FDA faces a brewing scandal, a drug to reverse cognitive decline, and stem cells for MS patients’ mental skills

Hold on to your hat, because this week we’re offering a whirlwind of new discoveries, exciting developments in biomarker research, and even a cry of “j’accuse!” directed at the FDA and a major pharmaceutical company.

Neuro Flashback

In its earliest days, neurology, like all medical specialties, was a little loose with its ethics. Here’s an example: One of the most lauded medical practitioners of antiquity was Galen of Pergamon. He was a physician, mathematician, logician, and philosopher. He was able to contribute so heartily to the world’s founding medical literature because he operated on the mutilated bodies and corpses of gladiators in the ancient Turkish city of Pergamon. Much of Galen’s work focused on migraines, and while he certainly moved the needle on the subject, his proposed treatments were pretty suspect: Devices inserted into the nostrils, devices that could be eaten to help remove phlegm, plasters and poultices, the application of sneeze-inducing sternutatories, and the wearing of amulets.

In the News

Brain pills—for real. In some cases, age-related mental decline can be warded off with a healthy lifestyle, but in others memory loss seems unavoidable. A new experimental drug, however, has shown promise as an effective way to begin reversing this process in just a matter of days.

Lab studies have already demonstrated that the drug, called ISRIB, can be used to help restore memory function following traumatic brain injury, reverse cognitive impairments in those with Down Syndrome, prevent noise-related hearing loss, and fight certain types of prostate cancer. Now, a new study has indicated it can reverse age-related declines in memory and mental flexibility in mice. The study, published this month in ELife, showed the rapid restoration of youthful cognitive abilities in aged mice, as well as a regrowth of brain and immune cells that could help explain improvements in brain function. The drug works by inhibiting a cellular quality control mechanism called the integrated stress response, which halts the production of proteins. Researchers concluded that the study suggests something potentially game-changing: That age-related mental decline is not a loss of cognitive function, but rather a blockage of it.

Is drug-maker Biogen too close to the FDA? Activist group Public Citizen has called out “inappropriate close collaboration” between FDA and Biogen over the Alzheimer’s drug we all love to love or love to hate: Aducanumab. In a scorching letter sent to the US Department of Health, the group accused the firm of having too close of a relationship with the FDA, both before and after the submission of the license application for the drug, and urged the department to investigate.

After the drug went up for review last month, a group of outside experts announced that it shouldn’t be approved. Official documents from the FDA released several days prior to the review, however, said the administration backed the drug, despite the fact it had failed previous trials. In response, Public Citizen accused the FDA of “unbridled enthusiasm” for the drug that was “not supported” by data. The Prescription Drug User Fee Act (PDUFA) action date is set for March 7, 2021, and it’s anyone’s guess as to what could happen between then and now.

How likely is COVID-19-related brain damage? We know COVID-19 is causing long-term neurological harm, but until now it’s been unclear whether the severity of the disease impacted the severity of neurological symptoms. Now we have a better idea: Even some moderate cases of COVID-19 can cause brain damage. That’s according to a new study, which found neurological complications in patients who weren’t critically ill.

Thanks to an influx of new data, it’s become increasingly clear that SARS-CoV-2 can have impacts on organ systems throughout the body—particularly in already-vulnerable patients. But the new study, published in Neurology Clinical Practice, found that neurological complications caused by COVID-19 were wide in range and occurred even in patients who were only moderately ill with the disease. Using the records of more than 900 patients with COVID-19, researchers found that 74 needed neurological attention for stroke, seizures, encephalopathy, nerve damage, or movement problems. According to the researchers, some of these problems are related to an overactive immune response, while others are caused by the virus’ impact on the vascular system, where it causes blood clotting. Yet another reason to keep social distancing and stop the spread.

Is there more dementia? Or are we just better at spotting it? In the past several decades, atypical forms of dementia have been diagnosed in people in their 50s and 60s with increasing frequency. So far, it’s unclear whether these rarer types of dementia are becoming more common, or if doctors are getting better at detecting them—but there is growing interest in studying these atypical forms in order to ascertain why they affect people much earlier in life than the more common Alzheimer’s disease.

While Alzheimer’s usually affects older people, atypical forms of dementia, like the behavioral variant of frontotemporal dementia (bvFTD), primary progressive aphasia, posterior cortical atrophy, and Lewy body dementia, can occur decades earlier. These forms of dementia exhibit the same pathology as Alzheimer’s: Build-ups of amyloid plaque and tau tangles in the brain. Some of the rarer forms of dementia are caused by clusters or other abnormal proteins, but the result is the same: The distortion of how the brain processes inputs. Various studies are currently recruiting participants to examine how these diseases progress and whether an effective treatment can be developed. So, if you fit the criteria, maybe you should think about signing up. Future generations will thank you.

Neuro Trivia

How did migraines get their name?

The word migraine is derived from the Latin word “hemicrania” meaning “half” (hemi) “skull” (crania), a term Galen first used around 160 CE to describe the pain felt across one side of the head during a migraine.

Novel Diagnostics

New blood biomarker of AD in Lewy Body patients. Some biomarkers are common among different combinations of diseases, and researchers are always looking to establish new biomarkers that could indicate co-pathology. Thanks to new research, they may have uncovered one such connection. Plasma phospho-tau may identify Alzheimer’s co-pathology in patients with Lewy Body disease.

The study, published in Movement Disorders, sought to investigate whether levels of phospho‐tau217 and phospho‐tau181 can be used to detect Alzheimer’s pathology in patients with Lewy body disease with dementia. Researchers looked at 35 patients using tau‐PET imaging and found that plasma phospho‐tau217 and phospho‐tau181 correlated with tau‐PET signal in the temporal cortex, and predicted abnormal tau‐PET status and β‐amyloid status. Researchers concluded that the proteins could be a useful marker for Alzheimer’s co-pathology in these patients. These blood biomarkers are also more accessible and less expensive to detect than alternatives, opening the door to a potentially useful new avenue for earlier, less costly diagnosis.

An eye for vascular changes in MS. Because there is no specific test for multiple sclerosis, an accurate diagnosis of the presence or progression of the disease relies on a range of biomarkers. Now, a new study has found a possible biomarker for the disease that uses a non-invasive technique: Optical coherence tomography angiography.

The study examined whether there were differences between superficial retinal microvascular plexuses in patients with MS and healthy individuals. Using optical coherence tomography angiography, researchers examined the eyes of 92 patients with relapsing-remitting MS, along with the eyes of a control group. The researchers found that MS patients showed a significant decrease in vessel density in the superior, nasal, and inferior parafoveal retina when compared with healthy controls. They concluded that MS produces a decrease in retinal vascularization density in the superficial plexus of the parafoveal retina, establishing these subclinical vascular changes as a possible biomarker for diagnosing the presence and progression of MS.

Got migraines? Blame your genes. The cause or causes of migraines are still yet to be conclusively established. But new research suggests that your genetic make-up may have something to do with it.

The study, led by scientists from the Institute of Research and Innovation in Health of the University of Porto, Portugal, discovered a new gene that may predispose people to having migraine headaches. At the onset of a migraine, there are several mechanisms in the central nervous system that work in a domino effect. First a nerve is activated, which causes the release of neurotransmitters, and subsequently inflammation and the dilation of blood vessels. The study focused on neurotransmitters and a gene called neurexin, which is involved in their release and helps them to make connections between neurons. Researchers concluded that the neurexin gene plays an essential role in migraines and, if you have it, you’re more likely to suffer from them regularly. So next time your migraine sets in, blame your parents!

New biomarker candidate for ALS. Early and accurate diagnosis of amyotrophic lateral sclerosis (ALS) is still tricky. Because ALS progresses rapidly and can result in death within just a few years, development of new methods of early detection is key in combating the disease. Up until now, only disease-unspecific biomarkers have been available. Fortunately, the research is catching up. A new study has established a possible biomarker for ALS: Misfolded forms of the protein TDP-43.

The TDP-43 protein plays a pivotal role in ALS by forming small inclusions in nerve cells. These inclusions are neuropathological markers in some ALS cases and have been detected in numerous brain autopsies of ALS patients. The researchers in the new pilot study, however, used an innovative method to successfully identify conformational changes of TDP-43 proteins in the cerebrospinal fluid of ALS patients for the first time. Beyond diagnosis, these biomarkers can be used for drug-testing and therapy development, bringing us a step closer to tackling this fast-progressing disease.

Novel Treatments

Extended-release Parkinson’s meds lead to longer benefits. While there’s still no cure for Parkinson’s disease, there are a number of ways to treat its symptoms, including the oral drug carbidopa-levodopa. Now, a new study has shown that extended-release formulations of this drug increase the duration of symptom-alleviation by more than 1 hour vs immediate-release formulations.

Researchers were aiming to determine the average duration of ‘on’ time per dose, as well as to compare the duration of on time without troublesome dyskinesia with a dose of carbidopa-levodopa immediate release vs a dose of CD-LD extended-release capsules. Researchers found that the mean baseline on time per dose of CD-LD IR (n=393) was 2.20 hours, and that CD-LD ER significantly increased on time per dose by an average of 1.21 hours. Extended-release capsules also provided significantly more on time per dose (3.55 hours vs 2.38 hours). The study’s authors hope that the information will help physicians make medication decisions and be able to anticipate the effects of those changes.

Bumetanide may be best bet for neonatal seizures. Due to a lack of controlled trials, there hasn’t been much progression in the treatment of neonatal seizures, even though current medications are consistently shown to perform poorly. That may change, however, after a new study indicated that bumetanide may be a good treatment option.

The study, published in Annals of Neurology, used a randomized, double‐blind, dose‐escalation design to test the efficacy of bumetanide added to phenobarbital. The trial included neonates aged 33 to 44 weeks with confirmed risks of seizures. Patients still experiencing seizures after 20-40 mg/kg phenobarbital were randomly allocated to get additional phenobarbital with either placebo or 0.1, 0.2, or 0.3mg/kg bumetanide. While further research is required for definitive evidence, the study showed that the addition of bumetanide tended to further decrease numbers of seizures with no increase in adverse side effects. It’s a baby step, but it could be another step toward solving seizures for good.

Alzheimer’s indicator discovered in spinal fluid. Researchers are consistently pushing the envelope when it comes to finding new ways to diagnose people in the early stages of Alzheimer’s, when it’s far easier to treat symptoms and fight the disease’s progression. This month, researchers at Washington University School of Medicine in St. Louis found another: A novel form of an Alzheimer’s protein in the fluid that surrounds the brain and spinal cord.

The study, published in Brain, looked at CSF from 100 people in their 70s, some with no cognitive impairment and others at various stages of Alzheimer’s progression. Researchers found that levels of MTBR tau 243 were elevated in those with the disease and that the levels increased as the disease advanced. The researchers then verified this by following 28 of the study’s original participants over 2 to 9 years. They found that over time, levels of the protein increased as the disease progressed and as cognitive function declined. The study could improve diagnostics and help more people keep their brains limber for longer.

From MS stem cells to normal nerve cells. One of the hallmarks of multiple sclerosis is that patients with the disease gradually lose levels of myelin, the fatty substance that both insulates nerves and bolsters their signal-sending efficiency. Now, a new study indicates that stem cells may be able to help mitigate this loss.

The study, published in Science Advances, saw an international team of scientists create induced pluripotent stem cells using skin cells from three MS patients and three healthy people. The team then tweaked the cells to become oligodendrocyte precursor cells (OPCs), which are the myelin-producing stem cells that the brain typically sends to damaged areas. Scientists then grafted these OPCs into the forebrain of mice that lacked myelin. They found that the cells survived, spread throughout the brain, and eventually matured into myelin-producing oligodendrocytes. Surprisingly, the researchers found no difference between the stem cell debris from the MS patients and those derived from the healthy patients. The results suggest that it’s environmental factors, rather than faulty OPCs, that inhibit myelin regrowth in those with MS.

New in Patient Management

Japanese diet is brain food. If your favorite cuisine is Japanese food, here’s some good news: It may help you to protect against neurodegenerative diseases like Alzheimer’s. According to a recent study, sticking to a Japanese diet is associated with a reduced risk of dementia.

The study, published this month in Clinical Nutrition, analyzed dietary information collected from over 14,000 older individuals living in Ohsaki city. Researchers used a 39-item food frequency questionnaire to assess adherence to a Japanese diet and followed the progression of dementia among participants. During follow-up, 231 cases of dementia were reported. The study’s authors found that a decreased risk of incident dementia was correlated with an increase in adherence to the Japanese diet, and vice versa. So, if you want to evade cognitive decline, it may be best to stick to green tea, sushi, and miso soup.

Computer rehab boosts mental skills for those with MS. The nerve damage experienced by those with MS also tends to cause cognitive problems. Researchers estimate that this issue may affect 40% to 70% of MS patients. But new computerized cognitive rehabilitation programs aim to mitigate this—and now a new study has demonstrated their effectiveness.

The study, published in Disability and Rehabilitation: Assistive Technology, looked at a tool called MS-Rehab and its impact on eight MS patients. The tool simulates real-life situations and helps users improve at handling these moments by letting them practice easier versions of them. The trial’s participants (aged 18-72 years) underwent psychological and cognitive neuropsychological evaluations at the beginning and end of the trial. They were also asked to fill out quality of life questionnaires and provide other types of feedback. After 3 weeks of the program, the participants scores had improved significantly across all indices, indicating a marked improvement in mental skills. Participants even reported lower levels of depression. That’s some screen time you don’t have to feel guilty about!

Four strategies for better brain health. An estimated 50 million people around the globe live with dementia, which amounts to a $1 trillion cost to economies, patients, and their families. And research suggests it’s a growing problem, with dementia cases expected to increase to 152 million worldwide by 2050. But it doesn’t have to be this waythere are a plethora of paths to better brain health. So, because we’re all bored of hearing the usual (stop smoking, get some exercise, etc) MDLinx looked at four novel ways to help protect against dementia.

The story looked at clinical studies which sought to establish links between activities like playing board games or learning a second language, and the progression of early onset dementia symptoms. From a game of chess to a glass of wine, there’s no shortage of ways to get big-time brain benefits. But you’ll have to read the full story to get the low-down on alternative ways to protect against cognitive decline.

Touch a nerve, eliminate migraines. Migraines affect between 20 to 40 million people in the US, and they can be truly debilitating. One of the problems with trying to treat these intense headaches is that we are still grappling with exactly what causes them. The current theory is that migraines start with an abnormal activation of cells in the nervous system, leading to inflammation near pain-sensitive parts of the brain. As a result, treatments have typically focused on blocking the chemical messengers involved in pain signals. Recent studies, however, have shone light on a new kind of treatment, which the FDA recently approved for over-the-counter purchase: A nerve stimulation device that delivers mild electrical shocks to the forehead.

Evidence of the efficacy of this kind of treatment has been mounting for several years. Last year, a study looked at its impact on 106 people. Half of the participants received electrical stimulation while they were experiencing migraine symptoms, while the other half received a sham treatment. Those who were given the actual electrical stimulation reported a pain reduction of nearly 60%. Nerve stimulation has been used as a treatment for migraines since 2014, and it is not considered a truly effective cure. But if nothing else is getting rid of your migraines, no studies have indicated any side effects from it, so it may be worth a shot.

Latest in Journal Summaries

BMI changes related to faster cognitive decline among older African Americans.

Impact of OSA on cognitive and motor functions in Parkinson’s disease.

TBI and school readiness among preschool-aged children in the US.

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Upcoming Medical Meetings

The following meetings are entirely virtual:

TOXINS 2021 Virtual Meeting: Basic Science and Clinical Aspects of Botulinum and other Neurotoxins. January 16-17, 2021.

Mayo Clinic Multiple Sclerosis and Autoimmune Neurology Update 2021 – Livestream. February 5-6, 2021.

The following meeting is scheduled to have an in-person and virtual component:

American Academy of Neurology 73rd Annual Meeting (AAN 2021). San Francisco, CA. April 17-23, 2021.

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