The new Holy Grail of neurology? Plus, a common drug class for cognitive impairment, and answering an age old question in Alzheimer’s research

The layers of the Alzheimer’s onion keep peeling back, but we’ve yet to answer the simplest question: What causes it? That may have changed this week, as researchers set their sights on a new mutation that could lead to our best therapies yet. On top of that, we’re still short on therapies for tons of neurological conditions—is it possible that endocrinologists have had the answers all along? 

Neuro Flashback

A true renaissance man, Sir Charles Bell (the Bell behind Bell’s Palsy) was a Scottish surgeon, anatomist, physiologist, neurologist, artist, and, if that weren’t enough, a philosophical theologian too. His biggest contributions were made to the field of neurology, where he’s credited with discovering the difference between sensory nerves and motor nerves in the spinal cord (another one of his namesake discoveries, known as Bell’s Law). Of course, he was the first to describe Bell’s Palsy, too. And here’s an interesting fact for your next Zoom meeting—he’s also the scientist behind Bell’s phenomenon (a defense mechanism in the eye), Bell’s spasm (involuntary facial muscle twitching), and the Charles Bell House, part of University College London that’s used for teaching and research in surgery. Busy guy!

In the News

New white blood cell, scores of possibilities. The Ohio State University and University of Michigan might be bitter football rivals, but they sure know how to work together peacefully in the lab—a collaboration that has produced some pretty promising results. In a new study, researchers from both universities have discovered that a new type of granulocyte could have a positive effect on reversing nerve damage and slowing the progress of neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Parkinson’s.

Researchers studied mouse models to see whether the new type of granulocyte was similar to immature neutrophils, an infection-fighting white blood cell, by injecting granulocytes into mice with injured optic nerves or broken nerve fibers. These mice saw growth in nerve fibers, but those who had been injected with mature neutrophils did not—an unprecedented scientific feat, the authors said. There are still many unanswered questions, but the long-term goal will be to see if these cells can reverse damage to the central nervous system in humans. If so, a wide array of treatment applications could be at play, and not just those for multiple sclerosis, ALS, and Parkinson’s, but for traumatic brain and spine injuries, too.

The Tao of Tau. Even though it’s one of the more common conditions in older people, Alzheimer’s disease largely remains a mystery. Among the few key things we do know is that it stems, at least in part, from tau proteins that begin to function abnormally, then build up and damage neurons. Now, according to a new study, we’re learning that tau buildup may be caused by a specific mutation to an enzyme called Microtubule Affinity Regulating Kinase 4 (MARK4)—the possible cause of Alzheimer’s disease. What’s more, this mutation could become a new pathway for Alzheimer’s drug development.

MARK4 mutations have been shown in previous studies to lead to overexpression of tau. Now, Researchers at Tokyo Metropolitan University in Japan have shed light on how this mutation and its overexpression works. By introducing artificial mutations in fruit flies, they found that the mutant form of MARK4 creates a pathological form of tau that misfolds, clumps, and aggregates more easily, which causes neurons to degenerate. That’s bad news, but here’s the silver lining: Having this knowledge puts us in a position to potentially create better therapies. On top of that, MARK4 has been found to play a part in other protein-buildup-related diseases like Parkinson’s. That means its potential for drug development could reach beyond Alzheimer’s and help people across multiple degenerative diseases. MARK4 our words—keep your eye on this one!

A link between the future of COVID-19 and the future of Parkinson’s? There are so many scary aspects of the COVID-19 pandemic. It may feel old by now, but it’s still relatively new and its impacts are still being understood. And what about its neurological implications? Though we don’t know all that much about the long-term effects COVID-19 has on the development of neurological diseases, a new study published in Trends in Neurosciences takes us one step closer.

In the study, researchers followed three patients who developed Parkinson’s-like symptoms after contracting COVID-19. So far, they haven’t been able to establish causation between COVID-19 and Parkinson’s, but they’ve uncovered a correlation between the way COVID-19 affects the body and an increased likelihood for neurodegenerative diseases. Researchers theorized three possible ways this could happen: Blood clots damage the area of the brain that produces dopamine; chronic inflammation from COVID-19 could trigger brain inflammation and cell death; and the hypothesis that SARS-CoV-2 might be a neurotropic virus, meaning that it attacks the nervous system and leads to increased alpha-synuclein production. More long-term, larger scale studies in COVID-19-infected patients are needed, but in the meantime, pay close attention to the possible neurological effects of COVID-19.

New testing innovations in brain cancer. Tons of studies have shown that aggressive early-stage treatment can improve prognoses for glioblastoma, a ruthlessly aggressive and deadly disease. But diagnostic testing for the condition often comes too late. We need better tests and we need them to work earlier.

Enter Johns Hopkins University researchers. They’ve created a new lab test designed to capture the deadliest glioblastoma cells, which we can analyze and hopefully use to inform the development of new drugs—and to help us predict which patients have the most aggressive forms of disease. The test scores the cells on three elements of metastasis: Ability to move, compression through channels, and reproduction. As they reported in Nature Biomedical Engineering, the accuracy in predicting length of survival varied from 86% in a blind retrospective study with 28 patients, to 100% in blind prospective study with five patients. Researchers caution that more testing with a larger sample size is needed. But this is a ray of hope in what has so far proven to be a devastating and difficult-to-treat disease.

Neuro Trivia

Who was the first person to propose the idea of an MRI scan?

That distinction goes to Raymond Damadian, MD, an American physician and inventor. After experimenting with nuclear magnetic resonance, he proposed the idea of an MR scanner in 1969. Eight short years later, the first MRI body exam was performed on a human being–one of Dr. Damadian’s colleagues. The 106-voxel point-by-point scan of a thorax took almost five hours to produce.

Novel Diagnostics

A simple speaking test for Alzheimer’s. The world of neurology is notoriously complex, so we welcome this next announcement as a breath of fresh air. A simple language test, when combined with an artificial intelligence model, can predict which people will develop Alzheimer’s disease later in life, according to a new study. So how early can it detect this disease, and how accurate are its methods? Researchers say it predicted Alzheimer’s 7.5 years before its diagnosis with an accuracy of 74%—not too shabby!

If you’re thinking that 74% is a little bit low, consider that this rate is higher than those attained by the predictive methods we use today, like neuropsychological testing, the researchers said. Plus, it lets a robot do most of the heavy lifting and helps people avoid the big expenses and invasiveness of brain scans and spinal taps for diagnosis. Researchers trained AI algorithms on hundreds of short, noninvasive, standardized speech samples and tested it on speech samples taken from 80 people who had not yet showed signs of cognitive decline. While the AI likely won’t replace the predominant forms of diagnosis, it can assist by recommending people for brain scans, where their disease could be detected earlier and potentially slowed.

New biomarkers for asymptomatic and symptomatic AD. We’re just gonna admit it—Alzheimer’s disease is getting worse, and despite our best efforts, we haven’t closed much ground on finding ways to achieve earlier diagnosis or better therapies. Maybe it’s time we ask ourselves why? That’s just what researchers at Emory University School of Medicine did in a new study. The answer? Alzheimer’s lacks protein biomarkers reflective of its diverse underlying pathophysiology. So what else can we do?

In their study, the Emory researchers leaned on integrative proteomics to identify CSF biomarkers representing a wide spectrum of Alzheimer’s pathophysiology. With multiplex mass spectrometry they identified ~3,500 and ~12,000 proteins in Alzheimer’s CSF and brains, respectively, and used network analysis of the brain proteome to resolve 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF Alzheimer’s disease markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Researchers found that synaptic and metabolic panels were decreased in Alzheimer’s disease brains but increased in CSF, while glial-enriched myelination and immunity panels were increased in the brain and CSF. These panels identified biological subpopulations within asymptomatic Alzheimer’s disease, too. The bottom line? These results are a promising step toward a network-based biomarker tool for Alzheimer’s disease clinical applications.

Brain imaging biomarkers could boost treatment response. When it comes to patients with post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), we have no way of predicting how standard treatments like antidepressants and psychotherapy will perform. That might change thanks to a new study that generates new evidence in support of a critical brain imaging biomarker that could help point people suffering from PTSD and MDD towards the most effective treatment.

Researchers used advanced machine learning techniques on data from high density resting-state EEG signals to identify robust and distinct functional connectivity patterns in brain circuits, enabling subtyping of patients independent of clinical diagnosis. Patient subtypes didn’t differ in terms of clinical symptom severity prior to treatment, but they had different responses to treatments. These subtypes were identified based on functional connectivity patterns found through low-cost EEGs. “These discoveries have significant implications as they help stratify individuals independent of clinical diagnosis based on what may represent a new transdiagnostic biomarker. This will enable discovery of a new generation of precision therapeutic discoveries and targeted treatments,” researchers said.

 A link between the gut and dementia in Parkinson’s. Allow us to introduce you to unacylated-ghrelin, which is most definitely not the name of one of those Orcs from The Lord of the Rings. Rather, it is the most prevalent form of ghrelin (acyl-ghrelin), a gut hormone with neuroprotective properties. A new study suggests unacylated-ghrelin can do something pretty incredible—it can suppress nerve cell growth in the hippocampus that affects special memory in mice.

Here’s where it gets even more interesting—the study team also found unacylated-ghrelin levels to be higher than normal in patients with Parkinson’s disease dementia. The findings highlight a previously unknown damaging effect of unacylated-ghrelin in the hippocampus, suggesting a potential link between this form of the hormone and dementia in Parkinson’s disease patients. Unacylated-ghrelin “represents an important target for new drug research, which could lead ultimately to better treatment for people with Parkinson’s,” study authors said. Their data also suggested the ratio between acyl and unacylated forms of ghrelin “could also serve as a biomarker, allowing earlier identification of dementia” in these patients.

Novel Treatments

A diabetes drug for a movement disorder? We’ve never studied pioglitazone for Parkinson’s disease. Why? Because pioglitazone is a diabetes drug. Physicians prescribe it, along with diet and exercise, to control high blood sugar. But there’s a brewing hypothesis in the field that points to diabetes as a possible risk factor for Parkinson’s, thanks to some studies that have indirectly shown that dopaminergic expression might be associated with insulin signaling. So is it possible that a drug like pioglitazone that effectively controls diabetes could have a positive effect on Parkinson’s incidence? Let’s review the data and find out.

Taiwanese researchers pulled data on 48,828 patients in the National Health Insurance database from 1996 to 2013, and categorized them equally into a pioglitazone or non-pioglitazone group. The number of patients with Parkinson’s in the pioglitazone and non-pioglitazone group was 275 and 417, respectively. Researchers found that the pioglitazone group had a lower incidence of Parkinson’s, with an adjusted hazard ratio of 0.66, with a dose-dependent benefit. As compared with either pioglitazone or statin treatment, results first showed that the combination of pioglitazone and statins further lowered the risk of Parkinson’s, with an adjusted hazard ratio of 0.78. The bottom line? Pioglitazone could be a promising agent for reducing the incidence of Parkinson’s in patients with diabetes—and it works synergistically with statins, too. Let’s see where else this neuro-endo collaboration could take us.

How about diabetes drugs for cognitive impairment? Okay, we’re not saying you should put all your patients on antidiabetics, but diabetes drugs do certainly seem to be in a position to make a big difference for patients suffering from neurological conditions. A new study suggests that our good friend pioglitazone and its antidiabetic compatriots intranasal insulin, metformin, and liraglutide could be useful in the treatment of Alzheimer’s disease.

It all started with this big idea: Considering that Alzheimer’s disease and diabetes share pathophysiological features and that Alzheimer’s still has no cure, why not give antidiabetic drugs a shot? In a new systematic review, that’s just what researchers did. They found 23 eligible studies with some incredible findings. Among them was data suggesting that intranasal regular insulin improved verbal memory, especially in apoE4 patients. Insulin detemir improved cognition after 2 months of treatment (although those results failed to sustain after 4 months). Pioglitazone improved cognition in diabetic patients with Alzheimer’s or mild cognitive impairment in three clinical trials, but had no effect in two. And metformin and liraglutide showed some promising results as well, but sample sizes were small. The big takeaway here is that the link between diabetes drugs and neurological disease is heating up. We’ll most certainly be watching closely.

Phase 2 biomarker study forging ahead. Progress is tough to come by in Alzheimer’s disease. Most of the time, when new discoveries happen, we’re left with a consolation prize—something like, “this could lead to better therapies for the condition.” In a new study, scientists are working hard to bring that promise to life. Alzheon, a clinical-stage biopharma company, has launched a phase 2 study that will evaluate the biomarker effects of ALZ-801, an oral treatment blocking formation of neurotoxic soluble amyloid oligomers, in patients with early Alzheimer’s disease who carry one or two copies of the ε4 allele of the apolipoprotein E (APOE4) gene.

The study’s primary objective is to assess the effects of ALZ-801 (265 mg oral tablets, administered twice daily for 2 years) on fluid and imaging biomarkers shown to be sensitive early markers of Alzheimer’s disease progression. The biomarkers selected for this study have been shown to correlate with clinical benefit in Alzheimer’s disease patients in trials with amyloid-targeted antibody therapies, but this is the first Alzheimer’s biomarker study to prospectively evaluate APOE4 carriers using CSF and plasma biomarkers, as well as volumetric MRI evaluating brain atrophy. Positive results from the study could “open the exciting possibility of preventive treatment for Alzheimer’s,” Alzheon’s chief medical officer said.

Status epilepticus showdown. Which drug do you think is the most effective second-line epilepsy treatment: Levetiracetam, phenytoin, fosphenytoin, or valproate? According to a new systematic review and meta-analysis, they’re all about the same. Researchers pulled together data from 10 randomized controlled trials and measured the success of levetiracetam against the other three by these main outcomes: Cessation of seizure activities; time to cessation of seizure activities; need for rapid sequence intubation (RSI); intensive care unit admission; recurrence of seizures at 24 hours; and adverse events and all-cause mortality.

They found that there was no significant difference in cessation of seizure activities when levetiracetam was compared with phenytoin, fosphenytoin, or valproate. In fact, no significant differences were found on any of the main outcomes of the review. The takeaway? Levetiracetam is comparable to its counterparts as a second-line treatment for pediatric convulsive status epilepticus.

New in Patient Management

Digging into depression and dementia. Scientists have known for some time that psychiatric disorders are associated with a higher risk for later-life dementia. It’s been theorized that depression increases inflammation in the brain, or that depression may be the first sign of brain malfunction. Now, researchers are looking into the potential connections between childhood trauma, depression, adult cognitive function, and risk of dementia in a new study published in the Journal of Neurology, Neurosurgery & Psychiatry.

Using linear and logistic models on data from 378 patients between the ages of 40 and 59 years, the researchers found that childhood trauma was linked to depression and reduced hippocampal volume. Additionally, they found that a poor performance on a face/name recall task was associated with depression, while childhood trauma was associated with lower hippocampal volume. The data has led researchers to conclude that depressive symptomatology, via multiple pathways, can be correlated with dementia risk.

Gut check for Parkinson’s drug. Our gut microbiome is known for doing some amazing things. But when it comes to Parkinson’s disease, it may be working against us—or at least the drugs we take to combat it. According to a new study published in BMC Biology, bacteria in the small intestine can deaminate—or remove an amino group from—levodopa, the main drug used to treat Parkinson’s disease.

Researchers found that while most of the levodopa that patients with Parkinson’s disease take is absorbed in the small intestine, 8% to 10% travels further to a more distal part of the gut—a percentage that increases with age and drug dose. In this part of the gut, the drug will encounter a bacterial species called Clostridium sporogenes, which can deaminate aromatic amino acids. In the study, researchers found that this contact led to a 73% reduction in gut motility after about 10 minutes, causing additional constipation. This is some seriously uncomfortable news for people suffering from Parkinson’s who use levodopa to manage the symptoms of their disease—one of which is constipation.

Focus on focal epilepsy. Focal epilepsy has more subtle symptoms than epilepsy proper. That means it often goes undiagnosed long enough to cause unexpected seizures. Bad, right? Well, according to a new study, it gets a whole lot worse: these unexpected seizures lead to big increases in car crashes, too.

Researchers at the NYU School of Medicine found that it can take an average of 2 years for physicians to recognize the early signs of focal epilepsy, particularly in a subset of patients with seizures that don’t involve uncontrolled movements of their arms and legs. Patients like these can have non-motor symptoms that include brief recurring hallucinations, strong senses of déjà vu, and dreamlike states when awake. In a study of 447 patients with focal epilepsy, they found that 246 were diagnosed as long as 6 years after experiencing initial symptoms. Among the study’s other findings, 23 patients reported having one or multiple car accidents before diagnosis. So how much could earlier diagnosis affect these outcomes? Researchers estimate that for every 13 diagnoses, one car accident could be prevented—that’s an estimated 1,816 prevented accidents nationwide.

A hard day’s night is harder on the brain. Sedentary jobs can be rough on the heart. But working too hard with your hands might spell disaster—not just for your muscles and joints, but for your brain as well, according to a new study from the University of Copenhagen in Denmark. Results showed that people doing hard physical work have a 55% higher risk of developing dementia than those doing sedentary work, a figure that stood even after adjustment for lifestyle, lifetime, and other variables.

The study, which pulled data on 4,721 Danish men, is the first to connect hard physical labor with an increased risk of dementia. It paints a rather nuanced contrast to the WHO guide to preventing dementia, which encourages physical activity as a means of dementia prevention. This study, though, suggests that the type of physical activity matters, and that there may be reason to believe that the physical activity you get at work has different effects than the kind you do for leisure. But how, exactly, does hard physical labor at work lead to brain damage? Researchers aren’t sure just yet. Until further studies are completed, they point to previous data suggesting that such work could negatively affect the blood supply to the brain.

Latest in Journal Summaries

Guillain-Barré syndrome associated with SARS-Cov-2 infection.

Association between cognitive declines and disability in activities of daily living in COPD.

Postanoxic electrographic status epilepticus and serum biomarkers of brain injury.

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Upcoming Medical Meetings

The following meetings are entirely virtual:

Society of Vascular and Interventional Neurology (SVIN) 13th Annual Meeting. November 18-21, 2020.

9th Annual Scientific Sessions of the Cardiac Neurodevelopmental Outcome Collaborative (CNOC 2020). November 18-20, 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.

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