A smart machine to hunt down Alzheimer’s treatments, novel therapy to repair damaged upper motor neurons, and new hope for opioid-free neuropathic pain management

It seems like all the news surrounding CRISPR gene-editing tools focuses on designer babies and the possible ecological harm caused by modifying animals. But, as scientists and doctors know, the tool has less fear-inducing applications as well. This week, a study suggests that temporarily repressing a gene involved in sensing pain could be a safer alternative to opioids. In this issue, you’ll also find how a machine-learning framework set its sights on finding a drug to treat Alzheimer’s disease, why cerebrospinal fluid could be used as a biomarker for response to immunotherapies, and more. 

Neuro Flashback

Today, electroencephalography (EEG) is commonly used to determine the diagnosis and prognosis for various brain conditions, particularly epilepsy and other seizure disorders. But electrical signals in the brain weren’t discovered until the late 1800s. Richard Caton, a Liverpool physician and medical school lecturer, discovered these signals by probing the surface of animals’ exposed brains. He published the findings of these experiments in 1875. Caton used a reflecting galvanometer, which was invented in 1858 by Lord Kelvin. He used a primitive form of amplification, in which small changes in the position of a mirror attached to galvanometer coils were transposed into a much larger movement using a reflected spot of light. Through this, he was able to measure microamperes. In 1887, Caton presented his findings to the Ninth International Medical Congress in Washington, DC. He explained that when he interrupted light falling on an animal’s eye, he could detect negative variations in the electrical activity of the brain. He also discovered that electrical activity occurred in the opposite side of the brain from the eye that was exposed to stimulation.

In the News

Intellectual disability increases risks of dying from COVID. People with intellectual disabilities are already at a higher risk of dying earlier in life compared with the general population. Recently, researchers found that these individuals, who make up 1% to 3% of the US population, are particularly vulnerable in the context of the ongoing pandemic––intellectual disability is second only to older age as a risk factor for dying from COVID-19.

The study, published in the New England Journal of Medicine Catalyst, involved an analysis of 64 million patient records from 547 healthcare organizations between January 2019 and November 2020. Researchers found that those with intellectual disabilities were 2.5 times more likely to contract COVID-19. Additionally, these patients were about 2.7 times more likely to be admitted to the hospital with the disease, and 5.9 times more likely to die from the infection vs the general population. Researchers noted that patients with intellectual disabilities may be less able to adhere to health measures, such as wearing a mask or social distancing, and are more likely to have underlying health conditions.

Parkinson’s: A disorder of the brain…and the blood? Scientists have long viewed Parkinson’s as a brain disorder, but the findings of a new study suggest this may not be the whole story. The new research has revealed a close link between Parkinson’s disease and certain immune cells in the blood, which could pave the way for developing a treatment for the disease.

The study, published in Proceedings of the National Academy of Sciences, examined a group of patients suffering from REM Sleep Behavior Disorder (RSBD), a condition which shares some pathologies with—and almost always leads to—Parkinson’s. Researchers conducted brain scans of 15 patients with RSBD and 10 healthy patients. Results showed that while the RSBD patients didn’t present any Parkinson’s symptoms, their brains showed inflammation and a loss of neuronal activity. Researchers also discovered that these changes in the brain were directly linked with changes to immune cells in the blood called monocytes. This was the first study to show that changes in the body’s immune system influence the condition of the neurons in the brain in Parkinson’s patients, and points to the immune cells in the blood as potential targets for new therapies. 

Study unveils enzyme responsible for rallying stem cells. When a person suffers a brain injury, neural stem cells cluster and travel to the site of the injury, but researchers have long been in the dark about what prompts this clustering. Now, a new study has shown for the first time that an enzyme known as metalloproteinase-2 (MMP2), secreted from endothelial cells, is what triggers that response—a discovery that could lead to advances in treatment for brain injuries.

The study, published in the FASEB Journal, involved the examination of brain injuries caused by stroke, and a 3D model of the brain’s workings to understand the mechanisms at play. In cases of brain injury, stem cells move out of the subventricular zone and are guided to the injury site by chemical signaling from the endothelial cells lining the blood vessels, as well as pericytes, which surround the endothelial cells. Researchers found that the endothelial cells not only promoted the migration of the stem cells, but also promoted their clustering by secreting MMP2. This enzyme activates a protein called N-cadherin, which leads to arm-like extensions on the stem cells, causing them to stick together and cluster. The findings have implications for conditions like concussion, Parkinson’s disease, Alzheimer’s, and other neurological disorders.

Dr. ROY G. BIV can improve long-term memory. We all remember the useful mnemonic devices we learned in school to remember bits of information for exams. But new research suggests that these memory tools can be beneficial beyond just cramming for tests: A well known mnemonic device used to improve short-term memory can also boost longer-term memory.

The study, published in Science Advances, involved testing the memories of 17 top-ranked memory athletes and a control group. The memory athletes and a group of 50 ordinary participants were asked to memorize a list of items. Some of the recruits were taught how to use a mnemonic device in which the participants imagine themselves walking along a familiar path and assigning items to milestones along the way. Researchers found that the memory athletes could recall all 50 of the words they were tasked with remembering; in the control group, those with mnemonic training could recall an average of 30, while those with no training could recall an average of 27. Significantly, the participants were asked to recall the words 4 months later, and those who’d had training could recall more of them than those who didn’t. 

Neuro Trivia

Question: Could your neurons outlive you?

Answer: Hypothetically, yes. A study published in 2013 found that neurons grafted from mice to longer-living rats outlived their original hosts by as much as two mouse lifespans. Creepy, but neat.

Novel Diagnostics

E-selectin for detectin’ cognitive decline. Past research has shown that patients who’ve had a stroke have an increased likelihood of developing cognitive decline, which has prompted scientists to hunt for a biomarker to discern which stroke patients will develop this condition. A new study may have found an answer, suggesting that the presence of serum E-selectin could aid in the early detection of cognitive decline in stroke patients.

The study, published in the International Journal of General Medicine, looked at the serum levels of E-selectin in 322 patients with stroke at baseline. Researchers found that serum levels significantly and independently correlated with cognitive decline after adjusting for age, gender, BMI, smoking, drinking, admission systolic and diastolic blood pressure, and CVD history. Additionally, they determined that serum E-selectin levels had independent predictive value for cognitive decline in stroke patients. Researchers concluded that serum E-selectin could serve as a diagnostic tool for cognitive decline among patients who’ve had a stroke.

ADAM10 in platelets and plasma spells mild cognitive impairment. Prior studies have shown that mild cognitive impairment (MCI) precedes Alzheimer’s disease, which suggests that finding a way to accurately diagnose MCI could be key to preventing or slowing the development of Alzheimer’s. Now, a new study has found that concentrations of ADAM10 (A Disintegrin And Metalloprotease), along with other clinical criteria, can be used as a minimally invasive, inexpensive, and fast-processing biomarker to help in the early diagnosis of MCI.

The study, published in Experimental Gerontology, focused on platelet and plasma concentrations of ADAM10 as a possible blood biomarker for MCI and cognitive frailty. Researchers tested this hypothesis using a cohort of 61 adults aged 60 years or older. They found that those with MCI had decreased ADAM10 levels in platelets and increased levels in plasma vs healthy controls. In analyzing the ROC curve of ADAM10 in platelets, researchers found a sensitivity and specificity of 72.7% and 73.9%, respectively, to correctly discriminate between those with MCI and cognitively healthy individuals. For plasma samples, ADAM10 presented 62.5% sensitivity and 90.0% specificity for differentiating individuals with MCI.

Immune cells in CSF are soothsayers for immunotherapy outcomes. While treatment with immune checkpoint inhibitors (including anti-PD1, anti-PD-L1, and anti-CTLA4) can be effective in some cancer patients with brain metastases, these immune-based therapies don’t work for most. The challenge in predicting which patients will respond favorably is that new lesions can differ from original tumors, and accessing samples from brain malignancies can be difficult. But now, a new study has found that immune cells can be tested using CSF, which mimics some of the characteristics of cells in brain metastasis, as a biomarker of response to immune-based therapies.

The findings of previous studies indicate that CSF provides vital information about the genomic characteristics of brain tumors, and it can be used as a liquid biopsy specimen. For the new study, published in Nature Communications, researchers attempted to see if they could characterize the immunological phenotype through an analysis of CSF. Using samples from 48 patients with brain metastasis, researchers compared the immune cells present in metastatic lesions with those in the CSF. They were able to observe identical T cell receptor clonotypes in both the brain lesions and confirm cell exchange between the two. As such, the researchers concluded that the analysis of immune cells in the CSF can provide a noninvasive alternative to predict the patient’s response to immune-based therapeutic strategies.

Biomarker found for neonatal encephalopathy. Neonatal encephalopathy (NE), a syndrome characterized by disturbed neurological function in the first hours and days after birth, contributes substantially to child mortality and disability around the globe. But a team of researchers may have found a way to provide physicians with a prognostic tool for the condition. Their recently published research has shown that elevated serum IL-10 is associated with the severity of neonatal encephalopathy and could serve as a biomarker for adverse early childhood outcomes.

The study, published in Pediatric Research, involved comparing the cytokine profiles of more than 300 neonates both with and without NE, and with and without perinatal infection or inflammation. Serum levels of IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF were compared, and researchers monitored both neonatal and early childhood outcomes including severity of NE, mortality, and neurodevelopmental impairment up to 2.5 years of age. They found that infants with NE had higher IL-10 and IL-6 levels, and lower VEGF levels. Researchers also found that moderate and severe NE were associated with higher IL-10 levels compared to non-NE infants, and that IL-10 levels were associated with neonatal mortality and adverse early childhood outcomes. The findings suggest that IL-10 levels could serve as a biomarker for adverse effects following neonatal encephalopathy.

Novel Treatments

Finding Alzheimer’s drugs, with a little help from learned machines. Clinical trials of investigational drugs for Alzheimer’s are taking place all the time, but they often fail to produce promising results. Now, a team of researchers has turned to machine learning for a helping hand. The team recently developed a machine-learning framework that can screen currently available medications that could be repurposed as treatments for Alzheimer’s disease.

The team described the framework of their new system in an article published in Nature Communications. Drug Repurposing In Alzheimer’s Disease (DRIAD) uses machine learning to train itself to identify patterns in data. It works by analyzing the reactions of human brain neural cells to drug treatments, and then flagging drugs when those changes correlate with molecular markers of Alzheimer’s severity. This allows researchers to identify drugs that may protect against Alzheimer’s, but it also allows them to filter out neurotoxic drugs that accelerate neuronal death instead of preventing it. Additionally, DRIAD can be used to pinpoint which proteins are targeted by possible Alzheimer’s drugs and check if there are common trends among them. Researchers have already used the system to screen 80 FDA-approved and clinically tested drugs. Those screenings revealed a ranked list of candidates, with a number of antiinflammatory drugs used to treat rheumatoid arthritis and blood cancers among the most promising. 

New compound revs up motor neurons, shows promise for ALS. There’s currently no treatment that will stop or reverse the progression of amyotrophic lateral sclerosis (ALS), but new research has uncovered a compound that could change the way we treat the condition. The compound, called NU-9, has been shown to improve diseased upper motor neurons (UMNs) in mice and shows promise for treating ALS in humans.

NU-9 is the first compound that can boost the health of UMNs that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology, which are two key causes of motor neuron degeneration. In research published in Clinical and Translational Medicine, investigators tested the compound in mice. They found that it improved the integrity of mitochondria and the endoplasmic reticulum, reduced misfolded SOD1 in UMNs, significantly improved UMN retention in the motor cortex, and eliminated UMN degeneration in animals with TDP-43 pathology. After 60 days of treatment, the diseased neurons in the mice became comparable to their healthy counterparts. Due to the similarities of the cellular defects in both mouse models and ALS patients, researchers believe the compound will be effective in humans, but further research is required before clinical trials are conducted.

Protein fibril architecture may lead to neurodegenerative treatments. There are no known treatments for neurodegenerative disorders like ALS, which are on the rise in the United States and around the world. New research, however, may have uncovered a key piece of this puzzle. The researchers recently determined the structure of protein “fibrils” that accumulate in the brains of patients. This could lead to the development of drugs to treat diseases such as ALS and frontotemporal dementia (FTD).

The findings of the study, published in Nature Communications, provide vital clues on how TDP-43 proteins clump together into amyloid fibrils and spread between nerve cells in the brain in cases of neurodegenerative disorders. Researchers used cryo-electron microscopy (electron microscopy at very low temperature) to analyze thousands of images of fibrils, and discovered the template on which more copies of TDP-43 can lock, among other things. The findings could lead to the development of drugs to treat ALS, Alzheimer’s, chronic traumatic encephalopathy, and other brain disorders.

900 epilepsy-linked proteins identified. Even though epilepsy affects more than 3 million Americans, its causes have long baffled scientists, which means treatment can often feel like guesswork. But a recent study has brought us one step closer to understanding this elusive neurological disorder. It involved an analysis of adult human brain tissue revealing more than 900 proteins tied to epilepsy, which points to new targets for drug treatment.

In the study, published in Brain Communications, researchers examined the molecular differences between the brains of 14 epileptic patients and 14 healthy controls. They found altered levels of proteins in various parts of the brain, primarily in the hippocampus, which is involved in memory and learning. In the hippocampus and frontal cortex—which is responsible for controlling thought and body movements—134 altered proteins were found. While many of the proteins were tied to genes that had been linked to epilepsy in past studies, four of the 20 most-altered proteins had never been associated with the condition in the past. Currently, drug treatments fail to work for one-third of epilepsy patients. Researchers hope that these findings will provide specific targets for future drugs.

New in Patient Management

Gene genies conjure pain-relief therapy. Managing chronic pain can be tricky, and researchers have long sought a safer alternative to highly addictive opioid painkillers. Hope may have arrived in the form of a new gene therapy. According to recently published research, the therapy works by temporarily repressing a gene involved in sensing pain. 

In the study, published in Science Translational Medicine, researchers used the CRISPR gene editing tool to temporarily repress a gene called NaV1.7, which is involved in the activation of a protein in pain-transmitting neurons in the spinal cord. They tested the therapy on mice with inflammatory and chemotherapy-induced pain. After the mice received spinal injections of the therapy, they exhibited higher pain thresholds vs control mice, and they were slower to withdraw a paw from painful stimuli. The mice didn’t lose any sensitivity or show any changes to normal motor function. Researchers also observed that the therapy was still effective at 44 weeks for mice with inflammatory pain and at 15 weeks in those with chemotherapy-induced pain. Further studies are due to take place on primates, but the findings indicate that the gene therapy could be used to treat a variety of conditions in humans, including rare neuropathic pain disorders.

Migraines may mean you’re in it for the long haul. While most people who experience mild traumatic brain injuries (mTBI) recover within several weeks, some patients take months to fully recuperate. Now, a new study may have found a signpost for these cases. According to the new research, young people who sustain mTBI may have a longer recovery if they experience migraines when compared with other types of post-traumatic headache.

In the study, published in JAMA Network Open, researchers examined data on 281 youths between 5 and 18 years of age who were treated for concussion between December 2017 and June 2019. At the beginning of the study period, 98 patients reported no headache symptoms, 57 reported non-migraine headaches, and 133 reported migraines. Three months in, researchers found that far more patients with migraine at baseline were reporting headaches (29.3%) than those with non-migraine headache (12.2%) or no headache (11.4%) at baseline. Significantly, they also found that the median recovery time for those with migraine was 95 days, which was significantly longer than for those with non-migraine headache (41 days) or without headache (67 days). 

Evidence for the link between diabetes and Parkinson’s. Past research has found a biological link between type 2 diabetes and Parkinson’s disease. This should come as no surprise given that both diseases involve aberrant protein accumulation, lysosomal and mitochondrial dysfunction, and chronic inflammation. But a recently published analysis has taken us a step forward in this field. Researchers have found convincing evidence that type 2 diabetes is associated with an increased risk of Parkinson’s disease and may contribute to faster disease progression in patients who already have Parkinson’s.

The research, published in the Movement Disorders Journal, used meta-analyses of observational and genetic data from 28 studies to evaluate the effect of type 2 diabetes on risk and progression of Parkinson’s disease. Researchers found that type 2 diabetes increases the risk of future Parkinson’s, and that type 2 diabetes may increase the rate of motor progression in Parkinson’s patients. They also found weaker evidence that type 2 diabetes has an effect on cognitive progression in Parkinson’s. The findings suggest that treatment with drugs already available for type 2 diabetes may reduce the risk and slow the progression of Parkinson’s, and that screening for diabetes in patients with Parkinson’s may be advisable.

To reach the brain in time to protect against stroke, grab a ride on a nanoparticle. NA1 is a small peptide designed to protect brain cells from dying after stroke. In a past trial, this neuroprotectant showed mixed results when administered to patients undergoing clot removal for severe stroke. But a new study appears to have found a way to deliver NA1 to the brain in a way that renders it effective in improving survival following stroke: Attach it to nanoparticles. 

The preliminary research was prompted when scientists recognized that NA1 was binding to organs, cells, and proteins in the body before managing to reach the brain. As such, researchers created stroke-targeting nanoparticles, which they used to deliver NA1 to parts of the brain that were deprived of oxygen in a stroke mouse model. They found that stroke size was reduced by almost 70% in mice treated with the NA1-loaded nanoparticles when compared with those treated with NA1 alone. Researchers also observed that brain swelling was reduced and chances of survival were drastically improved. The findings represent a major advancement in the delivery of brain-protective agents for stroke and could lead to human applications.

Latest in Journal Summaries

Prognostic value of CT perfusion and permeability imaging in TBI.

Olfactory dysfunction predicts the development of dementia in older patients with type 2 diabetes.

Relation of atrial fibrillation to cognitive decline.

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Upcoming Medical Meetings

The following meeting is entirely virtual:

American Academy of Neurology 73rd Virtual Annual Meeting (AAN 2021). April 17022, 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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