CBD vs brain cancer, plus new studies show impact of sex and hormones on dementia

Good and bad news about dementia abounds this week, as MDLinx covers the incredible worldwide reductions in the disease (good news) that disproportionately benefit certain people (bad news), as well as risk factors for the disease we can all control (good news) and some we can’t (there’s that bad news again). Beyond dementia, we highlight the meteoric rise of CBD as a proven and unproven treatment for some neurological conditions, plus a tag team of new treatment options for migraine as diverse as the people who suffer from the condition—and so much more.

Neuro Flashback

Most of us think of Leonardo da Vinci as an artist and an inventor. It turns out that the guy who painted the Mona Lisa and drew up blueprints of whimsical flying machines way back in the 15th and 16th centuries (when roughly 85% of the population couldn’t even read) was somehow more impressive than we thought—he was an amateur neuroscientist, too. During a lifelong search for the physical seat of the human soul, da Vinci drew up tons of detailed medical anatomical sketches. In 1487, three of these sketches showed what he believed to be our senso comune—or common sense—residing in the lateral ventricles, with rational thinking in the third ventricle and memory in the fourth ventricle. As time went on, his sketches became more detailed and marked several important scientific breakthroughs: he was the first to sketch and describe olfactory nerves, the maxillary antrum, and even the supply of blood to the brain via the meningeal arteries. Brillante!

In the News

Let’s start off with great news, shall we? Results from a 27-year study of dementia incidence involving seven cohort studies and nearly 50,000 people in Europe and the United States are in, and they give us reason to feel good. The incidence rate for dementia has declined by 13% per decade during the past 25 years, with results consistent across studies. Predictably, the incidence increased with age (similarly for women and men), ranging from about 4 per 1,000 person-years in people aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. Of course, there’s got to be a catch: the decline was much more pronounced in men (24%) than women (8%). More on this in our next story.

Back to the good news, though. If we assume continuation of this trend in Europe and North America into the coming decades, it could imply that 15 million fewer people will develop dementia by 2040 in high-income countries. If the same could be achieved worldwide, this could lead to a reduction of up to 60 million new cases of dementia by 2040. So what’s causing this reduction, and how can we keep it going? The main challenge in pinpointing an answer is that there have been many recent changes that involve dementia risk factors, like lifestyle education, blood pressure control, and more (particularly in high-income countries). Basically, it’s a question for future studies.

Future studies? You mean, like this one? Yes we do! Despite the impressive reductions in dementia incidence described above, there are still 5.8 million Americans living with Alzheimer’s disease, and two-thirds of them are women. Why the difference? Understanding why such biological factors affect the disease could lead to meaningful change. Fortunately, a researcher at the University of Pittsburgh is tackling the question, thanks to a $2.6 million award from the National Institutes of Health (NIH).

It’s a massive question and a monumental undertaking made all the more impressive by the fact that the effort is led by just one person—Bistra Iordanova, PhD, a bioengineering assistant professor at Pitt’s Swanson School of Engineering. In her study, she’ll look at the brain to see how sex differences influence the connection between neural activity and changes in cerebral blood flow. She’ll also examine the flow of energy within the brain in real time, and track how hormonal changes during aging may affect the energy consumption of the brain. “We hope our data will uncover personalized molecular targets for therapy and improve treatment of dementia,” she said.

Leading dementia experts talk about modification. In a new Lancet Commission report, a team of the world’s foremost experts in dementia lay out the 12 modifiable risk factors (which, by the way, account for 40% of cases of worldwide dementia) with pooled data from previous studies and meta-analyses. Their goal? To cue worldwide policy and personal changes that can delay dementia, as well as to find better ways to support and treat people who have the condition now.

The team’s 12 modifiable factors are specific to different stages of life: early life (< 45 years), midlife (45-65 years), and later life (> 65 years). In early life, the only key risk factor mentioned in the report is receiving less education. More education is associated with improved cognitive reserve, which is the brain’s way of improvising, finding alternate ways of getting a job done, and dealing with setbacks. In midlife, risk factors include hearing loss, traumatic brain injury, hypertension, alcohol consumption (> 21 units/week), and obesity (BMI ≥ 30). In later life, risk factors include smoking, depression, social isolation, physical inactivity, diabetes, and air pollution. “Our ambition is for worldwide provision of resources for an adequate level of wellbeing to people with dementia and their [caretakers], with a better evidence base to guide individual care and policy making alike,” researchers said.

How else can we protect the brain? How about cannabidiol (CBD)? Yes, we know the evangelists say CBD can cure every ailment known to humankind. We’re just here to show you where the science lends credence to the hype, so here it is: Findings from a new study in human and canine brain cancer cells suggest that CBD could be a useful therapy for difficult-to-treat brain cancer.

Researchers at Colorado State University tested the effects of CBD isolate (100% CBD) and CBD extract (CBD plus cannabigerol and THC) in human and canine glioblastoma cells and found that CBD in either form can slow cancer cell growth. Plus, it’s toxic to both canine and human glioblastoma cell lines. Researchers believe CBD’s anti-cancer actions target the mitochondria by causing it to dysfunction and release harmful reactive oxygen species, because cells treated with CBD exhibited significant decreases in mitochondrial activity. The positive results allow researchers “to move forward in studying CBD’s effects on glioblastoma in a clinical setting using live animal models. This could lead to new treatments that would help both people and dogs that have this very serious cancer,” they said.

Neuro Trivia

How many nerve cells exist within each adult human brain?

Roughly 86 billion. If you lined them up and tried to count each nerve one by one, it’d take you 2,724 years. See you in August 4744!

Novel Diagnostics

Serious science-backed concussion repercussions. Here’s the takeaway from new research published in the journal of Family Medicine and Community Health (it’s a scary list, so bear with us): Concussion is linked to heightened risk of dementia, Parkinson’s disease, mood and anxiety disorders (particularly in women), and attention deficit hyperactivity disorder (ADHD). Plenty of data has implicated concussion in neurological disorders, but most of it relied on self-reported data or failed to consider confounders. This study represents a more thorough investigation because it accounted for confounders and pulled data directly from medical records in Manitoba, Canada, from 1990 to 2015.

During that period, 47,483 people were diagnosed with concussion. Compared to those who hadn’t been concussed, they were 72% more likely to have mood and anxiety disorders, 72% more likely to develop dementia, 57% more likely to develop Parkinson’s disease, and 39% more likely to develop ADHD. A second concussion strengthened the association with dementia, while three or more concussions strengthened the association with mood disorders and Parkinson’s disease. But why? Concussion upsets the workings of the autonomic nervous system as well as blood flow to and around the brain. Recovery is common, but it’s increasingly clear that long-term consequences may persist.

Pulse pressure: a relevant cognitive vital sign? When elevated, pulse pressure (the difference between systolic and diastolic blood pressure that commonly increases with age) could be a risk factor for dementia, according to new research published in Frontiers in Neuroscience. Previous studies in animal models suggest that elevated pulse pressure deregulates cerebral endothelial cells and increases cellular production of oxidative and inflammatory molecules. The resulting cerebral microvascular damage can induce breakdown of the blood-brain barrier, which in turn triggers brain cell impairment and death. What’s more, this type of environment might have prevented previous treatment strategies from working optimally against dementia, potentially skewing the results of clinical trials.

Because of that, researchers argued that novel therapeutics should be developed to target pulse pressure as a potential preventative solution or treatment for dementia. “Combination therapy has been paramount in the treatment of other challenging diseases, in particular cancer,” said Rachel Levin, PhD, lead author of the paper. “Therefore, in dementia, reducing elevated pulse pressure could prove to be synergistic with other therapeutic approaches such as anti-amyloid-beta drugs or stem cell therapy.” It’s important to reiterate that researchers drew their conclusions based on studies in animal models. Still, the data might be convincing enough to push the pulse pressure hypothesis toward progress in human trials.

What’s serum netrin-1? It’s a laminin-related protein involved in neurovascular protection. OK, but why does it matter? Because researchers had previously discovered that decreased serum netrin-1 was associated with a poor prognosis for ischemic stroke, but the relationship between serum netrin-1 level and the risk of ischemic stroke was unclear—until now, that is. A new study published in Nutrition, Metabolism & Cardiovascular Diseases—the first to investigate this association—found that serum netrin-1 was inversely associated with ischemic stroke, and that the association was dose-responsive.

In a case-control study that included 591 ischemic stroke patients and 591 age-and sex-matched healthy individuals, researchers found that serum netrin-1 levels were significantly lower in the ischemic stroke patients than those in matched controls. What’s more, the addition of netrin-1 to a model containing main cardiovascular risk factors substantially improved the discriminatory power for ischemic stroke. Next up, additional studies are needed to clarify the potential protection role of netrin-1 in the pathogenesis of ischemic stroke.

Glowing blood particles: sounds spooky, but it’s actually amazing. A chemical that facilitates glioblastoma surgeries by making tumor cells glow fluorescently may also help physicians safely diagnose the disease and monitor its response to treatment, according to a new study from researchers at Massachusetts General Hospital. Why does this method hold promise? Because brain cancer is hard to diagnose, and conventional methods like tissue biopsies and radiation are extremely dangerous when directed at the brain. This method is much less invasive and not nearly as risky. The chemical, called 5-ALA, is an FDA-approved imaging agent used in brain surgeries. Its value lies in the fact that tumor cells in the brain absorb the chemical, while others do not. While all cells release extracellular vesicles (EVs), investigators set out to determine whether EVs in the blood of patients with brain cancer might turn fluorescent pink when they ingested 5-ALA, just like their brain tumors do.

In the presence of 5-ALA, researchers showed that brain cancer cells do become fluorescent and secrete fluorescent EVs. When given to mice with and without brain cancer, fluorescent EVs were only present in the blood of those with brain cancer. The process also played out in humans. When the research team collected blood samples from patients before and after they ingested 5-ALA prior to undergoing brain cancer surgery, patients with fluorescent tumors had a significantly higher number of fluorescent EVs in their blood. “This confirms that what we see in blood is directly correlated to the tumor tissue, telling us about the tumor size,” researchers noted.

Novel Treatments

CBD gets another nod from the FDA. CBD once again proved its scientific and medicinal legitimacy when it gained FDA approval on July 31—this time for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients 1 year of age and older. This is CBD’s second approval since 2018, when the FDA greenlit it for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of epilepsy. TSC is another rare disease where benign tumors grow in the brain and other parts of the body, including the eyes, heart, kidneys, lung, and skin. It affects the central nervous system and can result in seizures, developmental delay, and behavioral problems.

CBD underscored its effectiveness for TSC-associated seizures in a randomized, double-blind, placebo-controlled trial of 224 patients. Patients who took CBD 100 mg/mL had greater reductions in seizure frequency over the 16-week treatment period vs those who took placebo. Common side effects included diarrhea, elevated liver enzymes, decreased appetite, sleepiness, fever, and vomiting. The FDA warned clinicians dispensing CBD for seizures that the medication might lead to an increase in suicidal thoughts and behavior, as well as liver injury.

How does 50% fewer migraine days sound? Results from the STRIVE study, published last week in Neurology, suggest that erenumab can help make it happen. The CGRP inhibitor was given to patients in either 70 or 140 mg doses and brought a sustained reduction in monthly migraine days of more than 50% from baseline through 52 weeks, researchers reported. But there’s another reduction that’s just as important—patients in both dosing arms saw more than a 50% reduction in the number of days per month that they needed to use migraine-specific medications.

Here’s another huge kicker: Anyone who has suffered from migraines knows how serious the implications can be on overall quality of life. To identify improvements in well-being, researchers measured erenumab’s impact on overall physical functioning, too. They found that both dosing arms of erenumab experienced improvement in everyday activity and a reduction in physical impairment. Adverse events were consistent with previous studies and included upper respiratory tract infections, monocytopenia, idiopathic orbital inflammation, swelling of the tongue, and injection site pain.

More from the migraine pipeline. A phase 3 trial of rimegepant demonstrated that the drug was found to eliminate pain and reduce bothersome symptoms for some people with migraine in a large-scale trial published in the New England Journal of Medicine. Rimegepant is an oral calcitonin gen-related peptide receptor antagonist, a new class of drugs (called gepants) that are different from most migraine drugs (called triptans). Triptans can be risky for people with heart conditions, as they lead to tightening of the blood vessels and restriction of blood flow to the heart. Rimegepant, on the other hand, targets the underlying source of migraines without narrowing or tightening blood vessels, making it a potential safe option for those with cardiovascular conditions.

Rimegepant might also be a good option for patients who aren’t helped by triptans. In the NEJM study, which involved more than 1,000 people across 49 treatment centers in the US, participants were randomized to receive either rimegepant or placebo during a migraine attack. Two hours after taking the tablets, 19.6% of patients in the rimegepant group were free from pain, compared with 12% in the placebo group. Freedom from bothersome symptoms occurred in 37.6% of patients in the rimegepant group vs 25.2% the placebo group. Side effects included nausea and urinary tract infections.

First new therapy for narcolepsy in how many years? The FDA has approved calcium, magnesium, potassium, and sodium oxybates for the treatment of cataplexy or excessive daytime sleepiness (EDS) associated with narcolepsy in patients 7 years of age and older. It’s the first new FDA-approved treatment indicated for cataplexy and EDS in people with narcolepsy in more than 15 years. Plus, it contains 92% less sodium per nightly dose than the only other treatment option (and current standard of care for this patient population)—sodium oxybate—which carries warnings about its high sodium content.

The new drug’s approval is based on a global phase 3 double-blind, placebo-controlled, randomized-withdrawal, multicenter study that demonstrated highly statistically significant differences in the number of cataplexy attacks and Epworth Sleepiness Scale scores in patients who took it, compared to those who took placebo. The drug can be risky though. It contains a Boxed Warning as a CNS depressant and for its potential for abuse and misuse. The US Drug Enforcement Agency (DEA) has designated it as a schedule III drug, alongside the likes of ketamine, anabolic steroids, testosterone, and codeine. According to its manufacturer, calcium, magnesium, potassium, and sodium oxybates will be available by the end of the year, pending a Risk Evaluation and Mitigation Strategy (REMS) implementation.

New in Patient Management

Beware the ICU. Patients in the intensive care unit (ICU) are known to be at increased risk of developing delirium, but could time spent in intensive care bring other risk factors too? According to a new study published in Critical Care, it sure can. ICU-acquired delirium is associated with an increased risk of diagnosis of new onset neurocognitive disorders in the year following their ICU stay. This bolsters a growing tide of new data that suggests ICU stays can have serious undesirable downstream effects for patients, including depression, anxiety disorders, and worse quality of life—a particularly concerning detail during a time when ICUs in many southern states are overcrowded with COVID-19 patients.

To arrive at their findings, researchers conducted a retrospective cohort study pulling clinical and administrative data from inpatient and outpatient visits to find out whether patients experienced a new diagnosis of any neuropsychiatric disorder one year after their stay in the ICU. Of 16,005 patients with at least one ICU admission, 4,033 were included in the study, of which 1,792 (44%) experienced delirium during their ICU stay. Within 1 year, researchers found that the overall cumulative incidence of any neuropsychiatric disorder was 19.7%. After adjusting for confounders, patients with delirium during their ICU stay had a risk ratio (RR) of 1.14 of developing a neuropsychiatric disorder in the year after their ICU stay vs patients who didn’t experience delirium. Overall, delirium was significantly associated with neurocognitive disorders (1.59 RR), but not depressive disorders, anxiety, and trauma-and-stressor-related disorders.

Multiplied multiple sclerosis relapses. New research published in Neurology paints a grim picture for patients who have MS and comorbid conditions—those comorbidities negatively influence disease outcomes, including relapses. Investigators included 959 patients in the study who were followed up at roughly 3.4 years. Of those, 55% had at least one comorbidity at enrollment. After adjustment for confounders, results showed that patients with anxiety (1.25 hazard ratio) and dyslipidemia (1.32 hazard ratio) were more likely to be associated with an increased hazard of any disease activity. On the other hand, migraine (0.80 hazard ratio) was associated with a decreased hazard.

“The comorbidity burden of clinical trial participants with MS may be an important factor in the outcome of clinical trials,” the authors wrote. “Additional investigations of the impact of comorbidity on clinical trial outcomes and response to disease-modifying therapies are warranted.” Researchers also argue that two decades of research supports incorporating comorbidity management—including dyslipidemia, hypertension, diabetes, heart disease, obesity, depression, and anxiety—into MS care.

A less conventional way to reduce migraines by 50%? Smoke some weed. Yes, we’re serious. A new study published in The Journal of Pain suggests that self-reported headache and migraine ratings were reduced by nearly 50% after patients smoked marijuana. Researchers pulled archival data from Strainprint, a medical cannabis app that allows patients to track symptoms before and after using different strains and doses of cannabis. They used latent change score models and multilevel models to analyze data from 12,293 sessions where cannabis was used to treat headache and 7,441 sessions where cannabis was used to treat migraine.

All told, these patients reported significant (47.3%) reductions in headache and migraine after cannabis use, with men reporting larger reductions in headache than women. Use of cannabis concentrates was associated with larger reductions in headache than use of cannabis flower. The key downside? Researchers found evidence that cannabis’s effectiveness in reducing headaches and migraines diminishes with continued use, which, in turn, causes these patients to increase their cannabis consumption over time. Plus, we can only lend so much credence to self-reported claims, and there was no placebo arm of the trial to which results could be compared.

Attention deficit drugs need that deficit. Kids may be sharing ADHD medications on college campuses to boost productivity, cram for tests, and eke out that last-minute term paper, but a recent study suggests common ADHD medications not only fail to improve cognition in healthy students, but can actually impair proper functioning. Results of the study, published in Pharmacy, show that the standard 30 mg dose of amphetamine/dextroamphetamine improved attention and focus (a typical result from stimulants), but did not translate to better performance on a battery of neurocognitive tasks that measured short-term memory, reading comprehension, and fluency.

So why the divide? Brain scan research shows that people with ADHD often experience less neural activity in brain regions that control executive function, like working memory, attention, and self-control. For people with ADHD, these medications increase activity in those regions and appear to normalize functioning. But, “if your brain is functioning normally in those regions, the medication is unlikely to have a positive effect on cognition and may actually impair cognition. In other words, you need to have a deficit to benefit from the medicine,” researchers reported. Overall, study participants experienced the physiological responses to the drugs—increased heart rate and blood pressure, as well as elevated mood, for example—without any enhancements to their neurocognition.

Latest in Journal Summaries

Switching to once-daily dosing regimen appears effective for epilepsy.

Microstructural brain abnormalities in HIV+ patients with or without chronic marijuana use

A closer look at acute thrombotic complications following SARS-CoV-2 infection.

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Upcoming Medical Meetings

The following meeting has been rescheduled:

Congress of Neurological Surgeons (CNS) Annual Meeting, to be held in Miami, FL, has been rescheduled for October 16-20, 2021, in Austin, TX.

Neuroscience 2020: The Society for Neuroscience (SfN) 50th Annual Meeting, Washington DC, October 24-28.

The following meeting has been rescheduled:

American Academy of Neurology 73rd Annual Meeting (AAN 2021), to be held in Toronto, Ontario, Canada, has been rescheduled for April 17-23, 2021, in San Francisco, CA.

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