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Tag: Seizure

  • Exploring how gene variants affect brain cells in children with severe epilepsy

    Exploring how gene variants affect brain cells in children with severe epilepsy

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    Epilepsy is a brain disorder that causes recurring seizures. 

    It is one of the most common neurological diseases, and it affects approximately 50 million people worldwide, according to the World Health Organization. In 2023, nearly 450,000 children in the United States were diagnosed with the disease.

    Virginia Tech researchers at the Fralin Biomedical Research Institute at VTC are exploring how gene variants identified in children with severe epilepsy can have an impact on neurons, leading to abnormal electrical activity in the brain and recurrent seizures. 

    With two recent grants totaling $2.4 million from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, scientists led by Matthew Weston will use mouse models expressing these epilepsy-associated gene variants to understand how they alter neuron behavior to cause seizures.

    The Weston lab is particularly interested in a gene called KCNT1. This specific segment of DNA carries the instructions for a protein that forms an ion channel that acts like a tiny gate embedded in the membrane of neurons to control the flow of potassium ions. 

    This flow is essential to help neurons communicate properly and regulate the electrical activity in our brain, according to Weston, an associate professor at the Fralin Biomedical Research Institute. 

    Changes in this gene affect normal nervous system function and can lead to seizures by causing a dysregulation of electrical stabilization in neurons that can spread across networks throughout regions of the brain. Earlier investigations by Weston’s team examined the influence of KCNT1 genetic abnormalities on the excitability of neurons, indicating their potential connection to epilepsy.

    We’re using mouse models with the exact same KCNT1 mutations that cause severe and untreatable epilepsy in kids. By closely examining these models, we hope to discover a path to therapeutic intervention.”


    Matthew Weston, associate professor, Virginia Tech’s School of Neuroscience in the College of Science

    Weston is collaborating with Wayne Frankel, professor of Genetics and Development at Columbia University’s Institute for Genomic Medicine. Frankel recently designed new research models for this study: a model with the KCNT1 genetic mutation in all neurons and another model that allows the KCNT1 genetic mutation to be expressed only in a subpopulation of neurons to identify which neuron types are most important for the disease.

    By looking at the neurons in the brains of these models, Weston aims to uncover fresh perspectives on the alterations in neuronal function induced by KCNT1 mutations, resulting in heightened excitability and seizure occurrence. More importantly, he hopes to pinpoint the neuron types most susceptible to these changes, potentially guiding the development of innovative treatment strategies. 

    “With these models, we’re hoping to find new mechanisms underlying the disease and point to new therapies,” Weston said.

    Weston serves on the scientific advisory board for the KCNT1 Epilepsy Foundation, which supports research and drug development, with the ultimate goal of finding an eventual cure for KCNT1-related epilepsies.

    Amy Shore, a research scientist in Weston’s lab, finds inspiration in the connection with the foundation. 

    “Engaging with parents, and hearing stories about the devastation of this disease on their children and their daily lives, motivates us to focus and do our best to find answers that can translate into hope,” she said.

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  • Electroconvulsive Therapy found to be safe and effective treatment for some mental illnesses

    Electroconvulsive Therapy found to be safe and effective treatment for some mental illnesses

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    Researchers have found that Electroconvulsive Therapy (ECT), where an electric current is passed through the brain, can reduce the severity of mental illnesses.

    ECT is a safe and effective treatment for some mental illnesses including severe/psychotic depression, postnatal psychosis and mania. Patients are placed under general anaesthetic and the brain is stimulated with short electric pulses. This causes a brief seizure which lasts for less than two minutes.

    The use of ECT across Scotland was assessed over an 11-year period from 2009 to 2019 using data from the Scottish Electroconvulsive Therapy (ECT) Audit Network (SEAN). The Scotland-wide naturalistic study assessed the efficacy and side effects of ECT across a range of common mental illnesses such as depression, bipolar depression, schizophrenia, and mania.

    Key findings from the study include:

    • ECT was shown to be effective in reducing illness severity, as measured by Clinical Global Impression Scale (CGI-S). CGI-S is a validated clinician administered assessment tool which measures illness severity.
    • 2,920 ECT episodes had CGI-S scores recorded for patients before and after treatment. The mean CGI-S score prior to treatment indicated marked illness severity (5.03 95% CI 4.99-5.07), whilst after treatment, the mean CGI-S score was reduced to 2.07, (95% CI 2.03-2.11) indicating a reduction to borderline illness severity.
    • The study also assessed side effects of ECT. Anaesthetic complications and prolonged seizures were rare, occurring in <1% of treatment episodes. Cardiovascular complications were reported in 2.2%. Nausea was reported in 7.2% and muscle aches in 12%. Confusion was reported in 19% and cognitive side effects in 26.2%.

    Dr Julie Langan Martin, Senior Clinical Lecturer in Psychiatry, Director of Education at the University of Glasgow, Scotland, said “Our findings from this large naturalistic study across Scotland from over an 11-year period reinforce the widely held, but nonetheless underexplored view, that ECT is both a safe and effective treatment when delivered to appropriate groups of people with severe mental illness. Monitoring of side effects, especially cognitive side effects should be undertaken carefully and rigorously in all patients receiving ECT.”

    This study on ECT presents compelling evidence of its effectiveness in reducing the severity of mental illnesses, with major side effects found to be rare. It challenges common misconceptions and stigmas associated with ECT, providing valuable insights that can reshape public perceptions and stimulate informed discussions among healthcare professionals.”

    Dr Julian Beezhold, Secretary General of the European Psychiatric Association

    The European Congress of Psychiatry takes place from 6-9 April 2024 in Budapest, Hungary, and represents Europe’s largest congress dedicated to psychiatry, with over 4000 participants: epa-congress.org.

    Source:

    European Psychiatric Association

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  • Assistance dogs may detect PTSD flashbacks via breath

    Assistance dogs may detect PTSD flashbacks via breath

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    Dogs’ sensitive noses can detect the early warning signs of many potentially dangerous medical situations, like an impending seizure or sudden hypoglycemia. Now, scientists have found evidence that assistance dogs might even be able to sniff out an oncoming PTSD flashback, by teaching two dogs to alert to the breath of people who have been reminded of traumas. 

    “PTSD service dogs are already trained to assist people during episodes of distress,” said Laura Kiiroja of Dalhousie University, first author of the paper in Frontiers in Allergy. “However, dogs are currently trained to respond to behavioral and physical cues. Our study showed that at least some dogs can also detect these episodes via breath.”

    Stressed humans smell

    PTSD arises from exposure to a catastrophic event: symptoms include re-experiencing that catastrophic event, hyperarousal, avoiding any reminders, and cognitive or mood issues. Among other forms of assistance, dogs can help patients by alerting to and interrupting episodes when their companions are struggling with their symptoms. If dogs could respond to stress markers on the breath, they could potentially interrupt episodes at an earlier stage, making their interventions more effective. 

    All humans have a ‘scent profile’ of volatile organic compounds (VOCs) -; molecules emitted by the body in secretions like sweat -; influenced by our genetics, age, activities, and other variables. There is some evidence that dogs may be capable of detecting VOCs linked to human stress. However, no studies have investigated whether dogs could learn to detect VOCs associated with PTSD symptoms.

    “This is a multidisciplinary collaboration between Dr Sherry Stewart’s clinical psychology lab and Dr Simon Gadbois’ canine olfaction lab, both at Dalhousie University,” said Kiiroja. “Neither lab could have done this work on their own. We brought together two distinct sets of expertise.”

    Catching the scent

    The scientists recruited 26 humans as scent donors. These participants were also taking part in a study about the reactions of people who have experienced trauma to reminders of that trauma; 54% met the diagnostic requirements for PTSD. To donate scents, they attended sessions where they were reminded of their trauma experiences while wearing different facemasks. One facemask provided a calm breath sample that acted as the control, and another, which was worn while the participants recalled their trauma, provided a target breath sample. Participants also completed a questionnaire about their stress levels and their emotions.

    In the meantime, the scientists recruited 25 pet dogs to train in scent-detection. Only two were skilled and motivated enough to complete the study: Ivy and Callie.

    Both Ivy and Callie found this work inherently motivating. Their limitless appetite for delicious treats was also an asset. In fact, it was much harder to convince them to take a break than to commence work. Callie in particular made sure there was no dilly-dallying.”


    Laura Kiiroja of Dalhousie University

    Ivy and Callie were trained to recognize the target odor from pieces of the facemasks, achieving 90% accuracy in discriminating between a stressed and a non-stressed sample. They were then presented with a series of samples, one sample at a time, to see if they could still accurately detect the stress VOCs. In this second experiment, Ivy achieved 74% accuracy and Callie achieved 81% accuracy. 

    Humans’ best friend

    Comparing Callie and Ivy’s successful identifications with the human participants’ self-reported emotions revealed that Ivy’s performance correlated with anxiety, whereas Callie’s correlated with shame. 

    “Although both dogs performed at very high accuracy, they seemed to have a slightly different idea of what they considered a ‘stressed’ breath sample,” said Kiiroja. “We speculated that Ivy was attuned to sympathetic-adreno-medullar axis hormones (like adrenaline) and Callie was oriented to the hypothalamo-pituitary-adrenal axis hormones (like cortisol). This is important knowledge for training service dogs, as alerting to early-onset PTSD symptoms requires sensitivity to sympathetic-adreno-medullar axis hormones.”

    Next, the team plans to carry out experiments to confirm the involvement of the sympathetic-adreno-medullar axis.

    “With 40 sample sets, ours is a proof-of-concept study that needs to be validated by studies with larger sample sizes,” cautioned Kiiroja. “In addition to enrolling more participants, validation studies should collect samples from a higher number of stressful events to confirm dogs’ ability to reliably detect stress VOCs in the breath of one human across different contexts.”

    Source:

    Journal reference:

    Kiiroja, L., et al. (2024) Can scent-detection dogs detect the stress associated with trauma cue exposure in people with trauma histories? A proof-of-concept study. Frontiers in Allergy. doi.org/10.3389/falgy.2024.1352840.

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  • Novel treatment approach to halt epilepsy progression identified

    Novel treatment approach to halt epilepsy progression identified

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    Only a very small percentage of neurons show changes after an epileptic seizure in mice, but these alterations can be permanent and trigger future seizures that can affect the whole brain and lead to impaired cognition, like memory and learning, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The researchers identified an experimental treatment that, if provided within the first 48 hours after the first seizure, can prevent these long-term changes. The findings, which were published recently in The Journal of Clinical Investigation, suggest a promising target for developing treatments for epilepsy and preventing downstream effects of seizures.

    Epilepsy is characterized by excessive activity of brain cells – neurons – which generate seizures. Research is increasingly showing that the development of epilepsy involves changes of synapses, which are structures that connect one neuron to another. While an estimated 3.4 million people in the United States live with some form of epilepsy, it is still unknown what causes it, and there is no cure. Further, half of individuals with epilepsy experience cognitive impairment, such as problems with memory, or with emotional regulation, but it remains unclear why or how epilepsy changes brain cells to cause this. What’s more, epilepsy is common in children with autism and individuals with dementia. 

    It is clear that there is some connection between an epileptic brain, impaired memory and trouble controlling emotions and how we act on those feelings, but we don’t understand the underlying mechanisms. Existing treatments for epilepsy only help manage seizures. This research gives us a promising starting point for developing therapies that prevent them from happening.”


    Frances E. Jensen, MD, chair of the Department of Neurology, and senior author of the study

    In this study, the researchers used a method that “tagged” neurons in the hippocampus-;an area commonly affected by epilepsy, and critical for memory-;of mice that were activated by epileptic activity. The researchers were able to monitor those activated neurons over time and observe how they responded to subsequent seizures. They found that only about twenty percent of neurons in the hippocampus were activated by seizures. Over time, the overactivity of these neurons diminished their ability to make connections with other neurons, called synapses, which is necessary for learning.

    “The overactive neurons lose their ability to build the strong synapses necessary for learning, which may explain why some people with epilepsy have trouble with learning and with memory,” said Jensen. “If we can stop these neurons from undergoing changes after being activated by seizures, our hope is that we can also prevent not only the progression of epilepsy, but also avoid these cognitive deficits individuals experience long-term.”

    To see if they could prevent neurons from becoming permanently epileptic, the researchers used an experimental glutamate receptor-blocker, called IEM-1460, which has been shown to reduce neuron hyperexcitability in models of mice with epilepsy. They found when they treated mice with this blocker in the first 48 hours after their very first seizure the neurons did not become permanently activated, and the subjects did not experience future seizures or the associated effects, like impaired cognition and trouble learning.

    “Now that we have identified the subgroup of neurons that are impacted by epilepsy, we can investigate what makes these cells vulnerable to becoming epileptic, and whether that is something we can develop a therapy to stop,” said Jensen. “We are also eager to determine whether there is a glutamate receptor-blocker that works similarly to IEM-1460 in humans, which could be given to people after their first seizure, and prevent the lifelong struggles associated with epilepsy.”

    Source:

    University of Pennsylvania School of Medicine

    Journal reference:

    Xing, B., et al. (2024). Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures. The Journal of Clinical Investigation. doi.org/10.1172/JCI175167.

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  • Researchers develop a cost-effective method to spatially characterize and map brain epigenomes

    Researchers develop a cost-effective method to spatially characterize and map brain epigenomes

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    An estimated one in six people suffer from a brain disorder worldwide, according to the American Brain Foundation. Current research has provided some insight into cell-communication inside the brain, but there are still a lot of unknowns surrounding how this crucial organ functions. What if there was a comprehensive map that took into consideration not just the biology of the brain, but the specific location where the biology occurs?

    Researchers in the College of Engineering have developed a powerful, cost-effective method to do just that. 

    Chang Lu, the Fred W. Bull Professor of Chemical Engineering, has been leading a research project that could be groundbreaking for brain research. The newly published article in the journal Cell Reports Methods features interdisciplinary research along with faculty in two additional departments within the College of Engineering:

    • Xiaoting Jia, associate professor in the Bradley Department of Electrical and Computer Engineering
    • Daphne Yao, professor in computer science and affiliate faculty at the Sanghani Center for Artificial Intelligence and Data Analytics

    Their goal? Mapping and visualization of the brain biology at genome scale in the most cost-effective way possible to improve healthy functioning.

    Many of the facts about the brain are phenomenological, meaning that we know it happens, but we don’t necessarily understand molecular activities underlying these events. I think this has been hindering the development of drugs. Treating brain disorders has historically been done not by rational design, but by trial and error. By having a reference map that explains how different parts of the brain operate at a molecular level, this can help researchers begin to develop different treatment options.”

    Chang Lu, the Fred W. Bull Professor of Chemical Engineering

    What’s new in brain mapping 

    Brain health is largely determined by gene activities in brain cells. When researchers talk about genetics, they are essentially referring to the DNA sequence and how it affects human health. For example, if something is wrong or altered within the sequence, then certain diseases can be diagnosed. Research has revealed that there can be other chemical changes occurring in the brain that do not alter the DNA sequence, but change how other molecules interact with DNA. This change that influences gene activity without altering the DNA sequence is known as epigenomics, and it can be equally responsible for changing the gene activity inside the brain and causing various diseases. 

    Lu and his colleagues are interested in exploring how brain epigenomics can be altered in various brain regions in response to activity changes or specific conditions like seizures, epilepsy, addiction, or other mental diseases. The current process of brain mapping involves profiling single cells one by one. While this approach offers high spatial resolution and presents important information about cell-communication inside the brain, it is costly and tedious. Lu and his team have developed a more cost-effective approach to the spatial method: epigenomic tomography. 

    Epigenomic tomography involves the creation of a detailed map of the epigenome, or the genome-scale profile of the epigenetic change, across a large area and volume of the brain. Lu believes this is an important method for scientists to use to understand the genetic and environmental factors that affect the ways genes behave outside of DNA sequences. 

    “When a person has a seizure, struggles with addiction, or suffers from any kind of brain disorder, they experience epigenomic alteration in the brain,” Lu said. “Creating a reference map of the brain to display what healthy brain epigenomes look like across various regions can provide a helpful point of comparison for when the brain suffers a change, such as a seizure.”

    The future of drug development 

    Through their collaborative process, the research team was able to create a map that demonstrates when the brain is experiencing a seizure versus when it is experiencing normal activity. Here’s their interdisciplinary approach:

    • Divide the brain into small sections, about 0.5 mm in thickness. These sections are registered, meaning the researchers know where a particular section is from in terms of the location and region of the brain. 

    • Profile each one of the sections separately using their low-input technology developed in Lu’s lab.

    • Group features across these sections into clusters based on their spatial variation patterns using clustering algorithms with help from Yao. 

    • Create brain tomographies for both healthy and diseased brains, with assistance from Jia’s model for investigating the effects of seizures and other brain disorders.

    Once the digital tomography of the brain is reassembled, the researchers have a map that is characteristic of the brain’s epigenome across a significant area. When the map changes, this reflects a significant change in terms of how the brain is performing at the epigenomic level, which Jia says is groundbreaking for understanding brain disorders. 

    “The missing piece to the puzzle is the fundamental understanding of the seizure process at the molecular level across a spatially distributed brain region,” said Jia. “Our method provides a powerful tool that allows us to investigate the molecular processes in the brain underlying seizure.”

    The results of their spatial epigenomic profiling will further help researchers understand how cells across various regions of the brain behave differently in terms of their epigenetic signatures. This cost-effective method also helps ensure that a sizable number of brain samples can be studied, something that yields statistical significance for the result.

    Funding for their research came from a variety of sources who are interested in future drug development for neurological disorders, including:

    • National Institute of General Medical Sciences
    • National Institute on Drug Abuse
    • National Institute of Neurological Disorders and Stroke

    Lu believes his team’s brain mapping method could make a big impact on drug development for brain disorders. He said, “We hope more researchers will join us in terms of making progress on brain disorders. It’s important research for people suffering from depression and addiction. That’s a large percentage of our population.”

    Collaboration inside the lab

    This interdisciplinary collaboration required specialties from all three departments. The research team was supported by the College of Engineering and the Institute for Critical Technology and Applied Sciences Center for Engineered Health. 

    “Our findings wouldn’t have been possible without the close collaboration across multiple disciplines,” Jia said. “It’s really exciting to see that epigenomic tomography facilitates the understanding of spatially dynamic processes across a large brain area underlying seizure, and I expect it can enable applications in a wide range of brain diseases in the future.”

    So what does research on the brain have to do with engineering? To Lu, this was the perfect project for a chemical engineer. 

    “The technology development part of this project is how you might traditionally think of engineering: solving a problem, designing an approach, and developing the technology. But I feel chemical engineers are particularly equipped with the vast skill set of chemistry, biology, and data analysis. Each of these aspects are involved in this project, one way or another,” said Lu. “When my students graduate, I believe they can do all of these things and see the importance of each of them in their work.” 

    The engineering expertise used in this project did not stop there. Yao used statistical algorithms to simplify and organize massive epigenomic data, making meaningful patterns stand out, such as how healthy and diseased brains’ epigenomes differ. 

    “The amount of biological data generated in this project is huge, requiring the design of customized data processing methods tailored for this specific problem,” Yao said. “It is super exciting to see clustering algorithms being used for biomedical research – something to brag about next time I teach machine learning.”

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  • New method developed for triggering and imaging seizures in epilepsy patients

    New method developed for triggering and imaging seizures in epilepsy patients

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    Researchers have developed a new method for triggering and imaging seizures in epilepsy patients, offering physicians the ability to collect real-time data to tailor epilepsy surgery. In contrast to previous practice, where physicians from neurology and nuclear medicine had to wait for hours to days in hopes of capturing the onset of a seizure, the new method is convenient, spares resources, and is clinically feasible. This research was published in the March issue of The Journal of Nuclear Medicine.

    People with epilepsy and seizures who do not respond to medication are often helped by brain surgery. The goal of the surgical procedure is to remove the epileptic brain tissue and spare the healthy brain tissue to control seizures but avoid neurological deficits. “Precisely delineating the epileptic brain tissue is essential for successful surgeries, and obtaining timely images of seizures may help formulate surgical plans with increased precision” said Sabry L. Barlatey, MD, PhD, resident in the Department of Neurosurgery at University Hospital of Bern in Bern, Switzerland.

    The ictal SPECT method has been used since the 1990s as the sole neuro-imaging technique able to capture an image of an epileptic seizure propagating in the brain. However, due to the growing cost and time constraints in health care, most epilepsy centers abandoned this potentially informative technique.

    In this study, instead of waiting for spontaneous occurrences, we imaged planned seizures that were triggered with targeted electrical stimulation to the brain. To our knowledge, this simple idea had never been tested before.”

    Maxime O. Baud, MD, PhD, Professor of Neurology, Department of Neurology, University Hospital of Bern

    Three adult participants with left temporal epilepsy were included in the case study. Authors identified and used stereotactic electroencephalography (sEEG) leads in targeted cerebral areas to trigger patient-typical seizures. The radiotracer 99mTc-HMPAO was administered within 12 seconds of ictal onset and SPECT images were acquired within 40 minutes.

    Seizures were successfully triggered in each participant, replicating the patient-typical seizure semiology and electrographic pattern on sEEG without any adverse events. Each triggered seizure was patient-specific, and the imaged early seizure propagation was unique. In the first two cases, ictal SPECT offered complementary information to sEEG and revealed early involvement of brain areas lacking electrode coverage. In the third case, sEEG and ictal SPECT provided overlapping information.

    “The finding of this study is of practical nature, as it greatly facilitates the acquisition of the ictal SPECT,” noted Thomas Pyka, MD, Privatdozent in the Department of Nuclear Medicine at the University Hospital of Bern. “This may help obtain images of greater quality and could contribute to the refinement of resection planning, improving seizure and cognitive outcomes in epilepsy surgery.”

    This study was made available online in January 2024.

    Source:

    Society of Nuclear Medicine and Molecular Imaging

    Journal reference:

    Barlatey, S. L., et al. (2024). Triggered Seizures for Ictal SPECT Imaging: A Case Series and Feasibility Study. The Journal of Nuclear Medicine. doi.org/10.2967/jnumed.123.266515.

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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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