brain activity across multiple brain regions. To achieve this, they designed a novel electrical stimulation wave to map brain activity, along with a machine-learning tool that learns the map from brain data collected during stimulation. The basic idea is that the wave can be applied to anyone’s brain, providing a personalized map of how it responds to stimulation. Researchers applied their wave on four different regions of the brain and, in each case, were able to successfully predict the outcome of stimulation on brain activity across multiple regions for the first time. The findings suggest that in the not-so-distant future, patients may be able to receive personalized “doses” of deep brain stimulation for a host of neurological and mental health maladies. 

For Parkinson’s, take…a prostate drug? Terazosin is a drug used to treat enlarged prostate, but past clinical research has shown that it also enhances cellular energy levels and can prevent or slow the progression of Parkinson’s disease in animal models. Now, a new study has shown that the drug is associated with a reduced risk of developing Parkinson’s disease in humans, too.

The study, published in JAMA Neurology, used data on almost 300,000 older men from two large, independent patient datasets—the Truven Health Analytics MarketScan database in the United States and national health registries in Denmark. Researchers identified 150,000 men newly started on terazosin or similar medications and matched them, based on age and clinical history, to 150,000 men newly started on tamsulosin—a similar prostate drug that has no effect on cellular energy production. They found that those taking terazosin were 12% to 37% less likely to develop Parkinson’s disease during follow-up than men taking tamsulosin. Further studies are required, but the findings suggest that drugs like terazosin could potentially provide neuroprotection for Parkinson’s—and for prostate enlargement, of course.

New in Patient Management

It’s not about Mars or Venus—it’s about a protein called AKT. Treating mental illness is tough, and the pursuit is confounded by the fact that men and women experience these conditions differently. But a new study sheds light on why sex differences exist in mental illnesses and why some drugs work for some and not for others: A key protein in the brain called AKT may function differently in males than in females. 

AKT was discovered in the 1970s and is best known for its roles in causing cancer when mutated and in promoting synaptic plasticity. Its mutations have also been linked to various neurological disorders, from schizophrenia to post-traumatic stress disorder and Alzheimer’s. The new study, published in the journal eLIfe, looked at the behaviors of single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice. They found AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. Their results highlight sex as a biological variable and suggest that isoform- or cell type-specific AKT signaling could be potential targets for developing improved treatment for neuropsychiatric disorders.

Attitudes toward medical cannabis for Parkinson’s are turning around. During the past decade, cannabis has been approved for medicinal use all over the globe, with Germany approving the drug for use as a medical treatment in 2017. But while German Parkinson’s disease (PD) patients can now obtain medicinal marijuana via prescription, it remained unknown whether patients knew much about cannabis, and how they felt about it as a treatment for PD—until now. According to a new survey, a majority of Parkinson’s patients in Germany who don’t currently use cannabis as a treatment are interested in exploring its potential.

The survey, published in the Journal of Parkinson’s Disease, involved a nationwide questionnaire used to assess general knowledge and interest in medicinal cannabis (MC), as well as the frequency, modalities, efficacy, and tolerability of application. Researchers received 1,348 responses. They found that 51% of respondents were aware of the legality of MC, 28% knew of the different ways to take it, and just 9% knew the difference between THC and CBD. The survey showed that 8.4% of Parkinson’s patients use MC, and these tend to be younger people who live in cities and have a far greater knowledge of the legal and clinical aspects of the drug. Of those MC users, 40% reported a reduction of pain symptoms, and more than 20% reported improvements in symptoms like stiffness, tremor, depression, anxiety, and restless legs syndrome. This high level of interest, along with positive results from users, suggest cannabis may be an easy way for physicians to improve patient satisfaction.

A bout of gout may be good news if you’re worried about dementia. Gout, a form of arthritis which causes intense pain and swelling around joints, can be a debilitating condition, but new research suggests there may be a plus side. According to a recently published paper, gout appears to be independently associated with a significantly lower hazard ratio of incident dementia in multivariable analyses, with an adjusted hazard ratio of 0.63. 

The study, published in the American Journal of Geriatric Psychiatry, used data from the National Health Insurance Service in Korea to examine an elderly cohort of 22,178 patients with gout and 113,590 without. Researchers found that 2,557 (11.53%) patients with gout also had dementia, vs 18,264 (16.08%) patients who didn’t have gout. The findings suggest a 37% lower risk of dementia in elderly patients with gout. Through a sub-group analysis, researchers determined that use of the gout drug febuxostat is associated with significantly lower incidence of dementia. Correlation is not causation, but this correlation is certainly worth exploring further.

Damage to reward pathway means fatigue for MS patients. Depression and anxiety are common symptoms in multiple sclerosis, and past studies have shown an association between these symptoms and patients experiencing a lower level of responsiveness to reward stimuli. Now, newly published research has found that microstructural changes in the left mesocorticolimbic pathway—known as the reward pathway—may play a role in the comorbid development of fatigue and depression in those with MS.

The study, published in the Journal of Neuroimaging, examined the link between fatigue and depression with superolateral medial forebrain bundle (slMFB) damage, stratified based on longitudinal fatigue patterns. The researchers separated the study cohort into three groups based on how often they experienced fatigue, alongside a healthy control group. Using diffusion MRI-derived measurements, researchers compared fractional anisotropy, axial, mean, and radial diffusivity of the slMFB between the groups, and then evaluated levels of depression on the Center for Epidemiologic Studies Depression Scale. They found that those highest on the depression and fatigue scales had a significantly higher radial diffusivity, and significantly lower fractional anisotropy than patients in other groups in their left slMFB. 

Latest in Journal Summaries

Effect of disease-modifying therapy on disability in RRMS over 15 years.

Increased pulse pressure variability within the first 24 hours leads to poor disposition in subarachnoid hemorrhage patients.

Prevalence and predictors of postictal confusion after electroconvulsive therapy.

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Upcoming Medical Meetings

The following meeting is entirely virtual:

10th Annual Jefferson Neurocritical Care Symposium. February 26-27, 2021.

The following meeting is scheduled to have an in-person and virtual component:

American Academy of Neurology 73rd Annual Meeting (AAN 2021). San Francisco, CA. April 17-23, 2021.

The following meeting is scheduled to be entirely in-person:

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

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