New, dangerous neurological effects of alcohol, a diet to save your brain, novel Alzheimer’s genes for effective therapy, and more 

COVID-19 got in the way of a lot of big plans, like that fitness routine that we totally would’ve gotten around to if the gym had been open. It also put the brakes on tons of sorely-needed scientific research. But the show must go on, and this week we find that things are looking especially promising in the ALS pipeline. Recent data also suggests that a new drug leads to incredible improvements in relapse rates for people with multiple sclerosis, and we find out just how much damage all that binge drinking we did in college (and quarantine) might have done to our cognitive health. (Hint: it’s a lot).

Neuro Flashback

Neurological diseases like multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease made their first appearance in the scientific literature in the last few centuries, but a few others have been around for a little bit longer. For example, the first historical record of epilepsy can be traced back to the ancient Babylonians, who described the condition in a treatise on medicine that was engraved on 40 stone tablets (slightly more crude than your iPad Pro) right around the year 2000 BCE. The Babylonians were moving the scientific ball forward more than 4,000 years ago! That’s pretty cool in its own right, but the coolest part might be the high degree of accuracy in their descriptions. The tablets covered many of the different seizure types we recognize today, placing ancient Babylonian science on the historical record loudly and proudly. Of course, these descriptions weren’t perfect and neither were the treatments—seizures were thought to be caused by evil spirits, so treatment was largely a spiritual matter with understandably underwhelming results. But hey, to their credit, we’re still a long way from a perfect understanding of epilepsy today, even 4,000 years later.

In the News

Boozy blackouts and the brain. Ever drank so much you passed out? Neither have we… Turns out the neurological consequences can be quite serious. A new study published in JAMA Network Open finds that heavy alcohol consumption increases the risk of subsequent dementia by 1.2-fold, but that’s not all. Those who reported drinking until they passed out—regardless of how much they drank on a weekly basis—had twice the risk of dementia compared with people who didn’t.

Researchers collected data from seven multicohort studies in the UK, France, Sweden, and Finland that included 131,415 participants without a diagnosis of dementia, making this the largest study to date to examine the association between alcohol and dementia. Overall consumption of alcohol and loss of consciousness due to alcohol was assessed at baseline. After a mean follow up of nearly 15 years, dementia diagnosis was examined. Risk for all-cause dementia, early- and late-onset dementia, Alzheimer’s disease, and dementia with features of atherosclerotic cardiovascular disease was higher in those who drank more often and in those who drank until they passed out. It looks like one who parties all the time, parties on borrowed time after all.

You’ve heard about the microbiome, but how about the mycobiome? Myco is a prefix formed irregularly from the Greek mukes, meaning fungus, or mushroom. So are we telling you there’s a host of fungus among our guts? Indeed we are—and it may have interesting links to the development of Alzheimer’s dementia. Here’s the low down:

A recent study found that patients with mild cognitive impairment harbor a specific signature of bacteria in their gut, and that a modified Mediterranean ketogenic diet (MMKD) improves the Alzheimer’s disease markers in CSF and the signatures of gut bacteria in these patients. Now, there’s new data to add to the mix: the mycobiome specific to patients with mild cognitive impairment has unique signatures. Scientists have found that distinct diets (like keto) can modulate the mycobiome in association with Alzheimer’s markers and fungal-bacterial co-regulation networks in patients with mild cognitive impairment. But what the heck does that mean? That means that the mycobiome (gut fungus) and microbiome (gut bacteria) work together—and the interaction between these two tiny little biomes and the food we eat could play an important part in determining our cognitive health. Truly fascinating, cutting edge stuff!

Genetic testing for autism spectrum disorder (ASD). Sometimes the best a doctor can do is make a professional recommendation and hope for the best. Perhaps unsurprisingly, recent evidence suggests that doesn’t always go so well. A new report in JAMA Psychiatry finds that even though several medical professional societies recommend offering chromosomal microarray (CMA) testing and Fragile X testing for people with ASD, only 3% of the 1,280 participants with confirmed ASD reported having undergone recommended clinical genetic testing.

The results highlight a dissonance between professional recommendations and clinical practice, authors of the study said. They pointed to several reasons to explain the gap: 1) study participants may prefer to avoid genetic testing for personal reasons; 2) insurance coverage may preclude some patients from participating; 3) limits to clinician knowledge and comfort with genetic testing; and 4) changes in genetic testing practices over time. Why give genetic testing for autism? According to spectrumnews.org, “There are no drugs tailored to particular autism mutations. But the mutations [identified in genetic tests] are often linked to other health problems, such as epilepsy, kidney problems, or obesity, so having the information could help prevent or treat those problems.”

CGRP antibodies help migraine, but how? If you prescribe calcitonin gene-related peptide (CGRP) antibodies to adults who suffer from episodic and chronic migraine, you’re likely to get some good results, mostly in the form of a reduction in monthly migraine days (MMD).That’s great, but here’s the catch: 66% of that reduction is from contextual effects—like the context in which the drug is given or expectations of improvement—which includes the placebo effect, according to new research published in Headache.

Previous studies have shown that CGRP antibodies’ treatment effect is due to the CGRP blockade as well as the context in which the treatment is given. This new systematic review assessed overall treatment efficacy alongside the proportion of contextual effect of CGRP antibodies in migraine patients. Researchers found that in patients with episodic migraine, treatment with CGRP antibodies reduced MMD by 1.5 days vs placebo. In those with chronic migraine, the active treatment was associated with 2.23 fewer MMD than placebo. But approximately two-thirds of the benefit of CGRP antibodies was due to the contextual effects rather than the direct effect of the CGRP blockade. That’s not necessarily bad for CGRP inhibitors—rather, it’s good for contextual effects, which “may offer a means to improve health outcomes for a modest investment by paying attention to patient expectations, physician behavior, clinical environment, and health system culture,” study authors said.

Neuro Trivia

How much of the oxygen in our blood is consumed by the brain?

Despite only comprising 2% of the body, our greedy brain consumes about 20% of the oxygen in our blood.

Novel Diagnostics

Novel genes associated with Alzheimer’s. For the scientific community, getting a grip on the functional role of genetic risk factors for Alzheimer’s is just one of many Holy-Grail-type tasks at hand. Just like everything related to Alzheimer’s, the effort is complicated, in this case by the fact that genetic influences are different from one brain region to another. Plus, they change with age. But now, a new analysis of region-specific co-expression networks reveals that Alzheimer’s-related risk factors could potentially be associated with brain region-specific effects on gene expression, and that these can be detected using a gene network approach.

Investigators found that co-expressions of the reproducible Alzheimer’s disease (RAD) genes are strongest in the cortical regions where neurodegeneration due to Alzheimer’s is most severe, and there was significant evidence for two novel Alzheimer’s-related genes—EPS8 and HSPA2. So why is this a big deal? It sets the groundwork for potentially ground-breaking future studies. In larger samples, analysis of gene expression in more fine-grained brain regions will allow investigators to draw conclusions about the influences multiple genes have on Alzheimer’s progression from preclinical to later stages. If researchers can use this data to validate differences in cross-regional correlation patterns between healthy and Alzheimer’s brains, scientific understanding of the mechanisms underlying Alzheimer’s progression would improve, potentially informing strategies for more effective therapies.

Tracing adolescent brain development to the womb. We might think of our brief stint in utero as one of unparalleled peace and relaxation, but the science suggests otherwise—our prenatal periods are more like the busy run up to the big show of life, where small setbacks can lead to big challenges down the road. A new study corroborates that narrative with this finding: In identical (monozygotic) twins, the twin with lower birthweight tends to have less brain connectivity by age 15.

Researchers focused on the limbic and default mode networks (DMNs), which are key regions for emotion regulation and internally generated thoughts, respectively. They recruited 106 healthy adolescent identical twins and followed them longitudinally from birth until an MRI session at age 15. Investigators found that lower birthweight twins had less efficient limbic network connectivity as compared to their higher birthweight co-twin, driven by differences in the efficiency of the right hippocampus and right amygdala when compared with their higher birthweight co-twin. On the other hand, there were no associations between birthweight and the DMN. “These findings highlight the possible role of unique prenatal environmental influences in the later development of efficient spontaneous limbic network connections within healthy individuals, irrespective of DNA sequence or shared environment,” the authors wrote.

A new marker to detect neurological deterioration. Here’s the takeaway from a new study published in BMC Neurology: Researchers have found a promising new neuroimaging marker for predicting early neurological deterioration (END) in patients with acute ischemic stroke who have severe intracranial arterial stenosis or occlusion (SIASO). So, what is it? Well, indulge us as we hit you with two more abbreviations: it’s APCVS on SWI, or asymmetrical prominent cortical vein sign on susceptibility weighted imaging.

Here’s how researchers got there. They recruited 109 acute ischemic stroke patients with SIASO who underwent SWI and found that 30 of the 109 patients (27.5%) developed END and 60 (55%) presented with APCVS on SWI. They also found that APCVS occurred in 80% of patients with END, but only 45.6% in patients without it. Patients with APCVS were more likely to have END (40%) than those without it (12.2%). APCVS was also a significant predictor of END in acute ischemic stroke patients with SIASO, adjusted for previous stroke history and acute infarct volume. So what happens next? First, further studies. Second, neurologists should mind the results, because APCVS might be a useful neuroimaging marker for predicting END, suggesting the importance of evaluating perfusion status.

A new non-invasive predictor of cognitive decline. Wouldn’t it be nice to have a new subclinical, non-invasive way to predict cognitive decline before it occurs? Researchers from Spain have pinned one down, cervico-cerebral stenosis. Here’s how they established the connection. First, they ran a population-based study that included a random sample of 933 patients with a moderate-high vascular risk, but no history of stroke or dementia. Then, subclinical carotid and intracranial stenosis was assessed at baseline visit and then followed up to determine incident long-term cognitive impairment.

After a median follow-up of 7 years, 91 patients (9.7%) developed cognitive impairment, 27 patients developed mild cognitive impairment, and 64 developed dementia. The incidence of cognitive impairment was significantly higher among those with subclinical cervico-cerebral stenosis (21% vs 9%). In multivariate Cox regression analyses, cervico-cerebral stenosis was independently associated with incident cognitive impairment (Hazard Ratio 2.07). Further studies will bear out the data, but until then, keep a keen eye on that stenosis.

Novel Treatments

New drug combo making a difference in ALS. Previous research has shown that both sodium phenylbutyrate and taurursodiol can reduce neuronal death—at least in experimental models. Now, the drug combo has made its way into human trials and is earning some small but significant results. According to a new study published in NEJM, sodium phenylbutyrate-taurursodiol resulted in a slower functional decline in patients with amyotrophic lateral sclerosis (ALS) than placebo over a period of 24 weeks.

To arrive at these results, investigators conducted a multicenter, randomized, double-blind trial of 137 patients with definite ALS who had onset of symptoms within the previous 18 months. Patients were randomly assigned in a 2:1 ratio to receive either sodium phenylbutyrate-taurursodiol or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R, ranged 0 to 48 with higher score indicating better function). The mean rate of change in the ALSFRS-R score was –1.24 points per month with the active drug and –1.66 points per month with placebo, for a difference of 0.42 points per month. Secondary outcomes, which included decline in isometric muscle strength and time to death, among others, were not significantly different between the groups. Researchers say larger and longer trials are needed to confirm the drug combo’s safety and efficacy, but initial results are promising.

New Orphan Drug designation for ALS. The promising news keeps rolling in for patients with ALS. The US Food and Drug Administration (FDA) has granted orphan drug designation to prosetin, a MAP4 Kinase inhibitor designed by scientists at Columbia University for the treatment of ALS. According to Project ALS, the nonprofit that subsidized the drug’s preclinical research, it took 6 years and more than 80 versions of the compound to get to prosetin. In early research, the drug displayed the ability to rescue motor neurons in cellular and animal models of ALS (how heroic!). The drug also crossed the blood-brain barrier with ease, and has been safe and well-tolerated in all tests to date.

A phase 1 clinical trial was due to start this summer, but has been paused because of concerns over the pandemic. Project ALS plans to initiate clinical studies in humans by the end of the year. Because of its new orphan drug status, prosetin is now eligible for new research grants, which could spur a more rapid and robust effort to develop the drug into a clinically useful compound. Although prosetin is still a long way from earning a spot as a viable treatment for ALS, initial results paint a promising picture and its status as an orphan drug means it should face fewer hurdles along the way.

Two new studies boost bona fides for pitolisant. Scientists and physicians are waking up to the positive data surrounding pitolisant, a histamine 3 receptor agonist/inverse agonist that recently garnered increased attention for its ability to reduce the burden of excessive daytime sleepiness and cataplexy without triggering any cardiac safety signals. Not triggering cardiac safety signals might not seem like much, but it’s pretty important—since cardiovascular diseases are comorbid in patients with narcolepsy, cardiovascular adverse events become a concern for those who take medication to treat their sleep condition.

In the first study, researchers pooled data from two randomized, placebo-controlled, 7- or 8-week studies and from one 12-month, open-label study. Mean change in heart rate from baseline to end-of-treatment was –0.5 beats/min with pitolisant and –0.2 beats/min with placebo. Mean change was also similar for pitolisant versus placebo in systolic and diastolic blood pressure, as well as QTc interval. No cardiac safety signals were observed up to the maximum recommended dose. In the second study, researchers pooled data from two randomized, placebo-controlled, 7- and 8-week studies of pitolisant in adults with narcolepsy. Mean change in the Epworth Sleepiness Scale from baseline was significantly greater for pitolisant compared with placebo. What’s more, a significantly greater percentage of patients treated with pitolisant were classified as treatment responders, and the decrease in mean weekly rate of cataplexy was significantly greater for the pitolisant group.

Ofatumumab crushing teriflunomide when it comes to MS relapses. A new post-hoc analysis from the phase 3 ASCLEPIOS 1 and 2 trials shows that ofatumumab has serious stopping power—compared to teriflunomide, patients with multiple sclerosis who took ofatumumab saw their annualized relapse rates drop by 50.3%. Ofatumumab also significantly reduced the number of both gadolinium-enhancing lesions by 95.4% and new or enlarging T2 lesions by 82% compared to teriflunomide.

It doesn’t end there. Ofatumumab showed a relative risk reduction of 38% in 3-month confirmed disability worsening (CDW) and a significant relative risk reduction of 46% in 6-month CDW. An additional post-hoc analysis showed that the odds of achieving no evidence of disease activity (no relapses, no MRI lesions, and no disability worsening combined) in the same newly diagnosed, treatment-naïve subgroup were more than 3-fold higher at the first year and more than 14-fold higher at the second year with ofatumumab vs teriflunomide. On top of all this, ofatumumab is the first and only FDA-approved, self-administered, targeted B-cell therapy for adults with relapsing MS. If you haven’t added it to your treatment arsenal yet, this data should help make the decision a bit easier.

New in Patient Management

Keeping comorbidities in mind. Everyone with neurological disease is just as likely—and in some cases, more likely—as everyone else to have common comorbidities like diabetes, cardiovascular disease, depression, and more. Why does that matter? Because those comorbidities can make a big difference in how effective your treatments will be. A new study published in the Journal of Neurology, Neurosurgery & Psychiatry finds that comorbidities are frequent in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and almost half of them have an impact on treatment choice.

In the study, researchers found that one or more comorbidities were reported by 75% of patients and potentially influenced treatment choice in 49% of cases, leading to a less frequent use of corticosteroids in these patients. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general population. Patients with diabetes had higher disability scores, worse quality of life, and a less frequent treatment response. The data can help physicians and patients with CIDP arrive at more realistic expectations for how effective frontline medications can be in treating CIDP.

More autism diagnoses, but why? In the 1960s, we estimated that as few as 1 in 10,000 people had autism spectrum disorder (ASD). In the 1980s, that number shot up to 72 in 10,000. In the 2000s, estimates suggested a 1% prevalence of ASD. Now, it’s 2%. How does the scientific community explain this steady increase? There’s little agreement among experts as to what’s causing numbers to climb so rapidly. Some speculate that environmental factors associated with ASD could be the culprit—phenomena like increasing prenatal air pollution exposure, paternal age, and maternal psychotropic medication use during pregnancy.

According to recent research, that’s probably not the answer. In a study of 22,678 twin pairs in the Swedish Twin Registry (STR) and 15,280 pairs in the Child and Adolescent Twin Study in Sweden (CATSS), evidence suggests genetic factors are more likely to underpin the increase in ASD diagnoses. The heritability of ASD diagnoses ranged from 0.75 to 0.97 and autistic traits showed a modest variance increase over time that was associated with increases in genetic and environmental variance, with the total variance increasing from 0.95 to 1.17 over time. What does that mean? Genetic factors played a consistently larger role than environmental factors in underlying ASD and autistic traits over time. While it can’t hurt to try to breathe cleaner air and practice safe maternal habits, environmental factors are not likely to explain the increase in ASD prevalence.

Post-op complications just got a little more complicated. The whole point of surgery is to improve health, but opening up the body, sticking in a bunch of instruments, and patching it back up is inherently risky. Complications following surgery are common, and now researchers are finding that these complications can be especially troublesome for older adults, who, in a new study, reported statistically significant decreases in self-perceived cognitive function in the year after surgery if they had one or more in-hospital complications. Certain types of complications, including respiratory and neural complications, made self-reported cognitive function even worse.

In the study, researchers followed 2,155 adults aged 65 years and over who were undergoing surgery and investigated the association between self-reported, in-hospital complications after surgery, as well as their results on a cognition survey at 30 days and 1 year after surgery. Having one in-hospital complication was associated with a decrease of 1.79 points on the survey, indicating lower self-perceived cognitive functioning. Having two or more in-hospital complications was associated with a 2.82 point decrease. Respiratory (–3.04 points), neural (–2.11 points) and general complications (–2.39 points) were associated with statistically significant decreases in cognitive function. The takeaway: Neurologists may consider teaming with geriatric specialists to intervene in the immediate perioperative period to reduce complications and mitigate cognitive decline.

How the tau depends on sex. By age 65, women have a 20% chance of developing Alzheimer’s, while men only have a 9% chance. Of the 5 million people living with Alzheimer’s in the US, 3.2 million are women. How does science explain this difference? It remains unclear, but new research suggests sex differences in tau distribution across the brains of older adults may play a part.

Investigators studied 343 clinically normal people (58% women) and 55 people with mild cognitive impairment (MCI; 38% women) from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative. They examined FTP-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest. Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle. β‐amyloid (Aβ)‐moderated sex differences in tau signal were localized to medial and inferio‐lateral temporal regions, and Aβ + women exhibited greater FTP‐signal than other groups. In all, the evidence suggests that tau vulnerability in women is not just limited to the medial temporal lobe, and it also significantly contributes to greater risk of faster cognitive decline.

Latest in Journal Summaries

TBI: Long-lasting blood-brain barrier dysfunction and neuroinflammation.

Magnesium vs conventional therapy for migraine.

Miglustat and swallowing outcomes in Niemann-Pick disease, type C1.

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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.

 

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