A breakthrough dementia drug, the dangers of being a ‘morning person,’ and common conditions lead to neurological repercussions

There’s nothing quite like waking up early on a crisp fall morning, sipping on a steaming cup of coffee, and watching the sun start to shine through the turning leaves. Or is there? As it turns out, even this simple pleasure might bring some serious risks for cognitive health. This week, MDLinx highlights the cognitive downsides of waking up too early, plus the ways hypertension and metabolic syndrome wreak havoc on the brain.


Neuro Flashback

The 1800s were breakthrough years for neurology. Scientists discovered and described multiple sclerosis, Huntington’s disease, Parkinson’s disease, and cerebral palsy—which was discovered  by a tag team of influential minds you may be familiar with. Dr. William John Little pioneered the study of cerebral palsy using his own childhood disability—clubfoot—as an inspiration. Sir William Osler, frequently described as the Father of Modern Medicine, wrote the first book on cerebral palsy. And Dr. Sigmund Freud, the father of psychoanalysis, posited that cerebral palsy might result from abnormal fetal development. In this regard, he was right—decades before the medical establishment embraced the concept.

In the News

Night owl’s revenge. Society loves a morning person. They’re up, dressed, and busy seizing the day before some night owls even make it home. But there’s always a catch, isn’t there? A new study published in Neurology finds that all those extra morning Zs may actually have a neuroprotective effect. In fact, the data suggests morning people could be at significantly higher risk for Alzheimer’s than those who sleep in.

In bidirectional two-sample Mendelian randomization analyses, researchers not only found that higher risk of Alzheimer’s was significantly associated with being a morning person, but that those who reported shorter sleep duration, fewer nights of self-reported long sleep (≥ 9 hours), a smaller number of sleep episodes, and earlier timing of a their least active 5 hours were also at much higher risk for Alzheimer’s. Higher risk of Alzheimer’s was also associated with lower risk of insomnia. Altogether, the data highlights a causal link between sleep patterns and Alzheimer’s risk. So next time someone’s calling you a lazy bum for sleeping in, pay them no mind—your mind will thank you.

Metabolic syndrome makes things much worse, much more quickly. Do you have patients with metabolic syndrome? Then it’s possible that their cognitive decline may happen at an alarming rate. A study of 823 Chinese adults aged > 55 years who were followed for more than 4.5 years found that metabolic syndrome was negatively associated with several cognitive domains, and that having more cardiometabolic risk factors was associated with worse declines in cognition.

Researchers found specific inverse cross-sectional associations of single cardiometabolic risk factors with cognition: central obesity with executive function; hyperglycemia with processing speed; and high blood pressure with processing speed, attention/working memory, and executive function. Dyslipidemia in particular was associated with significantly worse decline in memory and learning. And finally, these cardiometabolic risk factors taken together were significantly associated cross-sectionally with processing speed, executive function, and memory and learning.

What’s causing post-COVID-19 brain fog? You’ve probably heard about it in the news—both during and after COVID-19 infection, people’s brains just don’t seem to be working quite right. It’s not entirely clear how or why the coronavirus causes this phenomenon, known as “brain fog,” but a new report suggests neurologists looking to pin down a source ought to include post-traumatic stress disorder (PTSD) in the realm of possibilities.

Data on PTSD, brain fog, and COVID-19 survivors might be lacking, but that’s because the disease is so new. Historical data on previous human coronaviruses, such as SARS and MERS, gives us a glimpse of what could be in store. Survivors of these coronaviruses were at increased risk of PTSD-induced brain fog, so it’s entirely possible COVID-19 survivors will endure the same effects. Similarly, PTSD is known to occur in patient groups who undergo hospital courses similar to those who have severe COVID-19, including ICU survivors, patients who are intubated and mechanically ventilated, and those who experience delirium. So keep an eye out for PTSD—and its foggy neurological effects—in your patients who’ve had COVID-19.

Finally, some decent news around COVID-19 and neuropathology. We know we just spent the last two paragraphs scaring you with all the ways the pandemic is going to cause your patients trauma and wreak havoc on their cognition. But we believe in balance here at MDLinx, so here’s the other side of the coin. A new study published in The Lancet Neurology finds that neuropathological changes in patients with COVID-19 seem to be mild (phew!), with pronounced neuroinflammatory changes in the brainstem being the most common finding.

Here’s more solid news—in the postmortem case series of 43 patients, there was no evidence of CNS damage directly caused by SARS-CoV-2. This is the most comprehensive report of neuropathological findings of patients who died from COVID-19 to date. While it supported the hypothesis that SARS-CoV-2 can infiltrate the CNS, its presence there wasn’t associated with the severity of neuropathological changes. We must point out that absence of evidence is not evidence of absence, so keep your eyes peeled for future studies. But in the meantime, take this small piece of good COVID-19 news and cherish it—it’s all too rare these days.

Neuro Trivia

Can you name the researcher behind the debunked studies linking autism to vaccines?

The landmark paper that started the vaccine-autism conspiracy was authored by former physician Andrew Wakefield and 12 coauthors. His research was published in The Lancet in 1998 and wasn’t retracted until twelve years later in 2010.

Novel Diagnostics

RNAs and ischemic stroke. Ischemic stroke consistently ranks as a leading cause of death, but there’s no known treatment or cure. To make matters worse, scientists are essentially clueless when it comes to ischemic stroke’s pathological mechanisms. But researchers at Shandong First Medical University in Linqing City, China, are helping shed some light on the (gray) matter. In a new study, they identified differentially expressed microRNAs (miRNAs) and mRNAs that could be associated with the development of ischemic stroke.

In the study, researchers used differentially expressed mRNAs to construct a protein-protein interaction network followed by the functional annotation of mRNAs. In the process, they found up to 26 differentially expressed miRNAs and 1,345 differentially expressed mRNAs. They also identified several regulatory interaction pairs between miRNA and mRNAs, as well as the MAPK signaling pathway and the Notch signaling pathway. It’s pretty high science-y stuff, but suffice to say that these researchers were able to pin down eight differential miRNAs and mRNAs that have potential diagnostic value for ischemic stroke—a big leap from where we were before this study was published.

Better prediction after cerebral infarction. If you’ve ever had a patient with cerebral infarction, then you’ve seen what it can do to cognition. It’s not good. And now, researchers have gone as far as to say that cognitive impairment induced by cerebral infarction has become a legitimately devastating health problem. As such, we need better predictors so we can get ahead of it. Enter serum uric acid (UA) and high-sensitivity C-reactive protein (hs-CRP). These two factors have been reported to correlate with cognitive impairment, but understanding their link with cognitive dysfunction has been a big challenge.

We’re a step closer, thanks to a new study published in Dementia and Geriatric Cognitive Disorders. Researchers collected and analyzed clinical characteristics related to cognitive impairment, including age, sex, blood pressure, serum UA, and hs-CRP. They found that serum UA and hs-CRP were potential predictors for post-stroke cognitive function, and that higher hs-CRP levels correlated with worse cognitive impairment. There you have it—a new addition to the cognitive impairment prediction tool kit.

What does multifocal motor neuropathy progression look like? We know that multifocal motor neuropathy (MMN) is a rare neuropathy characterized by asymmetric muscle weakness and atrophy. But how does it progress? That’s less well known. Fortunately, we have a better understanding now, thanks to a new study that assessed the clinical course of the condition between May 2015 and February 2016 in a cohort of 100 patients—60 of whom had participated in a nationwide cross-sectional cohort study back in 2007.

Researchers found that age at diagnosis was significantly increased between 2007 and 2015-16 (45.2 vs 48.6 years), whereas diagnostic delay decreased by 15 months. They also found that seven of 10 outcome measures deteriorated over time. Patients who had a lower Medical Research Council (MRC) sumscore and absence of one or more reflexes at the baseline visit showed a greater functional loss at follow-up. While 87% of patients received maintenance treatment, their muscle strength, reflexes, vibration sense, and self-reported measures deteriorated significantly over time. The study, published in Neurology, provides Class II evidence that lower MRC sumscore and absence of reflexes predict the most progressive disease course.

Novel Treatments

New drug closer to approval for dementia with Lewy bodies closer to approval. It’s called neflamapimod, and no, it’s not the latest addition to the Pokémon family (but its powers might be just as astounding!). It’s an investigational oral small-molecular therapy that just earned some fantastic results in a new phase 2 study for the treatment of dementia with Lewy bodies (DLB)—a condition for which there is no cure and few available treatment options.

In the double-blind, placebo-controlled study, patients receiving neflamapimod three times daily demonstrated significant improvement on the Neuropsychological Test Battery (NTB) compared to those who received either placebo or neflamapimod twice daily. Statistically significant improvements were evident on multiple secondary clinical endpoints, too. The drug was well tolerated, with no treatment discontinuations in the study due to drug-related adverse events. Now that neflamapimod has passed the phase 2 proof-of-concept test, it’s on to phase 3.

We can’t always assume a drug works in kids, too. Calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) treatment works pretty well in adults with headaches. How about kids, though? Science abhors an assumption, so researchers set out to test the hypothesis, and they got pretty solid news. Results of CGRP mAb treatment in adolescents are similar to those reported in adult trials. That means CGRP mAb treatment appears to benefit at least some adolescents with chronic refractory headache disorders.

In the study, 112 adolescents received ≥ 1 dose of CGRP mAb. Mean age at first dose was 15.9 years. A total of 83.9% of these patients had chronic migraine, 10.7% had new daily persistent headache (NDPH), and 5.4% had persistent post-traumatic headache (PPTH). Mean baseline headache days per month was 26.9 and headache was continuous in 67.6% of patients. At the first follow-up visit, there was a 2-day reduction in headache frequency, and 29.5% of patients perceived significant benefit. Significant functional improvement, meanwhile, was perceived by 31% at the first follow-up and 22.4% at the second. The most common side effects were injection site reactions and constipation, and only five patients discontinued due to side effects. Chalk it up to an assumption proved.

Good results for cerebral palsy. How does “90 hours of fun” sound for your next cerebral palsy prescription? Here’s the backstory: Hand-Arm Bimanual Intensive Therapy (HABIT) is a new type of physical therapy intervention developed at Columbia University. It’s designed to help patients with cerebral palsy improve the use of both arms in daily function. It requires about 90 hours of intensive therapy, but it’s designed to be fun (and let’s be honest, who couldn’t use an extra 90 hours of fun right now?). The best part, though, is that it works. According to new study data published in Developmental Medicine & Child Neurology, HABIT succeeds in improving daily functioning in children with bilateral cerebral palsy.

In the study, researchers found that children participating in HABIT showed greater improvements in daily functioning and in the dexterity of their dominant hand compared with children who maintained customary care. But group or time effects didn’t explain any variance in bimanual performance or dexterity of the non-dominant hand. Still, children with asymmetric and symmetric hand use exhibited similar improvements after HABIT. Prescription: fun.

Not-so-good results for cerebral palsy. Results from the above trial of HABIT look promising, but unfortunately, a similar approach that measured the ability of progressive resistance training to improve outcomes in adolescents with cerebral palsy fell flat. In the study, 64 adolescents were randomized to usual care or to 30 sessions of resistance training over the course of 10 weeks. The primary outcome was gait efficiency indicated by net non-dimensional oxygen cost (NNcost). Secondary outcomes included physical activity, gross motor function, participation, muscle strength, muscle and tendon size, and muscle and tendon stiffness.

Median attendance to the sessions was 80%. Researchers found no between-group difference in NNcost at 10 or 22 weeks. Also, there was no evidence of between-group difference in any of the secondary outcomes at 10 or 22 weeks. On top of that, there were 123 adverse events reported by 27 participants in the resistance training group. The bottom line: 30 sessions of progressive resistance training of the ankle plantar flexors over 10 weeks didn’t improve gait efficiency; resistance training didn’t improve muscle strength, activity, or participation; and 90% of participants experienced an adverse event.

New in Patient Management

Hypertension and the brain. It pains us to say it, but half of American adults have hypertension. Such widespread prevalence may make it seem like we can look the other way and just accept it. As we mentioned in last week’s Neuro Brief, hypertension increases the risk of  ischemic strokes; but not only that, it also increases risk of aneurysms, brain fog, and dementia. Plus, a new systematic review finds those aren’t the only neurological conditions that hypertension worsens. Hypertension is also the most important risk factor for white matter lesions (WML) in the brain, particularly when it comes to diastolic blood pressure (DBP)—the association between DBP and WML is closer than the relationship between systolic blood pressure (SBP) and WML.

The systematic review gathered data from 12 studies, and found that increasing SBP and DBP both promote the progression of WMLs. But subgroup analysis found that patients with hypertension who were less than 70 years old were at a greater risk of WML progression when their DBP increased. “It is expected that more research will attach importance to the change in DBP and identify the range of blood pressure and strategies that control DBP, thus contributing to delay the progression of WMLs,” the researchers wrote. We’ll be keeping an eye out for that research.

Migraine differences in sexual orientation. There’s increasing recognition in the scientific community that migraine prevalence varies by race, sex, and socioeconomic status. But research into whether disparities exist depending on sexual orientation is harder to come by. Now, thanks to a new, first-of-its-kind study published in JAMA Neurology, we know that sexual orientation disparities in migraine exist, and they’re pretty significant.

In a sample of 9,894 adults with a mean age of 37.33 years, participants identified as exclusively heterosexual (85.8%), mostly heterosexual (10%), or lesbian, gay, or bisexual (4.2%). The prevalence of migraine was highest among lesbian, gay, or bisexual participants (30.7%) and mostly heterosexual people (30.3%). Comparatively, people who were exclusively heterosexual had a 19.4% prevalence of migraine. Researchers find possible explanations for this disparity in the fact that members of sexual minority groups experience prejudice, stigma, and discrimination—termed sexual minority stress—which could trigger or exacerbate migraine. What’s more, they may encounter barriers to healthcare and experience greater physical and mental health problems.

Sorry, no silver lining for SMA. Looking for some good news for people with spinal muscular atrophy (SMA)? Unfortunately, we can’t help, at least not right now. Researchers know that the disease causes declines in muscle strength, motor function, and maximal compound muscle action potential amplitudes (CMAPMAX), but how quickly does this decline occur? Are there periods of extreme downward trends? Plateaus? Ups and downs?

According to new research published in Neurology, declines in muscle strength and motor function in older patients with SMA are constant, with no periods of slower progression or plateaus. In the study, researchers included 250 patients with SMA types 1c through 4, with a median patient age of 26.8 years. Baseline muscle strength and motor function scores varied significantly between SMA types, but annual rates of decline were largely similar and mostly linear. Hammersmith Functional Motor Scale Expanded (HFMSE) floor effects were present for all patients with SMA type 1c, and adolescents and adults with types 2 and 3a. What’s more, the floor effects of the HFMSE precluded its use for long-term follow-up of adult patients with SMA types 1c through 3a. Instead, muscle strength sum scores could represent an alternative, feasible outcome measure for these patients.

Seizures and strokes. Seizures are risky business. In fact, observational cohort studies suggest that patients with epileptic seizures might be at increased risk of stroke. But should doctors use primary stroke prophylaxis when their patients have late-onset seizures? We’ll let the data help you decide.

In a new study published in Seizure, researchers pulled together data on patients ≤ 100 years of age with a first-ever stroke between 2001 and 2009, and stroke-free controls (matched for age and sex) in Sweden. They found that epileptic seizures prior to index stroke date were detected in 1,559 cases and 1,806 controls, yielding an odds ratio for stroke of 1.77. These ORs were similar in men and women, but higher below the age of 75 years. Seizure onset in the year preceding stroke date resulted in a higher risk for stroke (OR 2.21) compared to when more than 5 years had passed since the first seizure (OR 1.57). “The risk seems to be particularly high in the first year following seizure diagnosis, which supports the notion that unexplained late-onset seizures may merit swift assessment of vascular risk profile,” the authors wrote. So yes, primary stroke prophylaxis in patients with late-onset seizures may make sense.

When it comes to stroke, beware hyponatremia. Why the heck does hyponatremia lead to fatal complications in stroke? We still haven’t been able to pinpoint a causal relationship between the condition and its tough outcomes. But a new systematic review and meta-analysis moves us a little bit closer: The development of hyponatremia in the clinical course of stroke is associated with higher short-term mortality and longer hospital stay.

In the review, researchers pulled together 15 studies and defined the primary end point as mortality at 90 days. Secondary endpoints included in-hospital mortality and length of hospital stay. They found that the prevalence rate of stroke patients with hyponatremia across studies was between 7% and 59%. These patients had significantly higher 90-day mortality (OR 1.73) and longer length of hospital stay (by about 11 days) than patients without hyponatremia. Patients with hyponatremia also had a higher tendency of in-hospital mortality than those without. The bottom line? It appears clear that hyponatremia could be a significant predictor of seriously poor outcomes after stroke. Keep an eye out and stay ready.

Latest in Journal Summaries

Alzheimer-related cerebrovascular disease in Down syndrome.

Circadian abnormalities in older adults associated with Parkinson risk.

Radiological risk factors for neurological deficits after traumatic lumbar fracture.

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