Migraines linked to dangerous neurodegenerative disease, a diet for your brain, and a new risk factor for a common neurological condition

There’s a lot we still don’t know about COVID-19, but as time goes on the picture becomes a bit clearer. Unfortunately, it’s a pretty grim one. The virus has killed more than 775,000 people worldwide, damaged economies, and even those who survive tell stories of serious downstream difficulties, including some that affect cognition. In this issue, MDLinx helps you catch up with the latest science measuring COVID-19’s cognitive toll. But that’s not all—we’re highlighting Alzheimer’s-fighting foods, new links between obesity, migraines, and cognition, and a synthetic THC analogue’s promise for Parkinson’s management.

Neuro Flashback

Could we have seen the neurological effects of COVID-19 coming? As has often been the case during the pandemic, historical examples abound (whether we chose to pay them any attention is another question). The 2009 H1N1 pandemic, for example, was much more than just a respiratory illness. Literature reviews found that many patients experienced behavior changes after typical symptoms like fever subsided. Some even developed serious neurological illnesses, including seizures, encephalopathy, multiple sclerosis, and Guillain-Barré Syndrome. “Among the chronic manifestations, schizophrenia, Parkinson’s disease, mood disorders, dementia, and mental retardation have been hypothesized,” authors of one review wrote. It’s scary stuff, with horrifying implications for what’s to come in the wake of the current pandemic. While we can’t yet be sure how the coronavirus will affect our central nervous system, time is revealing the truth as we speak. Until that truth comes, history is there to give us clues that can help us get ahead of what’s coming.

In the News

A look into the future. By the time the worst of the pandemic began hitting the United States in April, people in Wuhan, China had been battling the disease for more than three months. We were slow to learn from them then, but perhaps we will pay attention now, as a new study out of the region suggests that 36% of patients with COVID-19 had neurological symptoms, including headache, changes in consciousness, stroke, and lack of muscle coordination. A smaller French study observed the same symptoms in 84% of patients. That’s scary to begin with, but to make matters worse, many of those symptoms persisted after people were cleared to leave the hospital.

Even though scientists have found the novel coronavirus in the CSF of infected patients, it’s still not clear how infection is causing neurological symptoms to manifest, or whether they could be prevented. Many US hospitals are trying to leverage new tech to monitor and image the brains of people with COVID-19, but there’s no guarantee these efforts will lead to immediate improvements in care or a reduction in neurological symptoms either. “Right now, we actually don’t know enough to say definitely how COVID-19 affects the brain and nervous system,” said Sherry Chou, MD, MMSc, a University of Pittsburgh neurology professor. “Until we can answer some of the most fundamental questions, it would be too early to speculate on treatments.”

The great flavorless headaches of 2020. Have COVID-19? Headaches are likely. Don’t have COVID-19? It’s probably still giving you headaches. Recovered from COVID-19? Don’t assume that the headaches will go away. New research published in Headache found that in a study of 139 patients with COVID-19, 59% reported new headaches during the acute phase of infection and 3.6% had persistent headaches 1 month after their fever and dyspnea subsided.

Anosmia (loss of smell) and ageusia (loss of taste) were also common, occurring in 60.4% and 58.3% of patients, respectively. These two symptoms were even more likely to persist. One month after fever remission, 14.4% of patients were still experiencing anosmia and 11.5% were still experiencing ageusia. But why? “We can speculate that cytokine release syndrome can induce headaches and that the levels of circulating pro-inflammatory cytokines can be elevated for several weeks in a sub-group of patients, maintaining headaches, as shedding of virus RNA has been shown to persist in body fluids for more than 6 weeks,” the authors wrote. 

Depression, anxiety, and COVID-19. You don’t need to have COVID-19 to have depression or anxiety, but if you have all three, it could be a sign that the virus is attacking your brain. In a new study published in the journal Laryngoscope, researchers conducted a prospective, cross-sectional telephone questionnaire of 114 COVID-19-positive patients to assess the severity of their loss of smell or taste, nasal obstruction, excessive mucus production, fever, cough, and shortness of breath during infection. Their objective was to find out whether depression and anxiety during infection were linked to other disease characteristics.

The links were clear: Depression and anxiety were more closely associated with a loss of smell and taste than with more severe symptoms of COVID-19, like shortness of breath, fever, and cough. “Intriguing explanations, ranging from highlighting the importance of chemosensory disturbance in emotional wellbeing (overwhelming even the impact of potentially lethal symptom manifestations of COVID-19) to demonstrating emotional disturbance as a possible CNS manifestation of COVID-19—must be considered and further studied,” the authors wrote.

The bad kind of breakthrough. Italian researchers are giving us another look at the possible downstream neurological effects of COVID-19 infection. In a new case report published in the Annals of Internal Medicine, they describe the first three reported cases of acetylcholine receptors (AChR) antibody-positive myasthenia gravis—a neurological condition caused by a breakdown in the communication between nerves and muscles that’s characterized by weakness and rapid fatigue—following COVID-19 infection.

The three patients—a 64-year-old man, a 68-year-old man, and a 71-year-old-woman—experienced symptom onset within 5 to 7 days after their fevers began. Several explanations exist, the authors said: First, COVID-19 infection may break immunologic self-tolerance of disease; secondly, antibodies directed against the virus proteins may cross-react with AChR subunits, because the virus has epitopes similar to components of the neuromuscular junction. Details remain scant, but researchers and neurologists should be on the lookout for increased cases.

Healthy brains love feasting on flavonoids. Sweet, earthy, delicious flavonoids are found in many of Mother Nature’s tastiest treats, from fruits and vegetables to chocolate, tea, and wine. In addition to being scrumptious and healthy, higher long-term dietary intakes of flavonoids can protect our bodies and minds: New research suggests such diets are associated with lower risks of Alzheimer’s disease and Alzheimer’s-related dementias (ADRD).

To arrive at these findings, researchers studied 2,801 individuals over the course of nearly 20 years. During that time, they identified 193 cases of ADRD and Alzheimer’s. After dietary adjustments, they found that individuals with higher intakes of flavonols, anthocyanins (a type of antioxidant that gives fruits and veggies a deep red, purple, or blue color), and flavonoid polymers were significantly less likely to develop AD or ADRD than individuals with the lowest intakes. Those who ate more flavonoids were 46% less likely to develop AD or ADRD, while those who ate more anthocyanins were 75% less likely, and those who ate more flavonoid polymers were 42% less likely. Researchers chalk the reduction up to flavonoids’ ability to increase cerebrovascular blood flow, scavenge free radicals, and reduce inflammation. Now go eat a blueberry!

Neuro Trivia

How much blood flows through the human brain each minute?

750 mL. That means we circulate one gallon of blood through our brains every five minutes. Over a lifetime, that’s enough to fill twelve and a half Olympic-sized swimming pools with blood, although we don’t recommend doing that.

Novel Diagnostics

Obesity weighing on the brain. Who’s at risk for migraines? We know that many sufferers have a family history of the condition and that they’re more common in women than in men. But new evidence suggests that obesity is also a risk factor. In a study published in The Journal of Headache and Pain, researchers found that total body obesity (TBO) and abdominal obesity (AO) were associated with a higher prevalence of migraine (45% and 29%, respectively) when compared to headache-free controls. The association was particularly strong in those under 50 years of age with TBO or AO, who experienced a 74% higher prevalence of migraines.

How do researchers explain this link? Some point to increased release of pro-inflammatory substances, neuroinflammation, and neuropeptides involving hypothalamic function in obese patients. What’s more, serotonin and orexin A, two neuropeptides that function as appetite regulators and that are also linked to obesity, could be linked to migraine pathophysiology. A clear causal explanation is hard to come by, but when combined with previous studies that demonstrated that weight loss reduces migraine symptoms, this study clarifies that neurologists should be urging their patients—especially those with migraine—to maintain a healthy weight.

From migraine to dementia. Super painful, never welcome, and always inconvenient, migraines are adding a new awful bona fide to their resume: they might be a midlife risk factor for dementia in later life. That’s the latest from a recent Danish study of birth cohorts between 1935 and 1956 that included more than 1.6 million people. Researchers found a 50% higher rate of dementia among people who had previously been diagnosed with migraine, even after adjustment for socio-demographic factors and several psychiatric and somatic morbidities. The rate of dementia was highest among individuals with more hospitalizations for migraine, and higher for patients with migraine with aura than in those with migraine without aura.

As if this news weren’t rough enough, researchers noted that their study only included migraine cases treated in hospital settings, which doesn’t account for any cases managed by general practitioners, potentially leading to an underestimation of the migraine-dementia association. In addition, studies show that general migraine prevalence is about 16% in Denmark, but the study only found a 1.3% prevalence—another factor suggesting a potential underestimation of this link.

The more biomarkers, the merrier. Plasma tau phosphorylated at threonine 217 (P-tau217) may have a horrendous name, but it also brings wondrous potential to usher in a brighter future, because it’s the latest candidate to show promise as a biomarker for Alzheimer’s disease, according to new data published in the Journal of the American Medical Association. Swedish researchers examined P-tau217 as a biomarker in AD using three cross-sectional cohorts among 1,402 patients, and found that it helped differentiate neuropathologically defined AD from non-AD in all three cohorts.

Differential accuracy was high across the cohorts, ranging from 89% to 98%. “Blood tests like p-tau217 have the potential to revolutionize Alzheimer’s research, treatment, and prevention trials, and clinical care,” said study senior author Eric Reiman, MD, executive director of Banner Alzheimer’s Institute in Phoenix. “While there’s more work to do, I anticipate that their impact in both the research and clinical setting will become readily apparent within the next 2 years.” We’ll certainly be watching.

Novel Treatments

More than motor symptoms. When we think of Parkinson’s, we tend to think of its motor symptoms. But there’s more to the disease that needs treating, including mood disorders, cognitive changes, and even hallucinations. New research suggests that the already approved nabilone, a synthetic tetrahydrocannabinol (THC) analogue, might be a great option to help ease these non-motor symptoms. In a phase II placebo-controlled, double-blind randomized withdrawal trial of 19 patients, researchers demonstrated the possible efficacy of nabilone in patients with Parkinson’s who had disturbing non-motor symptoms (≥ 4 points on the Movement Disorder Society-Unified PD Rating Scale). Researchers report that the results seem to be motivated by beneficial effects of nabilone on anxious mood and nighttime sleep issues.

In the nabilone group, patients saw their non-motor symptoms worsen by a factor of 1, according to a Movement Disorder Society test, while those in the placebo group saw their non-motor symptoms worsen by a factor of 2.63. Nabilone’s positive treatment effects were also reflected in patients’ self-ratings. On the other hand, 77% of the patients who took nabilone experienced adverse events including dizziness, dry mouth, and fatigue, although none of these were serious and no significant difference in AEs was found between those who took nabilone or placebo. While cannabinoid-related treatments like nabilone seem promising, the study size was small and much more evidence is needed before it becomes a legitimate treatment option.

MS therapy faceoff. A new study published in the New England Journal of Medicine has settled a bout between two heavyweight therapies for multiple sclerosis: ofatumumab, a subcutaneous anti-CD20 monoclonal antibody that selectively depletes B cells; and teriflunomide, an oral inhibitor of pyrimidine synthesis, which reduces T-cell and B-cell activation. The winner? Ofatumumab. The drug was associated with lower annualized relapse rates vs teriflunomide. To arrive at these results, researchers conducted two double-blind, double-dummy, phase III trials, where they randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab or oral teriflunomide for up to 30 months.

In the first trial, the annual relapse rate in the ofatumumab group was 0.11, and double that (0.22) in the teriflunomide group. In the second trial, those results held up. Annual relapse rates in ofatumumab were 0.10 and 0.25 in teriflunomide. In the pooled trials, the percentage of patients with disability worsening at 3 months was 10.9% with ofatumumab and 15% with teriflunomide. At 6 months, it was 8.1% and 12%, respectively. The most common adverse events were injection site reactions.

Facing your headaches head-on. Ever been upset about something and somebody told you to just get over it? Usually it’s not the best advice, but that’s the essential idea behind Acceptance and Commitment Therapy (ACT), a new therapy modality researchers are testing on people suffering from primary headaches. ACT is an empirically supported treatment for chronic pain, but it’s never been tested in headache sufferers. The big idea is to emphasize acceptance and valued living among pain rather than avoidance, which has been shown to increase pain potency and lead to lifestyle restrictions.

The results in headache sufferers are promising (they reported liking the treatment, too—more than half found it credible and acceptable). On average, 64% of ACT group participants showed significant reliable improvements across primary outcomes (including general disability, functional disability, and emotional disability) at 3 months, with the number reaching 70% improvement by the 6-month follow up. In addition, more than half maintained their effects at 12-month follow up. “These findings are comparable and better than the average improvement seen in behavioral treatment for migraine and [tension-type headaches], ranging from 33% to 55%, and provide additional support for the temporal consistency of the ACT approach across time,” the authors wrote.

First at-home oral treatment for SMA. The US Food and Drug Administration approved risdiplam on August 7, making it the first at-home, orally administered treatment for spinal muscular atrophy (SMA) in adults and children 2 months of age and over. The approval was based on results from two clinical trials: FIREFISH, in symptomatic infants aged 2 to 7 months; and SUNFISH, in children and adults aged 2 to 25 years. SUNFISH is the first and only placebo-controlled trial to include adults with types 2 and 3 SMA. In FIREFISH, 41% of infants achieved the ability to sit without support for at least 5 seconds and 90% were alive without permanent ventilation at 12 months, and reached 15 months of age or older. These results would not be expected in untreated infants with SMA.

In more than 450 patients, risdiplam exhibited a favorable efficacy and safety profile across the two trials. The drug is a survival motor neuron 2 (SMN2)-directed RNA splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. The most common adverse events were fever, diarrhea, and rash in later-onset SMA. In infantile-onset SMA, the most common adverse events were similar, with the addition of upper respiratory tract infection, pneumonia, constipation, and vomiting. None of these symptoms led to patient withdrawal from the trials. Next up, the drug’s manufacturer will seek its approval in Europe.

New in Patient Management

Statins, the trusty steed. Poststroke pneumonia is a scary thing. It causes the highest attributable mortality of all medical complications following stroke and affects as many as one-third of all stroke patients. Fortunately, a new South Korean study suggests statins could have a protective effect on these patients, significantly reducing their risk of pneumonia following a stroke. At this point we’re wondering, what can’t statins do?

To arrive at these results, researchers pulled claims data from the South Korean National Health Insurance Service and identified 7,001 patients with acute ischemic stroke and no prior history of pneumonia. During a mean follow-up of 2.96 years, they found that pneumonia occurred in 24.5% of patients. Those who were treated with statins saw a significant preventive benefit against pneumonia (Hazard ratio 0.86). Compared to no statin use, adjusted hazard ratios for current use of low-intermediate high-intensity statins were 0.88 and 0.49, respectively, suggesting a potential 51% reduction in poststroke pneumonia with statin treatment. The exact mechanism of action for pneumonia prevention remains unclear, but authors hypothesize that treatment with statins results in a protective immunoresponse against pathogens, and possibly the attenuation of tissue injury by proinflammatory pathways, which occur independently of statins’ lipid-lowering properties.

Getting ahead of Alzheimer’s? Start with the heart. From biomarkers to risk factors to genetics, we’re all looking for new ways to get ahead of Alzheimer’s disease. New research suggests there might be a straightforward way to make it happen: protect your heart health. The study, published in Alzheimer’s Research & Therapy, suggests that dyslipidemia and hypertension contribute to different neurodegenerative processes that make mild cognitive impairment worse. Also, dyslipidemia, especially in higher LDL cholesterol levels, may participate in Alzheimer’s specific neurodegeneration, while hypertension may contribute to cerebrovascular pathology. Finally, it’s possible that statin therapy could play a role in slowing the conversion from mild cognitive impairment to dementia.

How did researchers arrive at all these findings? They conducted a cross-sectional assessment of vascular risk factors and Alzheimer’s plasma and imaging markers, followed by a cognitive outcome assessment, on 295 patients newly diagnosed with mild cognitive impairment. At baseline, they found that higher LDL cholesterol level was associated with more advanced plasma biomarkers. In addition, a history of hypertension was associated with more advanced white matter hyperintensity, while statin therapy for dyslipidemia was associated with less advanced white matter hyperintensity. The mechanism underlying the interaction between vascular and Alzheimer’s pathology remains unclear, but this study marks a big step towards a better understanding.

The slippery slope of migraine pain. Recent research efforts mean new pharmacological treatments for migraine pain abound. Some patients are even trying Acceptance and Commitment Therapy (remember that? If not, check out the section on Novel Treatments). But for many, migraine pain lingers, even after receiving treatment. In fact, many migraine sufferers are resorting to self-medicating with opioids to beat the pain, even though doing so runs against the grain of clinical guidance and might cause them greater pain, according to a new study published in Neurology.

Of 2,388 respondents with migraine using prescription medications for acute treatment in the study, 36.3% reported that they currently used or kept opioid medications on hand to treat their headaches. Those who used opioids had significantly more comorbidities, greater headache-related burden, and poorer quality of life than those who didn’t. Males and those with higher BMI, anxiety, depression, and increasing headache frequency were at higher likelihood of using opioids. Those who had physician-diagnosed migraine or chronic migraine were less likely to use opioids. While the nature of this analysis doesn’t allow researchers to determine the causation behind opioid self-medication, further examination of the data may allow researchers to determine which patients are underserved by currently available migraine treatments.

Speaking of underserved, how about patients with dementia-related psychosis? How about their caregivers, too? Well, these two groups have joined forces with researchers in a new study presented at the Alzheimer’s Association International Conference to make it known: safe and effective therapies for patients with dementia-related psychosis are severely lacking. In the study, patients and care partners rated available treatments as less than moderately helpful in treating patients’ current symptoms, and more than 40% of patients and care partners reported no current treatment for dementia-related psychosis. Many of those who discontinued therapy did so because of serious side effects, poor tolerability, and lack of efficacy.

Here are some cold, hard facts to help paint the picture. Many patients with dementia experience dementia-related psychosis, which is associated with increased care partner burden, accelerated cognitive decline, and worse patient outcomes when compared with dementia without psychosis. Hallucinations—a hallmark of this condition—are associated with a 50% to 60% increased risk of institutionalization and death. The kicker? There are currently no FDA-approved therapies for dementia-related psychosis. Most patients are often treated on a short-term basis with existing antipsychotic medications, which bring unknown risks and uncertain benefits. Further research is sorely needed—both to better understand the side effects of current therapies and to uncover new ones.

Latest in Journal Summaries

Loneliness, sense of control, and risk of dementia in healthy adults.

Seismic imaging could deliver finely detailed images of the human brain.

National study: Pregnancy-related complications and risk of postpartum readmission for seizures and epilepsy.

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Upcoming Medical Meetings

The following meeting has been rescheduled:

American Academy of Neurology 73rd Annual Meeting (AAN 2021), to be held in Toronto, Ontario, Canada, has been rescheduled for April 17-23, 2021, in San Francisco, CA.

21st Annual Current Concepts in Sleep, to be held in Sarasota, FL, has been rescheduled for August 27-28, 2021. 

The following meeting has been cancelled:

Neuroscience 2020: The Society for Neuroscience (SfN) 50th Annual Meeting, Washington DC, October 24-28.

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