Game-changing Alzheimer’s diagnostic, new treatments for killer brain cancer, and a dangerous narcotic to combat depression?
Unraveling the many secrets of the CNS is, by no means, an easy feat. It can take decades of intense effort and dedication among the brightest minds to make even the smallest advancement. But, in the end, the resulting revelations are almost always worth it. In this edition of the newsletter, we’re celebrating the biggest, most recent breakthroughs to come out of the field of neuroscience. From a game-changing diagnostic that may allow clinicians to see the extent of brain damage caused by Alzheimer disease to the potential use of a Schedule III narcotic for the treatment of depression, check out this week’s NeuroBrief for the full details on these neuro stories and other top headliners.
When you hear the term “bobblehead,” you probably think of those funny little figurines with gigantic, spring-mounted heads that bob up and down. But, did you know that there’s a not-so-funny neuro disease called bobble-head doll syndrome? People with this disorder don’t have enormous heads. But they do present with frequent, involuntary, rhythmic, nodding head movements—usually in an anterior-posterior direction (aka bobbling). Bobble-head doll syndrome was first described in the scientific literature about 50 years ago in 1966. Since it’s considered to be a rare disease, you may not be familiar with it, making diagnosis a little tricky. Here’s what you need to know: Bobble-head doll syndrome usually develops in patients younger than 10 years old, but there’ve been reports in older patients, too. Emotional stress tends to aggravate head bobbing. But, the movement can be voluntarily diminished, and it stops altogether during sleep. Researchers don’t know what exactly causes the syndrome, but it’s usually associated with a cystic lesion in the brain that causes hydrocephalus. The lesion occurs in or near the third ventricle, putting pressure on the adjacent neuronal structures. Treatment generally involves reducing or removing the cyst with surgery, or using a shunt to drain excess water on the brain. Bobbing head movements usually stop immediately after surgery.
In the News
The brain’s defense roster includes…mucus? Some people have nothing but “spit” for brains, which might be a good thing after all. By “spit,” we’re actually talking about mucus—the protective layer in the gut that helps balance good and bad gastrointestinal (GI) bacteria. Previous studies have shown a link between imbalance of gut bacteria and a range of brain disorders, including Alzheimer disease and autism. Now, in a new research review of 113 neurological, gut, and microbiology studies, researchers have discovered that changes in gut mucus may be the underlying cause. They believe that these changes may not only have a hand in promoting bacterial imbalance, but could also be aggravating the core symptoms of neurological diseases. Previous researchers have shown an association between changes in GI mucus and the balance of gut bacteria. But, this is the first study to shed light on the gut mucus-brain connection.
In their review, the researchers found different types of bacteria and different amounts of good and bad bacteria in the gut mucus of people with autism, Parkinson disease, Alzheimer disease, and multiple sclerosis compared with healthy people. Previous research shows that brain disorders can affect neurons in the gut. So, in line with that evidence, this new review suggests that weakened gut mucus protection may put patients with neurological disease at further risk for GI problems. And, you guessed it, severe gut imbalance could worsen the symptoms of some brain disorders in a vicious circle. Still, the research into the gut mucus-brain link is just emerging, and it’s unclear the exact role that the gut mucus plays in brain disease development. But, the researchers are hopeful that their study—and further study of the gut-brain axis—will lead to the creation of potential therapeutics for neurological disorders down the line.
The neural link to love and marriage. We recently learned that the brain is hardwired for longing and physical comfort. Now, thanks to a select group of neurotransmitters and genetic mutations, researchers have discovered that we’re biologically engineered to sustain romantic love to maintain a successful marriage and family—all thanks to a select group of neurotransmitters and genetic mutations. Apparently, maintaining romantic love is associated with subcortical parts of the brain as well as higher-order brain regions. The natural tendency to sustain romantic love also appears to be affected by genes associated with dopamine, vasopressin, and oxytocin. These genes are associated with pair-bonding behaviors like fidelity and sexual behaviors, as well as social behaviors like trust, eye-gazing, and attachment. So, you know that little thing we call “chemistry,” when a new couple feels their hearts and minds connect? It may actually be more literal than figurative. This is the first study to look at the neural and genetic links to romantic love maintenance.
To uncover the biological mechanisms underlying the transition from romantic love to marriage, researchers studied the neural and genetic correlates of romantic love in 19 first-time newlyweds. Using functional MRI, newlyweds were scanned while looking at facial images of their partners vs those of familiar acquaintances at two timepoints: around the time of the wedding and a year after the wedding. At the beginning of each session, the newlyweds were told to recall non-sexual events with the person whose face was displayed. While still in the scanner, they rated their moods to confirm that the emotions they felt matched with the target image. Newlyweds also provided saliva samples for genetic testing, specifically for vasopressin, oxytocin, and dopamine genes. They also completed self-reported assessments on relationship quality including romantic love. Overall, there was strong evidence of the dopamine reward system’s involvement in romantic love. The researchers concluded that “romantic love maintenance is part of a broad mammalian strategy for reproduction and long-term attachment that is influenced by basic reward circuitry, complex cognitive processes, and genetic factors.”
Schedule III narcotic combats depression. A lot of good drugs can quickly get a bad reputation when they’re abused. Take morphine, for example. It’s one of the most effective pain relievers ever created, but the name “morphine” often strikes fear and anxiety in the hearts of patients and docs alike. Another effective but much-maligned drug? Ketamine. True, it’s a Schedule III substance that comes with a host of bad side effects as well as the potential for misuse. But, in low doses, it can have a quick effect on treatment-resistant depression. Although, the mechanism behind this has been unclear—until now. Researchers have just discovered a key target for the drug: specific serotonin brain receptors. Turns out, ketamine increases the number of, and binds to, serotonin 1B receptors. This reduces the release of serotonin and increases the release of dopamine. Research shows that low serotonin levels—namely serotonin 1B receptors—are linked to depression, while dopamine (part of the brain’s reward system) is known to increase feelings of positivity about life—something that’s often missing in people with depression.
Researchers conducted the largest PET study of its kind in the world to determine ketamine’s mechanism of action in major depressive disorder (MDD). They also wanted to find out if ketamine acts via serotonin 1B receptors. For the first phase of their double-blind study, the researchers enrolled 30 patients with selective serotonin reuptake inhibitor-resistant MDD, who were randomized to either a ketamine-infusion group (n = 20; 0.5 mg/kg) or a placebo (saline) group. Patients’ brains were imaged using a PET camera prior to the infusion and 24-72 hours afterward. In the second phase, 20 patients received ketamine twice weekly for 2 weeks. Results showed that more than 70% of those who received ketamine had fewer depressive symptoms. Overall, ketamine treatment increased the number of serotonin 1B receptors, reduced serotonin release, and increased dopamine release. The researchers hope to use their findings to fuel future studies, with the end goal of determining whether serotonin 1B receptors can be a target for new, effective drugs that don’t have the adverse effects of ketamine.
Dementia gene and COVID-19. More and more, we’re learning that COVID-19 isn’t just a respiratory disease. The infectious illness has far-reaching effects in all parts of the body, including the brain. And, brace yourselves, it gets worse: A new large-scale study shows that a faulty gene linked to dementia doubles the risk of severe COVID-19—even in people who haven’t developed Alzheimer disease. UK and US researchers, who analyzed data from the UK Biobank, found a high risk of developing severe COVID-19 among people of European ancestry who carry two defective copies of the ApoE gene (e4 genotype). (Of note, most people in the sample had not yet been exposed to the novel coronavirus.) This finding is concerning, given that 1 in 36 people of European ancestry have 2 faulty copies of this gene, which is already known to increase the risks of Alzheimer disease (up to 14-fold) and heart disease.
Previous research by this team of investigators showed that people with dementia are three times more likely to get severe COVID-19. (Yet, these folks aren’t one of the groups advised to “shelter in place” to reduce the risk of infection.) This study suggests that this significantly increased risk may not be due to the effects of dementia, old age, frailty, or viral exposure in care facilities. It also shows that disease risks that appear inevitable with aging might actually be due to specific biological differences, which could explain why some people stay active to age 100 while others become disabled and die in their 60s. Plus, these results could help scientists to pinpoint how the defective gene causes vulnerability to COVID-19, which may lead to new therapeutics down the line.
What common childhood disorder is often overlooked as an underlying cause of memory problems in adults? (Hint: It’s not dyslexia.)
If you haven’t already guessed it, you might be surprised to learn that attention-deficit/hyperactivity disorder (ADHD) may be the cause of memory deficits in some adults. ADHD is usually characterized as a pediatric disorder, but symptoms can carry over into adulthood for two-thirds of people who had ADHD as kids. With a prevalence of about 4.4% among adults, ADHD in adulthood can cause inattention, poor concentration, forgetfulness, distractibility, disorganization, lack of conscientiousness, irritability, emotional lability, and problems with working memory. Unfortunately, the condition is underrecognized in clinical practice. One reason for this is that ADHD is less prevalent in later life. Because of this, symptoms might be misattributed to age-related cognitive decline. There’s no cure for ADHD. But, certain interventions could help improve working memory, including mental exercises like brain teasers, using organizational tools such as calendars and daily planners, as well as behavioral therapies for time and money management. Stimulants like methylphenidate or dextroamphetamine have been shown to be effective in treating ADHD in adults, including the elderly.
Game-changing AD imaging tool. In a stunning breakthrough, researchers have created a new imaging tool that helps scientists see the widespread loss of brain synapses in early-stage Alzheimer disease (AD). They compared the density of synapses between people with and without early-stage AD. As predicted, synaptic loss in those with early-stage AD was high in the areas surrounding the hippocampus. But, the new imaging tech allowed the researchers to see the extent of the damage throughout the brain. The researchers posited that their results may be used as a biomarker outcome for clinical drug trials for quicker therapeutic development in the future.
Getting down to the nitty-gritty, here’s how they did it: To better understand the early effects of AD, the researchers used PET imaging of a protein found in nearly all brain synapses. Unlike previous imaging technologies that have only been able to show brain tissue loss or reduced brain metabolism in AD more generally, the new PET scans showed a more specific disease pathology present at the early stages of AD. These results represent a turning point in AD research, as these new methods may enable observable evidence of AD pathogenesis in people who haven’t manifested symptoms yet. The researchers recently received a grant to perform additional synaptic imaging and to investigate the link between synaptic loss and other disease markers for AD like amyloid and tau accumulation.
Cool new device for bipolar disorder. Researchers have developed a paper-based device that can detect lithium ion blood levels in patients with bipolar disorder (BD). The best part? The device is user-friendly, cheap, and quick (it takes about 1 minute)! Lithium carbonate is typically used for treating BD. But, because the therapeutic concentration range of lithium ions in the blood is close to the toxic range, using the drug requires extreme caution. In fact, doctors are advised to regularly check lithium ion blood levels in patients with BD who are given the drug. There’s just one problem with that: Current examination methods require a lot of blood from patients with BD, as well as special operations and the use of large, costly devices.
To address this problem, researchers created a colorimetric paper-based device that enables point-of-care testing in one easy step. The device is made of a blood cell separation unit that’s linked to a colorimetric detection unit. After a drop of blood is placed on the end of the separation unit, plasma is automatically separated and sent to the detection unit, which is dry-coated with a reagent that shows a diagnostic color. A digital camera secures the image for analysis without any fixed light condition to measure the color. Overall, the device’s detection capability is comparable to that of other traditional tools using the same colorimetric reaction. The researchers’ long-term goal is to create a smartphone app for the image analysis so that patients or non-medical workers can check lithium ion blood concentrations. And the device may have therapeutic potential for other health conditions. The researchers say that, by reworking detection reagents and other components, the device may be used for measuring the concentrations of blood components other than lithium ions.
New technique for small tumors. A team of scientists, led by researchers at the University of California, Davis, have made a groundbreaking advancement in diagnostic imaging: They’ve created a new double-contrast technique capable of distinguishing even the smallest tumors from normal tissue on MRI. So, how’d they do it? The researchers made a probe that creates two magnetic resonance signals that dampen each other until they reach the target. At that point, the two signals increase contrast between the tumor and the surrounding tissue. (The researchers have dubbed this process as “two-way magnetic resonance tuning.”) When combined with specially-made imaging analysis software, the double signal allowed researchers to identify brain tumors in mice with a high degree of sensitivity. The new imaging technique and study findings could help pick up on very small early-stage tumors. It could also open up new possibilities when it comes to non-invasive investigation of a range of biological processes via MRI.
New Tx for polyQ diseases? Researchers have identified a natural amino acid that could be used as a potential disease-modifying drug for polyglutamine (polyQ) diseases like spinocerebellar ataxia (SCA), Huntington disease (HD), and spinal and bulbar muscular atrophy. Until now, current treatments have focused only on symptomatic relief, which makes this a trailblazing discovery.
PolyQ diseases are caused by a defective expansion of a specific DNA sequence—cytosine, adenine, and guanine (CAG)—that results in protein misfolding and aggregate buildup, with concurrent damage to nerve cells. Because there’s no cure for this process of neurodegeneration, researchers looked to find a new disease-modifying drug for polyQ diseases. To that end, they screened a number of chemical chaperones—molecules that help with proper protein folding to prevent the buildup of aggregates—and found a winner: arginine. It had the strongest inhibiting effect on protein aggregation. In a separate set of experiments using living cells, researchers then found that arginine was indeed able to stop aggregate formation of polyQ proteins. Then, to test the therapeutic potential of arginine in living organisms, researchers used mouse models of SCA and spinal and bulbar muscular atrophy. When given to mice before symptom onset, arginine inhibited polyQ protein aggregation and suppressed motor impairment and neurodegeneration. Even after symptom onset, arginine was able to attenuate the adverse effects of SCA. The researchers’ next step is to conduct clinical trials of arginine as a potential novel therapy for polyQ disease.
New treatment for killer brain cancer? A new study shows that the addition of an FDA-approved antimalarial, lumefantrine, could boost the efficacy of current common treatments for glioblastoma multiforme (GBM), an aggressive and often fatal brain cancer. This is big news, given that GBM is often resistant to current standards of care—typically radiation and temozolomide (chemotherapy). Even worse, the 5-year survival rate of patients with GBM treated with standard of care is < 6%, and no current treatments prevent recurrence.
Focusing on FDA-approved drugs and more uncommon drugs that could help counter GBM’s resistance to treatment, researchers discovered that lumefantrine can bind to and inhibit Fli-1—a genetic element involved in cancer development and progression that controls GBM resistance to radiation and temozolomide. During in vivo experiments, researchers found that adding lumefantrine helped kill cancer cells and suppress tumor cell growth. And this worked for both glioblastoma cells sensitive and resistant to radiation and temozolomide. Also, in mice with transplanted human GBM, lumefantrine inhibited tumor growth caused by both therapy-sensitive and therapy-resistant glioblastoma cells. To further help treat glioblastoma, the researchers plan to explore other ways to counteract treatment resistance induced by Fli-1. This research could be extremely valuable for additional cancer patients in the future, as elevated Fli-1 expression can be seen in other cancer types like melanoma, ovarian cancer, and breast cancer.
Cutting-edge Tx for glioblastoma. Canada-based researchers have developed a new immunotherapy treatment for patients with glioblastoma. The treatment uses chimeric antigen receptor T cell (CAR-T) therapy, which involves genetically engineering a patient’s T cells in the lab so that they will bind to the CD133 protein in glioblastoma cells and kill them. When CD133-targeting CAR-T therapy was used in mice with human glioblastoma, it successfully reduced tumor burden and improved survival. These promising results led to the formation of a new brain cancer immunotherapy company called Empirica Therapeutics, which aims to start running clinical trials using the novel therapy in patients with recurrent glioblastoma by 2022.
In previous research, these investigators found that self-renewing cancer stem cells expressed the CD133 marker, which is linked to glioblastoma tumor growth. For this study, the researchers looked at whether targeting specific CD133+ cells would kill the most aggressive subpopulation of cells in the tumor. They also looked at the safety of CD133-targeting therapies on normal, non-cancerous human stem cells. They designed three types of treatments and tested them both in the lab and in mice. The first treatment created was a novel human synthetic IgG antibody, which binds to the CD133 protein on glioblastoma cells and stops tumor growth. The second treatment was a dual antigen T cell engager antibody, which uses the patient’s own immune T cells to kill the CD133+ glioblastoma. The third was the CAR-T therapy. Compared with the other two treatments, CAR-T therapy enhanced activity in preclinical models of human glioblastoma. Plus, CD133-specific CAR-T therapy did not trigger any acute systemic toxicity in humanized mouse models that had the human hematopoietic system. Pretty impressive. The researchers hope that their novel therapeutic approach will give patients with glioblastoma a better quality of life and better chances of survival. They are now exploring combination strategies with CD133-specific CAR-T to completely block glioblastoma tumor recurrence.
New in Patient Management
Anti-TNF drugs lower AD risk? A recent, large, retrospective case-control study shows that tumor necrosis factor (TNF)-blocking drugs could reduce the risk of Alzheimer disease (AD) in patients with certain inflammatory diseases. Researchers analyzed data from electronic health records of nearly 56 million adults to find out whether anti-TNF treatment is linked to lower AD risk in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases mediated, in part, by TNF, and for which a TNF blocker is an approved treatment. They compared AD diagnosis as an outcome measure in patients receiving ≥ 1 prescription for an anti-TNF agent (etanercept, adalimumab, and infliximab) or for methotrexate. The researchers found that RA, psoriasis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, and Crohn disease were all linked to higher risk for AD. But, AD risk in patients with RA was lower when patients were exposed to etanercept, adalimumab, or infliximab. Methotrexate was also linked to lower AD risk, and lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab were also linked to lower AD risk in patients with psoriasis. There was no effect of sex or race, but younger patients vs older patients showed greater benefit from a TNF-blocker. These findings suggest that systemic inflammation contributes to increased AD risk through a pathological mechanism involving TNF. So, patients with inflammatory disease—specifically those mentioned above—may benefit from anti-TNF treatment.
Does metformin lower dementia risk? Sadly, the answer is no—at least according to a new study funded, in part, by the National Institute on Aging. Prior research has suggested that metformin treatment may lower the risk of dementia. But it’s unclear whether treatment timing impacts this risk reduction. So, researchers looked at the association between metformin initiation and dementia risk. They analyzed electronic health records data from two healthcare systems: Veteran Health Affairs (VHA; n = 112,845) and Kaiser Permanente Washington (KPW; n = 14,333). The study sample included patients 50 years of age and older who had hemoglobin A1c (HbA1c) between 6.5 and < 9.5mg/dL, no history of dementia, and did not have any fills for antidiabetic meds prior to enrollment. Researchers compared people who started metformin monotherapy with those who used no antidiabetic drugs in the 6 months after the first qualifying HbA1c.
Overall, there were more than 7,500 new dementia cases in the VHA cohort during a median follow-up of 6.2 years and nearly 1,100 new cases in the KPW cohort during a median follow-up of 6.8 years. There was no link between metformin initiation (vs no initial treatment) and incident dementia in the VHA or KPW cohorts. And results did not differ based on patient age, baseline HbA1c, or race. According to the study authors: “Results do not support initiating metformin earlier to prevent cognitive decline and, thus, may dampen enthusiasm for metformin as a potential antidementia drug.” But, they did suggest that conducting randomized clinical trials may help “clarify” the impact metformin may have on cognitive decline in patients with type 2 diabetes.
Neuromyelitis optica and fracture risk. A new study shows that patients with neuromyelitis optica spectrum disorder with aquaporin-4 immunoglobulin G antibodies (NMOSD-AQP4) may be at higher risk for bone fractures. Because there aren’t much data available on the bone health of patients with NMOSD-AQP4, researchers looked at fracture risk and bone loss in these patients compared with healthy controls and patients with multiple sclerosis (MS). Participants included 71 patients with NMOSD-AQP4, 213 healthy controls, and 41 patients with MS. The researchers collected demographic and clinical data related to bone health, including bone mineral density (BMD) and fracture risk assessment tool (FRAX) score.
Overall, patients with NMOSD-AQP4 had a higher prevalence of fractures after disease onset vs healthy controls, but not compared with MS patients. The researchers also found that the risk for fracture was > 5-fold higher among patients with NMOSD-AQP4 vs healthy controls. The standardized BMDs of the femoral neck and total hip were also much lower in patients with NMOSD-AQP4 vs healthy controls. And the low BMD was more prominent in young patients with NMOSD-AQP4. There wasn’t any significant difference in the prevalence of fractures between the NMOSD-AQP4 and MS groups. But, patients with NMOSD-AQP4 had a higher risk for major osteoporotic fractures (as measured by the FRAX). Interestingly, researchers also found that a history of falls—and not the use of corticosteroids—was the only significant risk factor for fractures after NMOSD-AQP4 diagnosis. Total hip and femoral neck BMD were negatively linked to age and cumulative dose of oral corticosteroids. And, sex and prophylactic calcium supplementation were linked to BMD of the femoral neck. BMD at the lumbar spine was negatively associated with menopause. So, it might be a good idea to keep these findings in mind—especially the potential benefit of calcium supplements for BMD—when you see your patients with NMOSD-AQP4.
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Upcoming Medical Meetings
The following meetings have been rescheduled:
2nd International Tremor Congress: From Bench to Bedside Towards Tremor Therapy, to be held in New York, NY, June 12-13, 2020, has been postponed. Please check website for up-to-the-minute information.
4th International Conference on Functional Neurological Disorders, to be held in Boston, MA, June 14-16, 2020, has been postponed until 2022, with dates yet to be determined. Please check website for up-to-the-minute information.
The following meeting has been rescheduled and changed to a virtual workshop:
SLEEP 2020 – The 34th Annual Meeting of the Associated Professional Sleep Societies (APSS), to be held in Philadelphia, PA, June 13-17, 2020, has been rescheduled for August 27-30, 2020, when it will be held as a virtual meeting.