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Tag: Epilepsy

  • Fish oil’s significant role in cancer prevention

    Fish oil’s significant role in cancer prevention

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    In a recent study published in Scientific Reports, researchers used murine (A/J mice) models to evaluate the anti-cancer efficacy of different oils consumed as a part of ketogenic diets (KDs).

    Specifically, they compared seven commonly consumed, fat-enriched KDs with Western-style diets and a 15% carbohydrate diet as controls.

    Their results revealed that all ketonic diets proved better than Western-style and 15% carbohydrate diets at preventing nicotine-derived nitrosamine ketone (NNK)-induced lung cancer in mice.

    Study: A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice. Image Credit: Natalia Klenova/Shutterstock.comStudy: A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice. Image Credit: Natalia Klenova/Shutterstock.com

    Background

    This study highlights the anti-lung cancer potential of fish oils (FOs), which were found to increase plasma β-hydroxybutyrate (β-HB), reduce blood glucose, and attenuate fatty acid synthase (FAS) expression, thereby metabolically arresting lung tumor nodule formation.

    Notably, to address KD-induced high plasma triglyceride (TG) and cholesterol levels, researchers further characterized the impacts of long-term ketogenic diets on lipid profiles and liver health and found that, not only did standard KDs not induce liver damage, FO-enhanced KDs were even less harmless to liver and lipid profiles, attesting to their safety.

    What are ketogenic diets, and what makes them useful against cancers?

    Ketogenic diets (KDs) are diets that were initially developed to treat intractable epilepsy in the 1920s. They are characterized by very high-fat contents and low carbohydrates (CHO), forcing the body to metabolize lipids for energy.

    Most KDs are designed to supply 90% of total calories from fats, while only 2% are acquired from CHO. KDs acclimatize the body to depend on KD-derived ketone bodies instead of glucose.

    Ketone bodies, in turn, have been the source of recent scientific excitement due to the inability of most cancerous tumors to utilize ketones as fuel sources.

    Surprisingly, the systematic evaluation of KD-associated fats remains lacking. Still, scientists hypothesize that the differences in the fatty acid contents of these fats may result in vastly differing tumor cell proliferation profiles.

    Previous work by the present research team has established that reductions in easily digestible CHO from 50% (typical CHO content of Western-style diets) to 15% significantly reduce nicotine-derived nitrosamine ketone (NNK)-induced tumor nodules in A/J mice, further supporting the need for an investigation of the benefits of alternative fat-rich, CHO-poor diets as preventive interventions against cancer.

    “…saturated fatty acids like palmitic acid, the most common dietary fatty acid, are potent activators of Toll like receptor 4 (TLR4) signaling in macrophages, making them pro-inflammatory. As well, omega 6 fatty acids like arachidonic acid (AA) are known to be metabolized to prostaglandin E2 (PGE2), a prostanoid shown to help tumors grow, both directly and via suppression of anti-tumor immunity. Omega 3 fatty acids, on the other hand, have been shown to be anti-inflammatory, at least in part by inhibiting AA conversion to PGE2.”

    About the study

    In the present study, researchers compared the anti-NKK-induced lung cancer efficacies of three different dietary regimes – the Western-style diet (50% CHO), the 15% amylose diet (developed in-house; 50% fat-based), and KDs (seven types, each with a different fat source).

    The seven KDs comprised Western-type fats (standard KD), medium chain fatty acids (MCT-KD), milk fat (MF-KD), palm oil (PO-KD), olive oil (OO-KD), corn oil (CO-KD), and fish oil (FO-KD).

    All experiments were conducted on 12-week-old female A/J mice. Data collection included blood glucose levels (measured during nocturnal feeding), biochemical blood and plasma analyses (Plasma β-hydroxybutyrate [β-HB], cholesterol, and alanine aminotransferase levels), and immunohistochemistry of excised and preserved lung and liver tissue.

    Since the prolonged dependence on KDs has been hypothesized to alter lipid profiles and potentially damage the liver, researchers further investigated the liver health scores (via proxies and biomarkers) of the various KDs compared to Western and 15% amylose diets.

    For liver health evaluations, the thiobarbituric acid substances (TBARS) assay was used to determine liver TBARS levels, enzyme-linked immunosorbent assays (ELISAs) were used for liver 8-OHdG determination, and whole liver sections were scored for non-alcoholic fatty liver disease (NAFLD).

    Finally, in an attempt to unravel the mechanistic underpinnings of KDs’ (specifically, fats’) anti-cancer ability, mice fecal samples were used for microbiome analysis.

    Study findings

    The results of the five-month-long dietary interventions following NNK injections revealed that Western diets were the worst (mean nodule number = 18). In contrast, 15% of amylose diets only depicted ten nodules on average.

    KDs (even the standard KD containing common Western diet fats) performed much better than both diets. FO-enriched KDs, in particular, were found to perform the best and were the only KD cohort to differ significantly in nodule number from standard KD.

    Investigations into the mechanisms underpinning these observations revealed that FO-KD produced substantially more ketone bodies than other KD cohorts.

    In parallel, KD was shown to downregulate, attenuate fatty acid synthase (FAS) expression, and increase CPT1a levels within the liver. Notably, fish oil enrichment further exuberated these results.

    This suggests that ketosis improvements may contribute to FO-KD’s anti-cancer properties. FO-KDs were additionally observed to reduce the levels of inflammatory cytokines, including interleukin-6 (IL-6) and PGE2, in mouse lungs.

    “Interestingly, palm oil and corn oil-enriched KDs further lowered IL-6 levels, potentially challenging the long-held notion that palm oil and corn oil are pro-inflammatory. On the other hand, the PO-KD and CO-KD resulted in the highest levels of IFNγ and the lowest levels of IL-5 and IL-10 amongst the different KDs. Unexpectedly, even though the FO-KD was the most effective in preventing lung nodule formation, this diet had no unique impact on the pro-inflammatory cytokines/chemokines tested, other than a trend towards high IL-1β levels.”

    Immunohistochemistry results validate these assays and suggest that FAS, substantially lower in KDs (and lowest in FO-KD) than Western diets, may play the most crucial role in NNK-induced lung pathology.

    Encouragingly, liver health assays debunked previously hypothesized concerns, revealing that not only did KDs do no more damage than standard Western diets or the 15% amylose diet, but FO-KD and MCT-KD were found to cause even less liver damage than these.

    In contrast, while standard KD did not significantly alter lipid profiles compared to Western and amylose diets, FO-KD and MCT-KD substantially increased low- (LDL) and very low-density lipoprotein (VLDL) levels in mice plasma.

    Conclusions

    The present study validates the long-term safety of KDs on liver health and validates their anti-lung cancer properties in A/J mice.

    Fish oil was found to be the most effective of all tested KD fats and is assumed to confer anti-cancer protection through metabolic alterations, especially by reducing FAS levels.

    These findings highlight FO-KD as a future intervention against lung cancer, but its cardiovascular safety must first be confirmed before these interventions can be implemented.

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  • New psychological treatment for epileptic children lowers mental health problems

    New psychological treatment for epileptic children lowers mental health problems

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    A new psychological treatment for children with epilepsy, developed by a UCL-led team of scientists, has been shown to reduce mental health difficulties compared to standard care, a new study finds.

    Mental health problems such as worries, low mood and behaviour problems are more common in children and young people with brain conditions such as epilepsy, than in the general population – with up to 60% of those with epilepsy having associated mental health disorders and many having more than one mental health condition.

    These conditions can have a big impact on patients’ quality of life and overall health.

    Currently, mental health problems in children and young people with epilepsy are often not identified because centres that treat epilepsy are usually separated from those that treat mental health difficulties. When mental health difficulties are identified, standard treatment for children who also have epilepsy is usually carried out by specialists, such as child and adolescent mental health services (CAMHS) or hospital-based paediatric psychology services. The treatment given usually involves treating each mental health condition (ie. anxiety, depression, behavioural issues) individually.

    The new treatment, named the Mental Health Intervention for Children with Epilepsy (MICE), is based on the treatments that the National Institute for Health and Care Excellence (NICE) recommends for the treatment of common mental health difficulties, like cognitive behavioural therapy for anxiety and depression. However, it uses a modular approach, that enables multiple mental health conditions to be treated at once, instead of having different treatments for different mental health difficulties.

    It was also modified specifically for children and young people with epilepsy, for example including sessions that explain about the relationship between epilepsy and mental health.

    Additionally, the treatment can be delivered over the phone or via video call so that people did not have to travel to the hospital and miss time from school or work. And rather than being outsourced to services such as CAMHS, it was integrated into epilepsy services – meaning that it could be delivered by non-mental health specialists.

    Lead author Dr Sophie Bennett, who carried out the research while working at UCL Great Ormond Street Institute of Child Health, said: “This treatment breakthrough means that we have a new way to help children and young people with epilepsy who also have mental health difficulties.

    “The treatment can be delivered from within epilepsy services to join up care. It doesn’t need to be delivered by specialist mental health clinicians like psychologists.

    “Integrating the care can help children with epilepsy and their families more effectively and efficiently. We were particularly pleased that benefits were sustained when treatment ended.”

    The new treatment, outlined in The Lancet, was created together with young people and their families and the professionals who care for them, including doctors, nurses and psychologists.

    Patients were given an initial assessment followed by weekly calls with the clinician – although face-to-face therapy was available if preferred. The sessions were delivered to either the young person directly, or via their caregiver, based on their individual circumstances.

    Researchers trialled the treatment with 334 children and young people aged three to 18. Of these, 166 received the new MICE treatment and 168 received the usual treatment for mental health problems in children with epilepsy.

    They assessed adolescents’ mental health and overall well-being from a parent-reported Strengths and Difficulties Questionnaire (SDQ) – covering areas such as emotional problems, conduct, hyperactivity and peer problems.

    The results showed that the children who had the MICE treatment had fewer mental difficulties than those who had the usual treatment, and the change is equivalent to a decrease of 40% in the likelihood of having a psychiatric disorder.

    These groundbreaking findings not only promise brighter futures for children with epilepsy but also pave the way for a revolutionary shift in mental healthcare practices.


    The collaborative efforts of scientists, patients, and healthcare professionals have brought forth a new era of treatment of mental health challenges associated with epilepsy, offering a beacon of hope for families in the face of mental health challenges associated with epilepsy.”


    Professor Roz Shafran, Co-Chief Investigator, UCL Great Ormond Street Institute of Child Health and GOSH

    Co-Chief Investigator, Professor Helen Cross (UCL Great Ormond Street Institute of Child Health and GOSH), said: “This study shows real progress for clinicians considering the high rate of mental health problems in children with epilepsy, as we demonstrate the benefit of a therapy that can be implemented within existing epilepsy services.”

    Co-author, Professor Isobel Heyman (UCL Great Ormond Street Institute of Child Health and Clinical Co-Lead for mental health at Cambridge Children’s Hospital), said: “These promising results show that staff working in paediatric settings can be trained to deliver effective mental health treatment to children with a physical health condition (epilepsy).

    “It clearly demonstrates that children’s healthcare needs can be met in a holistic way to treat the ‘whole child’, in the same place at the same time.”

    The work was conducted in collaboration with experts at Great Ormond Street Children’s Hospital (GOSH), King’s College London and UCLA, and with funding from the National Institute for Health and Care Research (NIHR).

    Source:

    University College London

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  • Study reveals the body’s molecular response to prolonged fasting

    Study reveals the body’s molecular response to prolonged fasting

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    New findings reveal that the body undergoes significant, systematic changes across multiple organs during prolonged periods of fasting. The results demonstrate evidence of health benefits beyond weight loss, but also show that any potentially health-altering changes appear to occur only after three days without food. 

    The study, published today in Nature Metabolism, advances our understanding of what’s happening across the body after prolonged periods without food. 

    By identifying the potential health benefits from fasting and their underlying molecular basis, researchers from Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI) and the Norwegian School of Sports Sciences provide a road map for future research that could lead to therapeutic interventions – including for people that may benefit from fasting but cannot undergo prolonged fasting or fasting-mimicking, such as ketogenic, diets. 

    Over millennia, humans have developed the ability to survive without food for prolonged periods of time. Fasting is practiced by millions of people throughout the world for different medical and cultural purposes, including health benefits and weight loss. Since ancient times, it has been used to treat diseases such as epilepsy and rheumatoid arthritis. 

    During fasting, the body changes its source and type of energy, switching from consumed calories to using its own fat stores. However, beyond this change in fuel sources, little is known about how the body responds to prolonged periods without food and any health impacts – beneficial or adverse – this may have. New techniques allowing researchers to measure thousands of proteins circulating in our blood provide the opportunity to systematically study molecular adaptions to fasting in humans in great detail. 

    Researchers followed 12 healthy volunteers taking part in a seven-day water-only fast. The volunteers were monitored closely on a daily basis to record changes in the levels of around 3,000 proteins in their blood before, during, and after the fast. By identifying which proteins are involved in the body’s response, the researchers could then predict potential health outcomes of prolonged fasting by integrating genetic information from large-scale studies. 

    As expected, the researchers observed the body switching energy sources – from glucose to fat stored in the body – within the first two or three days of fasting. The volunteers lost an average of 5.7 kg of both fat mass and lean mass. After three days of eating after fasting, the weight stayed off – the loss of lean was almost completely reversed, but the fat mass stayed off. 

    For the first time, the researchers observed the body undergoing distinct changes in protein levels after about three days of fasting – indicating a whole-body response to complete calorie restriction. Overall, one in three of the proteins measured changed significantly during fasting across all major organs. These changes were consistent across the volunteers, but there were signatures distinctive to fasting that went beyond weight loss, such as changes in proteins that make up the supportive structure for neurons in the brain. 

    For the first time, we’re able to see what’s happening on a molecular level across the body when we fast. Fasting, when done safely, is an effective weight loss intervention. Popular diets that incorporate fasting – such as intermittent fasting – claim to have health benefits beyond weight loss. Our results provide evidence for the health benefits of fasting beyond weight loss, but these were only visible after three days of total caloric restriction – later than we previously thought.” 


    Claudia Langenberg, Director of Queen Mary’s Precision Health University Research Institute (PHURI)

    Maik Pietzner, Health Data Chair of PHURI and co-lead of the Computational Medicine Group at Berlin Institute of Health at Charité, said: 

    “Our findings have provided a basis for some age-old knowledge as to why fasting is used for certain conditions. While fasting may be beneficial for treating some conditions, often times, fasting won’t be an option to patients suffering from ill health. We hope that these findings can provide information about why fasting is beneficial in certain cases, which can then be used to develop treatments that patients are able to do.” 

    Source:

    Queen Mary University of London

    Journal reference:

    Pietzner, M., et al. (2024). Systemic proteome adaptions to 7-day complete caloric restriction in humans. Nature Metabolism. doi.org/10.1038/s42255-024-01008-9.

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  • Is posttraumatic epilepsy associated with long-term dementia risk?

    Is posttraumatic epilepsy associated with long-term dementia risk?

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    In a recent study published in JAMA Neurology, researchers assessed the associations between post-traumatic epilepsy (PTE) and the risk of dementia.

    Study: Posttraumatic Epilepsy and Dementia Risk. Image Credit: Orawan Pattarawimonchai/Shutterstock.comStudy: Posttraumatic Epilepsy and Dementia Risk. Image Credit: Orawan Pattarawimonchai/Shutterstock.com

    Background

    PTE is the occurrence of unprovoked seizures more than a week after a traumatic brain injury, and it accounts for up to 20% of acquired epilepsies.

    Research suggests that PTE is associated with poor short-term psychosocial, cognitive, and functional outcomes; however, less is known about the long-term impact of PTE.

    Moreover, epilepsy and traumatic brain injury are independently associated with the risk of dementia. Growing evidence implicates neurodegenerative mechanisms in PTE pathophysiology.

    As such, individuals with PTE may likely have adverse cognitive outcomes compared to those with epilepsy or brain injury alone.

    About the study

    In the present study, researchers examined the associations between PTE and dementia risk using data from the atherosclerosis risk in communities (ARIC) study.

    The ARIC study enrolled people aged 45–64 during 1987-89. Participants completed subsequent in-person visits and follow-up telephone calls. Subjects were asked about hospitalizations during telephone calls; reported hospitalization records were obtained.

    ARIC study data were linked to the United States (US) Centers for Medicare and Medicaid Services (CMS). Follow-up for the present analysis continued until the diagnosis of dementia, death, discontinuation, or administrative censoring.

    Head injury was defined using data from questionnaires, International Classification of Diseases, ninth and tenth revisions (ICD-9/10) codes from ARIC study hospitalization records, and ICD-9/10 codes from linked CMS records.

    Epilepsy/seizure was defined using seizure- or epilepsy related ICD-9/10 codes from ARIC and CMS records. PTE was defined as epilepsy/seizure occurring ≥ seven days after (diagnosis of) head injury.

    The researchers stratified participants into exposure groups – 1) reference (no epilepsy/seizure and no head injury), 2) head injury, 3) epilepsy/seizure, and 4) PTE. The associations between exposure variables and dementia risk were examined using Cox proportional hazard models.

    Model 1 was adjusted for sex, age, education, race, military veteran status, and center. Model 2 was additionally adjusted for smoking/alcohol status, hypertension, and diabetes.

    Model 3 was further adjusted for the apolipoprotein E ε4 genotype. Besides, Fine and Gray proportional hazard models accounted for the competing mortality risks individually and with stroke.

    Findings

    The team included 12,558 participants from the ARIC study for analysis. They were aged 54.3, on average, at baseline. Most participants (57.7%) were female, and 28.2% were Black.

    The team categorized 1,811, 640, and 145 participants as having a head injury, epilepsy/seizure, and PTE, respectively, over a median follow-up of 25.4 years.

    The median time from baseline to first head injury, epilepsy/seizure, or PTE was 15.1, 13.8, or 3.1 years, respectively. Overall, 2,498 cases of dementia occurred over a follow-up of 250,372 person-years. Notably, individuals with PTE had the lowest cumulative dementia-free survival.

    In the first model, PTE was associated with 4.85 times the risk of dementia compared to the reference group.

    In contrast, epilepsy/seizure and head injury were associated with 2.81- and 1.64-fold higher dementia risk, respectively. In models (2 and 3) with additional adjustments (for vascular and genetic risk factors), the elevated dementia risk associated with PTE was marginally attenuated.

    Nevertheless, this (PTE-associated) increased dementia risk was still significantly higher than that associated with epilepsy/seizure or head injury alone.

    PTE was associated with a three-fold increased risk of dementia in models that accounted for the competing risks of death individually and with stroke.

    Further, younger participants consistently showed stronger associations between PTE and dementia risk than older subjects across all models. There was no evidence of multiplicative interaction by race or sex.

    Conclusions

    In sum, the study demonstrated that subjects with PTE had about a 4.5-fold increased risk of dementia relative to those without epilepsy/seizure and head injury.

    After accounting for the competing risks of death and stroke, there was approximately three-fold higher dementia risk associated with PTE.

    Moreover, dementia risk was significantly higher with PTE than with epilepsy/seizure or head injury alone. Notably, the study population comprised older adults without prior head injury at baseline; thus, the findings may not be generalized to those who sustain a head injury early in life.

    The study could not account for physical functioning and frailty, which might confound the observed associations.

    Besides, the researchers did not have access to details of injury mechanisms, acute imaging findings, and clinical characteristics.

    Taken together, the findings reveal increased dementia risk among people with PTE that was significantly higher than in individuals with head injury or epilepsy/seizure alone.

    These results highlight the significance of prevention of not only head injuries but also PTE following these injuries.

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  • Neuroscientists uncover surprising role of glia in regulating neuronal responses in the brain

    Neuroscientists uncover surprising role of glia in regulating neuronal responses in the brain

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    Neuroscientists at Fred Hutchinson Cancer Center have found that an often-overlooked type of brain cell called glia has more of a role in brain function than previously thought.

    In the journal Cell Reports, Fred Hutch neuroscientist Aakanksha Singhvi, PhD, and her team report that a single glial cell uses different molecules to communicate with different neurons. Careful clustering of these molecules ensures that the glial cell can conduct a distinct “conversation” with each neuron. Through these molecular facilitators, glia can influence how neurons respond to environmental cues like temperature and smell.

    Cell Reports published the study online Feb. 27.

    It’s the first very clear indication that a glial cell is going to put specific molecules to specific contact sites to regulate those neurons, at the single-cell level, with consequences to how the animal will behave.”


    Aakanksha Singhvi, PhD, assistant professor, Basic Sciences Division at Fred Hutch

    Glial cells make up about half of the cells in the brain, but the other half of the cells -; neurons -; typically get the most of our attention for their central role in our thoughts, sensations and behaviors. Less glitzy than neurons that literally pulse with electricity, glia seemed to play a purely supporting role. Neuroscientists dismissed them a mere “glue” that help neurons stick together, or “nursemaids” that provide neurons sustenance but not guidance.

    Singhvi is among the cadre of neuroscientists leading the charge to reevaluate the importance of glia.

    “In the last few years there has been growing appreciation that glial cells may contribute to many diseases of the brain, from epilepsy to Alzheimer’s,” Singhvi said. “To have a more holistic and clinically-relevant picture of brain function, we need to go back to basics and more fully understand how glia and neurons work together.”

    To unearth glial cells’ basic biology, Singhvi helped develop the use of Caenorhabditis elegans, which are tiny, transparent worms (also called nematodes). Each worm has exactly the same number of cells, including 302 neurons per animal, and only 56 glia. While we may seem to have little in common with worms, their neurons and glia work much like ours.

    Singhvi and Sneha Ray -; first author of the Cell Reports study and a graduate student in Singhvi’s lab -; focused on one of these glial cells called amphid sheath (AMsh) to see how they interacted with a sensory neuron called AFD, which senses temperature for C. elegans.

    Using high-powered microscopes to zero in on individual neurons and glia, the researchers looked for a protein called KCC-3 that Singhvi had previously discovered helps with signaling across cell membranes. The researchers quickly saw that KCC-3 was not distributed equally along the glial cell’s membrane. Instead, the protein clustered in one spot along the interface between the glial cell (AMsh) and the sensory neuron (AFD).

    “We realized it’s sitting next to the temperature-sensing neuron -; but not any of the others -; which is essentially the glial cell knowing a half a micron [millionth of a meter] difference between the two neurons,” Singhvi said.

    The team detected at least three types of molecular clusters that connect the AMsh glia to different sensory neurons.

    Ray and Singhvi also found that even though every neuron enveloped by AMsh senses a different environmental cue, the glial cell can help integrate information across circuits and allow neurons within one sensory circuit (like temperature) to influence the function of neurons within a different circuit (like those that smell specific odors). In this way, a single glial cell can help the worm respond to the bigger environmental picture, instead of merely helping neurons relay individual external cues.

    “When you think about what it takes to be a nematode, it’s very complicated,” Singhvi said.

    What does a worm do when it encounters a tantalizing scent that signals food -; right when its environment starts getting dangerously warm? It must balance these different inputs and make a decision.

    “The worm won’t burn -; it’s too smart to burn,” Singhvi said.

    And the compartmentalization that she and Ray uncovered is likely critical to a nematode’s -; or human’s -; ability to weigh important factors like heat and smell, she said. This allows the animal to have multiple circuits working properly at the same time without confusing cross connections.

    For possible applications to human brain health, Singhvi noted that the same KCC-3 protein she studies in nematodes is also essential for brain function in humans. Disruptions of KCC-3 is linked to a severe brain development disorder called agenesis of the corpus callosum or Anderman Syndrome, and to seizure susceptibility and neurodegeneration. Differences in brain circuits is linked to conditions such as autism, epilepsy and schizophrenia.

    “Our brains routinely process multiple inputs or sensory cues in parallel,” Singhvi said. “Our research showing that glia can be conduits between brain circuits will help us understand the different ways that the circuits can be disrupted.”

    Source:

    Fred Hutchinson Cancer Center

    Journal reference:

    Ray, S., et al. (2024) Neuron cilia restrain glial KCC-3 to a microdomain to regulate multisensory processing. Cell Reports. doi.org/10.1016/j.celrep.2024.113844.

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  • Eye movement reflex reveals genetic association with autism

    Eye movement reflex reveals genetic association with autism

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    Scientists at UC San Francisco may have discovered a new way to test for autism by measuring how children’s eyes move when they turn their heads.

    They found that kids who carry a variant of a gene that is associated with severe autism are hypersensitive to this motion.

    The gene, SCN2A, makes an ion channel that is found throughout the brain, including the region that coordinates movement, called the cerebellum. Ion channels allow electrical charges in and out of cells and are fundamental to how they function. Several variants of this gene are also associated with severe epilepsy and intellectual disability. 

    The researchers found that children with these variants have an unusual form of the reflex that stabilizes the gaze while the head is moving, called the vestibulo-ocular reflex (VOR). In children with autism, it seems to go overboard, and this can be measured with a simple eye-tracking device.

    The discovery could help to advance research on autism, which affects 1 out of every 36 children in the United States. And it could help to diagnose kids earlier and faster with a method that only requires them to don a helmet and sit in a chair.

    “We can measure it in kids with autism who are non-verbal or can’t or don’t want to follow instructions,” said Kevin Bender, PhD, a professor in the UCSF Weill Institute for Neurosciences and co-senior author of the study, which appears Feb. 26 in Neuron. “This could be a game-changer in both the clinic and the lab.” 

    A telltale sign of autism in an eye reflex 

    Of the hundreds of gene mutations associated with autism, variants of the SCN2A gene are among the most common.

    Since autism affects social communication, ion channel experts like Bender had focused on the frontal lobe of the brain, which governs language and social skills in people. But mice with an autism-associated variant of the SCN2A gene did not display marked behavioral differences associated with this brain region.

    Chenyu Wang, a UCSF graduate student in Bender’s lab and first author of the study, decided to look at what the SCN2A variant was doing in the mouse cerebellum. Guy Bouvier, PhD, a cerebellum expert at UCSF and co-senior author of the paper, already had the equipment needed to test behaviors influenced by the cerebellum, like the VOR. 

    The VOR is easy to provoke. Shake your head and your eyes will stay roughly centered. In mice with the SCN2A variant, however, the researchers discovered that this reflex was unusually sensitive. When these mice were rotated in one direction, their eyes compensated perfectly, rotating in the opposite direction. 

    But this increased sensitivity came at a cost. Normally, neural circuits in the cerebellum can refine the reflex when needed, for example to enable the eyes to focus on a moving object while the head is also moving. In SCN2A mice, however, these circuits got stuck, making the reflex rigid. 

    A mouse result translates nearly perfectly to kids with autism 

    Wang and Bender had uncovered something rare: a behavior that arose from a variant to the SCN2A gene that was easy to measure in mice. But would it work in people?

    They decided to test it with an eye-tracking camera mounted on a helmet. It was a “shot in the dark,” Wang said, given that the two scientists had never conducted a study in humans. 

    Bender asked several families from the FamilieSCN2A Foundation, the major family advocacy group for children with SCN2A variants in the US, to participate. Five children with SCN2A autism and eleven of their neurotypical siblings volunteered.

    Wang and Bender took turns rotating the children to the left and right in an office chair to the beat of a metronome. The VOR was hypersensitive in the children with autism, but not in their neurotypical siblings.

    The scientists could tell which children had autism just by measuring how much their eyes moved in response to their head rotation. 

    A CRISPR cure in mice

     The scientists also wanted to see if they could restore the normal eye reflex in the mice with a CRISPR-based technology that restored SCN2A gene expression in the cerebellum. 

    When they treated 30-day-old SCN2A mice – equivalent to late adolescence in humans – their VOR became less rigid but was still unusually sensitive to body motion. But when they treated 3-day-old SCN2A mice – early childhood in humans – their eye reflexes were completely normal. 

    These first results, using this reflex as our proxy for autism, point to an early window for future therapies that get the developing brain back on track.”

    Chenyu Wang, UCSF graduate student

    It’s too early to say whether such an approach might someday be used to directly treat autism. But the eye reflex test, on its own, could clear the way to more expedient autism diagnosis for kids today, saving families from long diagnostic odysseys.

    “If this sort of assessment works in our hands, with kids with profound, nonverbal autism, there really is hope it could be more widely adopted,” Bender said.

    Source:

    University of California – San Francisco

    Journal reference:

    Wang, C., et al. (2024). Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD. Neuron. doi.org/10.1016/j.neuron.2024.01.029.

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  • Breakthrough research on glioma progression wins BIAL Award in Biomedicine

    Breakthrough research on glioma progression wins BIAL Award in Biomedicine

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    A team of researchers from Germany, the USA, the UK, and Norway won the third edition of the BIAL Award in Biomedicine, a 300,000 Euro prize promoted by the BIAL Foundation, which seeks to recognize a work in biomedicine of exceptional quality and scientific relevance published in the last ten years.

    Led by researchers Varun Venkataramani (first author), Frank Winkler, and Thomas Kuner (senior co-authors) from the University of Heidelberg in Germany, the study “Glutamatergic synaptic input to glioma cells drives brain tumor progression”, published in Nature in 2019, represents breakthrough research important for understanding human cancer, specifically glioblastomas, a very aggressive type of brain tumor with an average survival time of just 1.5 years, even with state-of-the-art treatment.

    In this work, the authors showed that glioblastomas and other incurable gliomas can integrate themselves into the function of the brain, and that input from healthy brain cells, normally used in functions such as thinking and memory, drives the progression of gliomas. This is possible by formation of synapses between neurons and cancer cells.

    For the president of the Jury, Ralph Adolphs, “these findings are a major and surprising advance in the understanding of how brain cancer progresses, by describing a new communication channel between neurons and the tumour and by suggesting specific avenues for treatment”.

    This paper shows that cancer cells cannot merely proliferate – they have to hijack healthy biological processes and integrate themselves into the normal function of tissues. “Nowhere is this more blatant – and surprising – than in the brain tumours studied in this paper”, says Ralph Adolphs.

    The award-winning research also provides a new explanation for why epilepsy and tumour progression are often observed together: epilepsy may be a cause, rather than a consequence of the tumour progression.

    The winning paper, chosen from 70 nominations, is co-authored by 29 researchers from Heidelberg University, Heidelberg University Hospital, German Cancer Research Center, University Hospital Mannheim, Otto-von-Guericke University (Germany), Johns Hopkins University School of Medicine (USA), University of Glasgow (UK), University of Bergen, and Haukeland University Hospital (Norway).

    It should be noted that two of the scientists who won the 2021 edition of this Award, Katalin Karikó, and Drew Weissman, were awarded the 2023 Nobel Prize in Physiology or Medicine for their discoveries that enabled the development of vaccines based on mRNA to prevent COVID-19.

    The next edition will take place in 2025.

    Authors of the award-winning work and respective institutions at the time the paper was published:

    Heidelberg University, Germany
    Varun Venkataramani, Dimitar Ivanov Tanev, Christopher Strahle, Christoph Körber, Markus Kardorff, Heinz Horstmann, Sang Peter Paik, Johannes Knabbe, Frank Herrmannsdörfer, Amit Agarwal, Felix Sahm & Thomas Kuner

    Heidelberg University Hospital, Germany
    Varun Venkataramani, Dimitar Ivanov Tanev, Alexander Studier-Fischer, Laura Fankhauser, Tobias Kessler, Ruifan Xie, Mirko Messer, Sevin Turcan, Wolfgang Wick, Felix T. Kurz & Frank Winkler

    German Cancer Research Center (DKFZ), Germany
    Varun Venkataramani, Dimitar Ivanov Tanev, Alexander Studier-Fischer, Laura Fankhauser, Tobias Kessler, Miriam Ratliff, Ruifan Xie, Mirko Messer, Wolfgang Wick, Felix Sahm, Azer Aylin Acikgöz, Hai-Kun Liu & Frank Winkler

    University Hospital Mannheim, Germany
    Miriam Ratliff & Daniel Hänggi

    Otto-von-Guericke University, Germany
    Christian Mawrin

    Johns Hopkins University School of Medicine, USA
    Amit Agarwal & Dwight E. Bergles

    Institute of Cancer Sciences, University of Glasgow, UK
    Anthony Chalmers

    University of Bergen e Haukeland University Hospital, Norway

    Hrvoje Miletic

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  • New treatment target found for CDKL5 deficiency disorder

    New treatment target found for CDKL5 deficiency disorder

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    Scientists at the Francis Crick Institute have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. 

    CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function.

    Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme’s activity to compensate for the loss of CDKL5. 

    In research published today in Molecular Psychiatry, the scientists studied mice that don’t make the CDKL5 enzyme. These mice show similar symptoms to people with CDD like impaired learning or social interaction. 

    The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn’t produced. 

    Interestingly, even in mice that don’t produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

    By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.

    The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining <5% from another enzyme yet to be identified. 

    Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development. 

    CDD is a devastating condition that impacts young children from birth, and we don’t know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we’ve identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse.”


    Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory, The Francis Crick Institute

    The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD. 

    Margaux Silvestre, former PhD student at the Crick and now postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: “Our discoveries offer fresh insights into the expression and regulation of CDKL5 in the brain. Moreover, the identification of CDKL2 as a potential compensatory enzyme provides hope for uncovering better treatments that could truly make a difference in the lives of the children with this devastating condition. This research owes its success to all the authors involved in the publication but also the unwavering support we received from the technical teams at the Crick – a big shoutout to them!”

    The research was funded by the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD.

    Source:

    The Francis Crick Institute

    Journal reference:

    Silvestre, M., et al. (2024). Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry. doi.org/10.1038/s41380-024-02434-7.

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