Advances in Alzheimer’s risk factors, epilepsy breakthrough, and drinking’s effects on thinking

Summer is in full swing. And while the hot weather can lead to many lazy days by the pool, don’t fall prey to the dreaded “summer brain drain.” Keep your mind active by checking out this week’s edition of the NeuroBrief for the latest buzzworthy neuroscience news.

Neuro Flashback

There are a lot of bizarre neuro disorders out there. Take Capgras syndrome, for example. Named after French psychiatrist Joseph Capgras—who first described the disorder in 1923—Capgras syndrome is a neuropsych condition marked by delusion. Specifically, affected individuals believe that their loved one or someone they know has been replaced by a double or an imposter. (This is why Capgras syndrome is also sometimes referred to as “imposter syndrome.”) According to some research, a significant proportion of people with Capgras syndrome may also have a neurodegenerative disease, notably Lewy body disease. There’s no standard treatment for Capgras syndrome, but treating any underlying neurological condition can help to mitigate or cure symptoms. Therapeutic strategies may include antipsychotics, anti-anxiety drugs, surgery, or memory and recognition meds.

In the News

Why more women develop Alzheimer’s. About two-thirds of people with Alzheimer disease (AD) are women. But, why is that? The general thinking has always been that because women live longer than men, they’re naturally more likely to develop AD, a disease more prevalent in those of older age. But, a new study—the first to look at the impact of sex-specific risks on AD-related brain changes in midlife—shows that this might not necessarily be the case, with hormonal changes actually being the underlying factor. For their study, researchers enrolled 85 women and 36 men (mean age: 52 years) without cognitive impairment and who had similar thinking and memory skills, thyroid function, AD family history, vascular risk factors, and physical lifestyles. Participants had PET scans to detect any amyloid-beta plaques and neurodegeneration in the brain. They also had detailed brain MRIs to measure volumes of gray and white brain matter.

Compared with men, women had 30% more beta amyloid plaques in their brains, 22% lower rates of glucose metabolism, and 11% less gray and white matter volumes each. Menopausal status—specifically, lower levels of estrogen before and after menopause—was found to be the strongest and most consistent factor associated with AD-related brain changes. Interestingly, despite their poor results, female study participants didn’t show any reduced levels of cognitive performance vs male study participants. Researchers posited that certain biomarkers—like menopausal status and estrogen loss—may be more sensitive and accurate than standard cognitive tests in detecting AD risk in people not showing symptoms. The researchers pointed out that their results were only applicable to healthy, middle-aged adults without serious cerebrovascular or cardiovascular disease, so more studies are needed to validate their findings. Still, the study’s bottom line is clear: Menopausal status may be the best predictor of AD risk in women.

Can drinking be good for the brain? Have you heard this latest bit of “buzz”-worthy news? Researchers have just found that light-to-moderate drinking may preserve brain function in older age. Their study looked at the link between alcohol intake and changes in cognitive performance over ~10 years among US middle-aged and older adults. Nearly 20,000 participants completed surveys every 2 years about their health and lifestyle, including drinking habits. Light-to-moderate drinking was considered to be < 8 drinks per week for women and ≤ 15 drinks per week for men. Tests designed to gauge mental status, word recall, and vocabulary were used to determine cognitive function in participants, with test results combined to form a total cognitive score.

Compared with non-drinkers, middle-aged and older adults who had a drink or two a day tended to score better on all cognitive tests and had lower rates of cognitive decline. (The optimal amount was between 10 and 14 drinks per week.) And these associations were strongest among white participants compared with black participants. Because the study doesn’t prove a causal effect, it goes without saying that those who drink less shouldn’t start drinking more to prevent cognitive decline. But, for those who do enjoy a daily brew after work or a glass of wine with dinner, you can rest easy in knowing that your simple indulgence could be doing your brain a world of good.

New insights into epilepsy and the brain. Researchers have discovered a new step in how brain cells work in people with one of the most common forms of epilepsy, which may lead to new therapies for those with the drug-resistant form of the disorder. Studies have shown that changes in gene activity are associated with epilepsy development. Normally, messenger RNA is made when a gene is active, and this becomes the template for the creation of the proteins that brain cells use to work. An important step in this process is the addition of a short sequence called a poly(A) tail—which has never before been studied in epilepsy.

In this study, researchers found that this tailing process (aka polyadenylation) is significantly altered for about one-third of the genes in someone with epilepsy, changing protein production in the brain. This discovery helps explain, in part, why gene activity is so different in people with epilepsy. What’s exciting is that, in addition to the potential development of new targeted treatments for this neuro disorder, this new research could allow future study of something even better: epilepsy prevention.

Is there still a treatment gap in stroke? About 20 years ago, in the early 2000s (yeah, we can’t believe that was 20 years ago either!), studies showed that women were 30% less likely than men to receive clot-busting treatment for stroke. Now, new research shows that this treatment gap has narrowed by more than half. In a systematic review and meta-analysis of 24 studies on thrombolysis for acute ischemic stroke, which were published from 2008 through 2018 and involved more than 1 million stroke patients, researchers found that women had 13% lower odds of receiving IV recombinant tissue plasminogen activator vs men.

While this is better than 30%, it doesn’t explain why a gap exists and persists after all these years. After all, undertreatment has greater consequences for women, since they tend to have more serious disability and are more likely to die after a stroke than men, noted the researchers. One reason for this gap, the researchers speculated, may be that women are more likely to live alone and, because of this, may arrive later at the hospital or not be aware of when their symptoms started. To be effective, clot-busting treatment has to be given within a few hours of when the stroke occurs. Another possible reason may be that women suffering from stroke may present with atypical symptoms—like weakness, incontinence, or loss of alertness—making diagnosis more complicated or time-consuming and, again, rendering thrombolysis ineffective. But, in all, the improvements are certainly encouraging.

Neuro Trivia

Which of the five senses is the strongest memory retainer?

While a certain tune or shade of color can take you on a trip down memory lane, smell is actually the strongest memory retainer. The human nose can remember thousands of different scents. And, according to some experts, memories triggered by our sense of smell are often some of the oldest and most potent. (Just think of how you feel when you smell the perfume your mother used to wear when you were a kid, for instance.) Studies have shown that brain waves link smells through memories via an associative process that links neural networks through synchronized brain waves of 20-40 Hz.

Novel Diagnostics

Common mineral increases Alzheimer’s risk. Despite their numerous health benefits, sometimes vitamins and minerals can work against us. Case in point: Using MRI, researchers have found that iron accumulation in the brain’s outer layer is linked to cognitive decline in people with Alzheimer’s disease (AD). Previous studies have shown that deep gray matter structures in patients with AD have higher brain iron levels, so the researchers chose to focus on changes in brain iron levels in a more understudied region: the neocortex. But, because the neocortex is difficult to assess by MRI—due to poor resolution (distortions and artifacts) and limited scan time—they created a 3T MRI scanner to help address these issues. Using their newly developed MRI system, the researchers looked at baseline levels of brain iron in 100 people with AD and 100 age-matched, healthy controls. Of the 100 participants with AD, 56 had subsequent neuropsychological testing and brain MRI at a mean follow-up of 17 months.

The approach allowed researchers to create a map of brain iron, figure out iron levels in brain regions like the temporal lobes, or the brain regions underneath the temples, and the occipital lobes in the back of the head. They found higher iron accumulation in the deep gray matter and total neocortex, and regionally in the temporal and occipital lobes, in participants with AD vs controls. Brain iron accumulation was linked to cognitive decline independently of brain volume loss. And changes in iron levels over time in the temporal lobes was associated with cognitive decline in participants with AD. In all, the findings are in line with previous research showing that high concentrations of iron significantly promote amyloid beta deposition and neurotoxicity in AD. The good news is that this research suggests that drugs like chelators, which remove excess iron from the body, may have a role in AD treatment—specifically, in future clinical trials as a treatment target. In the meantime, the researchers posit that MRI-based iron mapping may be useful as a biomarker for AD prediction.

Diagnostic marker for Huntington disease. SAFB1 is an important protein that modulates gene regulation in the brain, and it’s similar in structure to other proteins tied to age-related neurodegenerative diseases. In a compelling new discovery, UK researchers have found a novel pathology that occurs in a number of human neurodegenerative diseases, including Huntington disease (HD). Their study describes how SAFB1 expression occurs in both spinocerebellar ataxia (SCA) and HD, and may be a common marker of these conditions, which have a similar genetic background.

Researchers wanted to find out if SAFB1 might be correlated with certain neurodegenerative conditions. So, they analyzed SAFB1 expression in the post-mortem brain tissue of controls and patients with SCA, HD, multiple sclerosis (MS), and Parkinson disease (PD). They found that, in the nerve cells of brain regions associated with SCA and HD, SAFB becomes abnormally expressed. Interestingly, both of these neuro conditions are linked to a specific pathology, known as a polyglutamine expansion, which only occurs in SCAs and HD. Not surprisingly, the same pathology was not observed in control, PD, and MS brain tissues. According to the researchers, their findings shed light on a previously unknown mechanism causing disease, suggesting that SAFB1 may be a diagnostic marker for polyglutamine expansion diseases like HD. More importantly, they were able to show how SAFB1 binds the SCA1 gene with the disease causing polyglutamine expansion, which could lead to new therapeutics. The researchers plan to broaden their scope of study to include other neurodegenerative diseases like Alzheimer disease, and to investigate whether blocking SAFB1 expression protects patients.

MRI technique hailed as a “smart” cancer biopsy. A new study describes how using an MRI technique called T1 mapping could help clinicians determine whether a child has an aggressive brain cancer and pinpoint whether a treatment is working. T1 mapping scans measure how water molecules interact at a microscopic level inside cells to help clinicians better understand the cellular make-up of tissue. These scans are typically used in patients with heart disease to assess damage to heart muscle tissue. According to the researchers, theirs is the first study to look at the benefit of this MRI technique as a “smart” cancer biopsy.

In this study, the researchers believed that T1 mapping scans could help improve the use of precision medicine in children with neuroblastoma by ensuring that treatments are personalized and quickly stopped when they aren’t working. So, they studied T1 mapping in mice with an aggressive form of neuroblastoma to get a better picture of the microscopic and physical characteristics of the tumor. They used artificial intelligence to map the different cell populations in tumors and then compared these maps with those created using non-invasive T1 mapping MRI scans. They found that areas with high T1 values were linked to hotspots of more aggressive cancer cells. Likewise, areas with low T1 values corresponded to more benign or dead tissue. The researchers also looked at whether the MRI approach could help determine how mice with neuroblastoma would react to two drugs—alisertib and vistusertib—which target MYCN, a key protein linked to aggressive forms of the disease. They discovered that when alisertib and vistusertib blocked tumor growth in mice, T1 values decreased, suggesting that T1 measures may be useful as a biomarker. Their next step is to assess the clinical benefit of T1 mapping as part of clinical study in children.

Novel Treatments

New FDA-approved seizure drug. The FDA has approved Fintepla (fenfluramine, Zogenix), a Schedule IV controlled substance, for the treatment of seizures associated with Dravet syndrome (DS) in patients aged ≥ 2 years. Fenfluramine’s efficacy was proven in two double-blind, placebo-controlled trials involving patients 2-18 years of age (n = 202) with DS who were inadequately controlled on ≥ 1 antiepileptic or other antiseizure drug. In both studies, the primary endpoint was the change from baseline in the frequency of convulsive seizures per 28 days, with the median longest interval between convulsive seizures also assessed. Results showed a statistically significantly greater reduction in convulsive seizure frequency with fenfluramine vs placebo. Plus, a reduction in convulsive seizure frequency was seen within 3-4 weeks of starting treatment. And this effect was consistent over the treatment period (14 weeks in Study 1; 15 weeks in Study 2). Fenfluramine use was also linked to a statistically significant longer interval between convulsive seizures vs placebo.

The most common adverse reactions associated with fenfluramine included decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, blood pressure increased, drooling, salivary hypersecretion; pyrexia, upper respiratory tract infection, vomiting, decreased weight, fall, and status epilepticus. Importantly, Fintepla carries a Boxed Warning regarding the risks of valvular heart disease and pulmonary arterial hypertension. Prior to starting treatment, patients must complete an echocardiogram to rule out conditions. And the test should be repeated every 6 months, and then once 3 to 6 months after treatment is completed. Because of these potential risks, the drug is only available through a restricted distribution program called the Fintepla REMS program. Fintepla will be available as a cherry-flavored oral solution containing 2.2mg/mL of fenfluramine in 30-mL and 360-mL bottles. It’s expected to be available through Zogenix’s specialty pharmacy partner by the end of the month.

First-in-kind therapeutic targets several neuro disorders. The FDA has approved the Percept PC Deep Brain Stimulation (DBS) system (Medtronic) with BrainSense technology for a range of neuro disorders. The Percept PC DBS system is a small pacemaker-like device implanted under the skin of the chest or abdomen that delivers electrical stimulations through leads to a targeted area in the brain. The system includes BrainSense technology that captures and records brain signals while delivering therapy to patients with Parkinson disease, essential tremor, dystonia, epilepsy, or obsessive-compulsive disorder. 

The tech will allow clinicians to tailor treatment using the DBS clinician programmer. They’ll also be able to track patient brain signals and correlate these with patient-recorded actions or experiences, such as symptoms, side-effects, or medication use. Patients, on the other hand, will be able to customize therapy to their desired activities using the patient programmer. The DBS system also includes expanded MRI eligibility (3T and 1.5T full body MRI scans), a smart battery for personalized prediction of remaining battery life, improved battery longevity with a smaller design for patient comfort, and low pulse width to expand stimulation options. The Mayo Clinic will be the first in the United States to implant the new device.

Promising Tx targets AD agitation. The FDA has granted Breakthrough Therapy designation to AXS-05 (Axsome Therapeutics) for the treatment of Alzheimer disease (AD) agitation (for which there is currently no approved treatment). AXS-05 is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. The designation is supported by the positive results from the multicenter, double-blind, placebo-controlled phase 2/3 ADVANCE-1 study of the efficacy and safety of AXS-05 in 366 patients with AD agitation.

Patients were randomized to receive AXS-05, bupropion, or placebo. The primary endpoint was the change from baseline to week 5 in the Cohen-Mansfield Agitation Inventory (CMAI) total score. Results showed that AXS-05 was linked to a statistically significant mean reduction in the CMAI total score of 15.4 points at week 5 compared with 11.5 points for placebo (P = 0.01). AXS-05 was also shown to be superior to bupropion based on CMAI total score (P < 0.001). The investigational therapy was well tolerated and not associated with cognitive impairment or sedation. The most commonly reported adverse reactions included somnolence, dizziness, and diarrhea. Axsome Therapeutics is also investigating AXS-05 for the treatment of major depressive disorder, treatment-resistant depression, and smoking cessation.

New in Patient Management

Vitamin D linked to painful diabetic neuropathy. Previous studies have suggested a link between vitamin D deficiency and painless diabetic neuropathy, a type of nerve damage that can occur with diabetes. But, a new study shows that vitamin D insufficiency and deficiency are associated with a higher risk for painful diabetic neuropathy. For their study, researchers compared vitamin D levels in diabetic patients with either painless or painful neuropathy. Study participants included 43 patients with type 1 diabetes and painless (n = 20) or painful (n = 23) neuropathy as well as 14 non-diabetic controls who completed tests on neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal confocal microscopy (CCM) and serum 25(OH)D measurements.

Patients with painful diabetic neuropathy had significantly higher neuropathy symptom profile scores vs patients with painless diabetic neuropathy and controls. There were no differences for QST parameters, intra-epidermal nerve fiber density, and corneal confocal microscopy between patients with painful vs painless diabetic neuropathy. Patients with painful diabetic neuropathy had more significant symptoms of diabetic neuropathy, such as hyperalgesia, allodynia, paresthesia, and numbness. Mean serum 25(OH)D levels were 24.0±14.1 ng/mL in patients with painful diabetic neuropathy, 34.6±15.0 ng/mL in those with painless diabetic neuropathy, and 34.1±8.6 ng/mL in controls. Vitamin D deficiency (< 20 ng/mL) was tied to a 10-fold increased risk for painful diabetic neuropathy and vitamin D insufficiency (< 30 ng/mL) was linked to ≥ 4-fold increased risk. The study had several limitations, including small sample size, no data on sunlight exposure or daily activity, and the lack of a control group of patients with diabetes without neuropathy. Still, the study shows a link between vitamin D deficiency and painful diabetic neuropathy, which is in line with some previous research. The researchers highlighted the need for a well-constructed clinical trial of vitamin D in painful diabetic neuropathy to determine the efficacy of a simple treatment with no adverse side effects.

Severe COVID-19 risk factors in MS. In a new cohort study, researchers have uncovered multiple risk factors for severe COVID-19 in patients with multiple sclerosis (MS). They looked at clinical characteristics and outcomes in patients with MS and COVID-19, as well as factors linked to COVID-19 severity. The study sample included 347 patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19. The main outcome was COVID-19 severity, which was assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). The researchers found that 21% of patients had a COVID-19 severity score of ≥ 3, and 3.5% of patients died of COVID-19. Independent risk factors for a COVID-19 severity score ≥ 3 included age, obesity, and a high Expanded Disability Severity Scale score (EDSS). (As a side note, the researchers also found that disease-modifying therapies were not associated with an increased risk of severe outcomes, which supports the recommendation of not stopping DMTs in patients with higher disease inflammatory activity.)

COVID-19 neuropsych effects in MS. The COVID-19 pandemic has affected the general population by increasing symptoms of depression, anxiety, and stress. This is doubly bad news for patients with MS, who are already vulnerable to cognitive and neuropsych complications, and tend to experience a lower quality of life as well as increased fatigue and disability. In fact, studies have shown that cognitive dysfunction affects roughly 70% of MS patients, and symptoms of anxiety and depression affect around 57% and 40% of patients. The most prevalent effects of anxiety on cognitive function tend to present in information processing and episodic memory, which can prevent effective verbal learning in patients with MS. Even worse, the use of immunosuppressive and immunomodulatory therapies for MS—typical treatments for the disease—can increase the risk for viral infection, leading to greater health anxiety during the pandemic. And, because of social-distancing guidelines, support received from social groups, which provide patients access to cognitive and physical rehabilitation, has decreased.

Searching for ways to treat MS patients during this challenging time, Iranian researchers noted that there’s been a growing focus on therapies for cognitive dysfunction in MS. They encouraged providers to adopt preventive methods and monitor high-risk patients for neuropsych complications using strategies that conform with social-distancing measures, like phone-based anxiety scales. Other therapeutic options they suggested included online support, home-based yoga and exercise programs, and the prescription of anti-anxiety meds where appropriate. Overall, they posited that access to these preventive methods may help to alleviate some of the stress of the COVID-19 pandemic.

Latest in Journal Summaries

Mechanism of action of onabotulinumtoxinA in chronic migraine

Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer disease

Phase 2a safety and tolerability trial of IRL752 for Parkinson disease dementia

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Upcoming Medical Meetings

The following conference has not yet been cancelled. Please check website for up-to-the-minute information:

First Annual UCI Health Spine by the Sea Symposium, Newport Beach, CA, July 17-18, 2020.

The following meetings have been rescheduled and changed to virtual workshops. 

Sports Concussion Conference, to be held in Minneapolis, MN, July 17-19, 2020, has been rescheduled for July 31-August 1, 2020. 

3rd Annual Aspen Conference on Pediatric Cerebrovascular Disease and Stroke, to be held in Snowmass Village, CO, July 13-17, 2020, has been rescheduled for July 12-16, 2021. In place of this year’s live course, there will be a short virtual session on July 13, 2020 from 1-3 pm EST.  Please check the website for up-to-the-minute information.

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