New study discredits a decade of research, a first-of-its-kind MS therapy, and a new Alzheimer’s risk factor

This week, researchers added tons of new options to the neurologist’s diagnostic and preventive toolkit, including a simple algorithm to predict Parkinson’s disease risk, more robust data on common risk factors, and new biomarkers. But that’s not all. This week, we highlight several new treatments you’ll want to try (including the first self-administered B-cell therapy for MS), and one that you should probably give up on.

Neuro Flashback

You probably know Broca’s area, the region in the frontal lobe that’s linked to speech production and language processing. But did you know that it’s named after Pierre Paul Broca, a French physician, anatomist, and anthropologist who not only had the burliest sideburns of the 19th century, but was also the first person to provide anatomical proof of the localization of brain function back in 1861? Broca was an absolute fiend for brains—he studied them in living patients with traumatic brain injury and kept hundreds of samples in jars, which can now be found in special collections at the Pierre-and-Marie-Curie University in Paris. (Broca’s brain is there, too!) He can also stake claim to Broca’s aphasia—partial loss of the ability to produce language—as another medical namesake. His discovery of Broca’s area revolutionized the understanding of language processing, speech production, and comprehension, and laid the framework for new research into the area, which is still improving our understanding of speech disorders today.

In the News

A first-of-its-kind MS therapy. You know what’s really bad for medication adherence rates? Injectables that have to be administered in the clinic. You know what’s not so bad? Avoiding the infusion center altogether, but still getting the medication you need—especially when that medication works. That’s the promise of ofatumumab, the first and only self-administered, targeted B-cell therapy for patients with relapsing multiple sclerosis, which was approved by the FDA on August 20.

The approval was based on two phase 3 studies that demonstrated significant reductions in the risk of relapses, confirmed disability progression, brain lesions, and new or enlarging lesions. According to a post-hoc analysis, ofatumumab may halt new disease activity in patients with relapsing multiple sclerosis, with 47% and 89% of patients treated with the drug achieving no evidence of disease activity within the first and second year of treatment, respectively. Ofatumumab, which was previously approved by the FDA in 2009 for chronic lymphocytic leukemia, is expected to be available in the US as early as September 2020.

This Huntington’s risk factor is present in 29% of adults. And 63% of those aged 60 and over. Scary, right? Well, this risk factor also puts patients at risk for myocardial infarction, stroke, metabolic syndrome, and dementia. So what the heck is it? If you guessed hypertension, you guessed right. A new study published in Movement Disorders found that not only is hypertension a risk factor for Huntington’s disease, it’s associated with an earlier age of onset, too.

In the study, researchers found that participants with hypertension had a 29% increased annualized risk of motor conversion compared to normotensive participants with Huntington’s disease. While a previous study reported a protective effect of hypertension in Huntington’s disease, it didn’t account for that fact that hypertension increases with age. By controlling for this confounder, the authors were able to more accurately pinpoint the association between the age at hypertension diagnosis to demonstrate that hypertension may be associated with an early age of onset of Huntington’s disease. Keep an eye on those vitals.

Tragic neurologic outlook. We all know that patients with comorbidities fare worse when facing COVID-19. But a new study out of Lombardy, Italy, where the disease ran rampant before hitting American shores, sheds light on exactly how we can expect patients with neurologic conditions to fare against the disease. The answer? Much, much worse. In 173 patients with neurologic disease in the study, the 56 patients with COVID-19 had significantly higher in-hospital mortality (37.5% vs 4.3%), incident delirium (26.8% vs 7.7%), and higher disability overall than those without COVID-19. Patients with neurological disease and COVID-19 also experienced significant increase in stroke rates and worst stroke outcomes.

The not-so-silver lining in this study lies in the fact that conditions in the Lombardy hospitals were difficult—to say the least—during the time this data was collected. That means it’s possible the data is skewed because hospitals were overwhelmed and physicians were forced to provide care only to those who were most likely to have positive outcomes—potentially delaying or halting care to patients with stroke and other serious neurological conditions. Don’t get too hopeful, though. Despite that caveat, the situation on the ground in some US locales was, or is, similar to those seen in Lombardy during or near peak pandemic.

COVID mortality in Parkinson’s patients. We’ll shoot straight: it’s pretty bad. According to Johns Hopkins, COVID-19 mortality sits at around 3.1% in the US, on average. A new study published in Parkinsonism & Related Disorders paints a much more ominous picture for those who have COVID-19 and Parkinson’s—in 117 such patients included in the study, 23 died, suggesting an approximate mortality rate of 19.7%, or more than six times the national average of that in the US.

The good news is that this estimate is significantly lower than a previous one, which calculated Parkinson’s-COVID-19 mortality at 40% in a study of just 10 patients. What’s more, in this study, data was pulled from patients in four different countries, where mortality rates differ and are all higher than that in the US (Italy: 13.9%, Iran: 5.7%, Spain: 7.9%, and the UK: 12.9%). The bad news is that mortality in patients with Parkinson’s was still significantly higher than the highest recorded country (Italy). On top of that, study authors saw a significant effect of co-occurrence of dementia, hypertension, and Parkinson’s duration in those with COVID-19. Being homebound is usually a risk factor for worse Parkinson’s outcomes, but the pandemic continues to challenge everything we thought we knew.

Neuro Trivia

How fast can signals travel along neurons in the human body?

268 miles per hour. That’s 1 mph faster than the top speed of the world’s fastest car, the Bugatti Veyron Super Sport.

Novel Diagnostics

Serum albumin back at it again. A new study published in Neurology suggests that low serum albumin levels may increase the risk of Alzheimer’s disease dementia by elevating amyloid accumulation. How’d they get there? Researchers enrolled 396 older adults without dementia for comprehensive clinical assessments, measurements of their serum albumin levels, and multimodal brain imaging. They categorized each patient’s serum albumin as low (< 3.3 g/dL), middle (4.4 to 4.5 g/dL), or high (> 4.5 g/dL), and measured Aβ positivity, AD-signature region cerebral glucose metabolism (AD-CM), AD-signature region cortical thickness (AD-CT), and WMH volume, which were all used as outcome measures.

Investigators found that serum albumin levels were inversely associated with Aβ deposition and Aβ positivity. The low albumin group showed a significantly higher Aβ positivity rate compared to the high albumin group (OR 3.40), while the middle albumin group showed no difference (OR 1.74). So what does all this mean? Well, if we want better Alzheimer’s prevention, we’re going to need to pay more attention to serum albumin, especially in patients with low serum albumin levels.

Headaches make us depressed, and depression gives us headaches. Headaches, depression, and anxiety are like a rock and two hard places, according to new research published in The Journal of Head and Face Pain. Results from the study, which analyzed data from 16,788 respondents who were primarily white and female, suggested that people with either depression or anxiety alone are more likely to experience greater headache disability, and those with depression and anxiety together face the worst disability of all.

Depression was more likely in people with chronic migraines vs episodic migraines (57% vs 30%), as were anxiety (48% vs 28%) and coexisting depression and anxiety (42% vs 21%). After controlling for sociodemographic and headache features, investigators found that depression alone and anxiety alone were associated with 56% and 39% increased risk of moderate or severe migraine-related disability, respectively. The combination had an even greater effect (79%) on risk of moderate or severe disability. To make matters worse, previous research has found that people with comorbid depression, anxiety, and migraine respond differently to common treatments than those without depression and anxiety. If these are ineffective, researchers suggest that treating anxiety and depression aggressively can help—data points to reduced psychiatric symptoms as causing a downward curve in disability, even when they don’t improve migraine symptoms.

Smart screening for PD. Many of us think of algorithms as fancy, mysterious, AI-assisted magic, but the PREDICT-PD algorithm is anything but—it’s a simple questionnaire-based screening tool with a straightforward goal of identifying people with increased Parkinson’s risk. The best part? It just might work, according to new research published in Movement Disorders.

Investigators followed 574 study participants and issued PREDICT-PD risk scores to each, which were calculated based on risk factor assessments obtained at baseline in 2005. After a 5- and 10-year follow up, they identified 11 and 9 participants with incident PD, respectively. Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 after 5 years and 1.95 after 10 years of follow-up per doubling of risk scores. Higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, motor deficits, and signs of rapid eye movement sleep behavior disorder), and were significantly associated with higher probability for prodromal Parkinson’s disease. So far, so good! Next up: Larger studies in bigger patient populations.

Don’t you just love a study with a good-news title? We certainly do, so we’re going to share this one with you: Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterization of cognitive decline. It may be a little wordy, but it gets the job done, hitting all the key points and spreading the word on some positive, inspiring results. Here’s how it all went down, in a little more detail.

Researchers analyzed longitudinal blood collections from 115 people at 8, 4, and 2 years before neuropathological evaluation at death. They aimed to clarify whether the prediction of the eventual neuropathological confirmation of Alzheimer’s disease (as well as successful discrimination between AD and non-AD dementia pathologies) can be enabled by plasma phosphorylated tau181 (that’s p-tau181), measured years before the death occurred. They found that p-tau181 was related better to AD neuropathology and Braak staging vs a clinical diagnosis 8 years prior to post-mortem examination, and proved a high accuracy (97.4%) of plasma p-tau181 to differentiate AD from non-AD even 8 years before death was proven. All patients received a diagnosis of AD dementia during life. Good results, right? So, what happens from here? Plasma p-tau181 could be used as a rapid and cost-effective screening tool to help researchers select participants for therapeutic trials, or it could help clinicians confer earlier, more accurate diagnoses.

Novel Treatments

Your new cryptogenic sensory polyneuropathy treatment guide. Of the four most commonly prescribed medications for cryptogenic sensory polyneuropathy (pregabalin, duloxetine, nortriptyline, and mexiletine) which are you most likely to prescribe? According to new research published in JAMA Neurology, none of these four drugs were clearly superior in performance, but nortriptyline and duloxetine were the best tolerated and most effective for reducing pain in these patients. Food for thought for those currently prescribing pregabalin and mexiletine.

A Bayesian adaptive randomized clinical trial of 402 patients with cryptogenic sensory polyneuropathy found that all four drugs helped improve pain in at least some patients. So, even though nortriptyline and duloxetine were better tolerated and more effective in reducing pain, any of the four options could be prescribed if the others failed. What’s more, while these are the four most-prescribed options for patients with cryptogenic sensory polyneuropathy, they aren’t the only options—many physicians prescribe gabapentin, venlafaxine, tricyclic antidepressants, and other sodium channel inhibitors. “Additional comparative effectiveness research studies can be performed on those drugs, so physicians can have a library of data on all these drugs for CSPN,” the authors wrote.

Better late than never. Endovascular treatment (EVT) benefits patients after ischemic stroke due to large vessel occlusion even when delivered between 16 hours and 10 days after onset, according to a new study published in JAMA Neurology. Why is that big news? Because endovascular treatment in this patient population is usually administered to patients within a window of less than 16 to 24 hours after the time they were last known well (LKW).

In 150 patients with anterior circulation large vessel occlusion with moderate-to-severe neurologic deficits who arrived at least 16 hours after the time they were LKW (among 8,032 patients admitted for stroke or transient ischemic attack over 7 years), approximately one-third met eligibility for EVT. EVT was performed in 16% of these patients and was associated with 11-fold higher odds of having independent functional status at 3 months after stroke. This benefit was maintained during the inclusion period of 16 to 240 hours after onset, but there were downsides: patients who underwent EVT had a tendency toward an increased risk of intracranial hemorrhages. Results are promising overall, but the study was small and observational. Future randomized clinical trials are warranted to retest the hypothesis.

Pills or patches for Parkinson’s. Patients taking ropinirole for Parkinson’s disease can have it their way—the ropinirole patch is just as effective as the ropinirole tablet, while causing no serious safety concerns and maintaining superiority over placebo, according to a new study published in Movement Disorders. To arrive at these results, investigators randomized patients with Parkinson’s disease taking levodopa to receive the ropinirole patch (up to 64 mg/d), ropinirole tablets (up to 16 mg/d) or placebo once daily. The primary endpoint was change from baseline in the total score for the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at week 16.

Change in UPDRS at week 16 was –9.8 with the ropinirole patch, –10.1 with the ropinirole tablet, and –4.3 with placebo, demonstrating the patch’s superiority over placebo and non-inferiority with the tablet. In all three groups, most adverse events were mild or moderate and there were no safety concerns, the authors noted, adding that the ropinirole patch can be an alternative option for patients with Parkinson’s disease.

Drug for rare autoimmune disorder gets FDA nod. The FDA has approved satralizumab-mwge, a monoclonal antibody that targets IL-6, for the treatment of patients with neuromyelitis optica spectrum disorder (NMOSD) who are positive for anti-aquaporin-4 antibodies. NMOSD is an autoimmune disorder of the central nervous system that damages the optic nerve and spinal cord, and is often misdiagnosed as multiple sclerosis. According to the National Organization for Rare Disorders, NMOSD affects between 1 and 10 people per 100,000. Existing treatments include corticosteroids, azathioprine, mycophenolate mofetil, and rituximab.

Satralizumab-mwge’s approval is based on two phase 3, randomized, double-blind, placebo-controlled trials that investigated the drug as a monotherapy for NMOSD and as an add-on to baseline immunosuppressant therapies, respectively. Both studies’ primary endpoints were met. In the first study, the drug reduced relapses by 20% vs placebo. In the second, it had a similar effect, reducing relapses by 23% compared with placebo. “Having an approved therapy that can be administered subcutaneously in the home and has demonstrated an impact on the frequency of relapses is an important advancement for patients,” an investigator said.

New in Patient Management

Migraines. Muscle spasms. Excessive Sweating. Incontinence. And now, depression. What do all these conditions have in common (besides being pretty awful)? They can all be treated by onabotulinumtoxinA injections. A new study published in Scientific Reports found that these injections may be an effective treatment for depression. Researchers from the University of California San Diego used the FDA’s adverse event reporting system database to look for statistically significant differences between about 40,000 people who experienced an adverse event after being treated with onabotulinumtoxinA or other treatments for the same reasons.

They found that patients treated with onabotulinumtoxinA for six different conditions and in six different injection sites reported depression between 40% and 80% less often compared with those who received other treatments for the same conditions. Clinical trials are underway to test whether onabotulinumtoxinA can reduce depression when injected into the forehead, but this is the first study to demonstrate that its depression-beating effects could be realized at other injection sites on the body. “This finding is exciting because it supports a new treatment to affect mood and fight depression, one of the common and dangerous mental illnesses—and it’s based on a very large body of statistical data, rather than limited-scale observations,” the authors said in a statement.

Keeping on the topic of sticking needles in your forehead: A new review of randomized controlled trials over the past decade suggests that evidence for the effectiveness of acupuncture in controlling migraine is still limited. Now, that’s not to say that there’s no evidence for acupuncture’s efficacy in this area. There’s plenty, but authors of this review found that the evidence, collected from 49 randomized controlled trials, was not really the kind anybody should be using to draw conclusions.

Overall, researchers found that many emerging trials reported that acupuncture effectively treated migraine, mainly manifested as pain relief, reduced drug dependence, and prevention of recurrence. But several trials showed no difference between real and sham acupuncture. What’s more, the studies had relatively high risk for biases, so the quality of the evidence was too low to warrant clinical recommendation of acupuncture for migraine treatment. “To achieve international recognition of the effect of acupuncture in treating migraine, there is a need for more multi-center, large-sample, randomized controlled trials that use world-recognized evaluation methods and curative effect standards to develop standard criteria for selecting acupoints and creating treatment protocols,” the authors wrote.

Sleep apnea and Alzheimer’s disease. Sleep is critical for a healthy brain. Some evidence suggests that rather than resting, the brain actually cleanses itself of proteins that build up throughout the day, reducing the risk of dementia. New research published in The Laryngoscope supports this hypothesis: investigators found that obstructive sleep apnea (OSA) is independently associated with an increased risk for Alzheimer’s disease, and that treatment for OSA reduces the risk of Alzheimer’s disease in these patients.

Study authors monitored 3,978 patients newly diagnosed with OSA from 1997 to 2012 and 15,912 non-OSA patients. OSA was independently and significantly associated with a higher incidence of Alzheimer’s disease (hazard ratio 2.12). The average period of AD detection from the time of OSA occurrence was 5.44 years. Patients with OSA who received treatment via CPAP or surgery exhibited a significantly reduced risk of Alzheimer’s disease (0.23 incidence rate ratio) compared with those who didn’t receive treatment. “AD irreversibility renders OSA as a potential modifiable target for slowing or preventing the process of AD development,” the authors said. Now go get some sleep!

A little help goes a long way in PD. We know that Parkinson’s disease can take a serious toll on a person’s independence. For those who become homebound and can’t access neurologic care, the implications are serious. Fortunately, a new study suggests that patients with advanced Parkinson’s disease who are homebound experienced no significant declines in quality of life when they received interdisciplinary expert home visits, even when their disease became worse.

Study authors enrolled 27 patients with Parkinson’s disease who met Medicare homebound criteria in quarterly interdisciplinary home visits over one year. Each visit involved an evaluation by a movement disorders neurologist, a social worker, and a nurse. Disease severity, as measured by UPDRS, and quality of life were measured at visits one and four. Of 27 enrolled patients, 23 completed all four visits with high patient- and caregiver-reported satisfaction. After one year of home visits, total UPDRS worsened by a mean of 11.8 points, but there was no change in eight quality of life measurements. “Our findings highlight the disease severity and impaired [quality of life] of the advanced, homebound PD population, and the potential for novel approaches to foster continuity of care,” the authors noted.

Latest in Journal Summaries

Systematic review: Molecular biomarkers for spinal muscular atrophy.

Prognosis for ischemic stroke patients with prestrike dependency.

Stress hyperglycemia linked to poor functional outcomes following acute ischemic stroke and IV thrombolysis.

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Upcoming Medical Meetings

The following meetings have been rescheduled:

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

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.

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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