A new drug for faster MS diagnosis, lithium for Alzheimer disease, and nuts for cognitive decline
As usual, the world of neuroscience has been a buzz this week with new and exciting studies covering a range of different diseases, diagnostics, and treatments. For example, a new drug that could allow clinicians to actually see the damage to the myelin sheath caused by multiple sclerosis has been FDA-approved for its first human trials. In more exciting news, researchers have revisited the use of lithium—in a new encapsulated formulation—to treat Alzheimer disease, with fantastic results. Plus, the cognitive benefits of eating walnuts daily have been validated by results from the Walnuts and Healthy Aging Study. Plus, a whole lot more to catch up on this week!
Over 150 years ago, French neurologist Jean-Marie Charçot—known as the father of modern neurology—first described amyotrophic lateral sclerosis (ALS) in the medical literature. He initially named the condition Charçot disease in 1869, but later changed it to its current medical moniker (amyotrophic lateral sclerosis) in 1874. However, the disease is perhaps more commonly known as Lou Gehrig’s disease—named after beloved baseball player Lou Gehrig, who brought national and international attention to the debilitating condition.
According to the CDC, between 14,000 and 15,000 people in the United States have ALS, but the disease is also common worldwide. Heightened risk factors for ALS include age (55-75 years is a particularly high-risk time), sex (men), and race and ethnicity (Caucasians and non-Hispanics). However, the disease can affect people of all races, ethnicities, and socioeconomic backgrounds. The US Department of Veterans Affairs has also recognized ALS as a service-connected disease, with veterans 1.5–2 times more likely to develop ALS. However, the reasons underlying this association are unclear. Some researchers have suggested that exposure to environmental toxins, such as lead and pesticides, may increase the risk of ALS among veterans.
Notable individuals who’ve had ALS include, theoretical physicist Stephen Hawking, and actor David Niven.
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Getting an early start? Researchers have found that people who develop Parkinson disease (PD) before the age of 50 (young-onset PD) may have been born with disordered brain cells. Using cell samples from patients with young-onset PD, researchers grew induced pluripotent stem cells (iPSCs), and then used them to produce dopamine neurons from each patient. These neurons were then cultured and analyzed for neuronal function. Upon analysis, the researchers identified two key abnormalities. First, they noted that the neurons accumulated alpha-synuclein, a protein that is found in most forms of PD. Second, they found that the neurons exhibited malfunctioning lysosomes, which are responsible for protein breakdown and disposal. This malfunction could cause alpha-synuclein build-up. According to the researchers, these are the first signs of young-onset PD.
These defects in dopamine neurons could cause mishandling of alpha-synuclein over the next decades of life in affected individuals, eventually causing symptoms of PD to manifest. But, there’s a silver lining: The researchers found that PEP005 or ingenol mebutate—already FDA-approved for actinic keratosis—may reverse these cellular abnormalities by reducing elevated alpha-synuclein levels in dopamine neurons, as evidenced in both in vitro and preclinical models. Further studies are ongoing as researchers study how PEP005 could be delivered to the brain to treat or prevent young-onset PD.
Minty sensitivity? Can chewing a lot of minty gum change the way we process some sensory cues? Apparently, it can. In a recent study, researchers used functional MRI to assess the responses of 29 young adults to a trigeminal minty odor (L-menthol), non-trigeminal minty-odor (L-carvone), and a non-trigeminal non-minty odor (strawberry). Participants were divided into groups according to high or low frequency of gum chewing. Those who chewed minty gum experienced stronger activation in their trigeminal and somatosensory brain regions. Based on these study results, the researchers suggested that there may be an association between frequent exposure to minty odors and increased neurobehavioral sensitivity to intranasal trigeminal stimulation. More minty gum chewing equals more facial and motor function sensitivity? Maybe skip the minty gum before a dentist appointment…
Anemia and CVT: Not a good combo. Among patients with cerebral venous thrombosis (CVT), those who have anemia at admission may have a twofold increased risk of poor clinical outcome. This should come as no surprise, given that previous researchers have shown that anemia is also associated with poor outcomes in patients with ischemic and hemorrhagic stroke. These results are also significant considering that 9% to 27% of patients with CVT present with anemia at admission.
In a recent study, researchers assessed 874 patients with CVT, among whom 22% had anemia at admission. They defined poor clinical outcomes as a modified Rankin Scale score of 3-6 at last follow-up. Patients with anemia were more likely to have a history of cancer and were more likely to have poor clinical outcomes and increased risk of mortality. In fact, after adjusted analysis, researchers found that the risk of poor clinical outcomes were doubled in patients with CVT and anemia at admission. Something to consider when these patients present.
How heavy is the average adult human brain?
The average adult brain weighs about 1,300-1,400 g, or roughly 46-49 oz (2.8-3.0 lb). That is a lot of growth when you consider that newborn brains only weigh approximately 350-400 g (0.75 lb). Want some more “brainy” trivia? The brain is also comprised of 60% fat. As such, it is one of the fattiest organs in the human body. It is also an energy hog and gets about 20% of all the blood and oxygen produced by the body.
Seeing the unseen. A new drug that could aid earlier diagnosis of multiple sclerosis (MS) has been FDA-approved for its first human trial. Created by researchers at Case Western Reserve University, Myeliviz targets and binds to myelin sheaths, acting as a marker in PET imaging. It may help clinicians detect damage to the CNS caused by MS and accurately assess the extent of it. After uptake of Myeliviz, damaged myelin sheaths will appear as dark spots on PET images. This is big news, especially since myelin has never been directly imaged. Researchers are hopeful that Myeliviz will one day provide earlier, more accurate diagnosis of MS.
AI disease tracker? Predicting and tracking disease progression in patients with neurodegenerative diseases may have just gotten easier. Researchers found that artificial intelligence (AI) analysis of blood samples could predict and explain disease progression in these patients. They used an AI algorithm to analyze blood samples of 1,969 patients with either Alzheimer disease or Huntington disease in hopes of finding molecular patterns that were specific to these diseases. They also did a separate analysis of post-mortem brain samples. With the algorithm, they were able to detect aberrations in gene expression over time, giving them the first long-term view of these changes. This is of vital importance in neurodegenerative diseases, which usually develop over years. Even better—the blood test was capable of detecting 85% to 90% of the top predictive molecular pathways of post-mortem brain data. This lays the foundation for the future use of this blood test to help evaluate patients and individualize treatment. The next step will be to test the model in other diseases, including amyotrophic lateral sclerosis and Parkinson disease.
Lithium vs Alzheimer disease. Lithium treatment for Alzheimer disease (AD) is controversial. But, researchersrecently found that—when given in a microdosed formulation that enables it to pass through the blood-brain barrier—encapsulated lithium can both stop signs of advanced AD pathology and help recover lost cognitive abilities, and, in doses that were up to 400 times lower than those currently being prescribed for mood disorders.
The team used a newer encapsulated lithium formulation with good preclinical benefits in Huntington disease. Building on their previous positive research findings on greatly reduced lithium concentrations for early AD, they studied the effects of lithium in later AD in transgenic rats. Even in rats with later disease, low-dose lithium decreased the pathology of advanced AD-like amyloid plaques. Although they admit that it is “unlikely that any medication will revert the irreversible brain damage at the clinical stages of Alzheimer,” researchers continue to be hopeful. Smaller doses, increased blood-brain barrier permeability, decreased AD pathology. What’s not to like?
Getting some zzzzz’s. Daridorexant, a new antagonist for insomnia disorder, was found to be safe and effective, according to the results of a recent phase 2 randomized, double-blind, placebo-controlled, active-controlled, dose-response study. This is great news because there’s an unmet need for sleep medications that are safe, effective, well-tolerated, and do not have residual effects on next-day functioning. Daridorexant is a dual orexin receptor antagonist similar to suvorexant. Approved in 2014, suvorexant improved latency to sleep onset and the time to wake after sleep onset. However, improvements with suvorexant were mostly observed with doses higher than those currently approved for the drug.
In this study, 359 participants were randomized to daridorexant (5, 10, 25, and 50 mg), placebo, or zolpidem (10 mg). Researchers observed a significant dose-dependent reduction in wake time following sleep onset. They also observed reduced latency to persistent sleep compared with baseline. These reductions were sustained through days 28 and 29 of the study, respectively. Treatment-emergent adverse events were comparable to those seen with placebo and 10-mg zolpidem. None of these events were clinically relevant. A phase 3 trial of daridorexant is underway, and FDA approval is expected in mid-2020. You may soon have a new option in your armamentarium for treating insomnia.
Acupuncture vs propranolol? Researchers conducted the first head-to-head comparison of acupuncture and propranolol as first-line treatment for the prevention of migraine attacks. Propranolol is the recommended first-line treatment for migraine prevention. However, the researchers found that acupuncture was more effective in reducing migraine episodes in indirect comparison with propranolol. This is important news because it highlights the efficacy of acupuncture for migraine prevention.
For their review, the researchers included 19 randomized clinical trials in which acupuncture or propranolol were compared with sham acupuncture, placebo, waiting-list control, or usual care. Acupuncture demonstrated a significant advantage over propranolol in reducing migraine episodes over 4 weeks. It was also shown to have a significant advantage over waiting-list control in decreasing migraine frequency. Acupuncture was also associated with fewer adverse events compared with propranolol. Although these results need confirmation in further studies, it’s good to know that an effective option as simple and easy-to-access as acupuncture may have a role in preventing migraine attacks.
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This is your brain on hot flashes. Researchers of a preliminary study have just shown what we’ve all probably suspected: Menopausal symptoms can take over the brain! Well, that may be a bit dramatic…but, hot flashes were shown to decrease verbal memory and change brain function during the encoding and retrieval of memory—particularly in the hippocampus and prefrontal cortex. The researchers used functional MRI to document hot flashes and their effects on the function of the hippocampus and prefrontal cortex in 14 postmenopausal women (mean age: 53.5 years) with moderate-to-severe vasomotor symptoms (VMS) while they were engaged in several tasks (word encoding and recognition and memory testing).
They found an association between more physiologic—but not reported—VMS with worse verbal memory on immediate and delayed logical memory. During the coding task, physiologic (but not reported) VMS were associated with greater activation in the left orbitofrontal cortex, left medial and superior frontal gyrus, right superior frontal gyrus, and right parahippocampal gyrus. During the recognition task, physiologic VMS were associated with greater activation in the left medial and superior frontal gyrus, left parahippocampal gyrus and hippocampus, right medial and superior frontal gyrus, and right parahippocampal gyrus and hippocampus. VMS were also associated with decreased activation in the ventral medial prefrontal cortex. These preliminary results have yet to be validated, but consider them the next time one of your postmenopausal patients complains that her memory is failing, and that she can’t remember certain words.
Of proteins and soccer balls. Bad news for soccer players: Heading the ball too much is very bad for your brain—especially if you have a certain allele, according to a recent study. Researchers set out to determine whether having the apolipoprotein E Ɛ4 (APOE Ɛ4) allele—a common risk factor for neurodegeneration—and ball-heading in soccer are associated with verbal memory. They assessed 352 amateur soccer players (median age: 23 years) in the Einstein Soccer Study. Participants were genotyped.
Players completed the HeadCount 12-month Questionnaire every 3 to 6 months to estimate their 12-month exposure to heading soccer balls. Researchers used the International Shopping List Delayed Recall task (CogState) to assess verbal memory. They found that high exposure to heading soccer balls was associated with worse verbal memory performance. Although they found no association between APOE Ɛ4 and verbal memory, they did find a significant association between APOE Ɛ4, heading, and performance on the recall task. Players who were APOE Ɛ4-positive demonstrated a 4.1-fold greater association between poorer verbal memory and high exposure to ball-heading compared with low exposure. These individuals also had an 8.5-fold greater association compared with moderate ball-heading. So, having the APOE Ɛ4 allele puts soccer players who frequently head the ball at greater risk for worse memory. These results are proof that assessing players’ genetic risks could lead to playing safer soccer. Who knew?
Nuts to you! Did you know that eating walnuts could help slow cognitive decline in certain at-risk older individuals? This is precisely what researchers of the Walnuts and Healthy Aging Study found. The benefits were confined to elderly adults who smoked more and had lower baseline neuropsychological test scores. The omega-3 fatty acids and polyphenols in walnuts have been shown to mitigate oxidative stress and inflammation, both culprits in cognitive decline. Researchers studied 636 independent-living elderly people from Loma Linda, CA, and Barcelona, Spain, who included walnuts in their daily diets for 2 years. Participants from Barcelona smoked more, were less educated, and had lower baseline neuropsychological test scores compared with those from Loma Linda. Researchers found that in healthy adults, walnut supplementation had no effect on cognition. But, upon analyzing data from brain functional MRI and post hoc analyses by site, they found that walnuts may delay cognitive decline in those subgroups who were at higher risk. Not definitive results, but they are encouraging.
Kids-tested screening. Researchers have developed an easy way to predict drug-resistant epilepsy in children with cerebral palsy. After conducting a retrospective chart review of 188 children with cerebral palsy who either had drug-resistant epilepsy or controlled epilepsy, they came up with a simple predictive model that’s easy to apply in the clinical setting. Here’s what to look for: a low 5-minute Apgar score, neonatal seizures, focal-onset epilepsy, and focal slowing ion EEG. Screening your young patients for these simple features may help you—and them—achieve better seizure control.
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Upcoming Medical Meetings
53rd Annual Recent Advances in Neurology, in San Francisco, CA, February 12-13, 2020
American Society of Spine Radiology (ASSR) 2020 Annual Symposium, in Dana Point, CA, February 12-16, 2020
International Stroke Conference 2020, in Los Angeles, CA, February 18-21, 2020
North American Spine Society’s (NASS) Evidence & Technology Spine Summit, in Park City, UT, February 19-22, 2020