Your diet and stroke risk, ‘broad-spectrum’ treatment for neuro disorders, and what went wrong with an Alzheimer drug in late stage clinical trials?
Spring is in the air, and although we lost an hour this week, don’t let that deter you from catching up on the latest happenings in neurology. This week, we explore the link between nutrition and the brain, as well as some novel approaches for better diagnostics and treatment (ping-pong anyone?). And find how some unlikely factors play into the risk of neurological disorders, especially later in life.
Breaking through the blood-brain barrier. In July 2018, researchers discovered that they could safely access the blood-brain barrier (BBB) in patients with Alzheimer disease (AD) by using simple magnetic resonance-guided focused ultrasound combined with intravenously injected microbubbles. In preclinical models, they succeeded in reducing beta-amyloid and tau pathology by using this technique. Specifically, they directed ultrasound waves across focal points to generate microbubbles in the BBB, thus opening tiny gaps with microscopic precision. Because these gaps are sealed naturally within 24 hours, the process is safe. They replicated their findings in a small, phase 1 safety trial in humans. Their research is hoped to pave the way to finding new delivery methods for therapies that otherwise cannot access the BBB in patients with AD.
In the News
You are what you eat. Can your diet lower your risk of stroke? Absolutely, say researchers who found that a diet rich in nuts, vegetables, and soy will lower the risk of stroke more than a diet that includes meat and fish. They studied and followed two cohorts for an average of 6 and 9 years, respectively. All participants were from Buddhist communities in Taiwan, where a vegetarian diet is encouraged. In fact, about 30% of those in both groups were vegetarians. Compared with non-vegetarians, vegetarians ate more nuts, vegetables, and soy, and less dairy.
In the first cohort of 5,050 participants, 54 strokes occurred. Of these, ischemic strokes occurred at a rate of 0.21% among vegetarians, compared with 0.77% among non-vegetarians. This translated to a 74% lower risk of ischemic stroke in vegetarians vs non-vegetarians after adjusting for age, sex, smoking, and comorbid conditions. In the second group of 8,302 participants, 121 ischemic and hemorrhagic strokes occurred, at a rate of 0.88% among vegetarians vs 1.73% among non-vegetarians. Thus, compared with non-vegetarians, vegetarians had a 48% lower risk of overall stroke, a 60% lower risk of ischemic stroke, and a 65% lower risk of hemorrhagic stroke, after adjustment. Researchers noted that these study populations didn’t drink or smoke; thus, the results may not be generalizable to the global population. Nevertheless, it’s good news for vegetarians in Taiwan!
What’s good for the goose… In more nutrition news, infants may get a big boost in cognitive development if their moms eat more fruit during pregnancy. In the original CHILD Cohort Study, researchers found that eating fruit during pregnancy positively affected measures of cognition in infants up to 1 year after birth. But, they couldn’t establish a causal relationship. So, researchers from the University of Alberta did a follow-up study in rats to explore these findings. Rat moms’ diets were supplemented with fruit juice, and rat infants born to these moms performed significantly better on memory tests. It all seems pretty simple: Want smarter kids? Eat more fruit!
Internet connectability for neurons? Researchers have created a hybrid neural network that allows biological and artificial neurons from all over the world to communicate over the internet through a hub of artificial synapses. In Italy, researchers cultivated rat neurons in the lab, while, in Switzerland, researchers created artificial neurons on Silicon microchips. The research groups connected their virtual labs through a setup that controlled nanoelectronic synapses via devices known as memristors, developed at the University of Southampton. It was there—to Southampton, England—that spiking events from the biological neurons in Italy were captured and sent over the internet, where they were distributed to the memristive synapses. British researchers then forwarded the responses to the artificial neurons in Germany, also in the form of spiking activity. The chain also worked in reverse, sending responses from Germany to Italy via England. And voila! The artificial and biological neurons communicated in real-time and bidirectionally. Researchers anticipate that these findings will help advance the field of neural interfaces research. Talk about hooking up on a global scale!
Scrooge’s brain was not in sync? Researchers have now observed that different parts of the brain work in synchronization when making the generous choice, but these areas aren’t in sync when making the selfish choice.
For this study, researchers at Yale University tracked neuronal activity in monkeys that were given such a choice. Monkeys could either keep a drink of fruit juice to themselves or share it with another monkey. In another scenario, the monkey could give the fruit juice to another monkey or see it thrown away. For the most part, the monkeys usually kept the drink to themselves. But, in the second scenario, they preferred to give the drink to a friend rather than see it go to waste. In both scenarios, researchers found that when the monkeys were generous, neuronal activity between the amygdala and the medial frontal cortex were highly synchronized. But, when they were selfish, this synchronization was markedly suppressed. “We all know there are individual differences in levels of generosity,” said Yale neuroscientist Steve W. C. Chang, PhD, who led the study. “Maybe Scrooge did not have high levels of synchrony after all.” To that we say: Bah, humbug!
What oral phenomenon can wreak havoc on daily conversations?
Anomia is the impaired recall—but not comprehension—of words. It’s also known as anomic aphasia, amnesic aphasia, and nominal aphasia. The condition can be genetic or caused by damage to the parietal or temporal lobes of the brain by trauma, stroke, or a brain tumor. Anomia can also be caused by Alzheimer disease or other neurodegenerative disorders. Imagine how strange and frustrating it would be to forget the word for “milk,” for example.
Better blast diagnostics. In veterans exposed to battlefield blasts, brain trauma could now be easier to diagnose than in the past. This would be done with a series of tests that combine functional assessment with blood test and brain scans. Roughly 10% to 20% of veterans serving in Iraq and Afghanistan sustained mild traumatic brain injury (TBI), a risk factor for developing neurodegenerative diseases later in life. Researchers performed neuroimaging and blood analyses in veterans exposed to IED blasts on the battlefield. Veterans included in the study sustained between 1 and 50 blast exposures and had chronic behavioral and cognitive complaints. Using PET scans and a biomarker ([18F]AV1451 tau ligand) that lights up tau proteins upon imaging, researchers found that 50% of veterans had excessive retention of this biomarker. They also measured serum levels of Nf-L, another biomarker that has been reported in patients who suffer from mild TBI, neurodegenerative diseases, and other brain injuries. Levels of Nf-L were elevated in those veterans who had excess retention of [18F]AV1451 tau ligand. In a related study in rats, the same researchers found that those exposed to repetitive low-level blasts had a range of anxiety and behavioral traits that resembled PTSD, as well as accumulations of abnormal tau in nerve cells and astrocytes. Identifying these brain and blood biomarkers may help better diagnose and define risks in veterans who sustain blast-related TBI. Very useful indeed!
Blood test for early AD? Let’s have it! Monitoring the gene Presenilin 1 (PSEN1) could—in the future—help diagnose Alzheimer disease (AD) earlier. Researchers in Rome have discovered that methylation of PSEN1 is a common feature of AD. They analyzed DNA modification patterns that affect PSEN1 gene expression during brain development and during the progression of AD in mice. In mice that were prone to AD, PSEN1 gene overexpression was common, and in females only, associated with lower DNA methylation.
Researchers also checked their results in humans via post-mortem brain tissue analysis from patients with AD as well as pre- and post-natal infants and adolescents. They not only found an upregulation of the PSEN1 gene in patients with AD, but also a significant inverse relationship between gene expression and DNA methylation. To determine whether changes to DNA methylation were detectable in human blood, the researchers analyzed serum samples from 20 patients with late-onset AD and compared them with samples from 20 healthy controls. Those with AD had lower PSEN1-related DNA methylation compared with controls. Because lower methylation is detectable in the serum samples and is associated with higher PSEN1 expression, such blood testing may offer a new diagnostic method for early AD. And, another plus: It’s much less invasive than brain tissue sampling!
A broad-spectrum treatment for neuro disorders? Transcranial magnetic stimulation (TMS) may help treat a wide range of neurological disorders—including stroke, dementia, and migraine—according to results from a recent review. TMS uses a device that is positioned externally on a patient’s scalp to produce brief, magnetic pulses via one or two copper coils that penetrate to a depth of approximately 2 to 2.5 cm. This magnetic field can trigger changes in neuronal activity and neuronal communication, and can also change undesirable activities in the brain.
TMS can be both a stimulant and an inhibitor of cerebral activity. It also has few side effects and is well tolerated by most patients. It has already been shown to be effective in the treatment of major depressive and obsessive-compulsive disorders. The amount of research on TMS is staggering, with 1,641 studies testing the use of TMS to treat a wide array of neurological disorders. These included over 60 studies exploring how TMS can reverse or diminish the effects of early dementia alone! The most promising results were those on the treatment of acute migraine and primary progressive aphasia and the side effects of stroke. According to the researchers, TMS has opened the door for many new ways to tackle neurological diseases, and holds promise in improving brain functionality and network connections.
The grass is greener on the pharma side? For children and teens with epilepsy, pharmaceutical cannabidiol (CBD) offers much better seizure control than “artisanal” CBD, according to a preliminary study being presented at the upcoming American Academy of Neurology’s Annual Meeting. Pharmaceutical-grade CBD is FDA-approved to reduce seizures in two severe forms of childhood epilepsy: Dravet syndrome and Lennox-Gastaut syndrome. Artisanal CBD is manufactured using different techniques and can contain variable amounts of CBD. Neither form of CBD contains tetrahydrocannabinol (THC), the psychoactive ingredient that produces a “high.”
For their study, researchers reviewed the records of 31 children and teens with epilepsy. Of these, 22 took pharmaceutical CBD and 9 took artisanal CBD. The researchers found that those taking pharmaceutical CBD had four times the average amount of CBD in their blood than those taking the artisanal strains (124 ng/mL vs 31 ng/mL). Also, children and teens taking prescription CBD had a 39% reduction in seizures during the study, while those taking artisanal CBD had a 70% increase. So, for controlling seizures, at least, researchers would probably recommend patients get their CBD at the pharmacy, not the mom-and-pop pot shop.
Back to the drawing board? Lanabecestat does not slow cognitive or functional decline in those with early or mild Alzheimer disease (AD) dementia, according to results from the AMARANTH and DAYBREAK-ALZ studies. This news is particularly disheartening because lanabecestat is a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1, which was specifically developed to modify the clinical course of AD by slowing disease progression. In these two large, global, multicenter, double-blind, randomized clinical trials, researchers assessed the efficacy of lanabecestat to slow the progression of AD compared with placebo. Both studies were terminated early after a futility analysis, when researchers found that there were no consistent dose-related findings on either the primary measures—which included change from baseline on the 13-item Alzheimer Disease Assessment Scale (cognitive subscale)—or secondary outcomes.
New in Patient Management
An unexpected risk factor for AD As if things weren’t bad enough, researchers found that widowhood may be an important and understudied risk factor for the cognitive decline associated with Alzheimer disease (AD). Widowhood may actually accelerate cognitive decline in women already at risk for AD. Researchers assessed older, cognitively normal participants enrolled in the Harvard Aging Brain study. In all, 260 adults aged 62-89 years who had no cognitive impairments were categorized according to their marital status (married, widowed, or unmarried). Researchers measured ß-amyloid levels via PET at baseline, and then evaluated cognitive performance annually for 4 years. The widowed group demonstrated greater declines in cognitive performance compared with their married counterparts. There were no differences in cognitive performance between the married and unmarried groups. Among those with the highest beta-amyloid levels, widowers had the sharpest declines in cognition—up to three times faster than those who were married.
Social relationships can protect against cognitive decline. Being in a healthy marriage naturally affords opportunities for more emotional support and social engagement, which in turn leads to more cognitive stimulation. Widowhood not only negates these benefits, but is also a highly stressful life event. Although more study is needed, clinicians would do well to pay particular attention to AD risks in older widowers.
A stroke calculator for migraineurs? Predicting risk of ischemic stroke in patients with migraine with aura just got a little easier. Researchers developed the Migraine With Aura as a Risk for Ischemic Stroke (MARS) risk score using data from the Atherosclerosis Risk in Communities Cohort (ARIC) study—a long-running robust trial in which researchers have followed participants since 1987. Researchers used the MARS risk score to calculate five risk factors for stroke. Each was given points according to its potential to affect risk: diabetes (7 points), age over 65 years (5 points, regardless of age), heart rate variability (3 points), hypertension (3 points), and female gender (1 point).
Among the 429 ARIC participants with a history of migraine with aura, risk was classified as low (0-4 points), intermediate (5-10 points), or high (11-21 points). After a mean follow-up of 18 years, 32 participants suffered strokes: 3% in the low-risk group, 8% in the intermediate-risk group, and 34% in the high-risk group. MARS needs to be further validated, but clinicians may soon have a new tool to help predict risk of stroke!
Ping-ponging Parkinson disease. Also known as table tennis, ping-pong is an aerobic exercise that can improve hand-eye coordination, sharpen reflexes, and stimulate the brain. Now, researchers have found that playing ping-pong may improve the symptoms of Parkinson disease (PD). PD patients who took part in a ping-pong–based exercise program weekly for 6 months demonstrated improvements in their PD symptoms, according to a preliminary study to be presented at the upcoming American Academy of Neurology’s Annual Meeting in late April this year.
Researchers studied 12 people (mean age: 73 years) with mild-to-moderate PD who had been living with their diagnosis for a mean of 7 years. Participants took part in weekly ping-pong sessions for 6 months. Each session lasted for 5 hours, during which participants did stretching exercises followed by ping-pong exercises that were led by an experienced ping-pong player. The program was developed by ping-pong players from Fukuoka University in Japan specifically for patients with PD. At 3 and 6 months, participants demonstrated significant improvements in facial expression, posture, rigidity, movement slowness, and hand tremors. A few side effects occurred, including one fall and a backache. But, we can’t think of a better treatment for PD (or anything else, for that matter!) than ping-pong—non-invasive, effective, and fun!
Lifelong bad behavior? It’s structural. In a recent study, researchers found that people who exhibit bad behavior for most of their lives—specifically, life-course-persistent antisocial behavior—may have thinner cortexes and smaller surface areas in brain regions linked to antisocial behavior. This was not true, however, in those who exhibited antisocial behavior only during adolescence. Theirs is the first study to compare structural brain differences using neuroimaging in these two specific groups of ‘people with’ and ‘people without’ antisocial behavior. Researchers performed MRI brains scans on 672 participants aged 45 years who were then categorized according to patterns of behavior. In those with life-course-persistent antisocial behavior, the researchers found smaller mean surface area in 282 of 360 brain regions and lower mean cortical thickness in 11 of 360 regions compared with those without persistent antisocial behavior. This is the first time that researchers have found evidence to suggest that there are neuropsychological differences in people exhibiting life-course-persistent antisocial behavior vs those who do not, and these results could affect future diagnostic and treatment efforts in these patients.
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Upcoming Medical Meetings
North American Neuro-Ophthalmology Society (NANOS) 2020 Annual Meeting, in Amelia Island, FL, March 7-12, 2020
American Neuropsychiatric Association (ANPA) 31st Annual Meeting, in Philadelphia, PA, March 18-21, 2020.
The 2020 Lennox-Lombroso Pediatric Epilepsy Conference, in Boston, MA, March 20-21, 2020.
24th Annual Children’s Neuroscience Symposium, in Phoenix, AZ, March 20-21, 2020.