Your last NeuroBrief: Diet and dementia, another rejected Alzheimer’s therapy, positive ASD news, and the nefarious molecule behind most brain disorders

A neurological tug-of-war is taking place between patients, physicians, and the FDA. The agency (or its committees) keeps rejecting Alzheimer’s therapies (for good reason), but patients and physicians keep sounding the alarm (also for good reason), claiming that any therapy that poses even a modest benefit is sorely needed for a condition that affects millions. We’ll cover the latest developments, plus new preventable drivers of Alzheimer’s, and great news for patients with autism spectrum disorder, in this week’s issue.

Neuro Flashback

Historical heavyweights like Hippocrates and Galen knew about “water” and “excremental liquid” in the brain’s ventricles thousands of years ago. But subsequent anatomists largely overlooked this watery stuff for 16 centuries—that is, until Emanuel Swedenborg, an engineer and miner who lived in Sweden from 1688-1772, gave it the name we know and love today: cerebrospinal fluid. How could great minds have missed cerebrospinal fluid for so many centuries? It might have something to do with the fact that many of these scientists studied the human brain by cutting heads off cadavers at the neck, causing cerebrospinal fluid and blood to drain out.

In the News

Room for optimism among those with ASD. Autism spectrum disorder (ASD) comes with its own unique blend of challenges. But new research suggests patients with the disorder may be handling them better than we’d thought. In a study of 272 children with ASD, researchers found that nearly 80% were “doing well” in at least one of five developmental areas by age 10, and nearly 25% were doing well in four of five areas.

Study authors took a broader view of what “doing well” means, examining patients’ proficiency and growth in five areas: communication, social skills, day-to-day activities, and internalizing and externalizing behaviors. Internalizing problems included anxiety, social withdrawal, and depression, while externalizing problems included rule-breaking or aggression. The wider view of “doing well” stems from the authors’ belief that proficiency—whether kids with ASD achieve a particular threshold in a measure—is only one measure of a good outcome. “Looking at growth in these areas is equally important,” they said.

FDA scraps another Alzheimer’s therapy—for now. While we were busy following the ongoing aducanumab saga, the FDA took the wind from the sails of a lesser-discussed Alzheimer’s ontender: pimavanserin—Acadia Pharmaceuticals’ latest effort to finally break through the decades-long Alzheimer’s therapy drought.

The drug, which Acadia hoped could become the first approved treatment for hallucinations and delusions associated with dementia-related psychosis, was rejected 1 month after the FDA pointed to deficiencies that should be resolved before discussions on labeling and post-marketing requirements could take place. The FDA claims that effectiveness data from the phase 3 HARMONY trial were unconvincing. However, Acadia representatives stand by positive data from the trial and have requested a meeting with the FDA to address their concerns, in an effort to reopen the pathway to approval in a therapeutic area where precious few options exist.

13 reasons why we’re closer to understanding Alzheimer’s. In a herculean scientific feat that involved sequencing the genomes of 2,247 people in a genome-wide association study, researchers have identified 13 variants of genes connected to Alzheimer’s that were previously unknown to science. The variants were associated with synapse function, neural development, and neuroplasticity.

“This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn’t do before,” the study’s lead author said in a statement. Identifying rare versions of genes can contribute important information about the biology of the disease. For example, thanks to the ground covered in this paper, researchers can begin studying the gene variants in animal models to explore how they affect brain function. Even better news: Scientists can now begin thinking about how to assess the risk for developing Alzheimer’s once they gain a better understanding of how prevalent these genes are across the general population.

For patients with MS, a reason to breathe deep. Forget infusion centers, the latest hope for the administration of therapies for multiple sclerosis is through the nose. But first, researchers will have to test the approach in a single patient. That’s because, for the first time, an immune-modulating antibody will be given via nasal administration to treat a patient with secondary progressive multiple sclerosis.

It all started with the FDA’s recent approval of a request on behalf of Tiziana Life Sciences to use its drug, foralumab, a fully human anti-CD3 monoclonal antibody, under an Individual Patient Expanded Access Program. Foralumab binds to the CD3 receptor on immune T cells to calm the immune response. That means the drug has potential to treat a wide range of autoimmune and inflammatory diseases in addition to progressive forms of multiple sclerosis. The drug has already passed phase 1 trials, as it was well-tolerated in healthy volunteers, with no treatment-related safety issues reported in 10, 50, or 250 μg doses. Treatment in this program is expected to begin by late June and last for 6 months.

Neuro Trivia

How much cerebrospinal fluid does the average adult have?

The total volume of CSF in adults ranges from 140 to 270 mL. CSF is produced at a rate of 0.2-0.7 mL per minute, or 600-700 mL per day.

Novel Diagnostics

The malicious molecule behind many brain disorders. UNC-Chapel Hill researchers have made a significant breakthrough in the way we understand brain disease. The scoop: Many of the best-known disorders of the brain may start with microRNA-29 (miR-29), an important cellular switch that controls late-stage brain development. This discovery may help researchers gain a better understanding of the underlying mechanisms of brain disease and explore new therapeutic approaches for neurodevelopmental conditions.

The researchers arrived at this discovery after observing problems in mice similar to those seen in autism, epilepsy, and other neurodevelopmental conditions after they deleted the mice’s miR-299. The key takeaway from their study: MiR-29 could play an important role in the normal maturation of the brain, and disrupting that process could contribute to multiple human brain diseases. “Our work suggests that boosting levels of miR-29, perhaps even by delivering it directly, could lead to a therapeutic strategy for neurodevelopmental disorders such as autism,” the authors wrote.

Earlier autism detection and fewer disparities with data science. Thanks to recent technological breakthroughs, we can now diagnose patients with autism spectrum disorder as early as 6 to 12 months of age. Despite that capability, most autism diagnoses happen much later—typically after the 4 years of age—which makes the disorder more difficult to treat. Now, a new detection method could facilitate earlier diagnoses: digital assessments administered via apps.

Currently, autism spectrum disorder is often detected via questionnaires given to parents. But there are many challenges with this approach, not the least of which is that it’s plagued by literacy and language barriers and requires caregivers to have a relatively deep understanding of child development. Recent studies suggest that replacing these questionnaires with digital assessments—administered on phones or tablets with games that monitor the child via the hardware’s selfie camera—could potentially address these challenges by allowing for direct observation of the child’s behavior, which in turn allows clinicians to collect more data and better inform diagnosis. “Our goal is to reduce disparities in access to screening and enable earlier detection by developing digital behavioral screening tools that are scalable, feasible, and more accurate than current paper-and-pencil questionnaires that are standard of care,” the authors said.

Diagnosing Alzheimer’s via the retina. Want to know where to look to improve Alzheimer’s diagnosis? The back of the eye may hold the clues we need. New research suggests that biomarkers in the retina may reflect Alzheimer’s disease-related brain abnormalities in cognitively normal older people.

Several postmortem studies link retinal changes to Alzheimer’s disease pathology, but optical coherence tomography (OCT) studies yield inconsistent findings. To get to the bottom of this, researchers carried out a complete ophthalmic examination, including swept-source OCT and multifocal electroretinography in 49 cognitively normal participants who also underwent PET and MRI scans. The 16 participants who were amyloid-beta positive had significantly reduced inner nasal macular thickness and retinal nerve fiber layer thickness when compared with the others. All told, the findings suggest that retinal biomarkers may be used as a screening tool for early detection of Alzheimer’s, although further evidence is needed to validate the findings.

Diagnosing Parkinson’s? Focus on the extracellular vesicles. New data suggests that extracellular vesicles in the cerebrospinal fluid may be the next best way to diagnose Parkinson’s disease—but we’ve still got a ways to go before this new method becomes a clinical reality. In a recent cross-sectional multicenter study, researchers determined that identifying total and aggregated numbers of alpha-synuclein-positive extracellular vesicles in CSF via nanoscale flow cytometry assays could help successfully identify Parkinson’s.

The study involved 170 patients with Parkinson’s and 131 healthy controls. Researchers determined the number of CSF extracellular vesicles carrying alpha-synuclein or aggregated alpha-synuclein with antibodies against total or aggregated alpha-synuclein and highly specific, sensitive, and rapid assays. Results showed no significant differences in the number or size distribution of total extracellular vesicles in CSF in patients with Parkinson’s when compared with controls. But the researchers did find that the numbers of both total alpha-synuclein-positive and aggregated alpha-synuclein-positive extracellular vesicle subpopulations among all detected CSF extracellular vesicles were significantly lower in patients with Parkinson’s when compared with controls. “Our assays could be useful to improve diagnostic accuracy of Parkinson’s disease in clinical practice and to increase power and reduce costs in clinical trials by lowering the misclassification rate during subject recruitment,” the authors said.

Novel Treatments

Docs rallying for Alzheimer’s drug. The Alzheimer’s therapy pipeline may be a long and lonely one, but physicians aren’t giving up hope. In a recent JP Morgan survey, physicians opined that there is a “clear need” for a drug that provides even a modest level of treatment benefit for patients with Alzheimer’s disease. But which drugs have the right stuff? Physicians reported that donanemab could be the ticket, but they were lukewarm on aducanumab.

Survey results suggest that doctors can foresee broad utilization of donanemab if it’s approved, with 30% to 40% of eligible patients using the therapy within the first 5 years of its approval. Physicians felt good about its short duration of therapy vs other anti-amyloid antibodies. However, they were largely split on aducanumab. In all, both drugs face an uphill battle—they both received the thumbs-down from FDA advisory committees. While the agency isn’t bound by their committees’ opinions, they typically align.

Protein inhibition for glioblastoma. Scientists may have unearthed a promising therapeutic approach to treating glioblastoma in a new study published in Nature Cell Biology: inhibiting novel protein variants.

Researchers found a novel E-cadherin protein variant called C-E-Cad, which is overexpressed in glioma stem cells. C-E-Cad binds to EGFR via a novel 14 amino acid sequence at its tail, and it activates the EGFR signaling pathway independent of EGF—the prototype ligand that activates EGFR—thereby promoting cell proliferation and glioblastoma tumor growth. “A specific anti-E-C-Cad antibody against this new 14 amino acid sequence, together with EGFR antibodies, enhances tumor suppression,” the authors said.

Ponesimod vs teriflunomide:Which comes out on top? The phase 3 OPTIMUM study marked the end of a massive showdown between ponesimod and teriflunomide, two drugs comparatively tested for their efficacy in treating patients with relapsing multiple sclerosis. The winner, and still champion? Ponesimod

In the study, participants were randomized 1:1 to ponesimod 20 mg once daily, teriflunomide 12 mg once daily, or placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators. When all was said and done, ponesimod outperformed teriflunomide in measurements of annualized relapse rate reduction, fatigue, MRI activity, brain volume loss, and no evidence of disease activity status. It fell short in just one measure: confirmed disease accumulation.

For those with migraine, fly by the seat of your zavegepants. A new phase 2/3 trial is underway to examine zavegepant for the preventive treatment of migraine. The drug, a high affinity, selective, and structurally unique third-generation CGRP receptor agonist, is currently in development for both migraine and non-migraine CGRP-mediated diseases.

The randomized, double-blind, placebo-controlled trial will enroll roughly 2,900 people with migraine and evaluate the efficacy and safety of 100 mg and 200 mg doses of oral zavegepant. While it’s a sizable study, it represents just one portion of the investment made into the drug. Overall, the zavegepant program encompasses intranasal and oral formulations for migraine and non-migraine indications. Previously, intranasal zavegepant beat out placebo in a phase 2/3 study for the treatment of acute migraine. In the future, Biohaven, the drug’s manufacturer, is looking to test the drug for pain-related disorders and additional non-migraine indications. Keep an eye out.

New in Patient Management

The cause of Alzheimer’s? For some, it can be found in the mirror. We’ve been searching for Alzheimer’s origins for as long as we’ve known about the world’s most common form of dementia. Still, it has eluded us. But we may have solved part of the riddle, thanks to a new study led by a team of Brigham Young University Researchers: Alzheimer’s might be the result of metabolic dysfunction in the brain. In other words, there’s growing evidence that diet and lifestyle are at the heart of the disease.

In the study, researchers examined RNA sequences in 240 postmortem Alzheimer’s disease-impacted brains, looking specifically at the gene expression of nervous system support cells during two types of metabolism: glucose metabolism and ketolytic metabolism. They found widespread glucose metabolism impairment in those nervous system support cells of deceased Alzheimer’s patients, but limited ketolytic metabolism impairment. “Alzheimer’s Disease is increasingly being referred to as insulin resistance of the brain or Type 3 Diabetes,” authors said. “Our research shows there is likely a lifestyle origin to the disease, at least to some degree.”

Sugar is sweet, or is it? We can’t remember. If your grandparents spoiled you with sweets as a child (or if you’re the grandparent doing the spoiling these days), you may not be the biggest fan of a new study published in Translational Psychiatry—it’s the first to show that a specific change to the gut microbiome caused by sugar can alter the function of a particular brain region, potentially impacting our memory later in life.

In the study, researchers at UCLA and the University of Georgia, Athens, explored whether a direct link exists between the microbiome and memory function. They gave rats free access to a sugar-sweetened beverage similar to the ones humans drink. When the rats grew to be adults after about one month, researchers tested their memory in the hippocampus and perirhinal cortex, finding that, compared to rats that drank just water, those that consumed high levels of sugary drinks had more difficulty with memory tasks that involve the hippocampus, with no effect on the perirhinal cortex.

Disparities still plaguing stroke-to-CT time. Fewer than 40% of stroke patients have CT imaging performed within 25 minutes of hospital arrival. But who’s faring the worst among stroke patients? A new study has found the answer, and it points to disparities that have long existed in healthcare: Female and Black patients with acute ischemic stroke were less likely to achieve door-to-computed tomography (DTCT) time within 25 minutes relative to male and White patients, respectively.

The small silver lining is that DTCT times have improved overall since 2010. But as long as these disparities exist, researchers must do what they can to understand why they persist and how they can curb them. More research is needed to draw these conclusions, but study authors pointed to previous research suggesting that stroke symptoms in women may not be as quickly recognized or may differ when compared with early stroke symptoms in men.

Loneliness, isolation, and memory. The downsides of the pandemic stretch far beyond millions of deaths and infections. According to a new study published in Alzheimer’s & Dementia, persistent midlife loneliness—which has increased during lockdowns and quarantine—has been identified as an independent risk factor for Alzheimer’s disease.

Researchers from Humboldt University of Berlin assessed loneliness in cognitively normal middle-aged adults participating in the Framingham Heart Study using one item from the Center for Epidemiologic Studies Depression Scale and then tracked future Alzheimer’s and dementia. After adjusting for demographics, social network, physical health, and apolipoprotein E ε4, persistent loneliness was associated with a higher risk for dementia onset (HR 1.91) when compared with no loneliness. Transient loneliness, on the other hand, was associated with lower risk for dementia onset (HR 0.34) compared with no loneliness. “Our findings are in line with evolutionary theories stating that loneliness could be both adaptive and maladaptive for humans, depending on its persistency,” the authors wrote.

Latest in Journal Summaries

Cognitive and behavioral disorders in patients with precuneal infarcts.

Long-term effectiveness of fingolimod for MS in a real-world clinical setting.

Association of sinonasal inflammation with functional brain connectivity.

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Upcoming Medical Meetings

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

PAINWeek Conference 2021. Las Vegas, NV. September 7-11, 2021.

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

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




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