Approved neuro drugs could have deadly consequences, genetic variation linked to cognitive decline, and new Alzheimer’s biomarker key to early detection

World Alzheimer’s Day arrived last week and brought with it a host of new research into the world’s most common form of dementia. We’re celebrating with an influx of new dementia insights, including the condition’s ancient history, two new cutting-edge biomarkers, and a pandemic-related condition that doubles its risk. Plus, shocking new data on your favorite “brain-boosting” supplements and a chilling link between COVID-19 and brain damage.

Neuro Flashback

Dementia can be traced back through human history to around 2,000 BCE, but the word ‘dementia’ first appeared in the record around 600 CE. It was coined by Saint Isidore, the archbishop of Seville, Spain, who introduced the world to the term in his encyclopedic book Etymologiae. Dementia has roots in Latin—de means a deprivation, loss, or away, ment means mind, and ia indicates a state. In short, dementia refers to “a state out of mind.” By the 2nd century CE, a Turkish physician by the name of Aretaeus had offered a distinction between the irreversible chronic disorder of dementia and the acute, reversible condition of delirium.

In the News

This is about as serious as side effects can get. Do you have patients with inflammatory nervous system diseases? Are you prescribing antiepileptics to any of these patients? Then you may want to take a seat before reading this next sentence. A new study published in the European Journal of Neurology finds that sub-groups of patients with these conditions and who are taking these medications may be at increased risk of primary brain tumors. It’s a horrifying discovery, but the devil is truly in the details.

Investigators matched 5,135 adults diagnosed with primary brain tumor with 19,572 general population comparisons to estimate age- and multivariable-adjusted odds ratios for the occurrence of primary brain tumor up to 10 years after hospital diagnoses or prescriptions for nervous system diseases and mental and behavioral disorders. They found that increased odds for primary brain tumor after nervous system diseases and mental and behavioral disorders manifested up to 10 years before tumor diagnosis was made. Odds ratios were significant for patients with inflammatory nervous system diseases (OR 11.3), epilepsy (OR 9.0) and antiepileptic medications (OR 3.6). As concerning as these data are, we can’t just lay it on like that without sending you off with one silver lining, so here it is: anti-dementia medications actually provided a strong protective association for primary brain tumors (OR 0.5).

Playing the supplement guessing game. Want to know what’s in your “smart drugs,” “cognitive enhancers,” and other so-called brain-boosting supplements? We’d recommend reading the label, it only tells 25% of the story. According to a new study published in Neurology Clinical Practice, over-the-counter cognitive enhancement supplements may contain multiple unapproved drugs. The health effects of consuming these supplements and their unapproved ingredients? Well, that’s anybody’s guess.

In 10 tested products, investigators found omberacetam and aniracetam along with 3 additional unapproved drugs: phenibut, often marketed as a sleep aid; vinpocetine, a synthetic compound that the FDA has never tested; and picamilon, a drug approved in Russia for neurological conditions, but not the U.S. All of these products fail to meet the FDA’s definition of a dietary ingredient, so any supplement containing them is mislabeled. By ingesting the label-recommended serving size of these supplements, consumers could be exposed to pharmaceutical-level dosages of the drugs. In many cases, several drugs detected in tests were not declared on the label, and several drugs that were declared on the label weren’t in the product. And in products that did include drug quantities on the labels, 75% of the declared quantities were inaccurate. The bottom line? These supplements are beyond sketchy, and by consuming them you could be exposing yourself to four-fold greater dosages than those typical of a pharmaceutical prescription—plus three, to as many as four, unapproved drugs in a single supplement.

In the dark on dementia. A new nationwide survey study paints a disconcerting picture of Americans’ understanding of cognitive decline. A full 80% of adult survey respondents said they wanted to reduce their risk of dementia and Alzheimer’s, but according to a Brain Health IQ quiz issued alongside the survey, most had way too little knowledge of the risk factors. Almost 75% were unaware that hearing loss damages the brain, 72% were unaware that diabetes is a major risk factor, 64% didn’t know that lack of sleep is bad for brain health, and 50% didn’t know about links between emotional well-being and brain health.

To make matters worse, surveyors found that roughly two-thirds of participants had experienced an increase in depression and anxiety during the pandemic and 40% had experienced “brain fog” characterized by forgetfulness or memory loss. On top of that, results suggested that roughly 65% of Americans over the age of 55 had never had a cognitive screening test. “As the Baby Boomer generation ages, the number of Americans diagnosed with Alzheimer’s is expected to skyrocket, underscoring the need to improve brain health literacy among physicians and patients,” a survey author said.

Don’t sleep on this news. Or do—it depends on how much sleep you’re getting. Are you part of the “I’ll-sleep-when-I’m-dead” crowd? Or are you a member of the Perpetual Snoozers? Either way, you’re not going to like the new research published in JAMA Network Open, which found that sleeping too much and sleeping too little are both surefire ways to mess with your brain function later in life.

In a pooled analysis of two nationally representative cohorts monitoring the association between sleep duration and cognitive decline, researchers found that global cognitive z-scores declined faster for people who slept ≤ 4 hours and ≥ 10 hours per night, compared to a reference group that slept 7 hours per night, even after adjustment for a number of covariates. There was also an inverted U-shaped association for sleep duration and global cognitive decline, which suggests that cognitive function should be monitored in middle-aged and older people who sleep too little or too much. Catch those Zs responsibly, folks.

Is COVID-19 causing brain damage? Individual case studies have led scientists to speculate as much for months, but population-level data trickles in slowly, so a conclusion has eluded us. Now, new research published in Neurology moves us closer to confirming the link between COVID-19 infection and neuronal injury—and it’s not looking good.

In a study of 47 patients with mild, moderate, or severe COVID-19, researchers measured two plasma biomarkers of CNS injury in samples collected at presentation and after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort. Patients with severe COVID-19 had higher plasma concentrations of GFAp (a marker of astrocytic activation/injury) and NfL (a marker of intra-axonal neuronal injury), while GFAp was also increased in patients with moderate disease. There you have it: neurochemical evidence of neuronal injury thanks to COVID-19. Thanks for the additional gut-punch, 2020.

Neuro Trivia

How many people have dementia worldwide?

According to the WHO, dementia affects 50 million people worldwide, with nearly 10 million new cases every year. Alzheimer’s is the most common form of dementia. In 2014, an estimated 5 million Americans aged 65 years or older had Alzheimer’s–a number that’s expected to nearly triple to 14 million by 2060.

Novel Diagnostics

LOOKING for the next Alzheimer’s bEYEomarker. SEE what we did there? Scientists have set their SIGHTS (ok, we’ll stop now) on a promising biomarker for Alzheimer’s—a protein in our eyes—that holds the potential to lay the foundation for diagnostic eye tests that catch neurodegenerative disease years before symptoms occur. A growing body of research suggests the protein, NfL, which is released as a result of brain cell damage, can be detected in blood and CSF years—and even decades—before clinical symptoms of neurodegeneration appear.

In a new study, researchers set out to see whether they could find NfL in the eye, and whether its levels in the eye correlated with other biomarkers of Alzheimer’s disease progression. They collected eye fluid samples during routine eye surgery from 77 participants at an average age of 56 years and were able to detect NfL levels in all 77. Higher NfL levels were associated with higher amyloid and tau proteins, plus the NfL levels detected were not associated with any clinical eye or chronic diseases. Further validation is needed, but this study suggests NfL in eye fluid can be a quantifiable protein-based biomarker for neurodegenerative disease. Time to get ex-EYE-ted!

A new genetic variation to predict cognitive decline. Deposits of amyloid ß and tau proteins may be required for a diagnosis of Alzheimer’s disease, but current thinking is that by themselves, they’re not enough to cause cognitive decline and dementia. If we could understand the genetic mechanisms that underpin Alzheimer’s progression, we might unearth the breakthrough needed to develop better treatments for the debilitating disease. Goodness knows we need them.

Researchers at the Korea Advanced Institute of Science and Technology have peeled back another layer of the Alzheimer’s mystery with a new study of 486 participants. The investigators were able to detect new genetic variations—known as single nucleotide polymorphisms—which are associated with cognitive decline but that couldn’t be explained by deposits of amyloid ß and tau. The variation leads to alterations in the metabolism of the antioxidant glutathione, and could cause cortical thinning. Study participants with the genetic variation performed worse on cognitive tests and were less likely to have normal cognition than those without the variant. They also had lower cortical thickness in their brains. Overall, researchers estimated that 5% of the amount of variance in cognitive function could be explained by the single nucleotide polymorphisms. If additional studies replicate these results, scientists will be a step closer to improved understanding of the causes behind Alzheimer’s disease.

A face is worth one thousand words. Facial analysis technology is helping us gain insights where words fail us. A new report suggests that at least 50% of people living with dementia in the UK’s 18,000 care and residential homes are regularly experiencing pain but are struggling to communicate it to their caretakers, often leading to the undertreatment of pain in this population. Because they struggle to convey their feelings, researchers are turning to technology to help identify non-verbal cues that could suggest the experience of pain.

“Many people with dementia struggle to communicate, so are frequently unable to verbalize their pain. This can lead to the emergence of behaviors and psychological symptoms like aggression, agitation, loss of inhibitions, and anxiety, which are all too often attributed to Alzheimer’s or other dementias, and not considered as an indicator of pain,” one of the authors wrote in the report. On the other hand, appropriate diagnosis of pain leads to better treatment, symptom and side-effect improvement, and improved quality of life. The pain recognition app, developed by Australia-based artificial intelligence company PainChek, has been granted a US patent for pain assessment invention and is on track to obtain clearance from the FDA this year. The sooner the better, we say.

This is about as serious as side effects can get. Do you have patients with inflammatory nervous system diseases? Are you prescribing antiepileptic medications to any of your patients? Then you may want to take a seat before reading this next sentence. A new study published in the European Journal of Neurology finds that sub-groups of patients with these conditions and who are taking these medications may be at increased risk of primary brain tumors. It’s a horrifying discovery, but the devil is truly in the details.

Investigators matched 5,135 adults diagnosed with primary brain tumor with 19,572 general population comparisons to estimate age- and multivariable-adjusted odds ratios for the occurrence of primary brain tumor up to 10 years after hospital diagnoses or prescriptions for nervous system diseases and mental and behavioral disorders. They found that increased odds for primary brain tumor after nervous system diseases and mental and behavioral disorders manifested up to 10 years before tumor diagnosis was made. Odds ratios were significant for patients with inflammatory nervous system diseases (OR 11.3), epilepsy (OR 9.0) and antiepileptic medications (OR 3.6). As concerning as these data are, we can’t just lay it on like that without sending you off with one silver lining, so here it is: anti-dementia medications actually provided a strong protective association for primary brain tumors (OR 0.5).

Novel Treatments

To beat pediatric migraine, grab that melatonin and catch a nap. Acute migraine medications aren’t always effective. Plus, they can cause some gnarly side effects, which are particularly concerning in kids. But studies have shown that melatonin, a hormone produced by our pineal glands, is effective for migraine prevention in adults, with some additional use cases for procedural pain in children. Now, researchers have found that it’s also effective in high and low doses for reducing pediatric migraine.

In a study of 84 children aged 4 to 17 years with episodic migraine, investigators split participants into two groups to receive either high-dose or low-dose melatonin (< 40 kg body weight: 4 mg vs 1 mg; ≥ 40 kg body weight: 8 mg vs 2 mg). Dropout rates were high (about 45% in both groups) but results were promising. Mean change in pain intensity at 2 hours was –2.7 cm in the high-dose group vs –2.3 cm in the low-dose group. Two-hour pain-freedom rate was 41% in the high-dose vs 27% in the low-dose group and 2-hour pain relief rate was 94% vs 80%. Most patients (67%) napped in the high-dose group, while 47% napped in the low-dose group, but catching a quick snooze was found to be independently associated with greater headache benefit in both groups. Despite the high dropout rates, melatonin is making its mark as a pediatric migraine treatment—and so are naps.

A targeted T-cell immunotherapy for MS. Epstein-Barr virus (EBV) is a member of the herpes virus family, one of the most common human viruses on earth. Sorry to have to break it to you, but according to the CDC, you’re probably going get it at some point. Infection with EBV isn’t a huge deal, but it is associated with the pathogenesis of multiple sclerosis (MS). So is it possible that a treatment for EBV could help reduce the burdens of this progressive disease? Scientists hope so. They’re pushing a treatment for EBV, known as ATA188, through the MS pipeline and so far, results are encouraging.

A small, phase 1 trial of 24 patients found that ATA188 was well tolerated by adults with progressive forms of MS, and that there was no evidence of cytokine release syndrome or graft versus host disease in any patients. Plus, increasing dosage was associated with reduced MS-related deterioration. It’s still early days, but the positive data from this small study warrant continuation of the current study and progression to a randomized, double-blind, placebo-controlled study. Stay tuned for more results.

Tackling a rare form of genetic epilepsy. Phase 3 results are in: Ganaxolone, an experimental anxiolytic and anticonvulsant developed by Marinus Pharmaceuticals, has reached its primary endpoint. The drug showed a 32.2% median reduction in 28-day major motor seizure frequency compared to placebo in children and young adults with CDKL5 Deficiency Disorder (CDD)—a rare, genetic form of epilepsy with refractory seizures. Results move the drug one step closer to becoming the first treatment indicated for CDD.

In the double-blind, placebo-controlled, phase 3 trial of 101 patients, ganaxolone was generally well tolerated, and its safety profile was consistent with previous studies. The most frequent adverse event was somnolence. The study represents two important scientific firsts: “It’s the first double-blind placebo-controlled study providing evidence of efficacy specific to CDD and the first phase 3 trial to examine three-times-a-day dosing of ganaxolone in pediatric patients,” Marinus CEO said. Based on these results, Marinus plans to submit a new drug application (NDA) for the treatment of CDD to the FDA midway through 2021. Here’s hoping.

Ozanimod gets the nod. This oral, once-daily selective agonist for the sphingosine-1-phosphate receptors 1 and 5 has shown some pretty solid results for the treatment of relapsing multiple sclerosis (RMS) in phase 2 and 3 efficacy and safety studies. But why stop there? A new open-label extension study of ozanimod’s long-term safety and efficacy finds that the drug continues to be associated with low annual relapse rates (ARR).

In total, 2,639 participants completed ozanimod’s parent trials. Phase 3 studies found that mean ARR was 0.153 with ozanimod HCl 1 mg and 0.246 with intramuscular interferon ß-1a (IFN). Among those who received IFN in parent trials, mean ARR was reduced to 0.123 after switching to ozanimod in the open-label extension, during which 1,704 participants (68.3%) had a treatment-related adverse event (AE), 144 (5.8%) had a serious AE, and 30 (1.2%) discontinued treatment because of AEs. Despite adverse events, continuing or switching to ozanimod HCl 1 mg was associated with the lowest ARR in the study, supporting the safe and effective oral use of ozanimod in patients with RMS.

New in Patient Management

T2D leads to dementia, but what kind? We’ve known for a while that type 2 diabetes (T2D) increases the risk of dementia (and a laundry list of other ailments), but we’ve never put that data to the test to determine what kinds of dementia are most probable—until now. A large observational study comparing more than 370,000 people with T2D to nearly 2 million matched controls over the course of 7 years finds that the risk is highest for vascular dementia—a subtype caused by vascular damage in the brain from blood clots or hemorrhages—and among people with poor blood sugar control.

In the study, people with T2D were 36% more likely to develop vascular dementia and 9% more likely to be diagnosed with non-vascular dementia than those who were diabetes-free. But because the study was observational, no conclusions can be drawn about causality, and evidence didn’t suggest that most people who have diabetes will go on to develop vascular dementia in later life. “But with the number of people with diabetes doubling over the past 30 years, the importance of a healthy lifestyle is clearer than ever,” study authors wrote. Further studies are needed to corroborate the evidence, especially considering that the underlying process of dementia typically starts up to a decade before diagnosis.

Keeping an eye on antiepileptic drugs. Even the most effective drugs are useless when patients don’t adhere to the regimen That’s especially true for complex drugs with narrow therapeutic ranges or serious adverse effects, and that’s where therapeutic drug monitoring (TDM) comes in. It’s the clinical practice of measuring drugs at intervals to maintain constant concentrations in a patient’s bloodstream, and new research suggests it can enhance clinical care for phenytoin and other antiepileptic drugs with complex pharmacokinetics.

In a systematic review of four randomized controlled trials (RCT), one meta-analysis, and 11 quasi-experimental (QE) studies, results from the analysis of RCTs showed no significant positive effect of TDM on seizure outcome. But some of the QE studies found that TDM was associated with better seizure control or lower rates of AEs. All told, when implemented optimally, TDM may enhance clinical care in these patients, but here’s the catch: the ideal method for implementation is unclear, and existing evidence comes from various designs with methodological inconsistencies. To get to the bottom of whether TDM can truly make a difference, we’ll need (you guessed it) more studies.

We’re missing pain cues—again. This time it’s in patients with cerebral palsy. According to a new cross-sectional study based on data from 1,591 adults with cerebral palsy, investigators found that 66% reported pain. In those patients, there was a higher proportion of self-reported pain (69.9%) compared to proxy-reported pain (62.4%). More adults classified in the Communication Function Classification System (CFCS) level 1 (72.5%) reported pain compared to those in CFCS levels 2 to 5 (56.5% to 64.9%).

Why is this important? Because pain is another serious challenge to daily life for people whose disease already turns minor tasks into huge undertakings. Adults in the study who had severe or very severe pain had a six-fold risk of their pain interfering with daily activities and work. Many reported pain strongly interfering with sleep—neurologists know all too well how serious that can be. What’s more, this pain is likely to be underreported, suggesting that pain in patients with cerebral palsy could be much worse than we think.

Neurological implications of PTSD. When does post-traumatic stress disorder (PTSD) occur? When symptoms from psychological trauma disrupt daily functioning for at least one month. Well guess what? We’ve been dealing with the impact of the coronavirus pandemic for around seven months now. Almost one-third of Americans are suffering from clinical symptoms of depression or generalized anxiety, suggesting PTSD is likely on the rise.

Take a peek a little further downstream and you’ll find disconcerting neurological implications attached to this river of despair, including those from a new study, which suggests that PTSD may double the risk of dementia. This research was the first meta-analysis of global evidence of PTSD on dementia risk, looking at data on nearly 1.7 million people from 13 studies conducted on four continents. Researchers found that people with PTSD faced a 1 to 2 times higher risk of dementia up to 17 years later. That data didn’t just apply to military veterans—people in the general population with PTSD from physical or sexual abuse, car accidents, and other trauma, were twice as likely to develop dementia than adults without a PTSD diagnosis were. “PTSD, which appears to be common among people who have been hospitalized with COVID-19, remains an underdiagnosed, undertreated, and under researched mental health condition, yet it can have serious long-term consequences,” the study authors wrote in a statement. Now we have robust evidence that cognitive decline is one of those long-term consequences.

Latest in Journal Summaries

Endovascular stroke treatment after 6-24 hours only needs non-contrast CT.

Obesity is associated with reduced orbitofrontal cortex volume.

Riboflavin prophylaxis for child and adolescent migraine.

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Upcoming Medical Meetings

The following meetings are entirely virtual:

21st International Conference on Alzheimer’s Drug Discovery. October 5-6, 2020.

145th Annual Meeting of the American Neurological Association (ANA 2020). October 4-9, 2020.

North American Spine Society 35th Annual Meeting (NASS 2020). October 5-6, 2020.

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