New genetic discovery shows the secret to a 100-year life. Plus, a new ALS-fighting compound, and old drugs for new pain

A healthy lifestyle will always help with longevity; however, it’s becoming clear that the secret to a long life is largely genetic. But why? This week, we’re bringing you a study that may offer the answer: a gene with a funny-sounding name that’s found in many centenarians. In this edition, you’ll also find data to suggest brain imaging within 2 years of a multiple sclerosis diagnosis can provide accurate prognosis for the next 9 years; the first-ever compound that may reverse the effects of amyotrophic lateral sclerosis; new data on how beta blocker propranolol can be used to treat cerebral cavernous malformations; and more.

Neuro Flashback

The first person to undertake the systematic, empirical study of memory was the German scholar Hermann Ebbinghaus (1850-1909). Ebbinghaus stands among those rare early scientists whose discoveries have stood the test of time. While common sense tells us that we either remember something or we don’t, Ebbinghaus was the first to argue that memory might not be so simple. He successfully developed a method to tap into memories that could not be brought to conscious awareness. He rejected the use of measures of recall and recognition (the ones almost universally used today) as “introspective,” and he argued that a better, more objective measure was needed.

In the News

Running away from risks of neuromuscular decline. One of the key contributors to age-related physiological decline is the loss of neuromuscular junction (NMJ) transmission, which is how electrical impulses are chemically transmitted from a nerve to a muscle to produce a contraction. This can lead to sarcopenia, which is characterized by the pathological loss of muscle size and strength and, ultimately, symptoms like immobility, falls, and loss of independence. But a new study points to a strategy for mitigating this. The study has shown that voluntary running can reduce neuromuscular decline in aging mice.

The study, published in Neurobiology of Aging, explored the neurobiological effects of exercise in mice with age-related declines in physical function. Researchers examined mice that undertook voluntary running exercises between the ages of 22 to 27 months—roughly equivalent to 55 to 80 years of age in humans. The mice were split into three treatment groups: running, sedentary, and a running group that also received gene therapy to increase expression of follistatin. Follistatin is a protein that blocks the action of myostatin, triggering increased muscle size. Researchers found that while the exercise didn’t slow age-related loss of motor neurons, it did significantly improve NMJ transmission. Interestingly, while the follistatin induced muscle enlargement, it provided no added neurological benefits compared with exercise alone. When it comes to neuromuscular junction transmission, use it or lose it!

Longevity gene keeps brain cells stress-free. Prior research into people who live to be over 100 years of age indicated that longevity may be linked to a gene called Forkhead box protein O3 (FOXO3). Past studies have also shown that mice without this gene can’t cope with stressful conditions, leading to the death of brain cells. Now, a new study has shown one of the mechanisms that may explain how the gene keeps people alive longer. Researchers have found that FOXO3 protects brain stem cells from the harmful effects of stress.

The study, published in Nature Communications, revealed that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until conditions can support the new cells’ survival. If stem cells divide in a hostile environment (ie, one caused by stress), they become depleted. FOXO3 puts this process on hold until the stress has passed. Researchers found that the FOXO3 protein is directly modified by oxidative stress, which sends the protein into the nucleus of the stem cell, where it activates stress response genes. This leads to the elimination of a nutrient called s-adenosylmethionine, which means the cell can’t form a protective barrier around the DNA. The cell mistakes the leaking DNA for a virus and stops producing neurons. The findings partially explain why certain versions of the FOXO3 gene are associated with long and healthy lives. It also explains why exercise (which boosts FOXO3) can help preserve cognitive health. 

Scientists crack blood-brain barrier conundrum. In cases of blood-brain barrier dysfunction after a stroke, the infiltration of peripheral immune cells can cause severe inflammation. While it’s known that the endothelial glycocalyx (a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells) functions as a barrier to these circulating cells, the relationship between stroke severity and glycocalyx dysfunction is still not entirely understood. Now, for the first time, a group of researchers has identified a possible mechanism that links acrolein accumulation to glycocalyx modifications, which results in damage to the blood-brain barrier.

The study, published in the Journal of Biological Chemistry, focused on glycosaminoglycans, a component of the endothelial glycocalyx. These were studied using a photochemically induced thrombosis mouse model. Researchers found decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) in ischemic brain tissues. The study showed that HPSE expression in cerebral vessels increased after stroke onset, and infarct volume greatly decreased after co-administration of N-acetylcysteine and glycosaminoglycan oligosaccharides vs N-acetylcysteine alone. The findings indicate that the endothelial glycocalyx is injured after stroke. Additionally, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein exposure. Researchers found ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, is attributable, at least in part, to the activation of proHPSE. Aside from testing the limits of the Neurobrief spell-checker, these findings also suggest that ACR-modified proHPSE could be a promising target to protect the endothelial glycocalyx. 

While you sleep, your memory factory is wide awake. Studies have shown that certain regions of the brain that are active while you learn have a tendency to stay active while you sleep. But now, researchers have tools that can track specific cells during specific periods of time, which has opened the door to an even deeper understanding of how the brain forms memories when you slumber. New research using these tools suggests that groups of neurons activated during learning while awake stay active during sleep as memories are formed, which is how emotions become associated with memories

The study, published in Nature Communications, looked at how fear-based memories are formed in relation to specific visual stimuli. Using mouse models, researchers were able to genetically tag a set of neurons in the primary visual cortex. They then showed the mice a neutral image and expressed the genes in the visual cortex neurons that were activated by the image. Researchers tested whether this approach had worked by selectively activating these neurons without showing the mice the image and simultaneously giving the mice a mild foot shock. They found that, subsequently, the mice became afraid when exposed to visual stimuli that looked similar to the image those cells encoded. Significantly, the mice did not have the same reaction when the tests were conducted after nights of disrupted sleep, leading the researchers to conclude that sleep is vital in the forming of fear memories. The findings could expand our understanding of conditions like anxiety and post-traumatic stress disorder.

Neuro Trivia

Question: At what age do humans begin accruing their earliest memories?

Answer: At around 3 to 3.5 years of age. A recent study found that around 40% of people’s first memories turn out to be fictional. This is why it pays to scrapbook!

Novel Diagnostics

Brain imaging can show what the future holds for MS patients. In general, patients with multiple sclerosis will experience worsening symptoms over time, but medications and physical therapy can help some patients manage the disease. Treatment can be more effective if doctors are aware of how the disease is progressing, which means finding tools to help with accurate prognoses is critical. New research has shown that, in pediatric MS, a complete baseline MRI evaluation and reliable clinical and MRI monitoring within the first 2 years of illness can lead to accurate predictions for a 9-year prognosis.

The study, published in Annals of Neurology, used clinical and MRI assessments of 123 pediatric MS patients, which were collected at the time of diagnosis, and again after year 1 and year 2. Researchers then conducted a 9‐year clinical follow‐up. They found that a number of factors could be used to predict certain aspects of the progression of the disease. For example, the time it took for a first relapse could be predicted by optic nerve lesions and high‐efficacy treatment exposure. They also found that disability was worse by the ninth year in patients who, at baseline, showed presence of optic nerve lesions, expanded Disability Status Scale changes over the first 2 years, and at least two new T2‐lesions within 2 years of disease onset.

High blood pressure at night could spell dementia. According to a new study, older men with higher systolic blood pressure at night compared with during the day have an increased risk of developing any dementia, particularly Alzheimer’s disease.

The study, published in Hypertension, included data on roughly 1,000 older men in their early 70s, none of whom had dementia, stroke, or cognitive impairment at baseline. The men underwent 24-hour ambulatory blood pressure monitoring at the start of the study and were then followed for 24 years. During this period, 286 of the men were diagnosed with dementia. Researchers found that reverse systolic dipping was associated with a significantly higher risk of any form of dementia (adjusted hazard ratio 1.64) and Alzheimer’s disease in particular (aHR 1.67). So when you go down for the night, make sure your blood pressure goes with you.

A simple blood test could predict Alzheimer’s decades earlier. In recent years, research into blood biomarkers has led to promising developments in alternatives to current methods of diagnosing Alzheimer’s disease, which are often expensive and/or invasive. Now, a new study has found that a unique brain protein measured in the blood could be used to diagnose Alzheimer’s decades before symptoms develop.

The study, published in the Nature journal Translational Psychiatry, is the first to find that those with high levels of glial fibrillary acidic proteins (GFAP) in the blood also tend to have increased amyloid beta in the brain, which is a known factor in Alzheimer’s disease. The study used a cohort of 100 healthy individuals between the ages of 65-90 years. Researchers found that GFAP, a protein normally found in the brain, is released into the blood when the brain begins to deteriorate early in the development of Alzheimer’s disease. The study suggests that a simple blood test could be used to detect early indications of the disease, which would allow for interventions before symptoms appear.

Spot the differences for a better prognosis for autoimmune brain inflammation. Encephalitis is a rare type of brain inflammation that affects roughly one in every 200,000 people. Half of the cases can be traced to an infection, while the other half are due to the patients’ immune systems inappropriately targeting and damaging the brain. The two most common forms of immune-related pediatric encephalitis are acute disseminated encephalomyelitis (ADEM) and autoimmune encephalitis (AE), the symptoms of which include disorientation, seizures, or motor and sensory abnormalities. The two conditions are distinct, but can be hard to distinguish. This means an accurate prognosis can be tricky. A new study, however, has established slight differences in the clinical features of the two conditions, which could help physicians provide patients and their families with a better prognosis and perhaps the ability to target treatments specific to each condition in the future.

The study, published in Pediatric Neurology, examined a cohort of 75 patients diagnosed with immune-related encephalitis: 23 with ADEM and 52 with AE. By comparing patient histories, lab and imaging results, and outcomes, researchers found small distinguishing features between the two conditions. For example, AE patients were more likely than those with ADEM to have markers of elevated inflammation present in their blood and cerebrospinal fluid, and those with ADEM universally had abnormal MRI findings compared with just 61% of those with AE.

Novel Treatments

ALS-fighting compound identified in new study. As movement-initiating nerve cells in the brain and muscle-controlling nerve cells in the spinal cord die, amyotrophic lateral sclerosis (ALS) patients experience upper motor neuron degeneration. This results in rapidly progressing paralysis and death, and currently there is no drug or treatment for the brain impacts of ALS. But we may be one step closer to a treatment that can put a halt to this process, after researchers recently identified the first-ever compound that can reverse the ongoing degeneration of upper motor neurons that become diseased and that are a key contributor to ALS.

The study, published in Clinical and Translational Medicine, was initiated after researchers found a nontoxic compound called NU-9, which can reduce protein misfolding in critical cell lines and cross the blood-brain barrier. After testing the compound in mice, they found that it improved the health and integrity of both the mitochondria and the endoplasmic reticulum, resulting in healthier neurons. Not only were the upper motor neurons more intact, the compound stopped their degeneration to the point that the diseased neurons became similar to healthy control neurons after just 60 days of NU-9 treatment. Next steps: Researchers will conduct toxicology and pharmacokinetic studies before starting on a phase 1 clinical trial.

Beta blocker effective for cerebral cavernous malformations. Cerebral cavernous malformations (CCMs) are caused by genetic changes and are characterized by vascular lesions on blood vessels in the brain and other parts of the body. There is currently no drug treatment available to these patients, who often have to undergo risky surgical procedures. But a new study has shown that propranolol can also be used to treat CCM.

The study, published in Stroke, used mouse models to investigate the effects of the beta blocker, which is typically used to treat cardiovascular diseases and conditions such as high blood pressure, as well as hemangioma, a common blood-vessel malformation in children. After giving the mice propranolol in their drinking water, researchers found that the cavernomas became fewer and smaller, and that blood vessels functioned better. Researchers are hopeful that the drug could be used for treatment in humans too, and a 2-year clinical study is already underway.

Novel drugs can rescue mutated muscle cells. The genetic condition Duchenne Muscular Dystrophy (DMD) is caused by a mutation in the dystrophin gene, and it can result in irreversible muscular degeneration. Symptoms include muscle atrophy, which can prevent the ability to walk. The condition is currently incurable. A new study, however, has identified a way to “rescue” muscle cells that have genetically mutated, which may lead to a possible new treatment for this rare childhood illness.

The condition is currently treated with steroids, but these often stop working and commonly have adverse side effects. Authors of the new study, published in the Proceedings of the National Academies of Sciences, found that animal models of DMD had lower levels of metabolic enzymes used for the generation of the gasotransmitter hydrogen sulfide in their muscles, and lower levels of the gas itself. They tested compounds called NaGYY and AP39, which replaced hydrogen sulfide and partially reversed some of the muscle and mitochondrial defects. Targeting mitochondria with hydrogen sulfide using the compound AP39 appeared to have the same effect as prednisone, however, it was effective at a 3.7 million-fold lower dose. The researchers are hoping that this will lead to the development of new treatments in the coming years.

Bone marrow connected to motor function improvements. A spinal cord injury often leads to permanent loss of sensation or function of body parts below the site of the injury. But a new study suggests that stem cells could come to the rescue, finding that intravenous injection of bone marrow-derived stem cells in patients with spinal cord injuries can result in significant improvement in motor functions.

The study, published in the Journal of Clinical Neurology and Neurosurgery, looked at patients with sustained, nonpenetrating spinal cord injuries that occurred several weeks prior to treatment with stem cells. Symptoms ranged from loss of motor function and coordination to sensory loss, including bowel and bladder dysfunction. Researchers used a specialized cell processing center to prepare stem cells using each patient’s bone marrow, before injecting the stem cells intravenously. More than half the patients saw substantial improvements in key functions—like the ability to walk or to use their hands within weeks of treatment—with no significant side effects. The results look great so far, but further research is needed. The study was not blinded and had no placebo controls. 

New in Patient Management

Oldies but goodies: Antibiotics for pain management. More than 100 million Americans suffer from chronic pain, and over the past few decades treatment with opioid painkillers has been highly prevalent. We all know that these drugs can lead to abuse and addiction, so the hunt for safer ways to manage chronic pain is critically important. A new study offers hope for many, after finding that three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, which could lead to an alternative to opioid-based painkillers.

The study, published in the Proceedings of the National Academy of Sciences, focused on EphB1, a protein found on the surface of nerve cells that plays a key role in neuropathic pain. Up until now, no drugs were known to inactivate EphB1. After searching a library of FDA-approved drugs, researchers found that three tetracycline antibiotics that have been used since the 1970s—demeclocycline, chlortetracycline, and minocycline—appeared to have the right molecular structures to bind to EphB1. By testing the drugs on the protein in mouse models, they found that the antibiotics inactivated EphB1 and resulted in pain resistance. The next stage of the research will be to test the antibiotics on humans.

Biomarker found for neurological involvement in Wilson’s disease. Wilson’s disease (WD), the genetic disorder in which excess copper builds up in the body, typically leads to symptoms in the brain and liver. However, outcomes can be unpredictable for neurological presentations of WD. While chelation therapy can reduce neurological symptoms in some patients, dosing is tricky and can result in debilitating adverse effects. New research, however, may make this easier. A study has identified plasma neurofilament light as a biomarker of neurological involvement in Wilson’s disease.

The study, published in Movement Disorders, used plasma samples from 40 patients and 38 age‐matched controls to measure neuronal and glial‐specific proteins. The WD patients were divided into neurological or hepatic presentations; those with recent neurological presentations were then subcategorized. Researchers then recorded WD Rating Scale scores and copper indices. They found that, unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than in hepatic presentations. This means that Nfl levels can be used as a biomarker of neurological involvement in WD, and could be used in guiding chelation therapy, or even for developing new treatments. 

High blood sugar means bad news for the brain. Past research has shown that diabetes is associated with higher risks of dementia, but a new study has found that this may even be the case in people who have high blood sugar levels but who haven’t been diagnosed with diabetes. The study found that hyperglycemia is associated with increased risk of vascular dementia, cognitive decline, and structural brain changes even in those without known diabetes.

The study, published in Diabetes, Metabolism and Obesity, examined a cohort of 210,309 participants in the UK Biobank who had low HbA1c levels (< 35 mmol/mol); 198,969 people who were normoglycemic (35–42 mmol/mol); 15,229 participants with prediabetes (42–48 mmol/mol); 3,279 individuals with undiagnosed diabetes (≥ 48 mmol/mol); and 22,187 people with a known diabetes diagnosis. Researchers found people with prediabetic HbA1c levels had a significantly higher risk of developing vascular dementia and cognitive decline when compared with normoglycemic individuals. They also found higher white matter hyperintensity volumes with prediabetes (3%), undiagnosed diabetes (22%) and known diabetes (7%) than with normoglycemia, as well as lower hippocampal volumes. Researchers believe that cardiovascular drugs could ameliorate some of this risk.

C‐reactive protein can help doctors arrive at epilepsy prognosis. Status epilepticus (SE)—a condition where a seizure lasts more than 5 minutes or when multiple seizures occur with quick succession—is associated with significant morbidity and mortality. But new research has found a biomarker that could help doctors figure out which patients are most at risk. The new study has found that initial C‐reactive protein (CRP) concentrations are linked to in‐hospital mortality and functional discharge outcome in status epilepticus, which means CRP levels can assist with prognosis predictions.

Researchers launched the study, published in Epilepsia, on a foundation of prior research, which established that neuroinflammation plays a role in the pathophysiology of seizures. Using a cohort of 231 individuals who had been admitted to a hospital with status epilepticus between 2007-2014, they analyzed CRP levels measured within 24 hours after SE onset. Their findings indicate that higher initial CRP concentrations were independently associated with in‐hospital deaths and poor functional outcome at discharge. The researchers concluded that measurements of CRP concentration could assist with outcome prediction in the very early stages of an SE episode.

Latest in Journal Summaries

Acute treatment of migraine with celecoxib oral solution.

Altered in vivo brain GABA and glutamate levels are associated with MS central fatigue.

Neurocognitive outcomes and their diffusion tensor imaging correlates in children with mild TBI.

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Upcoming Medical Meetings

The following meeting is entirely virtual:

7th Annual Neuro and Intensive Care: Review, Workshops, and Controversies 2021. May 6-8, 2021.

The following meetings are scheduled to be entirely in-person:

2021 Congress of Neurological Surgeons (CNS) Annual Meeting. Austin, TX. October 16-20, 2021.

Neuroscience 2021: The Society for Neuroscience (SfN) Annual Meeting. Chicago, IL. November 13-17, 2021.

 

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