Can researchers reverse Alzheimer’s? Plus, medical cannabis may do more harm than good in some patients, and a neurobiological basis for human sexuality

Ever found yourself wishing that you had been given a heads-up before something bad happened? For those with epilepsy, foreknowledge of an upcoming seizure could be life-saving. This week, an exciting development offers hope for those who live under the unpredictable threat of seizures. In this issue, you can also find a study casting doubt on cannabis for migraine relief, plus new answers to old questions about the ways placebos impact the brain.

Neuro Flashback

One of the key protective elements of the brain is the blood–brain barrier. This gateway between the brain’s capillaries and the cells and other components that make up brain tissue provides a critical defense against disease-causing pathogens and toxins in the blood. While we now understand the vital importance of this mechanism, the blood–brain barrier wasn’t discovered until the late 19th century, when German physician Paul Ehrlich injected dye into the bloodstream of a mouse. Much to his surprise, he found that the dye traveled through all tissues in the mouse except the brain and spinal cord. It would take nearly a century, however, to fully ascertain the reason. While Ehrlich found that a barrier existed between brain and blood, it wasn’t until the 1960s that researchers could use microscopes powerful enough to examine and describe the physical layer of the barrier.

In the News

Brain imaging study shows neurobiological basis to the differences in human sexuality. When Lady Gaga wrote “Born this way,” she may have been hitting on some truth. According to the findings of a new brain imaging study, same-sex sexual behavior-related differences in the brain exist, and some of these differences may be linked to a genetic predisposition for non-heterosexuality.

The study, published in Human Brain Mapping, used MRI and genetic data from more than 18,000 individuals in the UK Biobank. Researchers found that certain brain structures of non-heterosexual individuals appeared more like those found in the opposite sex. These differences were mainly in brain areas that involve the processing of sensory (including visual) information, indicating that some may be a result of genetic predisposition. But these differences don’t wholly explain sexual behavior. Researchers concluded that brain and genetic differences account for up to 25% of variations in male and female same-sex sexual behavior, which suggests that human sexuality is influenced by a complex mix of genetic and environmental factors, such as the effects of sex hormones.

Why drugs are effective, even when they’re not drugs. Much of the benefit patients receive from drugs is psychological. But while scientists know that the placebo effect works, the neural mechanisms driving the effect are still largely unclear. A new study, however, has shed light on the way placebo treatments reduce pain (known as placebo analgesia) by reducing pain-related activity in multiple areas of the brain.

The meta-analysis, published in Nature Communications, examined 20 neuroimaging studies with roughly 600 healthy participants. Researchers established the size, localization, significance, and heterogeneity of placebo effects on pain-related brain activity. Placebo effects were related to activity in areas of the brain like the basal ganglia and the thalamus, which functions as a gateway for sensory motor input including sight and sound. Researchers found that the parts of the thalamus most involved in pain sensations were most impacted by the placebo effect. Additionally, placebos changed activity in parts of the somatosensory cortex that are integral to the early processing of painful experiences, as well as changes in the posterior insula, which is one of the areas involved in early construction of the pain experience. Researchers hope that the findings can be used in clinical care applications and drug development in a context-specific, patient-specific, and disease-specific manner.

One simple protein keeps cerebrospinal fluid in check. A research team recently discovered that the SOX9 protein is an essential regulatory factor of choroid plexus function and keeps cerebrospinal fluid (CSF) in its correct composition. The finding sheds new light on the molecular regulatory mechanisms behind the function of the blood–CSF barrier, and could lead to the development of novel therapeutic strategies for preventing and treating neurodevelopmental disorders.

CSF surrounds the brain and spinal cord and provides protection from injuries. It also serves as a nutrient-delivery and waste-removal system for the brain. The fluid is produced and secreted by the regions of the choroid plexus, which filters the blood and restricts harmful molecules from entering into the central nervous system. It’s long been known that dysfunction of the blood–CSF barrier is common in many neurological diseases. The new study, published in the Proceedings of the National Academy of Sciences, shows that SOX9 in the choroid plexus plays a key role in preventing the leakage of undesired molecules into CSF. Researchers believe that the finding could lead to novel therapies for neurodevelopmental and neurological disorders that target the blood–CSF barrier or modify CSF constituents.

A very small solution to a very big problem. Finding a treatment for Alzheimer’s disease remains a challenge for many reasons—in particular, the protein aggregates that become the brain plaque which characterize the disease, are markedly difficult to study. To examine the amyloid beta proteins that cause the plaques, researchers must use techniques that disrupt them, which makes it tricky to see what’s really going on. But new research may have found a solution: Nanoparticles could be an effective way to study these proteins and, in the future, possibly even deliver treatments for Alzheimer’s Disease.

Nanoparticles are ultra-small structures that can be coated in therapeutics to provide targeted treatments for many diseases. Scientists have already found potential applications for nanoparticles, including coating them with chemotherapy agents to target a tumor without toxic side effects for the rest of the body. The new research focused on bowl-shaped nanoparticles—appropriately nicknamed “nanobowls”—as a possible delivery mechanism for Alzheimer’s treatments. Much to their surprise, researchers found that amyloid beta proteins clung to the nanobowls, even when they were coated in a lipid-polymer without any pharmaceuticals. This allowed the scientists to remove these toxic protein aggregates from the cells. Currently, nanobowls are used to gain a better understanding of the aggregates, but the research indicates that they could serve as a diagnostic tool or even a method of treatment for AD in the future. 

Neuro Trivia

Which invertebrate has the most complex brain?

Answer: The octopus takes home that honor, with a 16-lobe brain. A ventral motor portion consisting of several lobes is involved in the control of feeding, locomotion, and color change, and a dorsal portion exerts sensory information processing and higher cognitive functions. It takes a lot of work to keep track of all those arms.

Novel Diagnostics

No pain, no gain—but no pain could also point to Alzheimer’s. An early diagnosis of Alzheimer’s disease can improve patient outcomes and reduce healthcare costs, but diagnostic procedures are often invasive and costly. Now, new research may have found a novel way to identify those at high risk of developing AD, years before they develop symptoms. The study found that cognitively healthy people who are at increased genetic risk of late-onset Alzheimer’s disease show lower sensitivity to thermal pain and experience greater unpleasantness related to that pain when compared with people at lower risk of the disease. This suggests that altered pain perception could be used as a biomarker of late-onset Alzheimer’s disease before symptoms occur.

Past research identified a genetic allele called APOE4, which can be used as a marker for increased likelihood of developing late-onset AD. In the new study, researchers examined 49 cognitively healthy adults aged 30 to 89 years, 12 of whom had the APOE4 allele. Participants were assessed for differences in pain thresholds and feelings of unpleasantness in response to experimentally induced thermal pain stimuli. Researchers found that people with the APOE4 allele responded differently to experimentally induced painful stimuli when compared with cognitively healthy individuals without the allele. The findings suggest that this could be a less invasive method of diagnosis than lumbar punctures or positron emission tomography (PET) scans.

Depression signals accelerated dementia development. It’s long been known that depression is associated with an increased risk of developing Alzheimer’s disease. Now, a new study has found that those with depression, anxiety, or other psychiatric disorders may start experiencing dementia symptoms several years earlier when compared with those who don’t.

Researchers used a cohort of 1,500 people with Alzheimer’s disease who were screened for psychiatric disorders. Of these patients, 43% had a history of depression, 32% had anxiety, 1.2% had bipolar disorder, 1% had post-traumatic stress disorder, and 0.4% had schizophrenia. Researchers found a continuous decrease in the age when symptoms first started, which doubled with each additional psychiatric disorder diagnosis. Those with only one disorder developed symptoms an average of 1.5 years before those with no psychiatric disorders. Those with two conditions developed symptoms 3.3 years earlier, and those with three or more developed symptoms 7.3 years earlier. While further research is needed to examine the association, researchers hypothesize that the presence of psychiatric disorders could indicate underlying neuroinflammation.

Blood biomarker for autism identified. Despite a lack of treatments for autism spectrum disorder (ASD), researchers are working diligently to uncover new biomarkers that will allow them to make earlier diagnoses. A new study marks a leap forward in this effort, pinpointing a group of biomarkers in blood that could lead to an earlier diagnosis of children with autism spectrum disorder (ASD) and, in turn, more effective therapies.

The study, published in PLOS ONE, leveraged machine learning tools to analyze hundreds of proteins in serum samples from 76 boys with ASD and 78 from typically developing boys—aged 18 months to 8 years. Researchers identified nine proteins that were significantly different in those with ASD vs those who were typically developing. Additionally, they found that each of the nine serum proteins correlated with symptom severity. While more research is required, the findings suggest that blood biomarkers could be used to identify children most at risk of developing ASD, which could result in earlier therapeutic interventions. 

The tau of ALS biomarkers. Diagnosing and tracking amyotrophic lateral sclerosis (ALS) is a critical part of managing and treating the disease before it becomes debilitating. A new study has found total tau (tTau), tau phosphorylated at threonine 181 (pTau), and the pTau:tTau ratio in the CSF may be diagnostic and prognostic biomarkers of ALS.

The study, published in the European Journal of Neurology, looked at 196 ALS patients and 91 controls. The controls included those with ALS mimic syndrome and patients with non‐neurodegenerative diseases. All patients underwent a CSF analysis and had tTau and pTau levels in the CSF measured by chemiluminescence enzyme immunoassay. Researchers found that ALS patients showed significantly higher levels of CSF tTau and lower pTau:tTau ratio than controls, while no differences in pTau levels were detected. They also found that tTau and pTau:tTau ratio offered good diagnostic accuracy. Increased tTau levels were associated with the advanced age of onset, rate of progression, and spinal onset among ALS patients. The researchers concluded that the tTau and pTau:tTau ratio can be diagnostic biomarkers of ALS, and that CSF tTau level at diagnosis could serve as a useful prognostic role in managing the disease.

Novel Treatments

Wave goodbye to Alzheimer’s with ultrasound. Alzheimer’s disease accounts for an estimated 80% of all dementia cases, and it’s on the rise. By 2050, it’s estimated that 13.8 million Americans could be diagnosed with the disease. But new research may have found a breakthrough treatment. The new study suggests that ultrasound waves, which target a specific area of Alzheimer’s patient’s brains, may induce an immunologic healing response.

The study, published in Radiology, examined whether ultrasound targeting the hippocampus—the region of the brain involved in learning and memory—could open the blood–brain barrier in early-stage Alzheimer’s patients. Using MRI scans with contrast-enhancement dye, researchers found that the dye moved along the course of draining veins following the procedure. The findings suggest the presence of the glymphatic system, which has been studied in animals but has not proven to exist in humans. The system is a fluid-movement and waste-clearance system that’s unique to the brain. Researchers concluded that the focused ultrasound may modulate fluid movement patterns and immunological responses along this system. This suggests that ultrasound could present a noninvasive way to reversibly open the blood–brain barrier in deep brain areas, such as the hippocampus, which may point to possible new treatments for Alzheimer’s disease.

FDA OKs muscular dystrophy injections. Duchenne muscular dystrophy is a rare genetic disorder characterized by progressive muscle deterioration and weakness, and it’s also the most common type of muscular dystrophy. It’s caused by mutations in the DMD gene, which leads to a deficit of dystrophin—a protein found in muscle fiber. The condition affects roughly one in every 3,600 male infants across the world, and in rare instances, some female infants. Recently, the FDA granted approval for casimersen injections for DMD patients with a specific gene mutation that is amenable to exon 45 skipping, making it the first-ever approved treatment for those with this mutation.

The agency approved the drug after a study demonstrated its efficacy. The double-blind, placebo-controlled study involved 43 DMD patients who were given either intravenous casimersen at 30 mg/kg or placebo. Researchers found that all the patients who received casimersen showed a significantly greater increase in dystrophin protein levels from baseline to week 48 of treatment vs those who received placebo. Although the drug has not been shown to improve motor function, the FDA concluded that the findings of the study indicate an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients.

Yet another use for deep brain stimulation: ataxia. Deep brain stimulation (DBS) is used as a treatment to relieve motor dysfunction in a number of movement disorders, including Parkinson’s disease. More research has been centering on DBS lately, and new applications for the modality abound. Now, a new study may have found another use: A combination of DBS and exercise may be effective in helping to treat ataxia, a rare genetic neurodegenerative disease characterized by progressive, irreversible problems with movement.

The study, published in Nature Communications, used a mouse model of hereditary ataxia to explore the use of DBS on the cerebellum, a major motor center in the brain. Researchers found that low-frequency cerebellar nuclei DBS alone improved muscle function and mobility in the mice. When they added in tasks involving skilled exercise to the treatment regimen, they found additional limb coordination and stepping improvements. Significantly, researchers observed that these improvements continued even after they stopped administering the DBS. The findings could spark the development of future DBS strategies for treating ataxia and other movement disorders. 

The key to better TBI recovery was under our nose the whole time. Traumatic brain injuries can be life-threatening and lead to permanent disability and lasting brain damage. There are currently no FDA-approved treatments for the condition, but new research suggests that hope can be found in the air around us: High-dose oxygen given under pressure (hyperbaric oxygen) shows promise as a treatment to improve recovery following severe traumatic brain injuries.

The research, conducted by investigators at the University of Kentucky Departments of Emergency Medicine, Neurosurgery, and Anesthesiology, examined the efficacy of hyperbaric oxygen treatment. The treatment involves using a pressure chamber to significantly increase the amount of oxygen that can be delivered to body tissues. It’s already used to treat patients with chronic non-healing wounds to speed up the healing process. In these preclinical studies, researchers found that it can also increase oxygen delivery to the traumatized brain, which appears to prevent further cell death. The findings could lead to the prevention of disability or death in those who suffer traumatic brain injuries.  

New in Patient Management

Study suggests that marijuana may not be the best medicine for migraines. Migraines are notoriously difficult to treat, so it should come as no surprise that many people resort to self-medicating with cannabis. However, new research suggests this is likely a bad idea. According to the study, using cannabis for migraine relief appears to be associated with developing “rebound” headaches or medication-overuse headaches.

The preliminary study examined records of 368 people who had chronic migraine (15 or more headache days per month) for at least 1 year. Of those, 150 were using cannabis for migraine relief. Researchers monitored participants for frequency of migraines, overuse of other medications for acute migraine, and length of chronic migraine history. They found that those using cannabis were six times more likely to have medication-overuse headaches, and that cannabis users were also more likely to develop rebound headaches. Additionally, those using opioids to treat the pain were more likely to use cannabis. Past research has shown that both substances can influence the periaqueductal gray part of the brain, which has been linked to migraine. While longitudinal studies are necessary to further explore the cause and effect of cannabis use on those with migraine, the findings suggest that migraine patients may want to consider putting down that joint for now. 

Using math to give those with epilepsy a heads-up. Epilepsy affects more than 65 million people across the world. For many of them, seizures arrive without any kind of warning. This means that seizures can occur during risky situations, like driving or walking down stairs. Researchers, however, may have found a solution to this, in the form of a new seizure-predicting mathematical model that could give epilepsy patients an accurate warning between 5 minutes to 1 hour before they are likely to experience a seizure.

The research, published in the Journal of Neural Engineering, involved using brain signal data collected from an electrical implant that tracks the brain’s electrical signals in real-time—similar to an electroencephalogram. These data are plugged into a mathematical model, which can then “learn” the patient’s unique brain signals and recognize patterns that show a pre-ictal state—when the patient is most at risk of seizure onset. Researchers hope that the model will offer greater freedom to epilepsy patients and reduce the need for medical intervention in some cases.

Post-stroke apathy may spell bad news. Patients who’ve had a stroke often experience depression or apathy as they recover. While there’s overlap between these two symptoms, researchers hypothesized that they might be associated with different prognoses. The findings of a new study support this postulate, as researchers found that early apathetic symptoms are associated with worse outcomes after stroke, but depressive symptoms are not.

The study, published in the European Journal of Neurology, examined 443 patients with ischemic stroke, all of whom were assessed for depressive and apathetic symptoms 8 days after the stroke. Researchers divided the cohort into four groups: those without greater depressive and apathetic symptoms, those with only apathetic symptoms, those with only depressive symptoms, and those with both depressive and apathetic symptoms. They found that those in the groups that included apathetic symptoms had an increased risk of a poor outcome at 3 months and 1 year following the stroke when compared with the other two groups. 

More meds may mean more problems for stroke patients. Patients who’ve had an acute ischemic stroke are at a higher risk of having another one. Researchers estimate that the likelihood of recurrent stroke ranges from 6.2% to 11.1% in the first year and 12.9% to 26.4% within 5 years. Now, new research has shed some light on factors that may influence this. The study found an association between polypharmacy with increased LDL‐C control and reduced HbA1c control in stroke patients.

The research, published in the Journal of Internal Medicine, used a cohort of 664 stroke patients from the Norwegian Cognitive Impairment After Stroke study. They were assessed at 3 and 18 months following the stroke. Researchers found that 97% of patients were prescribed antithrombotics, 88% lipid‐lowering drugs, 68% antihypertensives, and 12% antidiabetic drugs at discharge. They also found that those prescribed multiple drugs had increased LDL‐C control and reduced HbA1c control. The findings suggest that risk factor control in post-stroke patients requires additional attention and research. 

Latest in Journal Summaries

ADAM10 as a biomarker of mild cognitive impairment, but not of cognitive frailty.

Preoperative CSF cortisol and the risk of postoperative delirium.

Outcomes of large vessel occlusion stroke in patients older than 90 years.

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Upcoming Medical Meetings

The following meeting is entirely virtual:

The Spectrum of Developmental Disabilities XLII: Language: Gateway to Neurodevelopmental Disabilities. March 22-24, 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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