First Alzheimer’s drug in decades draws criticism while on the verge of FDA approval, a controversial miracle drug reclaims its title, and more

All eyes are on aducanumab, the Biogen drug that has some folks leaping for joy and others scratching their heads. The Alzheimer’s needle is moving elsewhere, too—prepare for a new blood test that’s available right now in clinics across the US (if you don’t have it already), and get ready to open your mind to a fringe theory that pins the cause of Alzheimer’s on something unexpected.

Neuro Flashback

The presidential election is finally behind us. Or is it? Who knows. Speaking of presidents, did you know that nine US presidents have died from strokes or other brain diseases? That’s one in five, or 20%, of all presidents. So what’s causing our nation’s leaders to suffer from harmful and potentially deadly neurologic conditions? Presidents have several risk factors in common. They’ve all been men, many are older than 65, and, of course, being a president is an extremely stressful job—almost as stressful as being an American citizen these days.

In the News

First new Alzheimer’s drug in decades? An US Food and Drug Administration (FDA) advisory panel met last week to review an experimental Alzheimer’s drug called aducanumab. Their findings? Biogen, the drug’s manufacturer, has shown “exceptionally persuasive” evidence that aducanumab is effective. That means the drug is mere steps away from earning approval and becoming the first new FDA-approved Alzheimer’s therapy in decades.

Members of the committee said results from one of aducanumab’s pivotal trials were persuasive and strongly positive. But they also acknowledged a second large trial that didn’t succeed. Still, they said this failure didn’t detract from positive findings in the previous study. One FDA staffer, though, pointed out that there was “no compelling substantial evidence of treatment effect or disease slowing,” from aducanumab. In addition, the FDA’s statistician expressed concern about how Biogen interpreted data from the positive study, and some panel experts were confused as to how to interpret the conflicting results of the two identical studies. Some of the committee members criticized the FDA for its positive review. “I’m highly critical of the fact that the FDA presentation today was heavily weighted to giving the same conclusions as the sponsor [Biogen],” said Scott Emerson, MD, PhD, professor of biostatistics at the University of Washington. Patient advocacy groups, for their part, have largely argued that the drug needs to be approved because Alzheimer’s represents such a huge unmet medical need. A final approval decision is due in March 2021, and while the FDA is not bound by the advisory committee’s recommendation, they have historically abided.

Ultra-high dose radiation, ultra-low side effects. Here’s the problem with traditional cranial irradiation used for brain tumors: It exposes a tumor and nearby normal tissue to radiation for several minutes at a time. But FLASH radiation therapy allows for the same dose in just tenths of seconds. There are serious benefits to that kind of speed. First, it could eliminate many of the toxicities that normally plague cancer survivors after receiving radiation. Second, it could decrease common side effects, like inflammation and cognitive impairment. And while this tactic has only been proven to work in a recent study in mice, “it’s not unreasonable to expect that in 10 years, this may become a widespread option for radiotherapy patients worldwide,” an investigator said.

Just like in traditional radiation therapy, researchers fractionated the dose of radiation delivered, dividing it over several sessions. Using FLASH radiation therapy, they found that the same total dose of radiation delivered at quicker dose rates removed brain tumors just as effectively as traditional methods. The best news of all—FLASH has also been used to treat lung, skin, and intestinal cancers, while still preventing many radiation-induced complications. Next up, researchers are trying to figure out an effective way to bring FLASH to the clinic.

Depression and stroke. Depression doesn’t bode well for neurological disease—or any disease, really. We know that it can be an early sign of dementia and that it is rampant in patients with Parkinson’s disease and multiple sclerosis. Now, we’re learning that depression has strong ties to stroke, too, and that the more symptoms of depression a person has, the higher their risk of stroke becomes, according to new research. This is significant, as an estimated 17.3 million adults in the US (7.1%) had at least one major depressive episode in 2017 alone.

The study, which included more than 25,000 people across the US aged 45 years and older without history of stroke, used a four-item depression scale to measure how often they felt depressed, sad, lonely, or had crying spells. Across participants, there were more than 1,260 strokes after an average 9-year follow-up. Compared to participants with no depressive symptoms, those with scores of one to three had a 39% increased stroke risk. Those with scores of more than four had a 54% higher risk, after accounting for demographic factors. More research is needed to untangle this association, but thanks to this data, depression is earning its rightful place in conversations about stroke prevention.

Unearthing a link between infections and Alzheimer’s. It sounds like the plot of the next blockbuster thriller film. Immunologist and medical publishing baron Leslie Norins, MD, PhD, offers $1 million of his own money to any scientist who can prove that Alzheimer’s disease is caused by a germ. The theory has been quietly circulating on the fringes of neuroscience for decades, and it’s one that’s taken a backseat to the prevailing theory that amyloid buildup is the key culprit. But there’s some data out there that points to a more radical role for amyloids in neurons. Rather than just being a toxic waste product, amyloid might help protect the brain from infection. According to this way of thinking, Alzheimer’s occurs when genetics or age prevent amyloid from doing its job. But there might be more to it than that.

Scientists are now exploring the microbe theory as an avenue for more potential therapies. Researchers have gone hunting for microbes in thousands of post-mortem Alzheimer’s brains, and found them in many. Attention is largely being paid to herpes viruses, which had previously emerged as the pathogen most frequently linked to Alzheimer’s. But studies have only shown correlations, and causation is a long way away. Still, researchers found that 3 weeks after injecting HSV-1 into the brains of mice, their brains were dotted with amyloid plaques. There’s plenty left to be done, but 40 applicants have submitted work in hopes of winning the $1 million reward. We’ll know if anyone was up to the task by March 2021.

Neuro Trivia

Can you name all nine presidents who have died from strokes and other brain disease?

John Quincy Adams (stroke), John Tyler (stroke), Millard Fillmore (stroke), Andrew Johnson (stroke), Chester A. Arthur (cerebral hemorrhage), Woodrow Wilson (stroke), Franklin D. Roosevelt (cerebral hemorrhage), Richard Nixon (stroke), and Gerald Ford (arteriosclerotic cerebrovascular disease).

Novel Diagnostics

Alzheimer’s blood test coming soon to a clinic near you. It’s not the holiday season yet, but here’s an early present—the first blood test designed to assist physicians in determining whether a patient has Alzheimer’s disease is now available in most US states. How does it work? The test, from C2N Diagnostics, measures biomarkers that frequently reflect the presence of amyloid plaques in the brain, as well as the presence of a gene variant that increases Alzheimer’s risk. It relies on the ratio of two isoforms of the amyloid-β protein, Aβ42 and Aβ40, that aggregate to form amyloid plaques, combined with the presence of isoforms of apolipoprotein E (ApoE) that reflect whether the patient carries a genetic variant associated with Alzheimer’s risk. The results are combined into a score that indicates the probability that a patient would be found to have amyloid plaques if they were to undergo an amyloid PET scan. 

The new test has two key advantages over previous methods. First, it doesn’t require a spinal tap like those that measure biomarkers in the cerebrospinal fluid. Second, it doesn’t involve injecting radioactive tracers or cost thousands of dollars like amyloid PET. The test isn’t dirt cheap, though, with a price tag of $1,250. The catch? Insurers currently don’t cover the test, but patients who qualify for financial assistance can expect to pay only a fraction of the cost, anywhere between $25 and $400.

OCT for PD. They say the eyes are the window into the soul. That’s a bit too romantic for some scientists, so how about this instead: The eyes could be a promising new window into the risk of Parkinson’s disease. That’s the latest finding from a new systematic review and meta-analysis published in the European Journal of Neurology, which pooled data from 36 observational studies of 1,712 patients with Parkinson’s disease and 1,778 healthy controls.

Compared with the healthy control group, the Parkinson’s disease group showed significant difference in several metrics as measured by optical coherence tomography (OCT), including a significant reduction in mean peripapillary retinal nerve fiber layer (pRNFL) thickness, all quadrants at pRNFL, macular fovea, all outer sectors thickness at macula, macular volume, and macular ganglion cell complex (mGCC) thickness. What does that mean for the non-ophthalmologists in the room? There are robust associations between retinal OCT measurements and Parkinson’s disease, highlighting the usefulness of OCT measurements as potential imaging biomarkers for Parkinson’s disease.

Small extracellular vesicles, big biomarker potential. Scientists have uncovered differentially expressed genes (DEG) in serum small extracellular vesicles (SEV) of people with dementia with Lewy bodies (DLB), which is a very acronym-heavy way to tell you this positive news: Researchers may have discovered a new blood-based biomarker for DLB. Amazing, right? Here’s how it went down in the study.

Researchers investigated serum SEV total RNA profiles in 10 people with DLB and 10 age- and gender-matched comparisons using next-generation RNA sequencing. They were able to identify 846 nominally significant DEG, including 30 miRNAs in DLB serum SEVs. There was significant downregulation of proinflammatory genes and previously reported post-mortem DLB brain DEGs were significantly enriched among the identified DEGs, while the differential expression of 40 post-mortem DLB brain DEGs could be detected in serum SEVs of people living with DLB. Yes, we know that’s a whole lot of acronyms again. So we’ll leave you with this: Measuring SEV RNA has opened a new avenue for discovering blood-based biomarkers for DLB—potentially addressing an urgent clinical need for this population.

Big bucks for Alzheimer’s biomarkers. A multi-institution research team co-led by members of the University of California, Irvine, has been awarded an unprecedented five-year, $109 million grant by the National Institutes of Health to expand research into Alzheimer’s disease biomarkers in adults with Down’s syndrome. Down’s syndrome is the most common neurodevelopmental disorder, which affects more than 250,000 people in the US alone. The grant will be used to fund research aimed at improving patients’ quality of life through effective prevention.

People with Down’s syndrome have a very high risk of developing Alzheimer’s disease and nearly all have the brain pathology (amyloid plaques) of Alzheimer’s at the time of death. Their risk is thought to come from their three copies of chromosome 21, which leads to the overproduction of amyloid. The research teams will assess and examine a wide range of data from biofluid biomarkers to genetic factors, neuroimaging, and everyday cognitive and psychological function. Researchers will see participants every 16 months for up to four visits. “By expanding our research and increasing our studies involving Alzheimer’s risk in people with Down syndrome, we have a tremendous opportunity to better understand the development of the disease. This may lead us to new preventative therapies and treatments for Alzheimer’s in people with Down syndrome and the general population,” a UCI researcher said.

Novel Treatments

Perampanel gets a solid response rate. You know what’s tough to treat? Pretty much all neurological conditions. Refractory and super-refractory status epilepticus are no exceptions to that rule. But perampanel could soon make a difference for patients with these conditions, even if its only measure of success thus far is its ability to generate a response in people who take it. That’s the key metric measured in a new study published in Journal of the Neurological Sciences, which found that perampanel exhibited a 41.3% definite response rate, with just 9.3% of patients experiencing adverse effects attributable to the therapy.

In the single-center, retrospective, observational study of 75 patients with RSE admitted to the neurocritical care unit between April 2017 and September 2019, perampanel was initiated as a median sixth-administered antiseizure medication at a median initial dose of 12 mg. For the primary outcome (occurrence of a definite response to the drug), 31 patients were classified as a definite responder. This is certainly early days for perampanel in patients with refractory and super-refractory status epilepticus—further prospective studies are needed, but the groundwork has been laid.

Can’t beet this. Scientists are leaving no stone unturned in the search for new treatments for neurological conditions. Their most recent target would make Dwight Schrute proud—beets, and specifically beetroot peptide, for multiple sclerosis. According to new research, a small protein isolated from beetroot can block the activity of an enzyme called prolyl oligopeptidase (POP), which plays a role in breaking down certain hormones and signaling molecules, and is thought to control the body’s inflammatory responses.

According to researchers, the discovery of this plant-derived protein may make possible new therapies targeting POP, which is increasingly being explored as a target for multiple sclerosis and even Alzheimer’s disease. Researchers successfully used this approach previously to create a treatment candidate for multiple sclerosis, called T20K, based on a natural plant peptide called cyclotide. It’s shown promising efficacy at lowering the production of pro-inflammatory signaling molecules in multiple sclerosis animal models. Next up, researchers are planning a phase 2 trial assessing T20K in humans with the disease.

Can ketamine crack down on MS-related fatigue? Fatigue is one of the most common symptoms of multiple sclerosis, affecting about 80% of people with the disease and putting a huge damper on their independence. It’s also one of the primary reasons people with multiple sclerosis leave the workforce, putting them in a vulnerable financial position against a costly disease. But researchers think an unlikely drug may bring us closer to solving this all-too-common symptom—a new study published in Multiple Sclerosis Journal suggests low-dose ketamine infusion may be a safe and tolerable treatment strategy.

The double-blind, randomized, placebo-controlled study included 18 patients with multiple sclerosis between 18 and 65 years old, who were randomized to a ketamine (n=12) or midazolam (n=6) infusion. There was no change in the Daily Fatigue Severity score during the first 7 days following infusion, and no difference between groups in the trajectory of this score during the first 7 days following infusion, suggesting that low-dose ketamine didn’t show significant improvement in fatigue severity. But when multiple sclerosis-related fatigue was assessed using the Fatigue Severity Scale, there was a trend in reduced scores at 1 week, and a clinically significant reduction in Modified Fatigue Impact Scale score at day 28. Overall, low-dose ketamine did not meet the primary endpoint, but more data from larger populations could hold promise yet.

Checking in on a Phase 2 SMA treatment. A six-month interim analysis of the TOPAZ Phase 2 clinical trial is looking pretty good. Treatment with SRK-015, a highly selective inhibitor of the activation of latent myostatin for the treatment of Type 2 and Type 3 spinal muscular atrophy (SMA), led to improvements in Hammersmith scale scores in all three cohorts of patients. In other words, the drug met its primary endpoint. The high-dose arm of cohort 3 attained a 5.6-point mean improvement from baseline as compared to the low-dose arm, which attained a 2.4-point mean improvement. More good news: No safety signals were identified.

The phase 2 proof-of-concept trial enrolled 58 patients with Type 2 and Type 3 SMA across 16 study sites in the US and Europe. It will continue to evaluate the safety and efficacy of intravenous SRK-015 dosed every 4 weeks for 1 year. Top-line data from the 12-month treatment study are expected in the second quarter of 2021.

New in Patient Management

Statin the obvious. Cardiologists love statins. In fact, one cardiologist said that statins are to atherosclerosis what penicillin was to infectious diseases. Sounds too good to be true, right? Maybe. Back in 2012, the FDA issued a black box warning linking statins to cognitive impairment. If it was true, the huge amount of statin prescriptions issued by cardiologists might leave quite the mess for neurologists. Fortunately, we have some great news: A systematic review of randomized clinical trials and observational studies has found that there is no evidence of adverse cognitive effects with statin use—take that, boxed warning!

Researchers stitched together results from 24 studies with more than 1.4 million patients. Among three randomized controlled trials, which ranged from 3.2 to 5.6 years of follow up, there was no significant association between statin use and adverse cognitive effects. Mean difference in the mini mental state exam was insignificant. There was actually a reduced incidence of dementia in 10 observational studies, with seven showing no association with dementia and three showing a decline in cognition that was similar to those who didn’t use statins. Overall, it looks like the statin-cognition myth may be busted.

Modifiable factors in cognitive performance. Ever wonder what social and behavioral factors increase the likelihood of healthy cognitive performance in children? So have researchers at the University of California, San Francisco, who recently published a study on the matter in JAMA Pediatrics. In a cohort of 1,055 mother-child dyads, they were able to identify modifiable prenatal and postnatal exposures that were associated with childhood cognitive performance between the ages of 4 and 6 years.

Here’s the list: Breastfeeding (compared with no breastfeeding), higher parental education levels, fostering of cognitive growth during mother-child interactions, lower levels of parenting stress, and maternal reading ability. Together, these were associated with 0.5% of a standard deviation difference in cognitive test scores. These factors lead to notably lower levels of most of the beneficial cognitive performance exposures in Black children, the authors said, so increasing equity in early social environments may help reduce these disparities.

Nine risk factors for Parkinson’s disease. Want to give your patients tools that can help ward off Parkinson’s disease? Then keep reading: A new study published in Neurology set out to pin down factors that independently modify Parkinson’s disease risk by coexisting in the same patient rather than interacting with others, and they didn’t come up empty-handed. Italian researchers designed a large case-control study assessing 31 protective/risk factors for Parkinson’s, including environmental and lifestyle factors, comorbid conditions, and drugs. The study enrolled 694 patients with Parkinson’s disease and 640 healthy controls.

Among 31 variables, they found nine independent factors that modified risk. Coffee consumption (OR 0.6), smoking (OR 0.7) physical activity (OR 0.8) family history of Parkinson’s (OR 3.2) dyspepsia (OR 1.8), and exposure to pesticides (OR 2.3), oils (OR 5.6), metals (OR 2.8), and general anesthesia (OR 6.1) were independently associated with Parkinson’s disease. There was no evidence of interaction among risk or protective factors, but cluster analysis identified four subtypes with different risk factor profiles. In group one, all patients had a family history of Parkinson’s, while dyspepsia or exposure to toxic agents was present in 30% of patients. In groups two and three, a family history of PD was lacking, while exposure to toxic agents (group two) and dyspepsia (group three) played major roles. Group four consisted of patients with no risk factors. Thanks to this new study, we’re nine steps closer to getting ahead of Parkinson’s.

The best—and worst—diets for stroke risk. If you’re eating lots of processed meat, refined grains, and drinking tons of sugary beverages—no matter how tasty they may be—you are eating foods that are associated with an increased risk of inflammation in the body and a subsequent risk of heart disease and stroke. Fortunately, antiinflammatory foods can be just as tasty, and they can have just as powerful an effect—in the good direction. These are the conclusions drawn by two studies, both published in the Journal of the American College of Cardiology, that set out to determine which diets can cause and curb heart disease and stroke.

Researchers used data from men and women in the Nurses’ Health Studies I and II starting in 1986 and included up to 32 years of follow up. More than 210,000 participants were included in the analysis, where participants completed a survey every 4 years to ascertain dietary intake. After controlling for other factors, participants consuming proinflammatory diets had a 46% higher risk of heart disease and 28% higher risk of stroke compared to those consuming anti-inflammatory diets. “Using an empirically-developed, food-based dietary index to evaluate levels of inflammation associated with dietary intake, we found that dietary patterns with higher inflammatory potential were associated with an increased rate of cardiovascular disease,” said Jun Li, MD, PhD, lead author of the study and research scientist in the department of nutrition at Harvard T.H. Chan School of Public Health. “Our study is among the first to link a food-based dietary inflammatory index with long-term risk of cardiovascular disease.”

Latest in Journal Summaries

A clinicopathologic study of movement disorders in frontotemporal lobar degeneration.

The phenotype and genotype of congenital myopathies.

Serum Neurofilament light chain predicts long-term prognosis in Guillain-Barre.

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Upcoming Medical Meetings

The following meetings are entirely virtual:

2020 NAD+ Brain Restoration Summit. November 19-22, 2020.

49th Annual Meeting of the American Association of Neurological Surgeons (AANS/Congress of Neurological Surgeons (CNS) Section on Pediatric Neurological Surgery (PedsNeuro2020) December 2-4, 2020.

Mayo Clinic Multiple Sclerosis and Autoimmune Neurology Update 2021 – Livestream. February 5-6, 2021.

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