Is Dementia deadlier than we thought? Can we predict autism in the womb? Plus, how concussions can impact sleep quality
During the last week of summer break (yes, it’s really here) we’re zooming out to take a look at the big picture in neurology. What can we do to push harder for new Parkinson’s therapies? How can we undo damage done by degenerative diseases? Why aren’t we paying closer attention to racial disparities in neurological outcomes? In this issue, MDLinx is bringing you fresh stories to help you think outside the neurological box and prepare yourself for an end of the year that we all hope looks nothing like the beginning.
The scientific history of sleep is a long and complex one, but it officially kicks off around 500 BCE, when Alcmaeon of Croton, a Greek doctor and philosopher, postulated that sleep was the result of blood on the surface of the body withdrawing to the interior (good thing he was wrong). One hundred years later, Aristotle wrote that sleep is “a seizure of the primary sense-organ, rendering it unable to actualize its powers, arising of necessity…for the sake of its conservation.” Fast forward a few thousand years and scientists still haven’t come to a consensus as to why we sleep. The latest hypothesis: Our body uses sleep as a time to flush toxic metabolic particles out of the brain that accumulate during the day—this helps cleanse neurological connections that improve memory and ward off dementia.
In the News
Autistic people’s nerve cells differ before birth. Physicians typically do not diagnose autism in children until about 18 months of age, but new evidence could allow them to trace the disorder back to prenatal stages—a recent study suggests that atypical development starts at the very earliest stages of brain organization at the level of individual brain cells. So how did researchers arrive at this new discovery?
They modeled early brain development by isolating hair samples from nine autistic people and six neurotypical people, treating the cells with an array of growth factors and driving the hair cells to become neurons, much like those in the brain. The cells restarted their development as it would have happened in the womb, providing a window into our early brain development. At days 9, 21, and 35, the cells from neurotypical and autistic people differed significantly in a number of ways, suggesting that the makeup of neurons in the cortex differs in autistic and neurotypical brains early in development. Investigators were careful to point out that their goal is to form a better understanding of autism—not to prevent, cure, or eradicate it.
Worse than we thought. Three weeks ago, we reported on an awesome study—it found that dementia rates had decreased by 13% per decade during the past 25 years. Now, we have to give you the bad news: even with rates down, a new study published in JAMA Neurology finds that the condition could be nearly three times as deadly as we previously thought, representing a more important factor in US mortality than indicated by routine mortality statistics.
Of the 7,489 adults aged 70 to 99 years in the study, investigators found that approximately 13.6% of deaths were attributable to dementia, which was 2.7 times higher than vital statistics data. Numbers were roughly twice as bad for Black participants (24.7%) than for white participants (12.2%), and worse among those with less than a high school education (16.2%) than for those with a college degree (9.8%). “These results suggest that the mortality burden of dementia may be greater than recognized and highlight the importance of expanding access to population-based interventions focused on dementia prevention and care,” the authors wrote.
Undoing damage to myelin sheaths. Swedish researchers have pinned down an important mechanism that can be used to restore myelin sheaths, the thick fatty layer that protects axons and helps quickly transfer stimuli—even after their degradation from traumatic injury and degenerative diseases like multiple sclerosis. Led by neurobiology professor Claire Jacob, a team of investigators from the University of Fribourg were able to regenerate damaged myelin sheaths in mice by treating them with the active substance theophylline (which can be found in tea), thereby restoring their nerve cell function.
In a mouse model, the use of theophylline over a period of four days resulted in significant myelin sheath recovery. Restoration was particularly impressive in the peripheral nervous system, where they recovered completely. Recovery was also seen in the central nervous system to a lesser degree, as there was rapid and efficient rebuilding of myelin sheaths in both young and old mice. Theophylline appears to be “a very promising compound to test in future translational studies to accelerate and promote remyelination after traumatic lesions or in the context of demyelinating disorders,” the authors wrote. Next up, they plan to secure funding for additional trials.
Flu vaccines save lives (in more ways than one). Getting your flu vaccine can help you avoid becoming one of the thousands of people who die from the infection every year, but it may also help reduce your risk of Alzheimer’s disease, according to a new study from researchers at the University of Texas Health Science Center at Houston. They pulled data from more than 310,000 de-identified health records in the Cerner Health Facts database to explore links between flu shot adherence and Alzheimer’s disease.
Investigators found that overall, people who received at least one flu vaccination were 17% less likely to get Alzheimer’s disease over the course of their lifetime. More frequent flu vaccination and receiving vaccination at younger ages were associated with ever greater decreases in risk. More research is needed to determine whether this correlation can be tied to causation. In the meantime, the authors speculate that “some of the proteins in the flu virus may train the body’s immune response to better protect against Alzheimer’s disease…Providing people with a flu vaccine may be a safe way to introduce those proteins that could help prepare the body to fight off the disease.”
What causes the rare neurological disease kuru?
Kuru is caused by an infectious protein found in contaminated human brain tissue. The good news? You’ll never get it. Kuru has only been found among people in New Guinea who practiced a form of cannibalism—officially halted in 1960—in which they ate the brains of the deceased as part of a funeral ritual.
Losing sleep over head injuries. Headaches, nausea, dizziness, fatigue, and sleep problems. It’s common to experience all these symptoms in the days following a severe concussion, but some patients suffer these problems over the long-term, which can seriously affect their quality of life. Now, a new study from researchers at the Norwegian University of Science and Technology finds that lingering concussion symptoms can be especially detrimental to sleep, and that many concussion sufferers’ symptoms could last three months or longer, hinting at serious neurological complications.
In the study, investigators monitored 378 patients who had sustained concussions for one year following their discharge from two emergency rooms in Trondheim, Norway. These patients were compared to two control groups: patients with other types of injuries not involving the head, and volunteer participants without any head injuries. Compared to these groups, patients with concussion experienced increased need for sleep, poorer sleep quality, and more severe daytime drowsiness and fatigue—136 experienced sleep or daytime problems two weeks after injury, and of those, 72 patients, or 53%, had problems lasting three months or longer. Researchers said that their data suggests it may be time to personalize treatment for patients with concussions. Rather than treating all concussions the same, it might be more appropriate to address each patient’s specific concussion-related ailments.
The downstream consequences of poststroke infections. You had a stroke, now you have a poststroke infection. How much worse can it get? A whole lot worse, according to a new study from researchers in the UK. Contracting at least one poststroke infection increases the risk of early dementia (3 months to 1 year poststroke) by 44%, with stronger associations (84%) when hospitalized infections were included.
In the study, researchers collected data on 60,392 stroke survivors and found that 34.7% contracted at least one poststroke infection and 7.5% developed dementia from 3 months to 5 years after stroke, which is at the lower end of the reported range for poststroke dementia incidence. But how do they explain increases in dementia after stroke? Systemic inflammation, which impacts the progression of cardiovascular disease, partly explains the link. Major infection can also cause inflammatory brain changes, like those seen in multiple sclerosis. What’s more, infections are well-recognized to contribute to delirium, which is an independent risk factor for dementia. “Better understanding of this relationship will help to inform knowledge pathways to dementia poststroke and targeting of preventive interventions,” the authors wrote.
Matching an Alzheimer’s biomarker with a behavioral test. During the past decade, visual short-term memory (VSTM) binding tests have been getting attention for their sensitivity in identifying behavioral indicators of Alzheimer’s disease—especially when they require the binding of multiple features, like color and shape. Now, researchers have found another reason to put faith in the tests: A patient’s performance on the test correlates strongly with their amyloid tau levels—an Alzheimer’s biomarker—identified in PET scans.
In a new study, researchers compared VSTM performance with tau and amyloid concentrations in people who were certain to develop Alzheimer’s because they had an inherited presenilin-1 E280A mutation. VSTM performance correlated strongly with tau in the entorhinal cortex and inferior temporal lobe, and also with amyloid when examining asymptomatic carriers only. More studies are necessary to clarify the best time to issue these tests and verify their accuracy, but having VSTM available early on could allow treatment teams to flag individuals who warrant further diagnostic testing and improve Alzheimer’s clinical trials.
Protein and Parkinson’s. Here’s the idea behind one of the latest breakthrough studies for Parkinson’s: The disease is caused when a protein called alpha-synuclein (αS) “misfolds.” When this happens, it becomes distorted, malfunctions, and accumulates in large masses called Lewy bodies. Such masses consist of slender αS fibers that are toxic to dopamine-producing brain cells and cause them to die—this drop in dopamine triggers Parkinson’s disease symptoms. Most research on αS has taken place in test tubes, but researchers at the University of Bath in the UK know that this method overlooks the fact that in the living brain, αS fibers form in the presence of phospholipids—large fatty substances that make up cell membranes.
In a new study, investigators examined how αS misfolds in the presence of phospholipids, and discovered a series of misfolded protein structures that have never been observed. These new αS fibers were larger and took on a variety of shapes. This discovery lays the groundwork for a new era of research into Parkinson’s, and a detailed analysis of misfolded αS fibers. “The discovery of these structures in the presence of phospholipids may have far-reaching implications in our quest to find a disease-causing form of the protein,” researchers said.
Accelerating Parkinson’s therapy development. A clinical trial is a huge logistical, costly, and time consuming undertaking. To get a single therapy approved can take the better part of a decade. And despite 30 years of these trials, not one therapy has been found to successfully delay or stop the progression of Parkinson’s disease. It’s time to speed up the process, according to a new report published in the Journal of Parkinson’s Disease.
But how? The new report explores the potential of using a multi-arm, multi-stage (MAMS) trial platform to evaluate several potential therapies at once, using lessons learned from trials in other diseases, like prostate, renal, and oropharyngeal cancer. MAMS trials test many potential therapies at the same time, transitioning seamlessly through phases (eg, from a phase 2 safety and efficacy study to a phase 3 trial). Early analyses allow unsuccessful therapies to be replaced, and at interim checkpoints, ineffective arms can be dropped, allowing for continuous evaluation. “There are many promising drugs in the pipeline that have potential to slow down the progression of PD, but taking that hypothesis to the test is still a long and cumbersome process,” said Bas Bloem, MD, PhD, Co-Editor-in-Chief of the Journal of Parkinson’s Disease. “The new approach described here holds great promise for facilitating this complex procedure, so that we can gather the necessary evidence for new treatments much quicker than before.”
Fingolimod vs glatiramer acetate for MS. A new study published in JAMA Neurology pitted two dosages of fingolimod (0.5 mg and 0.25 mg) against glatiramer acetate (20 mg) to determine which was superior for treating patients with relapsing-remitting multiple sclerosis. The winner? Fingolimod. Compared with glatiramer acetate, the 0.5 mg dose of fingolimod performed best, reducing participants’ annualized relapse rate by 41%. The 0.25 mg dose also outperformed glatiramer acetate, but only by 15%, which was not statistically significant.
Why does this matter? Doses of fingolimod lower than 0.5 mg per day were never investigated during the drug’s clinical development program, so scientists had no way of knowing whether these lower doses were safe and effective (they were roughly as safe, but not as effective). The 0.5 mg dose not only improved annualized relapse rates, but brought improvements in other relapse-related outcomes, like a delay in the time to first relapse and an increase in the proportion of participants who were relapse-free at 12 months. Patients receiving the 0.5 mg and 0.25 mg doses of fingolimod saw significant reductions in T2 lesions and gadolinium-enhancing T1 lesions volumes from baseline compared with glatiramer acetate as well.
Lacosamide for tonic-clonic seizures. According to the results of a new double-blind, randomized, placebo-controlled trial published in BMJ, patients with a history of generalized-onset seizures had significantly lower risk (HR 0.54) of developing a second primary generalized tonic-clonic seizure (PGTCS) during 24-week treatment with lacosamide vs placebo. In the placebo group, median time to a second PGTCS was 77 days, but in the lacosamide group, less than 50% of patients had a second seizure, so this statistic couldn’t be estimated.
In patients who took lacosamide, freedom from PGTCS at 166 days was significantly higher (31.3% vs 17.2% in the placebo group), and consistent improvements were also observed across other efficacy endpoints, including median percent reduction in PGTCS frequency (–78% vs –57%), 50% responder rates (68% vs 57%), and observed seizure freedom rates (28% vs 13%-24%). Finally, lacosamide was generally safe and well tolerated in patients with PGTCS. The most common adverse events were dizziness, somnolence, and headache.
Immunotherapy combo for pediatric brain cancer. Combining immunotherapy with tumor necrosis factor (TNF) eradicated medulloblastoma in mice, paving the way for future studies to test its safety in humans, according to investigators at Sanford Burnham Prebys, a nonprofit medical research institute in San Diego, CA. Standard treatment for medulloblastoma—a deadly type of pediatric brain cancer—includes surgery, whole brain and spine radiation, and intensive chemotherapy. But one in four children who contract the disease will die, and those who survive often suffer long-term side effects, like intellectual disabilities, hormonal disorders, and an increased risk of cancer later in life.
In the study, researchers investigated why immune responses differed between one mouse model of medulloblastoma with p53 protein mutations and one without. They found that tumors lacking p53 do not display the major histocompatibility complex I (MHC-I), an important protein that allows tumors to be recognized and killed by the immune system. Without MHC-I, tumors can’t be detected by the body and will continue to grow. But scientists found that low doses of TNF increased expression of MHC-I on p53-mutant tumors, to the point where the body detected and destroyed them. “This work suggests that adding TNF to immunotherapy could benefit medulloblastoma patients with tumors lacking p53,” a study author noted. “If p53 is missing, low doses of TNF may boost MHC-I to the levels needed for immunotherapy to work.”
New in Patient Management
COVID-19 and African American stroke patients. Bad news broke at the Society of NeuroInterventional Surgery’s annual meeting earlier this month: Two new studies suggest that in North America, mortality rates in African American stroke patients with COVID-19 are significantly greater than all other races combined, and that these patients have far worse poststroke outcomes, too.
In the first study, researchers found the mortality rate of COVID-19 positive stroke patients was greater than that previously reported in either COVID-19 respiratory infection alone or acute ischemic stroke alone, but could not identify reasons for these increased risks. In the second, researchers found that minority participants had increased post-procedural NIH stroke scores, length of stay, and ICU days. “Clearly it is important to better understand the reasons for increased mortality in African Americans with COVID-19-associated stroke,” study authors said. “It is our hope that further research will help us reduce racial disparities and prevent negative outcomes.”
Nutrition supplements for neuropsychiatric symptoms. Want to know the best nutrition supplements patients can take to improve their neuropsychiatric symptoms? Well, so do we. Turns out a new systematic review and meta-analysis suggests nutritional supplementation has no significant impact on patients’ results on the Neuropsychiatric Inventory (NPI) questionnaire, an informant-based instrument to assess a participant’s neuropsychiatric symptoms during the previous month.
This doesn’t mean that nutritional supplements don’t help at all—the generalization of these results is limited because patients used different supplements at different stages of dementia, and follow-up was short. The review pulled data from four studies with a total of 377 people with dementia, in which two studies included a multicomponent supplementation, one study included an omega-3 supplement, and one used a special supplement tailored for cognitive improvement. Over a mean follow-up of 18 weeks, pooled data showed that nutritional supplementation had no effect on NPI results. Still, authors suggested considering continuation of nutritional supplementation to prevent malnutrition.
Anxiety makes us lose sleep. Lost sleep causes anxiety. Curious how much worse sleep can be for people suffering from anxiety? Five times worse, according to new data published in Psychiatry Research—and worse still for minorities and men. Epidemiological studies suggest that 24% to 36% of people with insomnia also experience anxiety, and that the relationship between the two is bidirectional: Sleep disturbances may surface as symptoms of mental disorders and could play a role in triggering anxiety.
In the study, researchers found that out of 957 participants aged 18 to 86 years, 34% presented with an anxiety disorder. Anxiety presence was significantly higher in people with short sleep duration and much lower in people with long sleep duration. Anxiety also led to increased daytime sleepiness and insomnia symptoms, poorer sleep quality, and higher risk for obstructive sleep apnea. It was also much higher in people who didn’t exercise often. While the results are pretty convincing, this study took place in Greece and is not necessarily representative of circumstances in the US. That’s part of the reason why “this study dictates conduction of larger scale prospective studies in order to assess causality on the clinically important relationship between sleep characteristics and anxiety disorders,” authors wrote.
Caffeine for Parkinson’s. Good news for coffee lovers—an analysis of data from the Harvard Biomarkers Study shows that lower levels of caffeine consumption and lower blood urate are inversely associated with Parkinson’s disease, strengthening evidence tying higher caffeine intake and urate levels to reduced risk of Parkinson’s disease. Caffeine and urate possess neuroprotective properties via adenosine receptor agonist and antioxidant actions, respectively, and have both been shown to display protective properties in animal models of Parkinson’s disease, suggesting they could slow the condition in humans, too.
In this study, researchers conducted a cross-sectional, case-control study of 369 people with idiopathic Parkinson’s disease and 197 healthy controls. Their urate was measured in plasma samples, and caffeine intake was assessed at each participant’s initial visit using a questionnaire. Researchers found that caffeine intake was lower in idiopathic Parkinson’s disease patients compared to healthy controls, and the odds of having Parkinson’s decreased significantly with increasing caffeine consumption—the prevalence of Parkinson’s was more than 70% lower in the highest group, compared with the lowest caffeine consumption group. Before you recommend that your patients chug coffee, here’s the catch: caffeine hasn’t been rigorously studied in a long-term trial in patients with Parkinson’s disease, so its safety and efficacy can’t be confirmed—yet.
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Upcoming Medical Meetings
The following meeting is entirely virtual:
145th Annual Meeting of the American Neurological Association (ANA 2020). October 4-9, 2020.
The following meeting has been cancelled:
Neuroscience 2020: The Society for Neuroscience (SfN) 50th Annual Meeting, Washington DC, October 24-28.
The following meeting has been rescheduled:
2021 Congress of Neurological Surgeons (CNS) Annual Meeting, to be held in Miami, FL, has been rescheduled for October 16-20, 2021, in Austin, TX.