POPULARITY
16 episodes with gfap
2 episodes with gfap
2 episodes with gfap
2 episodes with gfap
Send us a textIs chronic neuroinflammation the silent driver behind modern brain diseases like Parkinson's, Alzheimer's, Long COVID, and mood disorders? In this eye-opening episode, Dr. Brandon Crawford speaks with Cuong Do, the CEO of BioVie Pharmaceuticals, who came out of retirement to tackle the growing challenge of neurodegenerative diseases. They delve into the intricate science of TNF-alpha, explore the concept of insulin resistance within the brain, and discuss the potential of next-generation neurodrugs, such as BioVie's Bezisterem, to not only alleviate symptoms but potentially alter the trajectory of aging itself. Join them as they unpack the significance of ongoing clinical trials, the implications of biological clocks and mitochondrial health, and the often-overlooked connections between inflammation and crucial aspects of health, including cognition, hormones, longevity, and even autism.Key TakeawaysMany chronic conditions, including neurodevelopmental disorders and autoimmune diseases, may stem from fundamental light signaling failures at the cellular level.In Alzheimer's disease, TNF-alpha drives the production of amyloid precursor protein (APP) and the phosphorylation of tau, contributing to amyloid plaques and tau tangles, though these may be downstream effects of inflammation.Emerging research links the brain fog, fatigue, and malaise associated with Long COVID to inflammatory mechanisms that BioVie's drug candidate, Bezisterem, aims to modulate.Pre-clinical studies of Bezisterem in Parkinson's models showed it to be as effective as Levodopa in restoring muscle control and demonstrated a synergistic effect when used in combination.Bezisterem is a small molecule that readily crosses the blood-brain barrier and has shown a long half-life, potentially offering benefits for Parkinson's patients experiencing "off" states in the morning.BioVie is actively monitoring biomarkers of neurodegeneration, such as GFAP and neurofilament light (NFL), in their clinical trials and has observed a disruption in the typical correlation between disease progression and these markers in the treatment arm.ResourcesBioVie Pharmaceuticals: biovpharma.comClinical Trials Info: https://www.bioviepharma.com/clinical-trialsProducts 528 Innovations Lasers NeuroSolution Full Spectrum CBD NeuroSolution Broad Spectrum CBD NeuroSolution StimPod Learn MoreFor more information, resources, and podcast episodes, visit https://tinyurl.com/3ppwdfpm
If you’re worried about memory loss or have a family history of Alzheimer’s, this episode is a must-listen. Angela sits down with world-renowned neurologist and author Dr. Dale Bredesen to unpack the groundbreaking science behind Alzheimer’s prevention and reversal—even if you carry the APOE4 gene. With over 30 years of research, Dr. Bredesen shares how to optimise your brain health through metabolic flexibility, inflammation control, and personalised interventions. In this powerful and deeply personal episode, Angela also opens up about her own genetic risk and experience caring for her mum with Alzheimer’s. They explore why cognitive decline is not inevitable and how Dr. Bredesen’s new book, The Ageless Brain, is putting the power back into your hands. Whether you're 35 or 75, the steps to preserve your cognition start now—and the tools have never been more accessible. KEY TAKEAWAYS: Alzheimer’s Is Preventable and Reversible: Dr. Bredesen explains how addressing root causes like inflammation, metabolic dysfunction, and toxicity can stop and even reverse cognitive decline. Perimenopause and Brain Fog: Oestrogen loss affects brain energy metabolism, making perimenopausal women more vulnerable to cognitive decline. Your Brain Runs on Supply & Demand: Cognitive health depends on supporting your brain’s high energy needs while reducing inflammatory load and toxic exposure. Check Your Cognitive Biomarkers Early: Blood markers like P-Tau217, GFAP, and A-beta42 can reveal risk decades before symptoms appear. Lifestyle = Medicine: Sleep quality, insulin sensitivity, resistance training, brain stimulation, and even stress reduction all play a critical role. GLP-1s and Alzheimer’s Risk: While popular for weight loss, these drugs may negatively impact cognition in some people—especially APOE4 homozygotes. TIMESTAMPS AND KEY TOPICS:0:00 – Introduction 6:48 – Pathogens, toxins, and the real cause of Alzheimer’s 13:32 – Menopause, oestrogen, and female brain vulnerability 24:05 – Judy’s story: reversing cognitive decline for 13+ years 32:18 – Most common risky behaviours for brain degeneration 42:21 – Best exercises for insulin sensitivity and cognition 51:10 – Supplements that protect brain structure & function 54:22 – How to use The Ageless Brain as a practical guide 58:45 – Final thoughts + where to learn more from Dr. Bredesen VALUABLE RESOURCES Click here for discounts on all the products I personally use and recommend A BIG thank you to our sponsors who make the show possible: Get 20% off the Creatine I love at trycreate.co/ANGELA20, and use code ANGELA20 to save 20% on your firsts order. Brain Boost: Try Neuro Regenerate at lvluphealth.com/angela and use code ANGELA15 to save 15% ABOUT THE GUEST Dale Bredesen, M.D. is an expert in the mechanisms of neurodegenerative diseases such as Alzheimer's disease. He is a graduate of Caltech, and received his MD from Duke University Medical Center. His career has included serving as Chief Resident in Neurology at the University of California, San Francisco, and served as a NIH Postdoctoral Fellow. His faculty position included working at UCSF, UCLA, and the University of California, San Diego. He was the director of the Program on Aging at the Burnham Institute. He was the founding President and CEO of the Buck Institute. He has developed a new therapeutic approach to treating Alzheimer's disease. He is the author of The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline. Dr Dale Bredesen’s latest book: The Ageless Brain: How to Sharpen and Protect Your Mind for a Lifetime - https://amzn.eu/d/gdrjKQm https://www.apollohealthco.com/ https://www.instagram.com/drdalebredesen/ https://www.facebook.com/drdalebredesen/ ABOUT THE HOST Angela Foster is an award winning Nutritionist, Health & Performance Coach, Speaker and Host of the High Performance Health podcast. A former Corporate lawyer turned industry leader in biohacking and health optimisation for women, Angela has been featured in various media including Huff Post, Runners world, The Health Optimisation Summit, BrainTap, The Women’s Biohacking Conference, Livestrong & Natural Health Magazine. Angela is the creator of BioSyncing®️ a blueprint for ambitious entrepreneurial women to biohack their health so they can 10X how they show up in their business and their family without burning out. The High Performance Health Podcast is a top rated global podcast. Each week, Angela brings you a new insight, biohack or high performance habit to help you unlock optimal health, longevity and higher performance. Hit the follow button to make sure you get notified each time Angela releases a new episode. CONTACT DETAILS Instagram Facebook LinkedIn Affiliate Disclaimer: Note this description contains affiliate links that allow you to find the items mentioned in this video and support the channel at no cost to you. While this channel may earn minimal sums when the viewer uses the links, the viewer is under no obligation to use these links. Thank you for supporting the show! Disclaimer: The High Performance Health Podcast is for general information purposes only and do not constitute the practice of professional or coaching advice and no client relationship is formed. The use of information on this podcast, or materials linked from this podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for medical or other professional advice, diagnosis, or treatment. Users should seek the assistance of their medical doctor or other health care professional for before taking any steps to implement any of the items discussed in this podcast. This Podcast has been brought to you by Disruptive Media. https://disruptivemedia.co.uk/
Navy CAPT Travis Polk, MD, FACS, joins us to unravel the cutting-edge innovations transforming military medicine. What if AI and augmented reality could revolutionize battlefield medical care? Dr. Polk provides a compelling glimpse into the future of combat casualty care, shedding light on the Department of Defense's strategic approach to trauma research. From the 2024 Operational Medicine Symposium, we learned about prioritizing projects that extend resuscitation windows and improve blood products, paving the way for prolonged care and facilitating the return of injured soldiers to duty. This episode navigates the complexities of military research funding and underscores the essential role of technologies in situations where evacuation isn't an option. We also venture into the realm of military medical training advancements, with a spotlight on new diagnostic tools for traumatic brain injuries. Discover how FDA-approved biomarkers like GFAP and UCH-L1 enhance real-time TBI assessment in combat zones, challenging the need for immediate CT scans. Our conversation looks closer at the Department of Defense's trauma centers and the significant strides made through clinical studies in refining trauma care. The discussion further broadens to include military simulation training, from synthetic simulators to mixed reality solutions, despite current haptic technology limits. Join us to explore the dynamic evolution of training strategies and the collaborative efforts between military and civilian sectors, ensuring our medical teams are battle-ready. Chapters with Short Summaries: (00:04) Advancements in Military Medicine Research DoD's Combat Casualty Care Research Program prioritizes trauma-related research for the U.S. government, focusing on improving blood products and integrating autonomous solutions for battlefield medical care. (09:18) Advancements in Military Medical Training Military advancements in TBI diagnostics and treatment include blood-based biomarkers, trauma center studies, and medical simulation training. (14:07) Military Simulation Training and Experience Simulation plays a critical role in medical training, using various methods and technologies to maintain trauma competency. Take Home Messages: Strategic Research Funding: The Department of Defense prioritizes trauma-related research projects based on strategic military needs rather than investigator-driven interests, ensuring that innovations directly impact military operations. This approach is evident in the development of improved blood products, anti-shock drugs, and the integration of autonomous solutions like AI and augmented reality to enhance battlefield medical care. Advancements in TBI Diagnostics: Recent FDA-approved blood-based biomarkers, such as GFAP and UCH-L1, provide real-time assessment tools for traumatic brain injuries in combat zones. These innovations allow for better decision-making by identifying potentially serious head injuries without the immediate need for CT scans, which may not be available in the field. Simulation in Medical Training: Medical simulation tools, including synthetic simulators and mixed reality, play a critical role in training military medical personnel, from medics to neurosurgeons. These tools are essential for maintaining trauma competency and enhancing educational strategies in both military and civilian settings. Military-Civilian Partnerships: Successful collaborations, like the one at the Navy Trauma Training Center in Los Angeles, highlight the importance of military-civilian partnerships in providing just-in-time training for surgical teams before deployment. These partnerships are crucial for maintaining the readiness and effectiveness of military medical personnel. Future of Military Medical Care: The podcast emphasizes the importance of prolonged care when evacuation isn't possible and the need for technologies that can assist in returning injured personnel to duty. This includes optimizing therapeutic solutions for faster wound healing and functional recovery, ultimately improving military medical preparedness and excellence. Episode Keywords: Military Medicine, Combat Casualty Care, Trauma Research, Blood Products, Anti-Shock Drugs, AI, Augmented Reality, Prolonged Care, Medical Simulation, Synthetic Simulators, Mixed Reality, Traumatic Brain Injury, Blood-based Biomarkers, Medical Training, Military-Civilian Partnerships, Navy Trauma Training Center, Surgical Teams, Deployment, Trauma Competency Hashtags: #CombatMedicine #MilitaryInnovation #TraumaCare #MilitaryMedicalTraining #BattlefieldCare #ProlongedCare #TraumaticBrainInjury #MedicalSimulation #NavyMedicine #DefenseResearch Honoring the Legacy and Preserving the History of Military Medicine The WarDocs Mission is to honor the legacy, preserve the oral history, and showcase career opportunities, unique expeditionary experiences, and achievements of Military Medicine. We foster patriotism and pride in Who we are, What we do, and, most importantly, How we serve Our Patients, the DoD, and Our Nation. Find out more and join Team WarDocs at https://www.wardocspodcast.com/ Check our list of previous guest episodes at https://www.wardocspodcast.com/our-guests Subscribe and Like our Videos on our YouTube Channel: https://www.youtube.com/@wardocspodcast Listen to the “What We Are For” Episode 47. https://bit.ly/3r87Afm WarDocs- The Military Medicine Podcast is a Non-Profit, Tax-exempt-501(c)(3) Veteran Run Organization run by volunteers. All donations are tax-deductible and go to honoring and preserving the history, experiences, successes, and lessons learned in Military Medicine. A tax receipt will be sent to you. WARDOCS documents the experiences, contributions, and innovations of all military medicine Services, ranks, and Corps who are affectionately called "Docs" as a sign of respect, trust, and confidence on and off the battlefield,demonstrating dedication to the medical care of fellow comrades in arms. Follow Us on Social Media Twitter: @wardocspodcast Facebook: WarDocs Podcast Instagram: @wardocspodcast LinkedIn: WarDocs-The Military Medicine Podcast YouTube Channel: https://www.youtube.com/@wardocspodcast
Blood-based biomarkers for dementia diagnosis are emerging and rapidly evolving. These fluid biomarkers should be used when the results will impact management decisions, including patient and family counseling, symptomatic therapies, and disease-modifying therapies. In this episode, Allison Weathers, MD, FAAN, speaks with Joseph F. Quinn, MD, FAAN, an author of the article “Fluid Biomarkers in Dementia Diagnosis,” in the Continuum® December 2024 Dementia issue. Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Quinn is a professor in the Department of Neurology at Oregon Health & Science University in Portland, Oregon. Additional Resources Read the article: Fluid Biomarkers in Dementia Diagnosis Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Transcript Full interview transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Joseph Quinn, author along with Dr Nora Gray, of Fluid Biomarkers in Dementia Diagnosis from the December 2024 Continuum issue on dementia. Welcome to the podcast and please introduce yourself to our audience. Dr Quinn: Sure. I'm Joe Quinn. I'm a neurologist at the medical school in Oregon, Oregon Health Science University, and I work in neurodegenerative disease, Alzheimer's disease, and Parkinson's disease. Dr Weathers: Certainly some really weighty topics. But again, as I said, today we want to focus on a really fascinating one, the concept of fluid biomarkers in dementia diagnosis. And we'll perhaps get into monitoring of treatment as well. So, this search for reliable biomarkers in the diagnosis of dementia, certainly not a new topic, but you and your co-author Dr Nora Gray did a really fantastic job in the article right from the get-go, laying out the urgency around this now that there are FDA of treatments that depend on pathologic diagnosis. And it feels like they're more and more announced by the day. Even as I was preparing for this interview a few days ago, the FDA approval for donanemab was announced, with the news making every major media outlet. Well, there are several really critical points made by you both in the article. What do you feel is the most important clinical message of your article? What do you want our listeners to walk away with as their one key takeaway? Dr Quinn: I think we still have the best evidence for CSF biomarkers, cerebrospinal fluid biomarkers, really making a diagnosis with some confidence. PET scans are available for visualizing amyloid and Tau now, but they're so expensive and they're not covered. So, the spinal tap information is what most of us around here really rely on when we want to be sure about what's going on. The blood tests are very promising, very exciting, but as you probably know, there's a lot of different opinions about this out there. Some people are sure that it's a done deal and that we now have a blood test for Alzheimer's disease. After I sent the article off, I opened up my issue of Neurology and there was an editorial saying these blood tests will never work. So, there's different ends of the spectrum on this and we tried to strike a balance with that. So they're very promising. I think before the article is due for revision, things are going to be different. But right now, spinal fluid is probably where we have the most confidence. Dr Weathers: I think that's a really solid takeaway to start our discussion with. And then, I think you both did really strike that very delicate balance in what is right now an area where, as I said, you know, things still are changing by the day. I know for our listeners who do subscribe, and I hope that most of them do, Table 9.1, clinically useful CSF biomarkers for the differential diagnosis of dementia, is one that I personally think I will frequently return to. You and Doctor Gray did just a wonderful job organizing these very complex concepts into an easy read and really powerful tool, especially for use at the bedside. Along the lines of knowing which biomarker to use, how frequently routine care are you ordering these tests on your patients? And do you anticipate this changing the media future? Is this another one of those things that by next week, we'll have a different kind of answer in how we use these tests? Dr Quinn: Yeah, as you said in your preliminary comments, the whole picture has been changed by the approval of these antibody therapies for Alzheimer's disease, lecanumab and just last week, donanemab. Prior to the approval of those two medications, I didn't use spinal fluid tests routinely, but I relied on them when I really needed to make a diagnosis with certainty of something really important hung in the balance. If we were trying to rule out some other treatable, more treatable problem. You know, for example, if it was a question of whether somebody primarily had a psychiatric problem or a neurodegenerative disease, this is something that would really allow me to objectify things. And- but that was a minority of people that I would see for dementia evaluation. You know, now that the two therapies are approved, I'm not actively engaged in administering those therapies very frequently but I can see already that the, the patients that I am discussing this with that spinal fluid is where we're probably going to rely for making a diagnosis of the amyloid burden in the in the living patient until PET scans are approved. If amyloid PET scans are- not approved, but covered by insurance, then those will probably replace the spinal fluid. So those tests in that table, A beta 42, tau, p-tau, one of them that's relatively new is this test for aggregated alpha-synuclein. Those I order with some frequency when I'm in those circumstances. Dr Weathers: That's really helpful for our listeners to hear from an expert such as yourself and to think about as they encounter similar patients. Whenever discussing complex topics such as this one, I'm always curious about, what is the most common misconception or pitfall regarding the use of biomarkers for the diagnosis of Alzheimer's and other dementia that you encounter? Dr Quinn: With respect to the blood biomarkers, you know, we were saying a moment ago that there's a lot of evidence available, but the jury is still out to some degree as to how reliable they are. And I think an important message with respect to those blood biomarkers is that they really are confounded by comorbidities. Remember, we're dealing with an elderly population, so comorbidities like hypertension and renal insufficiency and those kinds of things are relatively common and they can really throw off the blood biomarkers in a more dramatic way than cerebrospinal fluid biomarkers. The other fact, and I can't remember how well we cited this in the article, was that the blood biomarkers don't perform as well in underrepresented minorities. And you know, all of us are appropriately paying more attention to that problem in our practice of medicine. And for these blood biomarkers, that's a real issue. And whether the inferior performance in underrepresented groups is due to more comorbidity or just due to genetic differences is unclear at this time. So those are really important cautions. We mentioned the renal insufficiency and, I think, some of the other comorbidities, but it's a reason to really be careful with the blood biomarkers. Dr Weathers: I think a really important point, especially again, kind of going back to what we were talking about at the beginning of our discussion, there's so much excitement around them. There's so much potential. People think we finally have that kind of silver bullet of diagnosis. So, I think really something to keep in mind. What about in the use of their- in monitoring the efficacy of treatments? Dr Quinn: So that's I think a little earlier in its history in terms of what biomarkers would be useful for monitoring. But the donanemab trial really relied on blood biomarkers as outcome measures and really showed some interesting phenomena. One of them was that plasma neurofilament light, which is all the rage now and all over neurology, people are measuring plasma neurofilament light. It's a nonspecific marker of neuronal damage that makes it out into the serum. So, you can measure it in serum and detect CNS damage in the serum. And intuitively, you would think that would be a good measure of efficacy, but in terms of detecting a treatment effect with donanemab, it didn't perform very well. Conversely, GFAP, which is a marker of astrocyte activation, which I would not have predicted was going to be a sensitive marker for treatment efficacy, performed well in at least the donanemab trial. So, I think it's early in the history of using these markers as outcome measures in clinical trials. And I think we're going to continue to learn as each therapy comes along and as these things come to pass. Dr Weathers: Don't make any assumptions yet? Would that be a good way to sum that up? Dr Quinn: I think that's, yes. I think that's very fair that that we have to be careful about these things. Dr Weathers: OK. So, in summary, I think, does it sound like it's fair to say that the pitfall might be to say it's too early to make any assumptions or any conclusions quite yet? Dr Quinn: That's right. And, and I think, you know, we're going to need to monitor these therapies. I think all of us in neurology have become very accustomed to how you do that in multiple sclerosis, right? We've got MRI scans to be used to monitor therapy, maybe NFL is going to be an appropriate assay there as well. But, you know, there we've all had the experience of a chronic disease and seeing how well your therapy is doing, changing therapy if it fails. So, we're absolutely going to need those things in in Alzheimer's disease and other neurodegenerative diseases, but it's a little early for us to be sure exactly what the right measures are to make those important decisions. Dr Weathers: And a lot more work to be done for sure. As I mentioned, this is a topic of such great interest and I know, you know, certainly most of our listeners are neurologists or people in our world, medical students and trainees. I know I have one regular nonneurologist listener, my father. He really gets a kick out of listening to my interviews. Even though he is a retired sales manager from IBM and most of the time the topics of discussion are pretty different from his usual favorite podcasts. But this one he will be particularly interested in and I'm sure I will get a list of questions about, particularly because my grandfather unfortunately had Alzheimer's disease. So, I'm sure one of his questions will be about the use of these biomarkers in asymptomatic patients. How do you counsel family members of patients when they inquire about the use of biomarkers for that youth case? What is their utility in presymptomatic testing? Dr Quinn: We know from studies like the Alzheimer's disease neuroimaging initiative and other biomarker studies that some of these markers will be sensitive to pathology. Even in asymptomatic people, that pathology appears long before people develop symptoms. Despite that, I don't recommend that asymptomatic people get any of the testing right now because we do not have evidence that early intervention at the completely asymptomatic stage is valuable. And those clinical trials are underway. There are trials underway right now for people who don't even meet the memory deficit required to have a diagnosis of mild cognitive impairment, people who are entirely cognitively intact, but who on one biomarker study or another have evidence of pathology burden. And the interventions are being started early. And in a few years, we'll know the answer to that. Right now, for somebody to find out that they have pathology without any ability to act on it, I think is not valuable. So, I discourage people from pursuing that. Dr Weathers: And that is really important guidance. Thank you. I know you have, as you mentioned, a beginning in a really diverse neurologic background with expertise, as you said, not only in dementia, but also in Parkinson's disease. And you didn't even mention this, but I know expertise in stroke as well, but your research has been primarily in Alzheimer's. What drew you to dementia and to this specific the aspect of it? How did you become an expert in biomarkers? Dr Quinn: Well, I'll start with the dementia part. So, you know, I was always just interested intuitively in trying to understand how, you know, the brain mediates the mind. So as an undergraduate, I got started working in a lab that was working on the cholinergic system in the brain, which was still being sorted out at that time. It is important in Alzheimer's disease, but it was really where the focus was. And that's what got me interested in Alzheimer's disease, which incidentally is what got Alzheimer interested in Alzheimer's disease. You know, he was very interested in trying to find the biological footprints of all these different neurological and psychiatric diseases. And he usually came up empty-handed until he came across the patient with Alzheimer's disease where there were actual footprints in the brain that he thought was pointing towards what was going on. And we're still wondering about that a hundred years later, I guess that's how I got interested in dementia and Alzheimer's disease. I think I have always spent part of my time as a clinician. I think that's what got me interested in biomarkers, that this problem has always been there that, you know, we've got quite, you know, research criteria for making diagnosis and all that sort of thing. But we've really needed some biological evidence to help us firm this up even before the availability of the therapies. And that's what got me interested in- I'm making another point. I thought that computer research biomarkers are going to help point me towards the causes of the disease, and unfortunately that part hasn't entirely panned out. We've got some research in that area on micro-RNA biomarkers that maybe will bear some fruit down the road, but that's been a tougher, tougher nut to crack. Dr Weathers: But it's so incredibly important work. Well, this has been wonderful. I really enjoyed our conversation, and I always like to end on a hopeful note. What developments in the biomarker space are coming on the horizon are you most excited about? Dr Quinn: I'm hoping that these biomarkers that allow us to evaluate disease efficacy, blood biomarkers that don't require extraspinal taps and that sort of thing. I hope that all comes to pass. And I do think that there is a lot of research underway looking at biomarkers in a novel way that I think could help point us to new targets for therapy, things that you and I haven't even thought of yet. Those are the two things. I guess you asked me for one, I gave you two. Dr Weathers: Oh I think very fair. I agree. Both of those would certainly be wonderful and, and I'm excited as well. Well, thank you, Dr Quinn, for taking the time to speak with me this evening. Dr Quinn: A pleasure. Thank you for having me. Thank you for inviting me to do the piece. It was really a great experience. Dr Weathers: Again, today I've been interviewing Dr Joseph Quinn, who's written with Doctor Nora Gray on fluid biomarkers and dementia diagnosis. This article appears in the December 2024 Continuum issue on Dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.
The Development of a Cocktail of Microglia and GFAP For Easy Diagnosis - Anisha Bhasin B.S, Sarah Holguin, MBA. B.S, Joe Vargas, M.S Microglia and GFAP are distinct neural markers, typically used separately to diagnose the degree of neurological infection and injury. Microglia, a glial cell, is used in the immune response of the central nervous system. GFAP is an astrocyte marker; astrocytes provide structural support and make up the blood-brain barrier. Using the two in conjugation with one another would prove to be an efficient diagnostic tool. A cocktail was constructed with optimal titration to observe the two markers in unison. In clinical usage, it will provide an efficient diagnosis of chronic inflammatory conditions of the central nervous system. The staining was conducted in IHC and fluorescence to compare morphology and count. Due to anatomical similarities, there tends to be morphological confusion between microglia and GFAP. However, when stained in conjunction with one another, notable differences can allow for easy distinction. This is why a cocktail run with a dual staining technique would be a superior diagnostic tool in comparison to testing the two markers independently.
The Rising Tide of Neurodegenerative Diseases: Prevention and Reversal Strategies In a recent episode of "Your Health Matters," host Karl Sterling and neurologist Dr. Dale Bredesen discussed the rising prevalence of neurodegenerative diseases like Alzheimer's, dementia, and Parkinson's. They emphasized the importance of lifestyle changes in preventing and managing these conditions, offering practical advice for maintaining cognitive health. Alarming Statistics Sterling shares concerning statistics: - Alzheimer's Disease: 65 million Americans aged 65 and older are living with Alzheimer's. - Parkinson's Disease: Nearly 1 million Americans are affected, with numbers potentially rising to 12 million by 2030. - Type 2 Diabetes: Over 37 million Americans have diabetes, with 90-95% having type 2. This is linked to a 50% increased risk of dementia. Lifestyle Changes for Brain Health Diet: Dr. Bredesen recommends a plant-rich, mildly ketogenic diet to optimize brain function and reduce inflammation: - Healthy fats: avocados, nuts, olive oil. - Limit processed foods and sugar. - Increase fiber intake with vegetables and whole grains. Exercise: Regular physical activity maintains brain structure and function: - Aim for 150 minutes of moderate aerobic activity weekly. - Include strength training and activities like yoga for balance and flexibility. Sleep: Quality sleep is vital for cognitive health: - Aim for at least seven hours per night. - Maintain a regular sleep schedule. - Create a restful environment and limit screen time before bed. Stress Management: Chronic stress harms the brain: - Practice meditation and mindfulness. - Engage in regular physical activity. - Maintain strong social connections. Brain Training: Cognitive exercises promote neuroplasticity: - Engage in puzzles, memory games, and new skills like learning a language. - Regular reading and writing can stimulate the brain. Detoxification: Reducing toxin exposure supports brain health: - Avoid environmental toxins. - Eat antioxidant-rich foods like berries and greens. - Support liver health with foods like garlic and turmeric. Targeted Supplements: Certain supplements boost brain function: - Omega-3 fatty acids from fish oil and flaxseeds. - Choline from egg yolks and supplements. - Lion's Mane Mushroom for neurotrophic benefits. Early Detection and Intervention Dr. Bredesen highlights the importance of early detection, advocating for cognitive assessments and blood tests for those over 40. Key tests include p-tau217 for tau protein levels and GFAP for brain inflammation. Genetics and Environment Genetics and environment both play a role: - APOE4 gene increases Alzheimer's risk, especially with two copies. - Factors like poor oral health and chronic infections contribute to cognitive decline. Conclusion This episode of "Your Health Matters" provides valuable insights into preventing and managing neurodegenerative diseases. By focusing on lifestyle changes, including diet, exercise, sleep, stress management, brain training, detoxification, and supplements, individuals can proactively protect their brain health and potentially reverse cognitive decline. Through these strategies, listeners are empowered to make informed decisions for a healthier future. Listen on audio platforms by visiting: https://www.karlsterling.com/past-radio-show-recordings-transcripts
Despite validated models, predicting outcomes after traumatic brain injury remains challenging, requiring prognostic humility and a model of shared decision making with surrogate decision makers to establish care goals. In this episode, Lyell Jones, MD, FAAN, speaks with Jamie E. Podell, MD, an author of the article “Traumatic Brain Injury and Traumatic Spinal Cord Injury,” in the Continuum June 2024 Neurocritical Care issue. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Podell is an assistant professor in the department of neurology, program in trauma at the University of Maryland School of Medicine in Baltimore, Maryland. Additional Resources Read the article: Traumatic Brain Injury and Traumatic Spinal Cord Injury Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Guest: @jepodell Transcript Full transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier, topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Jamie Podell, who has recently authored an article on traumatic brain injury and traumatic spinal cord injury in the latest issue of Continuum on neurocritical care. Dr Podell, welcome. Thank you for joining us today. Why don't you introduce yourself to our audience and tell us a little bit about yourself? Dr Podell: Thanks, Dr Jones. It's great to be here. As you mentioned, I'm Dr Podell. I'm neurocritical care faculty at University of Maryland Shock Trauma. I have a primary interest in traumatic brain injury, both from a research and clinical perspective. I previously have more of a cognitive neuroscience background, but I think it kind of ties into how I think about TBI and outcomes from traumatic brain injury. But what I really like doing is managing acutely ill patients in the ICU, and I think TBI really affords those kinds of interventions, and it's a really rewarding kind of setting to take care of patients. Dr Jones: Yeah, and I really can't wait to talk to you about your article here, which is fantastic. For our listeners who might be new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the best possible neurologic care to their patients, just like Dr Podell was talking about. We do that with high quality and current clinical reviews, and Dr Podell's article - it's a massive topic - traumatic brain injury and traumatic spinal cord injury. And, you know, as we start off here, Dr Podell, we have the attention now of a massive audience of neurologists. If you had one most important practice change that you would like to see in the care of these patients who have trauma, what would that practice change be? And, I think, maybe, we'll give you two answers, because you cover TBI and you cover spinal cord injury. What would be the most important practice changes you'd like to see? Dr Podell: So, this isn't that specific, but I think it's really important. I think we need more neurologists, and specifically neurointensivists, managing these patients. I think there's a lot of variability across institutions and how acute severe TBI and spinal cord injury patients are managed. They're often in surgical ICUs, and neurology may be involved in consultation but not in the day-to-day management. But I think what we're seeing is that, you know, there's a lot of multisystem organ dysfunction that happens in these patients, and that has a really strong interplay with neurologic recovery and brain function. And I think, you know, neurointensivists are very well equipped to think about the whole body and how we can kind of manipulate and really aggressively support the body to help heal the brain with special attention to, kind of, the nuance of any individual patient's brain injury. Because TBI is extremely heterogeneous and there's not just a cookie-cutter script for how these patients can be managed, I think, you know, people like neurologists, neurointensivists who have a lot of attention to the nuance - that's really helpful in their management. Dr Jones: I'm so glad you said that, and not just because I'm a neurologist who's a fan of neurologists, but I do think there are some corners of neuroscience care where neurologists could be a little more present - and trauma definitely seems like one of those, doesn't it? Dr Podell: Yeah, I think it's tough, because some patients with severe TBI and spinal cord injury can have a lot of multisystemic trauma with, you know, pulmonary contusions, intraabdominal pathology - you need to go to the OR for their other injuries, and so I think it really makes sense to have kind of a collaborative multidisciplinary approach to these patients, but I think neurologists should play a very big role in that approach, however that's done (there are lots of different ways that it's done). But I think having a primary neurology-trained neurointensivist – I know I'm biased, but I think that's where I'd like to see the field moving. Dr Jones: And, obviously, neurocritical care is an intuitive place for neurological trauma care to start, and even with the sequelae of downstream things, I think neurologists could be more engaged. I wonder if neurology hasn't historically been as involved because it's sort of gravitated to surgical specialists. And I think part of it is, you know, trauma is not usually a diagnostic mystery, right? The neurologist can't pretend to be Sherlock Holmes and try to figure out what's going on when it was pretty clear what the event was, right? Dr Podell: Right. Yeah, I agree with both of those points. I think, for one, I think postacute care is also a big area where neurologists can be involved more - and patients kind of fall through the cracks. A lot of times, these patients will just follow up with a neurosurgeon and get a repeat head CT and it'll look stable. We started implementing post-TBI neural recovery clinics, which I think other places are starting to do as well, and I think that's kind of a good model for getting neurologists involved - but also, rehab specialists are involved in that. But in terms of, yeah, the diagnostic mysteries and stuff, I think there still can be some, though, with TBI. Yes, obviously, the initial primary insult is obvious, but the secondary pathology that can happen in patients is really nuanced, and it is so variable, and, sometimes, it does take that detective eye to see, “Oh, this patient has one cerebrovascular injury, their risk of stroke to this territory? How are we going to manage it? and thinking about all the kind of sources of secondary decline that are possible. I think it takes that neurology detective sometimes to think about, too. Dr Jones: Yeah. We never stop pretending to be detectives, right? Dr Podell: Yeah. Dr Jones: And on a related note, you know, in your article, you mentioned some of the novel serum and electrophysiologic and imaging biomarkers that are being used to care for these patients. How are you using those in your practice, Dr Podell? Dr Podell: That's a good question. I think, unfortunately, as with a lot of clinical care, the clinical care does kind of lag behind the research and what we know what we can learn about these patients and their outcomes through retrospective studies. So, to be completely honest, you know, even the serum studies that I mentioned in the article (like GFAP, UCH-L1) - those kind of things, that's not clinically available at our institution. We don't use those. I think a lot of the imaging biomarkers that we see, some of them are coming from more advanced imaging – like, we're talking about FMRI - that requires a lot of post processing (so, again, we're not necessarily using that clinically). But what I would say is that we use imaging to kind of try to predict what complications patients might be at risk of and to try to predict their clinical course. And I think it comes down to trying to break down the heterogeneity of these patients and to try to kind of lump them into different bins of, “What's this patient at risk for?”, “What's their trajectory going to be like?”, “When can I start peeling back how aggressive I am with this patient?”. And, so far, I don't think any of the markers that we have are really clear black-white prescriptive indicators of what to do (I don't think we're quite there yet). So, again, I think we just kind of use all of the data in combination to come up with a management plan for these patients. I think some of the markers, (like some of the electrophysiologic markers), looking at EEG for things like background can provide prognostic information, especially in patients who are comatose that you're wondering about if they're going to wake up (so a lot of this can inform family discussions). But, you know, we used to think that grade three diffuse axonal injury on MRI portended a very poor prognosis (and in the past, some surgeons and ICUs might use that to limit care in patients), but more and more, we're finding that even that is quite nuanced and we're detecting more and more diffuse axonal injury on images in patients who then wake up, or have already woken up and they have the MRI later, and you're like, “Hmm, they had DAI. It's a good thing you didn't get the MRI early and decide not to move forward with aggressive care”. But, I think, in a patient who's comatose and you don't have a good explanation, sometimes, looking for those additional biomarkers to explain what kind of injury pathology you have can just provide more information for families. Dr Jones: Yeah, and that's a great point that comes up in a lot of our articles and interviews (that the biomarkers really do have to be in a clinical context). So, if I understand you correctly, really, no individual biomarker that has emerged as a precise predictor or prognosticator for outcomes - but you do talk a lot about recent advances in the care of these patients. What would you want to point out to our listeners that's come up recently in the care of trauma? Dr Podell: Yeah. I think the evidence basis for severe TBI is limited because, again, there's so much heterogeneity and different things going on with different patients, but some of the evidence that has come out more recently involves, kind of, indications for surgical procedures and the timing of those procedures. Some of that is still kind of expert consensus-based. But, for example, doing a secondary decompression for elevated ICP with the DECRA and RESCUEicp trials. We do have better high-quality evidence that doing a secondary decompression for more refractory, elevated ICP can improve both mortality and functional outcomes in patients, so that has kind of become more standard of care. Additionally, I think timing for spinal cord injury, neurosurgical procedures - that's been a topic that's been studied in more evidence-based to perform earlier decompressive surgeries. And then, I think, you know, more and more is emerging just about the pathophysiology of secondary injury - and some of those things haven't necessarily translated to what to do about it - but we've learned about things like cortical spreading depolarizations being associated with worse outcomes in traumatic brain injury, and we've also identified that ketamine or memantine can both actually stop those cortical spreading depolarizations. But the overall impact of managing them is still unknown, and the way that we detect those, it requires an invasive electrocorticography monitor which not all centers have. So, I think, one of the important things as we move forward in TBI care is, as we get this better mechanistic understanding of some of the pathophysiology that's happening in these TBI patients, figuring out a way to be able to translate that across all clinical settings where you can actually do the monitoring invasively - that's also an issue we see. Even intracranial pressure monitoring is pretty standard of care, but not all centers do that, and we have to be able to apply practice recommendations to centers where there isn't necessarily access to the same things that we have at large academic trauma centers. Dr Jones: Got it. Obviously, there's a lot of research in this area, a lot of clinical research, and I'm glad you mentioned the secondary injury - things that are happening at the tissue level are important for us to think about. As the care of patients with trauma has evolved (and I'm thinking now of patients with spinal cord injury), we still see patients who receive high-dose corticosteroids in the setting of acute spinal cord injury - and obviously, that's something that's evolved. Can you tell our listeners a little bit more about what they should be doing when they're seeing a patient with a traumatic spinal cord injury? Dr Podell: Yes. So, the steroids story for spinal cord injury is kind of interesting. There were a series of trials called the NASCIS trials that looked at corticosteroids and spinal cord injury, and they were initially interpreted that high-dose steroids had a beneficial effect on spinal cord injury recovery - but then, kind of in relooking at the data and recognizing that these were kind of unplanned subgroup analyses that showed benefit, and then looking at kind of pooled reanalysis and meta-analysis of all the data out there, it was determined that there actually was no clear benefit from steroids and that there was a clear incidence of more complications from high-dose steroids. So, in general, corticosteroids are not recommended for spinal cord injury. Same for traumatic brain injury, too (even though some people will still give steroids for that) - there was a CRASH study that looked at corticosteroids in TBI and found worse outcomes in TBI (so there actually is high-level evidence not to use steroids in that case). That's not to say that there's not an inflammatory process that's going on that could be causing secondary injury - I think that's still, really, you know, an area of active research is to try to figure out what is the balance between potential adaptive mechanisms of inflammation that are happening versus more maladaptive sources of secondary injury from inflammation and how and when do we target that inflammation to improve outcomes. So, there's still, I think, more to come on that. Dr Jones: And, you know, we are guided by evidence, obviously, but also, we learn from our experience as clinicians. You work in the neurocritical care unit. You take care of all patients with critical neurologic problems. When it comes to TBI and spinal cord injury, what kind of management tips or tricks have you learned that would be good for our audience to hear? Dr Podell: I think the way that I would sum it up is that you should be very aggressive - supportive care early on, and then thoughtfully pull back and let the brain and spinal cord heal itself. And, you know, the patients come in with TBI (for example) very sympathetically aroused. They do need sedation, they need blood pressure support, they need mechanical ventilation - they need help kind of maintaining homeostasis. And other autonomic effects with spinal cord injury happen, too - you get neurogenic shock (you need very aggressive management of blood pressure, volume assessments), you know, in both cases in trauma patients, managing things like coagulopathy - but, you know, over time, usually, these things start to, kind of, heal themselves to some degree. And then, kind of thoughtfully figuring out when you can peel back on the different measures that you're doing to support them through their acute injuries. Different protocols have been developed, and the Brain Trauma Foundation has developed evidence-based guidelines that have improved (just having a protocol, we know, improves) trauma outcomes overall at centers - but I think those protocols are just guidelines, and you really have to pay attention to the individual patient in front of you. For TBI, for example, our guideline will say to aggressively manage fever within the first seven days with surface cooling. But in a patient that, for example, developed kind of a stroke or progressive cerebral edema even on day five (or something) you're looking at them, and on day seven, they're still having a lot of swelling in their brain, I'm not going to peel off the temperature management. So, there is nuance - you can't just kind follow a rule book in these patients. Dr Jones: Got it. And I think that point about aggressive support early is a good takeaway for any listeners who might be engaged in the care of these patients. You know, I imagine working in that setting and taking care of patients who are in the midst of a devastating injury - I imagine that can be pretty challenging, but I imagine it could be pretty rewarding as well. What drew you to this particular area of interest, Dr Podell, and what do you find most exciting about it? Dr Podell: A lot kind of converged for me in this area. I went into neurology thinking I would be a cognitive neurologist. I had more of a neuroimaging background and an interest in neural network pathology that certainly happens to patients with TBI (and patients with TBI often will have neuropsychiatric and neurocognitive problems after injury). But then, during residency, I found myself. My personality clicked in the ICU, and I just liked managing sick patients - I liked the pace of it, I also really liked it. It's kind of a team sport in the ICU with multiple people involved - the bedside nurses, respiratory therapists, neurosurgeons, trauma surgeons - all working together to figure out the best management plan for these patients, so you don't feel alone in managing them. And not all outcomes are good, obviously, but you can see people get better even during their course of their ICU stay - and that's really, really rewarding. And I think what we're seeing even in the literature following patients out longer and longer, the recovery trajectory for TBI is different than what we see in other neurologic injuries (like stroke, where the longer you go - up to ten, twenty years, even - people are still improving). I think the idea that you can keep hope alive for a lot of these patients and try to combat any kind of nihilism - obviously, there's a time and place for that after a really devastating injury, but I've seen a lot of patients who are really, really sick, needing therapeutic hypothermia, barbiturate coma, decompression, still then recovering and being able to come back into the ICU and talk to us. Dr Jones: We might have some junior listeners who are thinking about behavioral neurology or neurocritical care, and it's probably - I don't know if it's reassuring, or maybe concerning, to them to know that they might swing completely to the other end of the spectrum of acuity, which is kind of what you did. Dr Podell: Yeah, and what I'm trying to do now is, I'm very interested in autonomic dysfunction that happens in these patients. It's related a lot to multisystem organ dysfunction and, I think, may contribute to secondary injury, too, with changes in cerebral perfusion, especially in patients who have storming or even just the early autonomic dysregulation that happens early on. I think it's induced by neural network dysfunction from the brain injury, kind of similar to the way that there are other phenotypes that would be induced by neural network dysfunction (like coma). So, we're trying to look at MRIs of acute TBI patients and trying to identify what structural imaging pathology then gives rise to these different kinds of clinical phenotypes - trying to bring it back to this neuroscience focus. Dr Jones: Well, that gives us and our listeners something to look forward to, Dr Podell. And again, I just want to thank you for joining us, and thank you for such a great discussion on the care of patients with TBI, and spinal cord disorders and thank you for such a wonderful article. Dr Podell: Thank you very much. It is my pleasure. Dr Jones: Again, we've been speaking with Dr Jamie Podell, author of an article on traumatic brain injury and traumatic spinal cord injury in Continuum's latest issue on neurocritical care. Please check it out. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this article. Thank you for listening to Continuum Audio.
Meet Dr. Shivani Gupta, entrepreneur, and PhD in Turmeric. Today we discuss the benefits of Turmeric, Ayurvedic medicine, and how this amazing plant and curcumin extra can help with pain management. Here are some scientific studies citing the benefits of turmeric in pain management like sciatica:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946321/These results indicated that curcumin exerted a therapeutic role in neuropathic pain by down-regulating p300/CBP HAT activity-mediated gene expression of BDNF and Cox-2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600446/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10610406/CUR decreased CD11b and GFAP gene expression in the spinal cord. BDMC decreased IBA-1 in the spinal cord and amygdala as well as CD11b and GFAP in the spinal cord. Both CUR and BDMC reduced PGC1α gene expression in the amygdala, PINK1 gene expression in the spinal cord, and TLR4 in the spinal cord and amygdala, while they increased Complex I and SOD1 gene expression in the spinal cord. CUR and BDMC administration decreased mechanical hypersensitivity in NP by mitigating glial activation, oxidative stress, and mitochondrial dysfunction.You can hear more from Dr. Shivani at shivanigupta.com and check out her other site: https://fusionaryformulas.com/ (affiliate link)You can use “sciatica” to get 15% off your order!Are you looking for a more affordable way to manage your pain? Check out the patient advocate program here: ptpatientadvocate.comHere's the self cheat sheet for symptom management: https://ifixyoursciatica.gymleadmachine.co/self-treatment-cheat-sheet-8707Book a free strategy call: https://msgsndr.com/widget/appointment/ifixyoursciatica/strategy-callSupport this podcast at — https://redcircle.com/fix-your-sciatica-podcast/donationsAdvertising Inquiries: https://redcircle.com/brandsPrivacy & Opt-Out: https://redcircle.com/privacy
Recent developments in disease modifying therapies have been proven to slow the progression of cognitive decline associated with Alzheimer's disease. And yet, we can only confirm a diagnosis of AD after a patient's death. But what if we could use biomarkers to identify preclinical stage Alzheimer's and step in long before a patient exhibits dementia? On this episode of Inside the Lab, your host, Ms. Kelly Swails, MT(ASCP) introduces us to Dr. Shih-Hsiu Jerry Wang, MD, PhD, Assistant Professor of Pathology and Assistant Professor of Neurology at the Duke University School of Medicine, and shares his talk on emerging biomarkers for the assessment of Alzheimer's disease from the ASCP 2023 Annual Meeting. Dr. Wang explains how we measure AD right now and why there's discordance between the clinical presentation and pathology of Alzheimer's. Dr. Wang walks us through the core biomarkers for identifying AD per the AT(N) framework, describing the pros and cons of current detection methodologies and offering recommendations around when to use blood biomarkers versus PET imaging or CSF. Listen in for insight into the ongoing search for better AD biomarkers and learn what we are doing to diagnose Alzheimer's in its early stages and intervene accordingly. Topics Covered · The clinical definition of Alzheimer's disease and how it impacts cognitive function· How we measure Alzheimer's in pathology by amyloid plaques and neurofibrillary tangles· Why there's discordance between the clinical presentation and pathology of AD· The core biomarkers for identifying Alzheimer's disease per the AT(N) framework· Identifying the stages of AD based on amyloid plaque, pathologic tau and neurodegeneration· Examples of PET imaging for the different stages of AD and how imaging biomarkers predict cognitive decline· The limitations of fluid biomarkers vs. imaging biomarkers to detect Alzheimer's disease· Some of the emerging ultrasensitive biomarker detection methods in development for AD· Using cerebral spinal fluids (CSF) vs. plasma biomarkers to identify Alzheimer's disease· A comparison of the mass spectrometry vs. SIMOA methods of analyzing p-tau biomarkers· Why Dr. Wang suggests blood biomarkers for AD screening (with confirmation by PET or CSF)· Why SNAP-25, NfL and GFAP are not considered core biomarkers for Alzheimer's disease· The ongoing search for better biomarkers and ultrasensitive detection methods for AD Connect with ASCPASCPASCP on FacebookASCP on InstagramASCP on Twitter Connect with Dr. WangDr. Wang at Duke University Connect with Ms. SwailsMs. Swails on TwitterResourcesDr. Wang's Slides from the ASCP Annual Meeting 2023‘NIA-AA Research Framework: Toward a Biological Definition of Alzheimer's Disease' in Alzheimer's & Dementia: The Journal of the Alzheimer's AssociationInside the Lab in the ASCP Store
Dr. Dale Bredesen discusses Reversing Alzheimer's Disease at the Functional Medicine Discussion Group meeting on July 27, 2023 with moderator Dr. Ben Weitz. [If you enjoy this podcast, please give us a rating and review on Apple Podcasts, so more people will find The Rational Wellness Podcast. Also check out the video version on my WeitzChiro YouTube page.] Podcast Highlights 5:35 Alzheimer's disease is now optional, because Dr. Bredesen's precision medicine approach can help to prevent and reverse Alzheimer's and it is hoped that this approach can be extended to all of the major neurodegenerative diseases. Dr. Bredesen and his group have published over 220 peer-reviewed papers on the underlying mechanisms of neurodegeneration. On the conventional treatment front, so many amyloid antibody drugs have failed including bapineuzumab, solanezumab, gantenerumab, and crenezumab. The newest drugs include aducanumab, which has a minimal effect, and lecanemab (aka, Leqembi), which does have a measurable effect. But these new drugs do not make anyone better, but instead they lead to a slowing of the progression and they often have some negative side effects like brain bleeding and brain swelling and several patients have died. 7:40 Homotaurine. This is currently a nutritional supplement that is currently in clinical trials. It prevents the oligomerization of A-beta, so it looks like it may be a very interesting adjunct to other parts of the Bredesen protocol. The dosage used was either 100 mg three times per day or 150 mg twice per day. [Manzano S, Agüera L, Aguilar M, Olazarán J. A Review on Tramiprosate (Homotaurine) in Alzheimer's Disease and Other Neurocognitive Disorders. Front Neurol. 2020 Jul 7;11:614.] Combined metabolic activators (CMA) shows benefit in improving cognition in patients with Alzheimer's disease. CMA dosage includes: 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. [Yulug B, Altay O, Li X, et al. Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Transl Neurodegener. 2023 Jan 26;12(1):4. ] 8:39 Dr. Bredesen is starting a randomized controlled trial of his ReCode system with six absolutely fantastic clinicians: Craig Tanio down in Hollywood, Florida, Nate Bergman in Cleveland, David Haase in Nashville, Kristine Burke in Sacramento, Kat Toups in the East Bay, and Ann Hathaway in Marin County. 9:25 KetoFlex. Dr. Bredesen's recommended dietary approach for Alzheimer's disease, the KetoFlex and he worked with Nutrition for Longevity, a group founded by Dr. Valter Longo, to develop KetoFlex meals for home delivery, which is now available. 11:30 New lab tests for help with analyzing Alzheimer's disease: 1. p-tau 181, 2. p-tau 217 is coming soon, 3. Abeta 42:40, 4. Neurofilament light, and 5. GFAP (glial fibrillary acidic protein), which will be available soon. P-tau 181 lets you know that you have the specific signaling characteristic of Alzheimer's. The Abeta 42:40 test lets you know whether you are making Amyloid beta protein, which is typically associated with inflammation and with Alzheimer's. Neurofilament light is not specific for Alzheimer's, but it tells you that you do have neuronal damage. This also goes up in frontotemporal dementia and ALS and certain other neurodegenerative conditions. GFAP lets you know that you have reactive astrocytes in the brain, which can precede Alzheimer's disease. 16:00 When you compare the state of the treatments for Alzheimer's disease, with no treatment the patient's MOCA score will decline by about three and a half points and if you take the Lecanemab, which is the newest drug given FDA approval that costs about ...
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.11.548638v1?rss=1 Authors: Kasanga, E. A., Soto, I., Centner, A., McManus, R., Shifflet, M. K., Navarrete, W., Han, Y., Lisk, J., Wheeler, K., Mhatre-Winters, I., Richardson, J. R., Bishop, C., Nejtek, V. A., Salvatore, M. F. Abstract: Background: Alleviation of motor impairment by aerobic exercise (AE) in Parkinsons disease (PD) points to a CNS response that could be targeted by therapeutic approaches, but recovery of striatal dopamine (DA) or tyrosine hydroxylase (TH) has been inconsistent in rodent studies. Objective: To increase translation of AE, 3 components were implemented into AE design to determine if recovery of established motor impairment, concomitant with greater than 80% striatal DA and TH loss, was possible. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), blood-based biomarkers of disease severity in human PD, were affected. Methods: We used a 6-OHDA hemiparkinson rat model featuring progressive nigrostriatal neuron loss over 28 days, with impaired forelimb use 7 days post-lesion, and hypokinesia onset 21 days post-lesion. After establishing forelimb use deficits, moderate intensity AE began 1-3 days later, 3x per week, for 40 min/session. Motor assessments were conducted weekly for 3 wks, followed by determination of striatal DA, TH protein and mRNA, and NfL and GFAP serum levels. Results: Seven days after 6-OHDA lesion, recovery of depolarization-stimulated extracellular DA and DA tissue content was less than 10%, representing severity of DA loss in human PD, concomitant with 50% reduction in forelimb use. Despite severe DA loss, recovery of forelimb use deficits and alleviation of hypokinesia progression began after 2 weeks of AE and was maintained. Increased NfLand GFAP levels from lesion were reduced by AE. Despite these AE-driven changes, striatal DA tissue and TH protein levels were unaffected. Conclusions: This proof-of-concept study shows AE, using exercise parameters within the capabilities most PD patients, promotes recovery of established motor deficits in a rodent PD model, concomitant with reduced levels of blood-based biomarkers associated with PD severity, without commensurate increase in striatal DA or TH protein. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546509v1?rss=1 Authors: Roshan, S. A., Gunaseelan, D., Swaminathan, J., Kandasamy, M., Muthuswamy, A. Abstract: Aim: After focal cerebral ischemia, intermittent hypoxia therapy (IHT) could be used as a non-invasive method to stabilize and stimulate neurogenesis in the innate stem cell niche in the brain, and disrupt the glial scar around the infarct to increase neuroblast migration in the striatal infarct area. Methods: We induced focal cerebral ischemia in Wistar albino rats using the MCAo model. A week later, animals were subjected to intermittent hypoxia (12%O2, 4hr/day) for a period of 14 days. Post-treatment analysis of functional recovery and cellular regeneration was done using immunofluorescence analysis of multiple neuronal cell markers including Doublecortin (DCX), Nestin, and Vimentin among others. Results: Observations of GFAP-positive cells revealed that IH treatment facilitates gliogenesis in the infarct striatal region of a rat model of MCAo stroke. The percentage of DCX and GFAP double-positive cells was increased in the IH-treated group. Also, there was a significant difference in the morphology of vimentin-positive cells and microglia cells between the stroke groups. Conclusion: These outcomes suggest that exposure of MCAo stroke-affected rats to intermittent hypoxia results in an increase in migrated neuroblasts resulting in a subsequent altered glial scar integrity in the infarct region, thus suggesting an alternative non-invasive method against the common stem cell transplant techniques, to increase endogenous neuroblasts in the infarct area after stroke. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.14.536712v1?rss=1 Authors: Grubb, S. Abstract: Efficient metabolic waste clearance is essential for optimal brain function. Waste accumulation can cause inflammation, tissue damage, and potentially lead to dementia and other neurological disorders. The primary waste exit route is debated, with evidence suggesting the lymphatic system or arachnoid villi/granulations as possible pathways. This study uses an ultrastructural dataset to emphasize the potential underestimation of macrophages and arachnoid villi/granulations in waste removal. The glymphatic system and neurovascular unit play crucial roles in this process, but their precise involvement is unclear. Based on brain surface ultrastructure analysis, waste clearance may occur through a transcellular route involving astrocytes to the perivascular space. Waste is then either phagocytosed by perivascular macrophages or directed to the subarachnoid space for meningeal macrophage phagocytosis. Evidence is provided that macrophages transport non-degradable waste in lysosomes to arachnoid villi for exocytosis into the villus lumen and venous system routing. Additionally, the study investigates fibroblast-macrophage interactions via primary cilia, potentially optimizing waste clearance. The role of astrocytes in brain water homeostasis and GFAP's potential significance in water filtration are also examined. This study offers valuable insights into waste clearance mechanisms in the brain, potentially aiding dementia understanding and treatment. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.12.536647v1?rss=1 Authors: Hedley, K. E., Cuskelly, A., Quinn, R. K., Callister, R. J., Hodgson, D. M., Tadros, M. A. Abstract: Early-life inflammation can have long lasting impact on pain processing and pain behaviours. For example, we have shown neonatal inflammation can result in changes within spinal neuronal networks and altered flinching of the hind paw 5 following formalin injection three weeks later. This suggests mechanisms for altered pain behaviours lie in first and second order neurons in the pain neuroaxis. Exactly how these changes progress during postnatal development is not known. Accordingly, we investigated neuroinflammatory markers in sensory neurons (dorsal root ganglia; DRGs) and spinal cords of Wistar rats (both sexes) after 10 early life inflammation. Rats were injected with LPS or saline on postnatal days (P) 3 and 5. DRGs and spinal cords (SC) were isolated on P7, 13 and 21, and the expression of six inflammatory mediators were quantified via RT-qPCR. In the DRG, four proinflammatory mediators were elevated in P7 rats exposed to LPS. By P13, only two proinflammatory agents were elevated, whereas at P21 the levels of all six inflammatory mediators were 15 similar between LPS and saline-treated rats. There were no sex-specific differences in the expression profile of any mediator in DRGs. In the spinal cord this expression profile was reversed with no change in inflammatory mediators at P7, elevation of two at P13 and four at P21 in LPS treated rats. Interestingly, these differences were greater in the spinal cords of female rats, indicating sex-specific modulation of neuroinflammation even at these early 20 stages of postnatal development. The increased inflammatory mediator profile in the spinal cords of P21 LPS-treated rats was accompanied by sex-specific modulation of astrocytic (GFAP) activation, with females showing an increase and males a decrease in GFAP following LPS exposure. Together, these data indicate sensory neurons are more susceptible to acute inflammation whereas inflammation in the spinal cord is delayed. The sex-specific 25 modulation of inflammation during critical phases of development may help explain altered pain behaviours in adult males and females. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.13.532440v1?rss=1 Authors: Battaglia, R., Faridounnia, M., Beltran, A., Robinson, J., Kinghorn, K., Ezzell, J. A., Bharucha-Goebel, D., Bonnemann, C., Hooper, J. E., Opal, P., Bouldin, T. W., Armao, D., Snider, N. Abstract: Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed significant involvement of astrocytes in GAN. To study the underlying cellular mechanisms, we generated human models of GAN using induced pluripotent stem cells (iPSCs). Skin fibroblasts from seven GAN patients carrying different KLHL16 mutations were reprogrammed to iPSCs, and isogenic controls were derived via CRISPR/Cas9 editing. Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic clones. While GAN iPSCs displayed normal organization of lamin B1 and keratin IFs, they exhibited patient-specific increased expression and perinuclear bundling of vimentin. Nestin IF morphology was unaffected, but fewer nestin-positive cells were present in GAN NPCs compared to controls. The most dramatic phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which displayed dense perinuclear IF accumulations and abnormal nuclear morphology. GFAP oligomerization and perinuclear aggregation were strongly potentiated in the presence of vimentin, and GAN cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529377v1?rss=1 Authors: Sanchez-Rodriguez, L. M., Bezgin, G., Carbonell, F., Therriault, J., Fernandez-Arias, J., Karikari, T. K. M., Ashton, N. J., Benedet, A., Zetterberg, H., Blennow, K., Triana-Baltzer, G., Kolb, H. C., Rosa-Neto, P., Iturria-Medina, Y. Abstract: Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we develop and validate a personalized brain activity model that incorporates functional MRI, amyloid-beta (Abeta) and tau-PET from AD-related participants (N=132). By simulating electrophysiological activity mediated by toxic protein deposition, this integrative approach uncovers key patho-mechanistic interactions, including synergistic Abeta and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Abeta-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
A new research paper was published on the cover of Aging (listed as "Aging (Albany NY)" by Medline/PubMed and "Aging-US" by Web of Science) Volume 15, Issue 3, entitled, “Immune-mediated platelet depletion augments Alzheimer's disease neuropathological hallmarks in APP-PS1 mice.” In Alzheimer's disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. In a recent study, researchers Diana M. Bessa de Sousa, Ariane Benedetti, Barbara Altendorfer, Heike Mrowetz, Michael S. Unger, Katharina Schallmoser, Ludwig Aigner, and Kathrin Maria Kniewallner from Paracelsus Medical University and Austrian Cluster for Tissue Regeneration in Austria depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. “The potential role of platelets in amyloid beta deposition led to the hypothesis that reducing platelet numbers might ameliorate AD pathology [30]. Here, we performed immune-mediated platelet depletion in APP-PS1 mice with an already fully developed amyloidosis and investigated its effects on classical hallmarks of AD: amyloid plaque pathology, plaque-associated neuritic dystrophy and gliosis.” In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, data from this study suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated. “In APP-PS1 females, acute thrombocytopenia aggravates AD neuropathology, suggesting that platelets might have a protective function in AD. However, the underlying molecular mechanisms by which platelets modulate amyloid plaque deposition remain elusive and need to be investigated in future experiments.” DOI: https://doi.org/10.18632/aging.204502 Corresponding Author: Kathrin Maria Kniewallner - kathrin.drerup@pmu.ac.at Keywords: Alzheimer's disease, platelets, amyloid-beta, microglia, astrocytes Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204502 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.15.528337v1?rss=1 Authors: Toro, C. A., Johnson, K. E., Hansen, J., Siddiq, M. M., Vasquez, W., Zhao, W., Graham, Z. A., Saez, J. C., Iyengar, R., Cardozo, C. P. Abstract: Membrane channels such as connexins (Cx), pannexins (Panx) and P2X7 receptors (P2X7R) are permeable to calcium ions and other small molecules such as ATP and glutamate. Release of ATP and glutamate through these channels is a key mechanism driving tissue response to traumas such as spinal cord injury (SCI). Boldine, an alkaloid isolated from the Chilean boldo tree, blocks both Cx hemichannels (HC) and Panx. To test if boldine could improve function after SCI, boldine or vehicle was administered to treat mice with a moderate severity contusion-induced SCI. Boldine led to greater spared white matter and increased locomotor function as determined by the Basso Mouse Scale and horizontal ladder rung walk tests. Boldine treatment reduced immunostaining for markers of activated microglia (Iba1) and astrocytic (GFAP) markers while increasing that for axon growth and neuroplasticity (GAP-43). Cell culture studies demonstrated that boldine blocked glial HC, specifically Cx26 and Cx30, in cultured astrocytes and blocked calcium entry through activated P2X7R. RT-qPCR studies showed that boldine treatment reduced expression of the chemokine Ccl2, cytokine IL-6 and microglial gene CD68, while increasing expression of the neurotransmission genes Snap25 and Grin2b, and Gap-43. Bulk RNA sequencing (of the spinal cord revealed that boldine modulated a large number of genes involved in neurotransmission in in spinal cord tissue just below the lesion epicenter at 14 days after SCI. Numbers of genes regulated by boldine was much lower at 28 days after injury. These results indicate that boldine treatment ameliorates injury and spares tissue to increase locomotor function. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.14.528561v1?rss=1 Authors: Swanson, M. E. V., Mrkela, M., Murray, H. C., Cao, M. C., Turner, C., Curtis, M. A., Faull, R. L. M., Walker, A. K., Scotter, E. L. Abstract: Microglia, the innate immune cells of the brain, are activated by damage or disease. In mouse models of amyotrophic lateral sclerosis (ALS), microglia shift from neurotrophic to neurotoxic states with disease progression. It remains unclear how human microglia change relative to the TAR DNA-binding protein 43 (TDP-43) aggregation that occurs in 97% of ALS cases. Here we examine spatial relationships between microglial activation and TDP-43 pathology in brain tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from the Neurological Foundation Human Brain Bank was obtained from 10 control and 10 ALS cases in parallel with brain tissue from a bigenic NEFH-tTA/tetO-hTDP-43deltaNLS (rNLS) mouse model of ALS at disease onset, early disease, and late disease stages. The spatiotemporal relationship between microglial activation and ALS pathology was determined by investigating microglial functional marker expression in brain regions with low and high TDP-43 burden at end-stage human disease: hippocampus and motor cortex, respectively. Sections were immunohistochemically labelled with a two-round multiplexed antibody panel against; microglial functional markers (L-ferritin, HLA-DR, CD74, CD68, and Iba1), a neuronal marker (NeuN), an astrocyte marker (GFAP), and pathological phosphorylated TDP-43 (pTDP-43). Single-cell levels of microglial functional markers were quantified using custom analysis pipelines and mapped to anatomical regions and ALS pathology. We identified a significant increase in microglial Iba1 and CD68 expression in the human ALS motor cortex, with microglial CD68 being significantly correlated with pTDP-43 pathology load. We also identified two subpopulations of microglia enriched in the ALS motor cortex that were defined by high L-ferritin expression. A similar pattern of microglial changes was observed in the rNLS mouse, with an increase first in CD68 and then in L-ferritin expression, with both occurring only after pTDP-43 inclusions were detectable. Our data strongly suggest that microglia are phagocytic at early-stage ALS but transition to a dysfunctional state at end-stage disease, and that these functional states are driven by pTDP-43 aggregation. Overall, these findings enhance our understanding of microglial phenotypes and function in ALS. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.10.528062v1?rss=1 Authors: Akopian, A., Ruparel, S., Hovhannisyan, A. H., Lindquist, K., Tram, M., Perez, D., Mecklenburg, J., Salmon, A., Merlo, J., Corey, T. Abstract: Myogenous temporomandibular disorders (TMD-M) are the most prevalent group of painful orofacial conditions, and the second most frequent among musculoskeletal pain conditions. TMD-M is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), medial pterygoid closing (MPM) and lateral pterygoid gliding muscles (LPM). Treatment of this disorder remains difficult and is further complicated by each muscle having diverse and functionally distinct nerve innervation. This study examined expression of sensory markers in MM, TM and LPM of adult male common marmosets, a type of non-human primate. Using immunohistochemistry, we found that masticatory muscles were predominantly innervated with A-fibers (NFH+). All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked antibody labeling for mrgprD, trpV1 and the silent nociceptive marker, CHRNA3. The proportion of C- to A-fibers was highest in LPM, while MM had a minimal percentage (6-8%) of C-fibers. Interestingly, C-fibers in masticatory muscle may have myelin sheath, since many NFH- nerves were labeled with GFAP+. A-fiber types were also dissimilar among these muscles. Thus, there are substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. Almost all A-fibers in MM expressed trkC, with some of them having trkB and parvalbumin (PV). In contrast, a lesser number of TM and LPM nerves expressed trkC, lacked trkB and had fewer PV+ fibers in LPM. Along with sensory fibers, the masticatory muscles contain sympathetic fibers (tyrosine hydroxylase; TH+), which are located around blood vessels. This TH expression was absent in trigeminal neurons. Overall, the masticatory muscles of male marmosets have distinct expression patterns when compared to each muscle of the jaw and cutaneous fibers innervated by DRG neurons. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.09.527854v1?rss=1 Authors: Kaur, G., Pant, P., Bhagat, R., Seth, P. Abstract: Neurotropic viruses can cross the otherwise dynamically regulated blood-brain barrier (BBB) and affect the brain cells. Zika virus (ZIKV) is an enveloped neurotropic Flavivirus known to cause severe neurological complications, such as encephalitis and foetal microcephaly. In the present study, we used human brain microvascular endothelial cells (hBMECs) and human progenitor derived astrocytes to form a physiologically relevant BBB model. We used this model to investigate the effects of ZIKV envelope (E) protein on properties of cells comprising the BBB. E protein is the principal viral protein involved in interaction with host cell surface receptors, facilitating the viral entry. Our findings show that ZIKV E protein results in activation of both hBMECs and astrocytes. hBMECs showed reduced expression of endothelial junction proteins - ZO-1, Occludin and VE-Cadherin, which are crucial in establishing and maintaining the BBB. As a result, ZIKV E protein triggered alteration in BBB integrity and permeability. We also found upregulation of genes involved in leukocyte recruitment along with increased proinflammatory chemokines and cytokines upon exposure to E protein. Furthermore, E protein resulted in astrogliosis as seen by increased expression of GFAP and Vimentin. Both BBB cell types exhibited inflammatory response following exposure to E protein which may influence viral access into the central nervous system (CNS), resulting in infection of other CNS cells. Overall, our study provides valuable insights into the transient changes that occur at the site of BBB upon ZIKV infection. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.07.527573v1?rss=1 Authors: Shalaby, R. A., Qureshi, M. M., Khan, M. A., Salam, S. M. A., Kwon, H. S., Lee, K. H., Chung, E., Kim, Y. R. Abstract: Background: Ischemic stroke typically accompanies numerous disorders ranging from somatosensory dysfunction to cognitive impairments, inflicting its patients with various neurologic symptoms. Among pathologic outcomes, post-stroke olfactory dysfunction is frequently observed. Despite the well-known prevalence, therapy options for such compromised olfaction are limited, likely due to the complexity of the olfactory bulb architecture, which encompasses both the peripheral and central nervous systems. As photobiomodulation (PBM) emerged for treating stroke-associated symptoms, the effectiveness of PBM on the stroke-induced impairment of the olfactory function was explored. Purpose: To address the efficacy of PBM therapy on the olfactory bulb damage caused by ischemic stroke using both behavioral and histologic and inflammatory markers in the newly developed stroke mouse models. Methods: Novel mouse models with olfactory dysfunction were prepared using photothrombosis (PT) in the olfactory bulb on day 0. Moreover, post-PT PBM was performed daily from day 2 to day 7 by irradiating the olfactory bulb using an 808 nm laser with the fluence of 40 J/cm2 (325 mW/cm2 for 2 minutes per day). The buried food test (BFT) was used for scoring behavioral acuity in the food-deprived mice to assess the olfactory function before PT, after PT, and after PBM. Histopathological examinations and cytokine assays were performed on the mouse brains harvested on day 8. Results: The results from BFT were specific to the individual, with positive correlations between the baseline latency time measured before PT and alterations at the ensuing stages for both the PT and PT+PBM groups. Also in both groups, the correlation analysis showed a significant positive relationship between the early and late latency time changes independent of PBM, implicating a common recovery mechanism. In particular, the PBM treatment largely accelerated the recovery of impaired olfaction after PT with the suppression of inflammatory cytokines while enhancing both the glial and vascular factors (e.g., GFAP, IBA-1, and CD31). Conclusions: The PBM therapy during the acute phase of ischemia improves the compromised olfactory function by modulating the microenvuronment and tissue inflammation. Keywords: Ischemic stroke, olfactory dysfunction, photothrombosis, photobiomodulation, buried food test, olfactory bulb, neuroinflammation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.06.527058v1?rss=1 Authors: Sabetta, Z., Krishna, G., Curry, T., Adelson, P. D., Thomas, T. C. Abstract: Traumatic brain injury (TBI) manifests late-onset and persisting clinical symptoms with implications for sex differences and increased risk for the development of age-related neurodegenerative diseases. Few studies have evaluated chronic temporal profiles of neuronal and glial pathology that include sex as a biological variable. After experimental diffuse TBI, late-onset and persisting somatosensory hypersensitivity to whisker stimulation develops at one-month post-injury and persists to at least two months post-injury in male rats, providing an in vivo model to evaluate the temporal profile of pathology responsible for morbidity. Whisker somatosensation is dependent on signaling through the thalamocortical relays of the whisker barrel circuit made up of glutamatergic projections between the ventral posteromedial nucleus of the thalamus (VPM) and primary somatosensory barrel cortex (S1BF) with inhibitory (GABA) innervation from the thalamic reticular nucleus (TRN) to the VPM. To evaluate the temporal profiles of pathology, male and female Sprague Dawley rats (n = 5-6/group) were subjected to sham surgery or midline fluid percussion injury (FPI). At 7-, 56-, and 168-days post-injury (DPI), brains were processed for amino-cupric silver stain and glial fibrillary acidic protein (GFAP) immunoreactivity, where pixel density of staining was quantified to determine the temporal profile of neuropathology and astrocyte activation in the VPM, S1BF, and TRN. FPI induced significant neuropathology in all brain regions at 7 DPI. At 168 DPI, neuropathology remained significantly elevated in the VPM and TRN, but returned to sham levels in the S1BF. GFAP immunoreactivity was increased as a function of FPI and DPI, with an FPI x DPI interaction in all regions and an FPI x Sex interaction in the S1BF. The interactions were driven by increased GFAP immunoreactivity in shams over time in the VPM and TRN. In the S1BF, GFAP immunoreactivity increased at 7 DPI and declined to age-matched sham levels by 168 DPI, while GFAP immunoreactivity in shams significantly increased between 7 and 168 days. The FPI x Sex interaction was driven by an overall greater level of GFAP immunoreactivity in FPI males compared to FPI females. Increased GFAP immunoreactivity was associated with an increased number of GFAP-positive soma, predominantly at 7 DPI. Overall, these findings indicate that FPI, time post-injury, sex, region, and aging with injury differentially contribute to chronic changes in neuronal pathology and astrocyte activation after diffuse brain injury. Thus, our results highlight distinct patterns of pathological alterations associated with the development and persistence of morbidity that supports chronic neuropathology, especially within the thalamus. Further, data indicate a convergence between TBI-induced and age-related pathology where further investigation may reveal a role for divergent astrocytic phenotypes associated with increased risk for neurodegenerative diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.13.523904v1?rss=1 Authors: Suda, K., Pignatelli, J., Genis, L., Fernandez, A. M., Fernandez de Sevilla, M. E., Fernandez de la Cruz, I., Pozo-Rodrigalvarez, A., de Ceballos, M. L., Diaz-Pacheco, S., Herrero-Labrador, R., Torres Aleman, I. Abstract: Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults by deleting it using tamoxifen-regulated Cre deletion in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detetected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion, including aquaporin 4, complement 1q subunit a, early growth response protein 1, and C-C motif chemokine ligand 2, were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.06.522870v1?rss=1 Authors: Riggins, T. E., Whitsitt, Q. A., Saxena, A., Hunter, E., Hunt, B., Thompson, C. H., Moore, M. G., Purcell, E. K. Abstract: Implanted microelectrode arrays hold immense therapeutic potential for many neurodegenerative diseases. However, a foreign body response limits long-term device performance. Recent literature supports the role of astrocytes in the response to damage to the central nervous system (CNS) and suggests that reactive astrocytes exist on a spectrum of phenotypes, from beneficial to neurotoxic. The goal of our study was to gain insight into the subtypes of reactive astrocytes responding to electrodes implanted in the brain. In this study, we tested the transcriptomic profile of two reactive astrocyte culture models (cytokine cocktail or lipopolysaccharide, LPS) utilizing RNA sequencing, which we then compared to differential gene expression surrounding devices inserted into rat motor cortex via spatial transcriptomics. We interpreted changes in the genetic expression of the culture models to that of 24 hour, 1 week and 6 week rat tissue samples at multiple distances radiating from the injury site. We found overlapping expression of up to ~250 genes between in vitro models and in vivo effects, depending on duration of implantation. Cytokine-induced cells shared more genes in common with chronically implanted tissue ( greater than or equal to 1 week) in comparison to LPS-exposed cells. We revealed localized expression of a subset of these intersecting genes (e.g., Serping1, Chi3l1, and Cyp7b1) in regions of device-encapsulating, glial fibrillary acidic protein (GFAP)-expressing astrocytes identified with immunohistochemistry. We applied a factorization approach to assess the strength of the relationship between reactivity markers and the spatial distribution of GFAP-expressing astrocytes in vivo. We also provide lists of hundreds of differentially expressed genes between reactive culture models and untreated controls, and we observed 311 shared genes between the cytokine induced model and the LPS-reaction induced control model. Our results show that comparisons of reactive astrocyte culture models with spatial transcriptomics data can reveal new biomarkers of the foreign body response to implantable neurotechnology. These comparisons also provide a strategy to assess the development of in vitro models of the tissue response to implanted electrodes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.21.521438v1?rss=1 Authors: Ruggiero, R. N., Marques, D. B., Rossignoli, M. T., De Ross, J. B., Prizon, T., Beraldo, I. J. S., Bueno-Junior, L. S., Kandratavicius, L., Peixoto-Santos, J. E., Aguiar, C. L. Abstract: Cognitive impairments and psychiatric symptoms affect up to half of temporal lobe epilepsy patients and are often more detrimental to their quality of life than the seizures themselves. Evidence indicates that the neurobiology of epileptogenesis shares common pathophysiological mechanisms with psychiatric comorbidities. However, these mechanisms and how they relate to specific behavioral alterations are unclear. We hypothesized that a dysfunctional communication between the hippocampus (HPC) and the prefrontal cortex (PFC), as a consequence of epileptogenesis, would be linked to behavioral and cognitive symptoms observed in the comorbidities of temporal lobe epilepsy. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status Epilepticus in male rats. We found that adult animals submitted to early-life seizure (ELS) presented behavioral alterations typically found in animal models of psychosis, such as hyperlocomotion, reduction in sensorimotor gating, working memory deficits, and sensitivity to psychostimulants. Noteworthy, ELS rats did not exhibit neuronal loss. Instead, sensorimotor alterations were associated with increased neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Surprisingly, cognitive deficits were linked to an aberrant increase in HPC-PFC long-term potentiation (LTP). Furthermore, ELS rats displayed an abnormal brain state during active behavior characterized by oscillatory dynamics oddly similar to REM sleep. Our results point to impaired hippocampal-prefrontal network dynamics as a possible pathophysiological mechanism by which an epileptogenic insult can cause behavioral changes without neuronal loss. These convergent patterns of dysfunctional activity between epileptogenesis and psychosis bear translational implications for understanding psychiatric and cognitive comorbidities in epilepsy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.05.518134v1?rss=1 Authors: Sullivan, M. A., Lane, S. D., Ball, S. R., Sunde, M., Neely, G. G., Moreno, C., Werry, E. L., Kassiou, M. Abstract: Background: Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimers disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. Methods: iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and A{beta}42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently labelled fibrillar A{beta}42. Results: AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100{beta} ; and increased secretion and phagocytosis of A{beta}42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells show exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. Conclusion: Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a primed phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered A{beta}42 production and phagocytosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.22.517403v1?rss=1 Authors: Pierson, S., Fiock, K., Wang, R., Balasubramanian, N., Khan, K., Betters, R., Lee, G., Hefti, M. M., Marcinkiewcz, C. A. Abstract: Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, all of which are disrupted in AD. We report here that tau pathology is present in the DRN of cognitively intact individuals 54-80 years of age, whereas synuclein and TDP-43 are relatively absent. Almost all AD cases had tau pathology in the DRN, whereas only a subset contained TDP-43 or synuclein, but not both. Mice overexpressing human P301L-tau in the DRN also exhibited depressive-like behaviors and hyperactivity without any deficits in spatial memory. There was a negative correlation between the density of Tph2-expressing neurons and phospho-tau (ptau) optical density in P301L-tauDRN mice, although mean Tph2 expression did not differ significantly from the controls. 5-HT neurons were hyperexcitable in P301L-tauDRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs) which is suggestive of increased glutamatergic transmission. Astrocytic density was also elevated in the DRN and accompanied by an increase in GFAP expression, as well as changes in Htr2a, Htr2c, and Htr3a gene expression. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen, suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together, these results suggest that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to prodromal AD symptoms, 5-HT neuronal dysfunction, and activation of local astrocytes. The presence of tau pathology in the DRN combined with psychiatric assessments for depression may be a useful screening tool for individuals at risk for AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.31.514523v1?rss=1 Authors: Popov, A., Brazhe, N., Morozova, K., Yashin, K., Bychkov, M., Nosova, O., Sutyagina, O., Brazhe, A., Parshina, E., Li, L., Medyanik, I., Korzhevskii, D. E., Shenkarev, Z., Lyukmanova, E., Verkhratsky, A., Semyanov, A. Abstract: How aging affects cellular components of the human brain active milieu remains largely unknown. We analyzed astrocytes and neurons in the neocortical access tissue of younger (22 - 50 years) and older (51 - 72 years) adult patients who underwent glioma resection. Aging decreased the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The total amount of protein was decreased in astrocytes and increased in neurons. Aged astrocytes showed morphological dystrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Dystrophy correlated with the loss of gap junction coupling between astrocytes and increased input resistance. Aging was accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker Ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling were observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of astrocytes, but not neurons. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.17.512526v1?rss=1 Authors: Ferreira, S. A., Li, C., Klaestrup, I. H., Toft, G. U., Betzer, C., Svedsen, P., Jensen, P. H., Luo, Y., Etzerodt, A., Moestrup, S. K., Romero-Ramos, M. Abstract: The aggregation of alpha-synuclein (-syn) and immune activation are both pathological events related to the neurodegenerative process in Parkinsons disease (PD). The PD-associated immune response involves both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. CD163 is a scavenger receptor specifically expressed in the monocytic lineage, but normally not in microglia. Therefore, the presence of CD163 positive cells into the brain in PD rodent models and in PD patients suggest a monocytic infiltration or otherwise ectopic CD163 expression. In addition, changes in CD163 expression profiles observed in PD patients might indicate a role for CD163-expressing cells in the disease. To elucidate the relevance of the CD163 receptor in the -syn-induced immune events in PD and associated degeneration we injected murine -syn pre-formed fibrils (PFF), or monomeric -syn into the striatum of CD163 knockout (KO) mice and wild-type (WT) littermates. Injection of -syn PFF in CD163KO females led to impaired early immune responses as revealed by the lack of ability to upregulate MHCII, CD68, GFAP, and promote CD4 and CD8 T cell infiltration after -syn PFF injection. An early and long-lasting sensorimotor impairment was observed in -syn PFF CD163KO males but not in the females. Transcriptomic analysis revealed that CD163 deletion induced phenotypic changes of macrophages and microglia in the brain that potentially impact the motor behavior and neuronal health induced by -syn in a sex-dependent manner. After 6 months, CD163KO females showed an exacerbated immune response and -syn pathology associated with autophagic defects, which ultimately led to increased dopaminergic neurodegeneration. Overall, our results support a novel sex-dimorphic neuroprotective role for CD163 in the -syn-induced neuropathology and immune response. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.21.508917v1?rss=1 Authors: Ravi, S., Criado-Marrero, M., Barroso, D., Braga, I. M., Bolen, M., Rubinovich, U., Hery, G. P., Grudny, M. M., Koren, J., Prokop, S., Febo, M., Abisambra, J. F. Abstract: Background: Repetitive mild traumatic brain injury (rmTBI) is a leading and severe threat to cognition that often goes undiagnosed. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps that explain how TBI promotes brain dysfunction. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. In this study, we defined the extent of altered brain functional connectivity (FC) and expression of neuropathological markers after rmTBI. Methods: We performed two rmTBI (2x 0.6 J impacts 24 h apart) in male and female C57BL/6J wild-type (WT) (~2.5-3mo) mice using CHIMERA or sham procedures. At 5-6 days post-injury (dpi), we measured changes in brain volume and FC using T2-weighted images, resting-state functional MRI (rsfMRI) and graph theory analyses. We used diffusion tensor imaging (DTI) to assess microstructural changes in white matter tracts. In addition, at 7dpi, we measured changes in Iba1 and GFAP in specific brain regions to determine the extent of gliosis. The expression of disease-associated protein markers in grey and white matter (WM) regions were evaluated using the NanoString-GeoMx digital spatial protein profiling spatial profiling (DSP) platform. Results: The rsfMRI data revealed aberrant changes in connectivity such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in thalamus and other key brain regions that process visual, auditory, and somatosensory information. Using DTI, we found that fractional anisotropy (FA) and axial diffusivity in the optic tract was significantly decreased. Also, mean, radial, and axial diffusivity (L1) were significantly increased in the hippocampus. DSP revealed that phospho-serine 199 tau (pS199) as well as glial markers such as GFAP, cathepsin-D, and Iba1 were significantly increased in the optic tract. In thalamic nuclei, the neuroinflammatory marker GPNMB was increased significantly, and the cell proliferation marker Ki-67 was significantly decreased in the rmTBI group. Our data suggest that rmTBI significantly alters brain functional connectivity and causes a profound inflammatory response in gray matter regions, beyond chronic white matter damage. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.19.508484v1?rss=1 Authors: Snellman, A., Ekblad, L. L., Tuisku, J., Koivumäki, M., Ashton, N. J., Lantero-Rodriguez, J., Karikari, T. K., Helin, S., Bucci, M., Löyttyniemi, E., Parkkola, R., Karrash, M., Schöll, M., Zetterberg, H., Blennow, K., Rinne, J. Abstract: Increased reactivity of microglia and astrocytes is known to be present at various stages of the Alzheimer's continuum but their relationship with core Alzheimer's disease pathology in the preclinical stages is less clear. We investigated glial reactivity and {beta}-amyloid pathology in cognitively unimpaired APOE {varepsilon}4 homozygotes, heterozygotes and non-carriers using 11C-PK11195 PET (targeting 18-kDa translocator protein), 11C-PiB PET (targeting {beta}-amyloid), brain MRI, and a preclinical cognitive composite (APCC). Plasma glial fibrillary acidic protein (GFAP) by and plasma A{beta}1-42/1-40 were measured using single molecule array and immunoprecipitation combined with mass spectrometry, respectively. We observed that (i) 11C-PiB-binding was significantly higher in APOE {varepsilon}4 homozygotes compared with non-carriers in all evaluated regions, (ii) regional 11C-PK11195-binding did not differ between the APOE {varepsilon}4 gene doses or between A{beta}-positive and -negative individuals, and (iii) higher 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, and elevated 11C-PiB-binding and plasma GFAP concentration with lower APCC scores. Increased glial reactivity might emerge in later stages of preclinical Alzheimer's disease in parallel with early neurodegenerative changes. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
Vidcast: https://youtu.be/lnfpbeZ7pqU Victims of Traumatic Brain Injuries, TBI for short, have a 23 to 63 fold higher risk of death during the ensuing 6 months when they have high levels of two protein biomarkers circulating in their bloodstreams on the day of injury. This conclusion stems from a collaborative study from the University of Michigan, UC-San Francisco, and the University of Pennsylvania. The researchers studied 1700 patients with TBI and measured their circulating levels of two proteins, GFAP and UCH-L1 as they were admitted to the hospital. The levels of these proteins were compared with the occurrence of patient mortality within 6 months post-injury. Those with the highest vs. the lowest GFAP values had a 23 times higher risk of death while those with the highest vs. the lowest UCH-L1 values had a 63 times higher risk of death. This prospective data is invaluable for setting realistic family expectations for patient recovery after these devastating episodes of head trauma. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(22)00256-3/fulltext #tbi #gfap #uchl1 #mortality tbi, gfap, uchl1, mortality
Microglial cells are responsible for sensing and driving the immune response in the central nervous system. Their activity, be it supportive or destructive, can be at the root of many different neuroinflammatory conditions including diseases like MS, ALS, Alzheimer's, Parkinson's, and TBI (Traumatic Brain Injury), but may also play a large role in the vague hallmark symptoms of complex and chronic disease like brain fog, fatigue, pain, alertness and mood changes including OCD, ADD, and depression. Dr Singhal systematically walks us through an easily understood description of the types of cells in the brain (neurons, macroglia (astrocytes & oligodendrocytes), microglia) and their functions. The microglia are a fascinating type of neuroimmune cell that sense and act protectively in good times and then can change shape and release various cytokines, chemokine and neurotransmitters in response to the development of disease, which then impacts microglia function further. We used to only be able to see this on autopsy- there are no blood tests available to measure microglial activation (although neurofilament light chains (NfL) from neurons and glial fibrillary acid protein (GFAP) from astrocytes can reflect central nervous system cellular injury). But PET imaging can visualize microglial activation! Dr Singhal explains in elucidating detail the nature, function, and power of Positron Emission Tomography (PET) imaging, like starting with the Big Bang, anti-matter particles, medical cyclotrons and gamma rays. “PET brings physics, chemistry and biology together in real time to provide novel insights at a cellular and molecular level”, including microglial activation. “If you know yourself and know your enemy, you'll win 1000 battles” is the way he describes what PET can do for neuroinflammatory conditions. We end the show with a discussion of treatment theories and options targeting microglial activation. It's a combination of re-evaluating known therapies (even the old antibiotic minocycline!) for their impact on microglia as well as mention of some novel therapies, including a nasal spray ‘vaccine' for MS. Of course, we bring up non-pharmacologic therapy potentials including exercise, the Ayurvedic perspective including panchakarma detoxification, the power of breathing to impact cerebrospinal fluid flow, ketogenic diet, and consideration of various adaptogenic herbs with the goal of supporting the immune system's intelligence.
Rapid recent advancements have led to blood tests (biomarkers) to track multiple sclerosis disease activity. A biomarker is something that can be measured to check normal functioning or the impact of a disease. Blood biomarkers are common in medicine to measure response to therapy such as measuring hemoglobin A1c levels for diabetic control and cholesterol levels for high cholesterol treatment. Injury to nerve cells (neurons) and other cells in the brain and spinal cord can be measured in the blood by checking levels of proteins such as neurofilament light chains (NfL) and glial fibrillary acid protein (GFAP). One panel of these blood markers helps identify people with multiple sclerosis with current active MRI scans. The future of MS biomarkers involves blood tests to diagnose multiple sclerosis, select the best treatment for an individual, and measure treatment response. Barry Singer MD, Director of The MS Center for Innovations in Care, interviews: Tanuja Chitnis MD, Professor of Neurology at Harvard Medical School, is the Director of both MGB Pediatric Multiple Sclerosis Center and Translational Neuroimmunology Research Center at Brigham and Women's Hospital. She is also Co-Director of the Brigham Multiple Sclerosis Center at Brigham and Women's Hospital.
Dr. Stacey Clardy discusses the clinical, biological, and imaging features—as well as the overall clinical course—of a French cohort of patients with glial fibrillar acidic protein (GFAP) autoantibodies with Dr. Jérôme Honnorat. Read the full article in Neurology.
Efectos de diferentes regímenes de Entrenamiento en Intervalos de Alta Intensidad -HIIT- sobre la resistencia y la neuroplasticidad después de derrame cerebral isquemico Caroline Pin-Barre, Nicolas Hugues, Annabelle Constans, Eric Berton, Christophe Pellegrino, Jérôme Laurin Originally published1 Feb 2021https://doi.org/10.1161/STROKEAHA.120.031873 Stroke. 2021;52:1109–1114 Abstracto Traducido del Original Antecedentes y objetivo: El objetivo es comparar los efectos del entrenamiento en intervalos de alta intensidad (HIIT) con intervalos largos versus cortos sobre la resistencia y el rendimiento motor. Su influencia sobre los marcadores de neuroplasticidad se evalúa en la corteza e hipocampo ipsilesional y contralesional ya que su remodelación podría mejorar la recuperación funcional. Métodos: Las ratas realizaron un HIIT4 adaptado al trabajo (intervalos largos: 4 minutos) o HIIT1 (intervalos cortos: 1 minuto) en una cinta rodante durante 2 semanas después de la oclusión transitoria de la arteria cerebral media. La fuerza de agarre de las extremidades anteriores evaluó la función motora, mientras que las pruebas de ejercicio incrementales midieron el rendimiento de resistencia. Los marcadores clave de neuroplasticidad se evaluaron mediante Western blot. Resultados: Ambos regímenes fueron efectivos para mejorar tanto la velocidad asociada con el umbral de lactato como la velocidad máxima en D8 y D15. Los marcadores de neuroplasticidad se regularon positivamente en el hemisferio contralesional después del entrenamiento contrario al lado ipsilesional. La fuerza de agarre se recuperó por completo, pero es más rápida con HIIT4. Conclusiones: El HIIT con intervalos cortos y largos indujo mejoras tempranas en la aptitud aeróbica y la fuerza de agarre. Nuestros hallazgos revelaron que los marcadores de neuroplasticidad se regularon positivamente en la corteza contralesional y el hipocampo para promover la recuperación funcional. Resumen Sujetos En este estudio se incluyeron 42 ratas Sprague-Dawley macho adultas. Los animales se asignaron aleatoriamente a 4 grupos: los animales se sometieron a la cirugía sin isquemia cerebral (n=12); los animales se sometieron a una oclusion transitoria de la arteria cerebral media sin entrenamiento tMCAO (n=10); y dos grupos que después de oclusion arterial realizaron HIIT con intervalos largos HIIT4 (n=10) o cortos HIIT1 (n=10). tMCAO, puntuación neurológica, fuerza de agarre y pruebas de ejercicio incremental Los ratones fueron sometidos a una oclusion arterial derecha por 2 horas. La recuperación funcional se evaluó midiendo primero la fuerza de agarre de cada miembro anterior y de los miembros anteriores combinados antes y en los dias1, 3, 8 y 15 despues de la oclusion. Se les realizaron pruebas de esfuerzo incrementales en los dias 1, 8 y 15 para definir la velocidad asociada al umbral de lactato (SLT) y la velocidad máxima (Smax; rendimiento de resistencia). Se recogió una muestra de sangre de la vena de la cola después de cada nivel de velocidad para medir la concentración de lactato. HIIT4 y HIIT1 emparejados en la cinta de correr HIIT4 (intervalos largos: 4 minutos) y el HIIT1 (intervalos cortos: 1 minuto) incluyeron 10 sesiones desde el dia 2 hasta el dia 13 despues de la oclusion. Segun los autores, estos protocolos de HIIT pueden extrapolarse fácilmente a los pacientes con esquemia cerebral porque: (1) el entrenamiento se basó en parámetros fisiológicos aplicables en pacientes a partir de una prueba de ejercicio incremental, es decir, velocidad asociada al umbral de lactato y velocidad máxima. (2) la velocidad y la duración se individualizaron de una manera emparejada con el trabajo para permitir dosis de ejercicio comparables (3) el HIIT es seguro durante el período crítico de rehabilitación en pacientes médicamente estables, y (4) la velocidad se incrementó progresivamente añadiendo una prueba incremental intermedia para reevaluar la velocidad de las sesiones. Western Blot En el dia 17 se extrajeron las proteínas totales del hipocampo y la corteza ipsilesional y contralesional para detectar GFAP (proteína ácida fibrilar glial), pTrkB (la forma fosforilada del receptor de tropomiosina quinasa B) p75NTR (receptor de neurotrofina p75), FNDC5 (proteína 5 que contiene dominio de fibronectina tipo III), VEGF (factor de crecimiento endotelial vascular) y CytC (citocromo C). Hallazgos importantes Ambos regímenes de HIIT promueven los marcadores de neuroplasticidad en el hemisferio contralateral, además de un aumento sustancial del rendimiento de resistencia y de la fuerza de agarre. Las mejoras funcionales podrían estar asociadas a los cambios en el hemisferio contralesional. El aumento de la pTrkB y del FNDC5 tras el HIIT podría contribuir a los resultados beneficiosos por su papel en la supervivencia neuronal, la neurogénesis del hipocampo, la plasticidad sináptica y la recuperación funcional. La recuperación efectiva de la fuerza de agarre confirma la necesidad de superar la velocidad asociada al umbral de lactato (SLT) para mejorar la función motora. Sin embargo, una mayor velocidad (HIIT1) no induce mayores ganancias porque se observan beneficios similares entre los regímenes. Curiosamente, el HIIT4 mostró una recuperación más rápida que el HIIT1, lo que sugiere que los intervalos largos podrían ser más adecuados. Esto tiene relevancia clínica, ya que los efectos beneficiosos más tempranos se asocian con frecuencia a una mayor recuperación a largo plazo. Ambos regímenes de HIIT generan una cinética similar de dos fuertes indicadores de calidad de vida, el SLT y el Smax. El SLT está poco estudiado en los pacientes, mientras que su aumento sugiere una reducción de la fatiga inducida por el ejercicio a una velocidad determinada. Las mejoras en el Smax, fuertemente correlacionadas con el consumo máximo de oxígeno, sugieren una mejora de las capacidades aeróbicas. En cuanto a las ganancias de fuerza, el aumento temprano del rendimiento de resistencia (en D8) podría ser prometedor para la recuperación a largo plazo. Al garantizar un estímulo fisiológico suficiente durante el período de entrenamiento, la prueba intermedia también permite observar que las velocidades individualizadas pueden aumentar fuertemente durante la segunda semana. Por lo tanto, la aptitud aeróbica sigue mejorando a lo largo del entrenamiento. Por lo tanto, debería considerarse la reevaluación periódica del rendimiento para optimizar la intensidad del entrenamiento. Por último, los pacientes con ictus podrían utilizar ambos regímenes HIIT en función de sus capacidades aeróbicas/motoras y de sus preferencias de ejercicio sin reducir la relevancia del entrenamiento. Mas Episodios
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.392548v1?rss=1 Authors: de Lima, C. K. F., Sisnande, T., da Silva, R. V., da Silva, V. D., do Amaral, J. J., Ochs, S. M., Roedel dos Santos, B. L., Miranda, A. L. P., Lima, L. M. T. d. R. Abstract: Zinc (Zn) is an essential micronutrient involved in a large diversity of cellular metabolism, included in the physiology of nervous system and pain modulation. There is little evidence for the role of Zn nutritional alternations to the onset and progression of neuropathic and inflammatory pain. We investigate the effects of a zinc restricted diet on the development of pain. Weaned mice were submitted to different diets: AIN-93 (38mg/kg of Zn) and Zn-deficient (AIN-93 with 11mg/kg of Zn), during four weeks. Mechanical allodynia was measured weekly using Von Frey hairs. Plantar assays for cold and heat allodynia, formalin-induced nociception and carrageenan-induced mechanical allodynia were performed at the 4th week. Plasma, DRG and livers samples were obtained for biochemical and metabolomics analysis. Zn deficient diet completely changed mice sensitivity pattern, inducing an intense allodynia evoked by mechanical, cold and heat stimulus since weaning and during four weeks. Showed also an increased sensitivity of neurogenic phase of formalin test but the inflammatory pain behavior was drastically reduced. Zn restriction increased the ATF-3 and SOD-1 levels at DRG and reduced that of GFAP, leading an increase of neuronal activation and oxidative stress, and reduced neuroimmune activity. Plasma TNF was also reduced and metabolomics analyses suggest a downregulation of lipid metabolism of arachidonic acid, reinforcing the impact of Zn restriction to the inflammatory response. Reduction of Zn intake interferes in pain circuits, reducing inflammatory pain, however enhancing nociceptive pain. Accordingly, Zn imbalance could be predisposing factor for NP development. Therefore, dietary zinc supplementation and its monitoring present clinical relevance. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.16.384354v1?rss=1 Authors: Geng, J., Liu, G., Wu, Y., Kong, F., Ma, S., Fu, L. Abstract: Multiple sclerosis (MS) is a complex, progressive neuroinflammatory disease associated with autoimmunity. Currently, effective therapeutic strategy was poorly found in MS. Experimental autoimmune encephalomyelitis (EAE) is widely used to study the pathogenesis of MS. Previous studies have shown that bone marrow mesenchymal stem Cells (BMSCs) transplantation could treat EAE animal models, but the mechanism was divergent. Here, we systematically evaluated whether BMSCs can differentiate into neurons, astrocytes and oligodendrocytes to alleviate the symptoms of EAE mice. We used Immunofluorescence staining to detect MAP-2 neurons marker, GFAP astrocytes marker, and MBP oligodendrocytes marker expression to evaluate whether BMSCs can differentiate. The effect of BMSCs transplantation on inflammatory cell invasion and demyelination in EAE mice were detected by Hematoxylin-Eosin (H&E) and Luxol Fast Blue (LFB) staining. Inflammatory factors expression was detected by ELISA and RT-qPCR. Our results showed that BMSCs could be induced to differentiate into neuron cells, astrocytes and oligodendrocyte in vivo and in vitro. In addition, BMSCs transplant improved the survival rate and weight, and reduced neurological function scores and disease incidence of EAE mice. Moreover, BMSCs transplant alleviated the inflammation and demyelination of EAE mice. Finally, we found that BMSCs transplantation down-regulated the expression levels of pro-inflammatory factors TNF-, IL-1{beta} and IFN-{gamma}, and up-regulated the expression levels of anti-inflammatory factors IL-10 and TGF-{beta}. In conclusion, this study found that BMSCs could alleviate the inflammatory response and demyelination in EAE mice, which may be achieved by the differentiation of BMSCs into neurons, astrocytes and oligodendrocytes in EAE mice. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.12.379800v1?rss=1 Authors: Brighi, C., Salaris, F., Soloperto, A., Cordella, F., Ghirga, S., de Turris, V., Rosito, M., Porceddu, P. F., Reggiani, A., Rosa, A., Di Angelantonio, S. Abstract: Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.03.366468v1?rss=1 Authors: Spirhanzlova, P., Sebillot, A., Vancamp, P., Gothie, J.-D., Le Mevel, S., Leemans, M., Wejaphikul, K., Meima, M., Mughal, B. B., Butruille, L., Roques, P., Remaud, S., Fini, J.-B., Demeneix, B. A. Abstract: North-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. TH represses MSI1. Being a suspected TH disruptor, we hypothesized that co-exposure to the main metabolite of PPF, 4'-OH-PPF, would exacerbate ZIKV effects through increased MSI1 expression. This was tested using in vitro mouse neurospheres and an in vivo TH signaling reporter model, Xenopus laevis. TH signaling was decreased by 4'-OH-PPF in both models. In mouse-derived neurospheres the metabolite reduced neuroprogenitor proliferation as well as markers of neuronal differentiation. The results demonstrated that 4'-OH-PPF significantly induced MSI1 at both the mRNA and protein level, as well as Fasn mRNA. Other TH target genes were also significantly modified. Importantly, several key genes implicated in neuroprogenitor fate and commitment were not dysregulated by 4'-OH-PPF alone, but were in combination with ZIKV infection. These included the neuroprogenitor markers Nestin, Egfr, Gfap, Dlx2 and Dcx. Unexpectedly, 4'-OH-PPF decreased ZIKV replication, although only at the fourth and last day of incubation, and RNA copy numbers stayed within the same order of magnitude. However, intracellular RNA content of neuroprogenitors was significantly decreased in the combined presence of the PPF metabolite and ZIKV. We conclude that 4'-OH-PPF interferes with TH action in vivo and in vitro, inhibiting neuroprogenitor proliferation. In the presence of ZIKV, TH signaling pathways crucial for cortical development are significantly impacted. This provides another example of viral effects that are exacerbated by drug or pesticide use. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.27.357814v1?rss=1 Authors: Stankowska, D. L., Zhang, W., He, S., Krishnamoorthy, V. R., Harris, P., Hall, T., Chaphalkar, R. M., Kodati, B., Chavala, S. H., Krishnamoorthy, R. R. Abstract: Purpose: To determine if dietary administration of the dual ETA/ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 (ET-1) mediated vasoconstriction in Brown Norway rats. Methods: Adult male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days followed by intravitreal injection of either 4 l of 500 M ET-1 (2 nmole/eye) or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out at various time points, including, 5, 10, 15, 25 and 30 minutes. Following the imaging of the vasculature, rats were either treated with macitentan (5 mg/kg/body weight in dietary gels) or untreated (control gels without medication). Following treatments, rats were euthanized, retinal flat mounts were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner. Results: Vasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 31% loss of RGCs which was significantly reduced in macitentan-treated rats. Following ET-1 administration, GFAP immunostaining was increased in the ganglion cell layer as well as in the retrolaminar region, suggestive of astrocytic activation by ET-1 administration. RGC numbers in macitentan treated and ET-1 injected rats were similar to that observed in control retinas. Conclusions: ET-1-mediated neurodegeneration could occur through both vascular and cellular mechanisms. The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.336446v1?rss=1 Authors: Lucas, T. Abstract: Glia are known to play important roles in the brain, the gut, and around the sciatic nerve. While the gut has its own specialized nervous system, other viscera are innervated solely by autonomic nerves. The functions of glia that accompany autonomic innervation are not well known, even though they are one of the most abundant cell types in the peripheral nervous system. Here, we focused on non-myelinating Schwann Cells in the spleen, spleen glia. The spleen is a major immune organ innervated by the sympathetic nervous system, which modulates immune function. This interaction is known as neuroimmune communication. We establish that spleen glia can be visualized using both immunohistochemistry for S100B and GFAP and with a reporter mouse. Spleen glia ensheath sympathetic axons and are localized to the lymphocyte-rich white pulp areas of the spleen. We sequenced the spleen glia transcriptome and identified genes that are likely involved in axonal ensheathment and communication with both nerves and immune cells. Spleen glia express receptors for neurotransmitters made by sympathetic axons (adrenergic, purinergic, and Neuropeptide Y), and also cytokines, chemokines, and their receptors that may communicate with immune cells in the spleen. We also established similarities and differences between spleen glia and other glial types. While all glia share many genes in common, spleen glia differentially express immune genes, including genes involved in cytokine-cytokine receptor interactions, phagocytosis, and the complement cascade. Thus, spleen glia are a unique glial type, physically and transcriptionally poised to participate in neuroimmune communication in the spleen. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.06.239111v1?rss=1 Authors: Blanco, I., Cabello, J., Urdanoz-Casado, A., Acha, B., Gomez-Orte, E. M., Roldan, M., Perez-Rodriguez, D. R., Mendioroz, M. Abstract: Adult hippocampal neurogenesis (AHN) study is still a challenge. In addition to methodological difficulties is the controversy of results derived of human or animal system approaches. In view of the proven link between AHN and learning and memory impairment, we generated a straightforward in vitro model to recapitulate adult neurogenesis in the context of Alzheimer's disease (AD). Neural progenitor cells (NPCs) monolayer culture was differentiated for a period of 29 days and A{beta} peptide 1-42 was administered once a week. mRNA expression of NEUROD1, NCAM1, TUBB3, RBFOX3, CALB1 and GFAP genes was determined by RT-qPCR. Phenotypic changes were observed during directed differentiation. Except for GFAP and CALB1, these changes correlated with altered expression profile of all genes since 9 days. Only TUBB3 expression remained constant while NEUROD1, NCAM1 and RBFOX3 expression increased over time. Moreover, A{beta} treated NPCs showed transient decreases of mRNA expression for NCAM1, TUBB3 and RBFOX3 genes at 9 or 19 days. Our in vitro human NPCs model is framed within the multistep process of AHN in the SGZ of the DG. Remarkably, its transcriptional assessment might reflect alterations detected in AD human patients, deepening our understanding of the disorder and possibly of its pathogenesis. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.27.223198v1?rss=1 Authors: Bathini, P., Dupanloup, I., Zenaro, E., Terrabuio, E., Ballabani, E., Fischer, A., Doucey, M.-A., Alberi, L. Abstract: Background: Alzheimer's disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. To date, very few mouse models reproduce the pathophysiological progression of sporadic AD, while the majority of studies have employed transgenic animals reproducing the familial form. Methods: We have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL). Results: We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD shows a general tendency of the genes to decline except for GFAP. Conclusions: The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-AD, with progressive tau hyperphosphorylation, changes in microglia morphology, and gene reprogramming reflecting the increased neuroinflammation and the loss of neuronal functionality seen to some extent in humans. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.24.215160v1?rss=1 Authors: An, H., Lee, H.-L., Cho, D.-W., Hong, J., Lee, H. Y., Lee, J. M., Woo, J., Lee, J., Park, M., Yang, Y.-S., Han, S.-C., Ha, Y., Lee, C. J. Abstract: In spinal cord injury (SCI), the scar-forming reactive astrocytes with upregulated GFAP proliferate aberrantly near the injury site, allowing themselves as a prime target for transdifferentiation into neurons to replenish dead neurons. However, the conventional use of GFAP promoter to target reactive astrocytes has two inherent problems: inadvertent conversion of normal astrocytes and low efficiency due to progressive weakening of promoter activity during transdifferentiation. Here, we report that the scar-forming reactive astrocytes are selectively transdifferentiated into neurons with 87% efficiency and 96% specificity via TRANsCre-DIONE, a combination of the split-Cre system under two different promoters of GFAP and Lcn2 and a Cre-loxP-dependent inversion and expression of Neurog2 under the strong EF1 promoter. After SCI, TRANsCre-DIONE caused transdifferentiation into Isl1-positive motor neurons, reduced astrogliosis, enhanced regeneration in surrounding cells, and a significant motor recovery. Our study proposes TRANsCre-DIONE as the next-generation therapeutic approach for patients suffering from SCI. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.06.189928v1?rss=1 Authors: Robison, L. S., Gannon, O. J., Thomas, M. A., Salinero, A. E., Abi-Ghanem, C., Poitelon, Y., Belin, S., Zuloaga, K. L. Abstract: Hypothalamic dysfunction occurs early in the clinical course of Alzheimer's disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observable years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high fat diet and metabolic disease (e.g. obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex. WT and 3xTg-AD male and female mice were fed a control (10% fat) or high fat (HF; 60% diet) diet from ~3-7 months of age, then tested for metabolic and hypothalamic disturbances. On control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-, IL-1{beta}). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1{beta}, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group. These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.16.155804v1?rss=1 Authors: Pereira, E. L. R., Dias, M. N., dos Santos, I. R., Ramos, A. C., Hamoy, M., Feio, D. C. A., Tavoni, T. M., da Silva, P. C. M., Gomes-Leal, W. Abstract: Methotrexate carried in lipid core nanoparticles (LDE-MTX) is a low toxicity compound effective in reducing inflammation and secondary damage in experimental models of arthritis, atherosclerosis, myocardial infarction, cardiac allograft vasculopathy and other pathological conditions. Nevertheless, whether it is neuroprotective after stroke is unknown. Here, we explored whether LDE-MTX could cross blood brain barrier (BBB) to exert anti-inflammatory and neuroprotecive effects after experimental cortical stroke in rats. Tissue uptake was assessed by injecting radioactively labeled-LDE through the caudal vein into both sham (n=18) and adult Wistar rats submitted to endothelin-1 (ET-1)-induced cortical stroke (n=11). To address possible neuroprotective effects of LDE-MTX after stroke, 10 adult male Wistar rats were randomly allocated in two groups: animals treated with LDE-MTX (1 mg/kg, i.v., n=5) or LDE-alone (i.v., n=5) at 4 hours after stroke induction. Animals were perfused with 0.9% saline and 4% paraformaldehyde at 7 days post-injury. Histopathology was assessed by cresyl violet staining. Mature neuronal bodies (anti-NeuN), astrocytes (anti-GFAP) and microglia (anti-Iba1) were immunolabeled by immunohistochemistry. Scintigraphy technique revealed accumulation of tritiated LDE in different brain regions and in non-neural organs without overt toxicity in both sham and ischemic rats. LDE-MTX treatment induced a 10-fold (1000%) reduction in microglial activation in the ischemic cortex and afforded a 319% increase in neuronal preservation in the ischemic periinfarct region compared to LDE-alone group. There was no effect of LDE-MTX treatment on primary infarct area and astrocytosis. The results suggest that LDE-MTX formulation must be considered a very promising neuroprotective agent for ischemic stroke. Future studies using different concentrations and longer survival times are needed before assessing the suitability of LDE-MTX as a neuroprotective agent for human stroke. Key-words: Stroke, Neuroinflammation, Neuroprotection, Methotrexate, Nanotechlogy, Nanoemulsions. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.08.140467v1?rss=1 Authors: Moura, D. M. S., Brandao, J. A., Lentini, C., Heinrich, C., Queiroz, C. M., Costa, M. R. Abstract: Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that three days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) led to a significant increase in the number of GFP+ cells in both ipsi and contralateral dentate gyrus. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. These different effects of KA and PL in the Dcx-lineage are associated with distinct alterations of the parvalbuminergic plexus and inflammatory responses in the hippocampi. Finally, we also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, indicating that Dcx-progenitors could regress to a multipotent stage. Altogether, our data suggest that cell lineage in the adult hippocampus is not unidirectional and can be modulated by environmental signals. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.29.123075v1?rss=1 Authors: Nguyen, T., Gao, J., Wang, P., Nagesetti, A., Andrew, P., Masood, S., Vriesmann, Z., Liang, P., Khizroev, S., Jin, X. Abstract: Non-invasive brain stimulation is valuable for studying neural circuits and treating various neurological disorders in humans. However, the current technologies usually have low spatial and temporal precision and poor brain penetration, which greatly limit their application. A new class of nanoparticles known as magneto-electric nanoparticles (MENs) can be navigated to a targeted brain region with a magnetic field and is highly efficient in converting an externally applied magnetic wave into local electric fields for neuronal activity modulation. Here we developed a new method to fabricate MENs of CoFe2O4-BaTiO3 core-shell structure that had excellent magneto-electrical coupling properties. Using calcium imaging of organotypic and acute cortical slices from GCaMP6s transgenic mice, we demonstrated their efficacy in reliably evoking neuronal responses with a short latency period. For in vivo non-invasive delivery of MENs to brain, fluorescently labeled MENs were intravenously injected and guided to pass through the blood brain barrier to a targeted brain region by applying a magnetic field gradient. A magnetic field (~450 Oe at 10 Hz) applied to mouse brain was able to reliably evoke cortical activities, as revealed by in vivo two-photon and mesoscopic imaging of calcium signals at both cellular and global network levels. The effect was further confirmed by the increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the subsequent magnetic stimulation caused any significant increases in the numbers of GFAP and IBA1 positive astrocytes and microglia in the brain. This study demonstrates the feasibility of using MENs as a novel efficient and non-invasive technique of contactless deep brain stimulation that may have great potential for translation. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.11.089144v1?rss=1 Authors: Antonovaite, N., Hulshof, L. A., Hol, E. M., Wadman, W. J., Iannuzzi, D. Abstract: There is growing evidence that mechanical factors affect brain functioning. However, brain components responsible for regulating the physiological mechanical environment and causing mechanical alterations during maturation are not completely understood. To determine the relationship between structure and stiffness of the brain tissue, we performed high resolution viscoelastic mapping by dynamic indentation of hippocampus and cerebellum of juvenile brain, and quantified relative area covered by immunohistochemical staining of NeuN (neurons), GFAP (astrocytes), Hoechst (nuclei), MBP (myelin), NN18 (axons) of juvenile and adult mouse brain slices. When compared the mechanical properties of juvenile mouse brain slices with previously obtained data on adult slices, the latter was ~20-150% stiffer, which correlates with an increase in the relative area covered by astrocytes. Heterogeneity within the slice, in terms of storage modulus, correlates negatively with the relative area of nuclei and neurons, as well as myelin and axons, while the relative area of astrocytes correlates positively. Several linear regression models are suggested to predict the mechanical properties of the brain tissue based on immunohistochemical stainings. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.05.078691v1?rss=1 Authors: Sullivan, M. N., Brill, S. A., Mangus, L. M., Jeong, Y. J., Solis, C. V., Knight, A. C., Colantuoni, C., Keceli, G., Paolocci, N., Queen, S. E., Mankowski, J. L. Abstract: HIV-associated neurocognitive disorders (HAND) remain prevalent despite implementation of antiretroviral therapy (ART). Development of HAND is linked to mitochondrial dysfunction and oxidative stress in the brain; therefore, upregulation of antioxidant defenses is critical to curtail neuronal damage. Superoxide dismutase 2 (SOD2) is a mitochondrial antioxidant enzyme essential for maintaining cellular viability. We hypothesized that SOD2 was upregulated during retroviral infection. Using a simian immunodeficiency virus (SIV)-infected macaque model of HIV, quantitative PCR showed elevated SOD2 mRNA in cortical gray (GM, 7.6-fold for SIV vs. uninfected) and white matter (WM, 77-fold for SIV vs. uninfected) during SIV infection. Further, SOD2 immunostaining was enhanced in GM and WM from SIV-infected animals. Double immunofluorescence labeling illustrated that SOD2 primarily co-localized with astrocyte marker glial fibrillary acidic protein (GFAP) in SIV-infected animals. Interestingly, in ART-treated SIV-infected animals, brain SOD2 RNA levels were similar to uninfected animals. Additionally, using principal component analysis in a transcriptomic approach, SOD2 and GFAP expression separated SIV-infected from uninfected brain tissue. Projection of these data into a HIV dataset revealed similar expression changes, thereby validating the clinical relevance. Together, our findings suggest that novel SOD2-enhancing therapies may delay the onset or reduce severity of HAND seen in ART-treated HIV-infected patients. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.27.053470v1?rss=1 Authors: Barbuti, P. A., Antony, P., Novak, G., Larsen, S. B., Berenguer-Escuder, C., Santos, B. F., Massart, F., Grossmann, D., Shiga, T., Ishikawa, K.-i., Akamatsu, W., Finkbeiner, S., Hattori, N., Krueger, R. Abstract: Parkinson's disease (PD) is characterized by the loss of A9 midbrain dopaminergic neurons and the accumulation of alpha-synuclein aggregates in remaining neurons. Many studies of the molecular and cellular basis of neurodegeneration in PD have made use of iPSC-derived neurons from patients with familial PD mutations. However, approximately half of the cells in the brain are glia, and their role facilitating neurodegeneration is unclear. We developed a novel serum-free protocol to generate midbrain astrocytes from patient-derived iPSCs harbouring the pathogenic p.A30P, p.A53T mutations in SNCA, as well as duplication and triplication of the SNCA locus. In our cellular model, aggregates of alpha-synuclein occurred only within the GFAP+ astrocytes carrying the pathogenic SNCA mutations. Assessment of spontaneous cytosolic calcium (Ca2+) release using Fluo4 revealed that SNCA mutant astrocytes released excess Ca2+ compared to controls. Unbiased evaluation of 3D mitochondrial morphometric parameters showed that these SNCA mutant astrocytes had increased mitochondrial fragmentation and decreased mitochondrial connectivity compared to controls, and reduced mitochondrial bioenergetic function. This comprehensive assessment of different pathogenic SNCA mutations derived from PD patients using the same cellular model enabled assessment of the mutation effect, showing that p.A53T and triplication astrocytes were the most severely affected. Together, our results indicate that astrocytes harbouring the familial PD mutations in SNCA are dysfunctional, suggesting a contributory role for dysfunctional astrocytes in the disease mechanism and pathogenesis of PD. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.28.064758v1?rss=1 Authors: Wiemann, S., Reinhard-Recht, J., Reinehr, S., Cibir, Z., Joachim, S., Faissner, A. Abstract: Previous studies demonstrated that retinal damage correlates with a massive remodeling of extracellular matrix (ECM) molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. 10 weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function was comparable in all groups. Although less severe in KO ONA, WT and KO mice displayed a significant loss of RGCs after immunization. Compared to KO ONA, a significant reduction of {beta}III-tubulin stained axons and oligodendrocyte markers was noted in the optic nerve of WT ONA. In retinal and optic nerve slices, we found an enhanced GFAP+ staining area of astrocytes in immunized WT. In retinal flat-mounts, a significantly higher number of Iba1+ microglia was found in WT ONA, while a lower number of Iba1+ cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2 and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA post immunization. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb expression was measured in KO ONA animals. Collectively, this study revealed that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model offers for the first time the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling. Copy rights belong to original authors. Visit the link for more info
Colin Mahoney, JNNP Podcast editor, is joined by Dr Jonathan Rohrer, MRC Clinician Scientist, Dementia Research Centre, UCL Institute of Neurology. Carolin Heller, Dementia Research Centre and UK Dementia Research Institute. to discuss how increased levels of GFAP may be used to detect advancing neurodegeneration and clinical change in those with Progranulin associated Frontotemporal Dementia. https://jnnp.bmj.com/content/91/3/263
Neonatal encephalopathy (NE) is associated with substantial morbidity and mortality and affects around 1.5/1000 live term births. Predicting the severity and outcome of neonates with NE is therefore vital in order to provide the best care for neonates with NE, and a biochemical marker obtained at birth would therefore be useful to bolster the current scoring system. In this episode, Geoff Marsh speaks to Early Career Investigator Dr. Imran Nazir Mir, from the University of Texas, Southwestern Medical Center. He's just published a paper testing the utility of two potential candidate proteins for determining the presence and severity of hypoxic NE, and to understand where these molecules are synthesized and cleared. See acast.com/privacy for privacy and opt-out information.
Show Notes for Podcast Seven of seX & whY, Part 2 Host: Jeannette Wolfe Guests: Dr. Neha Raukar, Emergency and Sports Medicine Physician Katherine Snedaker, Executive Director of Pink Concussions Topic: Sex and Gender Differences in Concussions This is part II of our discussion about concussion with Katherine Snedaker and Neha Rauker. Today's podcast focuses on recovery and prevention. Here are the take home points: Concussion research is rapidly changing, and it is important to stay up to date on the literature There is a large NCAA study whose results should be released soon Concussion treatment has to be individualized as symptoms can vary tremendously both within and between the sexes. Overall, however, women appear to be at greater risk for having an increased clustering of symptoms and a prolonged recovery Cocoon therapy (being isolated in a dark room with no stimulation) is out and has been replaced by the concept of “relative rest” which is the idea that you can do activities that don't exacerbate symptoms Screen time has pros and cons Cons the contrast of light between the screen and the environment and scrolling can lead to vestibular irritation Much of the activities associated with “screen time” also increase cognitive demands Pros It often helps people stay connected with their social circles which can decrease feelings of isolation and depression The new FDA blood test does not test whether or not someone has a concussion, it tests for specific proteins (UCH-L1 and GFAP) that are released by the brain into the blood after a severe injury and correlates with the likelihood of finding an intracranial bleed on CT. Prevention research and intervention targets multiple different levels including: Overall awareness Equipment- both in design and in proper fit Training of coaches/trainers Rule Enforcement Locker room culture Although sports related concussions get the most press, traumatic brain injuries lead to more than 2.8 million (2013 CDC data) emergency visits per year with car accidents, physical assaults and falls being big contributors. There is currently a large gap in treatment access and ownership for non-sports related TBI Thank you again to my guests!
Concussion Blood Test & Treatments for CTE, TBI and Brain ImpairmentsDr. Michael Lewis - Reports on a blood test for a concussion and what to do about CTE or TBI. The https://www.banyanbio.com/ (Brain Trauma Indicator Test at Banyan Biomarkers) measures two biomarkers: proteins known as UCH-L1 and GFAP, that are released upon injury to the brain and pass through the blood-brain barrier. Elevated levels of these proteins can be detected within 15 or 20 minutes of injury. The test can be taken within 12 hours of injury, and results can be obtained within three or four hours. Patients are currently diagnosed with concussion based on a combination of symptoms as well as imaging. However, CT scans don't always detect concussion. "Over 90% of CT scans (for concussion) are negative. And you get 200 times the radiation of a chest X-ray. It's expensive; it's not terrific," said Hank Nordhoff, chairman, and CEO of Banyan Biomarkers, maker of the new test. It can help determine whether a patient further needs a CT scan, based on a physician's concerns. It's not concussions that cause CTE. It's repeated hits, a study finds. Second Interview at CBJ on ConcussionListen up as Dr. Lewis, a West Point-trained Army officer and physician with specific interests in brain injury was a previous excellent CBJ Guest at http://corebrainjournal.com/171 (CBJ/171), details improved diagnosis and treatment for brain injury. Photo by https://unsplash.com/photos/DbJR10fEteE?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText (Aimee Vogelsang) on https://unsplash.com/@vogelina?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText (Unsplashcon) Dr. Lewis' Brain-Focused BioIn late 2011 upon retiring as a Colonel after a distinguished thirty-one-year career in the US Army. His pioneering work in the military and since has helped thousands of people around the world and is regularly featured in the media, including CNN's Sanjay Gupta, MD, show and numerous radio shows and podcasts. A graduate of the US Military Academy at West Point and Tulane University School of Medicine, Dr. Lewis is board-certified and a fellow of the American Colleges of Preventive Medicine and Nutrition. He completed postgraduate training at Walter Reed Army Medical Center, Johns Hopkins University, and the Walter Reed Army Institute of Research.http://geni.us/mlewis () He is currently in private practice in Potomac, Maryland (BrainCARE, http://www.BrainCARE.center (www.BrainCARE.center)); is a consultant to the US Army and Navy as well as several organizations, institutes, and nutrition companies around the world; and is a founding member of the Pop Warner Youth Football Medical Advisory Board. Ed Note: See his book give away offer below↓, open until June 20, '18 Concussion Testing Details - Radiation Exposure MinimizedThe US Food and Drug Administration has, for the first time, approved a blood test to help detect concussion in adults. "Today's action supports the FDA's Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging -- an effort to ensure that each patient is getting the right imaging exam, at the right time, with the right radiation dose," FDA Commissioner Dr. Scott Gottlieb said in a statement Wednesday. Concussion Diagnostic Costs ReducedThe test could also help reduce costs significantly. Whereas a CT scan can cost $800 to $1,500, Nordhoff predicts that the new test would cost closer to $150. The test would be available to hospitals, Nordhoff said, and he hopes a handheld sideline device could be commercially available in the near future. The Concussion - Subconcussion StudyThe FDA approved the test as part of its Breakthrough Devices program after evaluating a clinical study of 1,900 blood samples from people thought to have a concussion or mild traumatic brain injury. The clinical trials did not include any children, though Banyan plans to include them in future studies....
Beyond Stress: Busy Can Become OverwhelmingYvonne Tally is the author of Breaking Up with Busy and leads meditation, stress, and de-stressing programs for corporations, individuals, and private groups in Silicon Valley. Tally is an NLP master practitioner, Yvonne cofounded Poised Inc., a Pilates and wellness training studio, and is the founder of the Sisterhood of the Traveling Scarves, a charity that provides headscarves to cancer patients. She lives in Northern California. From The ER And Stress - to RecoveryAs a successful career woman, it was Yvonne's own struggles with life balance that landed her in the ER and ultimately fueled her curiosity to develop the methods and techniques she offers in Breaking Up with Busy. Throughout the book, she stresses the benefits of living a more sane and balanced life — encompassing everything from longevity, looks, and libido to self-actualization and spiritual connection. To get there, she details methodical, incremental ways to change habits, transform thinking and reconnect with one's own unique, personal sense of play and pleasure. Priorities, structure, and a redefinition of self - change the game. Photo by https://unsplash.com/photos/VnGac-kUflg?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText (Gabriel Matula) on https://unsplash.com/search/photos/stress?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText (Unsplash) -----------Treatment Links and Referenceshttp://wwww.yvonnetally.com/ (http://wwww.YvonneTally.com). http://geni.us/tally (Breaking Up With Busy - Real Life Solutions for Overscheduled Women,) Tally, 2018 - Global Amazon Link --------------Additional CBJ Experts on Anger Managementhttp://corebrainjournal.com/150 (CBJ/150) De-Escalate Anger With Wisdom and Mindset - Noll http://corebrainjournal.com/129 (CBJ/129) Stress, Decisions, and Parenting - Marshall http://corebrainjournal.com/168 (CBJ/168) Transform Stress into Success - Cooper http://corebrainjournal.com/mindset (CBJ/Mindset) CBJ Experts Discuss Perspectives For Self Management ------------Forward This Audio Message Link To a Friendhttp://corebrainjournal.com/223 (http://corebrainjournal.com/223) -----------ThanksThanks, Yvonne, for joining us here at CBJ to review these personal observations about your useful insights on the evolution of self-management. Have some feedback you'd like to share? Leave a note in the comment section below. If you enjoyed this episode, please share it using the social media buttons you see at the bottom of the post. Also, https://itunes.apple.com/us/podcast/corebrain-journal/id1102718140?mt=2 (please leave an honest review for the CoreBrain Journal Podcast on iTunes). Ratings and reviews are extremely helpful and much appreciated. Reviews do matter in the rankings of the show, and I read each one of them. Be counted. If this post with these several references is helpful, please take a moment to pass it on. QuestionsIn closing, if you have any questions, drop a comment on any posting here at CBJ, and I'll get back to you. This discerning show of world-class experts is here for you, your families, and your clients - to tighten our collective dialogue for more precise answers. SubscribeAnd finally, don't forget to subscribe to the show on http://corebrainjournal.com/itunes (iTunes )to get automatic updates, or if you're on an Android Device subscribe for timely updates at http://corebrainjournal.com/google (Google Play). Yes, these extraordinary experts with hundreds of years of combined experience are free. ------------Our Next CoreBrain Journal Episode224 Dr. Michael Lewis - Reports on a blood test for Concussion and what to do about CTE or TBI. The Brain Trauma Indicator Test measures two biomarkers: proteins known as UCH-L1 and GFAP, that are released upon injury to the brain and pass...
1. Featured Article: IgLON5 antibody: Neurological Accompaniments & Outcomes in 20 patients2. What’s Trending: Health policy update - Coding, Reimbursement & Quality Payment ProgramThis Neurology® Podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the March 27, 2018, print issue of Neurology. In the first segment, Dr. Stacey Clardy talks with Dr. Andrew McKeon about his Neurology: Neuroimmunology & Neuroinflammation paper describing IgLON5 autoimmunity. For the “What’s Trending” segment, Dr. Jason Crowell speaks with Luana Ciccarelli and Amanda Napoles on regulatory updates in coding and reimbursement, MACRA, and tips for private practitioners on participating in the Quality Payment Program.DISCLOSURES: Dr. Clardy has received research support from Western Institute for Biomedical Research (WIBR).Dr. McKeon has patent applications pending for GFAP and MAP1B as markers of neurological autoimmunity and paraneoplastic disorders; has consulted for Grifols, Medimmune, Inc., and Euroimmun (but did not receive personal compensation for these activities); and has received research support from Medimmune, Inc. and Euroimmun. Dr. Crowell reports no disclosures. Luana Ciccarelli and Amanda Napoles are employed by the American Academy of Neurology.
What does the new blood test for concussion measure? Why red pens are not ideal for grading and feedback. Flipped learning isn't as hard as it sounds if you use short video presentations. New blood test for concussion. Why red pens are not ideal for grading and feedback. Flipped learning isn't as hard as it sounds. If you cannot see or activate the audio player click here. (1:04) The FDA recently approved a new blood test for concussions. How is the test used and what does it tell us? FDA authorizes marketing of first blood test to aid in the evaluation of concussion in adults Concussions Can Be Detected With New Blood Test Approved by F.D.A. GFAP | glial fibrillary acidic protein UCH-L1 | ubiquitin C-terminal hydrolase L1 Concussions (Health and Medical Issues Today) (11:10) It's a small thing, for sure, but the color pen we use for grading student work can have an impact on the tone of communication in a class. No Red Pens! (Kevin's blog post on this topic; with links to additional information) Green Felt Tip Pens Green Gel Pens (13:50) Subscribing helps you and others stay up to date with the world of A&P teaching! And it helps other teachers find this podcast when they search for it. How to subscribe to this podcast. (14:35) Kevin flipped his first A&P course in 2006, a year before the term flipped learning was first coined by Bergmann and Sams. In this segment, he discusses how his case study may help you decide how to flip (or half flip) your own A&P course. Sextuple Backflip !!! (a video showing a REAL circus flip) Online Lectures and Previews (brief blog post on this case study) Online Lecture Previews (Kevin's online seminar on how he flipped his course, including a brief walk-through of the mechanics of producing an online lecture ) Flipped Learning: Gateway to Student Engagement If the hyperlinks above are not active, go to TAPPradio.org to find the episode page. More details at the episode page. Transcript available at the script page. Listen to any episode on your Alexa device. Join The A&P Professor social network: Blog Twitter @theAPprofessor Facebook theAPprofessor Instagram theAPprofessor YouTube Amazon referrals help defray podcasting expenses.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 17/19
In der hier vorliegenden Arbeit wurde die Hypothese überprüft, ob die mittlere Mikrogefäßlängendichte im Kleinhirn bei plötzlichem Kindstod (SIDS [„sudden infant death syndrome“]) als Ausdruck einer chronischen subklinischen Hypoxie größer ist als bei alters- und geschlechtsgematchten Kontrollen (d.h. bei Kindern, die innerhalb des ersten Lebensjahres nicht an SIDS verstorben waren). Diese Hypothese basierte auf Literaturangaben über hypoxische Veränderungen im Gehirn bei SIDS, insbesondere im Hirnstamm, aber auch im Kleinhirn. Zwischen Hirnstamm und Kleinhirn besteht eine enge topografische und funktionelle Nähe in Bezug auf die Gefäßversorgung; so werden sowohl der Hirnstamm als auch das Kleinhirn aus Ästen der Arteriae vertebrales und der Arteria basilaris versorgt. Untersucht wurden insgesamt n=23 Kleinhirnhälften (je eine Kleinhirnhälfte pro Fallnummer) von Kindern, die im ersten Lebensjahr verstorben waren. Von diesen n=23 Kleinhirnhälften stammten n=9 von SIDS-Fällen (im Alter zwischen zwei und zehn Monaten verstorben), n=9 von alters- und geschlechtsgematchten Kontrollen, sowie n=5 weitere von Kontrollen, die entweder in einem früheren oder einem späteren Alter als die SIDS-Fälle gestorben waren. Für jede Kleinhirnhälfte wurde an Serien von 100 µm dicken Schnitten, die immunhistochemisch zum Nachweis von Kollagen IV aufgearbeitet und mit Cresylviolett gegengefärbt wurden, mit modernsten design-based stereologischen Methoden das Volumen aller Kleinhirnschichten sowie die Mikrogefäßlängendichte in diesen Schichten bestimmt. Bei einer Nebenuntersuchung an weiteren Schnitten aus dem Vermis erfolgte ein immunhistochemischer Nachweis von GFAP. Bis auf die äußere Granularzellschicht zeigten alle Schichten des Kleinhirns mit zunehmendem Alter einen statistisch signifikanten, altersabhängigen Anstieg des Volumens. Bis auf die innere Granularzellschicht, die bei den SIDS-Fällen im Mittel statistisch signifikant größer war als bei den gematchten Kontrollen, fanden sich keine statistisch signifikanten Unterschiede zwischen den SIDS-Fällen und den gematchten Kontrollen. Sowohl bei den SIDS-Fällen als auch bei den Kontrollen fand sich die höchste Mikrogefäßlängendichte in der Purkinjezellschicht, und die niedrigste Mikrogefäßlängendichte in der äußeren Granularzellschicht. Die mittleren Gefäßlängendichten der einzelnen Schichten zeigten keine statistisch signifikanten Unterschiede zwischen den SIDS-Fällen und den gematchten Kontrollen. In allen fünf Kleinhirnschichten wurden altersunabhängig sowohl bei den SIDS-Fällen als auch bei den Kontrollen Gefäßverzweigungen gefunden. Der immunhistochemische Nachweis von GFAP zeigte in der Molekularschicht bei allen Altersstufen immunpositive Bergmann-Gliafasern, und in der Purkinjezellschicht, der inneren Granularzellschicht und der weißen Substanz bei allen Altersstufen immunpositive Astrozyten. Unterschiede zwischen den SIDS-Fällen und den jeweils gematchten Kontrollen lagen bei dem immunhistochemischen Nachweis von GFAP nicht vor. Insbesondere fanden sich bei den SIDS-Fällen keine Anzeichen für Astrozyten-Aktivierung wie z. B. vergrößerte Perikarien oder kürzere, erweiterte Fortsätze. Zusammen mit den Ergebnissen der hier vorliegenden Arbeit und den Publikationen von Kiessling et al. (2013a; 2013b) liegen somit erstmals für Kleinhirne von SIDS-Fällen und gematchten Kontrollen vier verschiedene schichtenspezifische Befunde zum möglichen Vorliegen von akuter und/oder chronische Hypoxie vor, die u. a. mit modernsten design-based stereologischer Methoden erhoben wurden (Mikrogefäßlängendichten, Form und Menge von Astrozyten, Gesamtzahlen von Purkinkjezellen, und Konzentration von Calbindin-D28k in den Purkinjezellen). Dabei fanden sich keinerlei Anzeichen für akute und/oder chronische Hypoxie im Kleinhirn bei SIDS, so dass die eingangs formulierte Hypothese verworfen werden musste.
Listen to Albee Messing discussing his recent ASN NEURO paper on how GFAP expression is an indicator of disease severity in mouse models of Alexander disease, and how this could be used as a potential biomarker in the human disease.
Purpose: To describe new details of epiretinal cell proliferation in flat-mounted internal limiting membrane specimens. Methods: One hundred nineteen internal limiting membrane specimens were removed en bloc with epiretinal membranes from 79 eyes with macular pucker (MP) and 40 eyes with vitreomacular traction syndrome. Intraoperatively, posterior vitreous detachment was assessed as complete or incomplete. Whole specimens were flat-mounted on glass slides and processed for interference and phase-contrast microscopy, cell viability assay, and immunocytochemistry. Results: Mean cell viability percentage was higher in MP than in vitreomacular traction syndrome. Two cell distribution patterns were found. Anti-CD163 labeling presented predominantly in MP with complete posterior vitreous detachment. CD45 expression was similar in all groups of diagnosis. Anti-glial fibrillary acidic protein (GFAP) labeling was found in MP irrespective of the extent of posterior vitreous detachment. Alpha-SMA (alpha-smooth muscle actin) labeling was mainly presented in MP with incomplete posterior vitreous detachment and in vitreomacular traction syndrome. Simultaneous antibody labeling included GFAP/CD45, GFAP/CD163, CD163/CD45, and CD163/alpha-SMA. Conclusion: Hyalocytes constitute a major cell type of epiretinal cell proliferation in eyes with MP and vitreomacular traction syndrome. Glial cells, notably retinal Muller cells, are involved as well. It appears that transdifferentiation of cells in vitreomacular traction might be more frequent than previously thought and that those cells possess a greater variability of immunocytochemical properties than expected. RETINA 33:77-88, 2013
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 04/06
Astrocytes perform many functions in the adult brain and even act as neural stem cells after brain injury (Buffo et al., 2008) or in regions where neurogenesis persists, e.g. in the subependymal zone of the lateral ventricle. The stem cell astrocytes possess an apicobasal polarity as they are coupled by adherens junctions to neighbouring ependymal cells and possess an apical membrane domain with CD133 and Par complex proteins and a basolateral membrane domain including contact of processes to the basement membrane (BM). This is notably different from parenchymal astrocytes that only have contacts to the BM under physiological conditions. The major underlying question is how differences between neural stem cells and 'normal' astrocytes are generated and how polarity mechanisms may be involved in generating this difference. Here, I set out to determine the role of BM contact and the Par complex for astrocyte function in the normal brain parenchyma as well as in the neurogenic niche. First, I examined the influence of BM-mediated signaling by conditional deletion of β1-integrin, one of the major BM receptors in the CNS. The use of specific Cre lines resulted in a loss of β1-integrin protein only at postnatal stages either in both glia and neurons or specifically in neurons. Strikingly, only the former resulted in reactive gliosis, with the hallmarks of reactive astrocytes comprising astrocyte hypertrophy and upregulation of the intermediate filaments GFAP and Vimentin as well as pericellular components, such Tenascin-C and the 473HD proteoglycan. This reaction to the loss of β1-integrin was further accompanied by non-cell autonomous activation of microglial cells. However, neither reactive astrocytes nor microglia divided, suggesting that the loss of β1-integrin-mediated signaling is not sufficient to elicit proliferation of these cells. Interestingly, this partial reactive gliosis appeared in the absence of cell death and blood-brain barrier disturbances. As these effects did not appear after neuron-specific deletion of β1-integrin, we conclude that β1-integrin-mediated signaling in astrocytes is required to promote their acquisition of a mature, non-reactive state. Interestingly, neural stem cell astrocytes in the SEZ were not affected in their proliferation and fate, suggesting that β1-integrins are not involved in the regulation of these stem cell properties. However, loss of β1-integrins interfered with the normal dedifferentiation of astrocytes into stem cells after brain injury. Next, I examined the role of Cdc42, a key activator of the Par complex, but also a mediator of β1-integrin signalling in adult stem cell astrocytes. Therefore, I genetically deleted this small RhoGTPase in astroglia at adult stages. In contrast to what has been observed during development, loss of Cdc42 had no influence on proliferation or fate of subependymal zone astrocytes. These effects on adult astroglia-like stem cells differ profoundly from effects on parenchymal astrocytes upon injury. Here, deletion of Cdc42 resulted in severe defects of astrocyte polarity as measured by centrosome reorientation and oriented process extension in the scratch assay in vitro. In vivo, astrocytes could still orient towards the injury site suggesting the existence of compensating signaling pathways. However, the increase of astrocyte numbers around the injury site was reduced. Impaired proliferation certainly contributes to this phenotype. Most importantly, loss of Cdc42 resulted in a significantly increased size of brain injury enlightening the importance of this pathway in the wound reaction towards brain injury. Conversely, no effects were seen by Cdc42 deletion in astrocytes in the absence of injury, suggesting that integrin-mediated signaling from the BM maintains the hallmarks of mature non-reactive astrocytes while Cdc42, most likely via activation of the Par complex, regulates polarity and dedifferentiation after injury. Taken together, this work elucidated for the first time specific signaling pathways regulating the role of astrocytes as stem cells during wound reaction of the injured brain.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06
Adult neural stem cells, as the source of life-long neurogenesis, reside in the subependymal zone (SEZ) in the lateral wall of the lateral ventricles and in the dentate gyrus of the hippocampus. In both neurogenic regions, subsets of glial fibrillary acidic protein (GFAP) expressing astrocytes are found, that have been shown to act as neural stem cells. So far, it is not known how to distinguish these stem cell astrocytes from other astrocyte populations within the SEZ. Towards this end we decided to isolate a subpopulation of adult SEZ astrocytes that expresses the CD133 by FACS. GFP-positive cells in the SEZ from hGFAP/eGFP mice that were also CD133+ve comprised all neurosphere-initiating cells that were self-renewing and multipotent from the SEZ. Moreover, single cell neurosphere analysis showed 70% efficiency in neurosphere formation. Further more Cre-mediated fate mapping of this double-positive population showed their contribution to adult neurogenesis. Transcriptional profiling of the GFP/CD133-double-positive cells allowed us to a) determine their similarity at the transcriptome level to both ependymal cells AND astrocytes and b) to identify their unique molecular neural stem cell signature. We also discovered that astrocytes outside this neurogenic niche could go some way towards dedifferentiation into neural stem cells. We have previously described (Buffo et al., PNAS 2008) a population of astrocytes in the adult cerebral cortex after stab wound injury that dedifferentiates as far to form multipotent and self-renewing neurospheres. Now we succeeded to establish the factor responsible for this dedifferentiation and sufficient to elicit the dedifferentiation response even in cells that were not exposed to injury. These data will be presented. Taken together, our work allows for the first time, the identification and characterization of the astrocyte sub-types acting as neural stem cells.
Background: The Y-box binding protein 1 (YB-1) is considered to be one of the key regulators of transcription and translation. However, so far only limited knowledge exists regarding its cellular distribution in the adult brain. Results: Analysis of YB-1 immunolabelling as well as double-labelling with the neuronal marker NeuN in rat brain tissue revealed a predominant neuronal expression in the dentate gyrus, the cornu ammonis pyramidal cell layer, layer III of the piriform cortex as well as throughout all layers of the parahippocampal cortex. In the hilus of the hippocampus single neurons expressed YB-1. The neuronal expression pattern was comparable in the hippocampus and parahippocampal cortex of adult macaques and humans. Double-labelling of YB-1 with the endothelial cell marker Glut-1, the multidrug transporter P-glycoprotein, and the astrocytic marker GFAP did not indicate a co-localization. Following status epilepticus in rats, no induction of YB-1 occurred in brain capillary endothelial cells and neurons. Conclusion: In conclusion, our study demonstrates that YB-1 is predominantly expressed in neurons in the adult brain of rats, macaques and humans. Lack of a co-localization with Glut-1 and P-glycoprotein argues against a direct role of YB-1 in the regulation of blood-brain barrier P-glycoprotein.
Aim: To demonstrate that interference microscopy of flat mounted internal limiting membrane specimens clearly delineates cellular proliferations at the vitreomacular interface. Methods: ILM specimens harvested during vitrectomy were fixed in glutaraldehyde 0.05% and paraformaldehyde 2% for 24 h (pH 7.4). In addition to interference microscopy, immunocytochemistry using antibodies against glial fibrillar acidic protein (GFAP) and neurofilament (NF) was performed. After washing in phosphatebuffered saline 0.1 M, the specimens were flat-mounted on glass slides without sectioning, embedding or any other technique of conventional light microscopy. A cover slide and 49,6-diamidino-2-phenylindole (DAPI) medium were added to stain the cell nuclei. Results: Interference microscopy clearly delineates cellular proliferations at the ILM. DAPI stained the cell nuclei. Areas of cellular proliferation can be easily distinguished from ILM areas without cells. Immunocytochemistry can be performed without changing the protocols used in conventional microscopy. Conclusion: Interference microscopy of flat mounted ILM specimens gives new insights into the distribution of cellular proliferations at the vitreomacular interface and allows for determination of the cell density at the ILM. Given that the entire ILM peeled is seen en face, the techniques described offer a more reliable method to investigate the vitreoretinal interface in terms of cellular distribution compared with conventional microscopy.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06
Radial glial cells are a widespread non-neuronal cell type in the developing central nervous system (CNS) of all vertebrates. In the cortex, distinct subsets of radial glial cells coexist that are either multipotent or specified towards the generation of neurons or glial cells (Malatesta et al., 2000). Radial glial cells in the cerebral cortex are also the source of a second type of neurogenic progenitors, called basal progenitors. However, whether the generation of basal progenitors occurs in a stochastic manner or whether a specific lineage of radial glial cells is specified towards the generation of these progenitors has not been previously known. To identify functionally distinct lineages of cortical radial glial cells, I developed a new strategy using fluorescence-activated cell sorting (FACS) to isolate them and study their progeny. I isolated radial glial cells by FACS from a transgenic mouse line in which green fluorescent protein (GFP) expression is under the control of the human GFAP promoter. Strikingly, GFP intensity was correlated with cell fate. Selective enrichment of cells with a higher GFP intensity separated a largely non-neurogenic from a neurogenic (low GFP-intensity) subsets of radial glial cells. Notable differences on the progeny of these distinct sets of radial glia were found. The neurogenic radial glial cells subset generated neurons directly and those that are largely non-neurogenic also gave rise to a small proportion of Tbr2-positive basal progenitors that are then neurogenic. Thus, this last subset comprises an indirect neurogenic population of radial glial cells present in the developing cortex. Microarray analysis of these distinct sets of radial glial cells revealed profound differences in their gene expression. Genes related to gliogenesis, proliferation and cell-cycle regulation were expressed at higher levels in the largely non-neurogenic set of radial glia while genes related to neurogenesis, cell adhesion, neurotransmitter secretion and axon guidance were expressed mostly in the neurogenic subset. Moreover, the set of genes expressed at higher levels in the neurogenic radial glia was down-regulated at later stages (cortical radial glia at E18). Thus, this analysis reveals differences at the transcriptional level between direct neurogenic and largely non-neurogenic radial glial cells, supporting their intrinsic lineage differences. The functional analysis of a key fate determinant for neurogenesis from radial glia discovered in this transcriptome analysis will also be presented. This gene is the transcription factor AP2γ which was expressed at significantly higher levels in radial glial cells generating basal progenitors. AP2γ is restricted to the ventricular zone (VZ)/subventricular zone (SVZ) regions of the developing cerebral cortex in the entire nervous system and is also highly expressed in primate and human cortical progenitors. Its genetic deletion within the mouse cerebral cortex results in the molecular misspecification of basal progenitors with decreased levels of Tbr2 and Math3 expression, as well as their overproliferation associated with increased cell death specifically in the occipital cortex. This causes a reduction in upper layer neuron generation with intriguing functional defects in visual acuity. Gain-of-function studies also revealed the important role of AP2γ for the adequate specification and development of basal progenitors in the cerebral cortex, while apical progenitors were not affected by the loss- and gain-of-function of this transcription factor. Thus, I show for the first time the prospective isolation of distinct radial glia subtypes in the mouse developing cortex demonstrated at the molecular and functional level.
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 03/07
Unmethylierte bakterielle DNA, die reich an CG Sequenzen ist stimuliert das angeborene Immunsystem. Die Vermittlung dieser Wirkung erfolgt über den Toll-like Rezeptor 9. Reine CG Sequenzen sind im Organismus nicht stabil, da sie sehr rasch von den körpereigenen Nukleasen abgebaut werden. Mit synthetisch hergestellten Oligodeoxyribonukleotiden, sogenannten CpG-ODNs, kann eine Nukleaseresistenz erzielt werden und der immunstimulatorische Effekt nachgeahmt werden. Weiterhin wirken sich CpG-ODNs positiv auf den Verlauf von bakteriellen Infektionen, Tumoren und Prioninfektionen aus. Man weiß, dass eine Aktivierung des Immunsystems durch einmalige Gabe von CpG-ODNs nur über einen kurzen Zeitraum stattfindet. Die CpG-ODNs führen im Organismus innerhalb von Minuten zu einem mRNA Anstieg und innerhalb von Stunden zu einer kurzfristigen Zytokinsekretion und IgM Produktion, werden dann aber rasch abgebaut, so dass der immunstimulatorische Effekt in der Regel nur kurz anhält. Um CpG-ODN als Therapeutikum besser nutzen zu können liegt der Wunsch nahe, die Wirkung von CpG-ODN zu verlängern. Eine mögliche Strategie ist hierbei eine repetitive Applikation. Ziel dieser Arbeit war, den immunstimulatorischen Effekt von repetitiver CpG-ODN-Gabe besser zu verstehen und mit der Repetition die Wirkung zu verlängern. Damit könnte CpG-ODN als Therapeutikum bei bakteriellen Infektionen, Tumoren und bei Prionerkrankungen wirkungsvoll eingesetzt werden. In dieser Arbeit wurden jeweils 12 Gruppen zu je 5 Mäusen gebildet, wobei die jeweiligen Gruppen an 5, 7 oder 21 aufeinanderfolgenden Tagen jeweils eine CpG-ODN, NaCl oder Neg-ODN Applikation i.p. erhielten. Die Mäuse wurden anschließend an Tag 7 oder 28 während bzw. nach der Behandlung getötet. So erhielt man folgende Gruppen: 5x-CpG-ODN, NaCl oder Neg-ODN behandelte, an Tag 7 getötete Mäuse 5x-CpG-ODN, NaCl oder Neg-ODN behandelte, an Tag 28 getötete Mäuse 7x-CpG-ODN, NaCl oder Neg-ODN behandelte, an Tag 7 getötete Mäuse 21x-CpG-ODN, NaCl oder Neg-ODN behandelte, an Tag 28 getötete Mäuse Im Verlauf der Arbeit, die die immunmodulatorische Wirkung auf das Gehirn und die Leber der Maus untersucht, konnten zusammenfassend folgende Ergebnisse herausgearbeitet werden, die mittels Real time PCR und Immunhistologie gewonnen wurden. Im Gehirn führt CpG-ODN zu einer mindestens einwöchigen Hochregulierung der mRNA von TNFα. Des Weiteren kommt es zu einer mindestens zweitägigen C1q und IFNg Hochregulierung. Eine IL-12p40 Hochregulierung findet nur ca. 18 Stunden statt, während eine STAT3 Hochregulierung nicht nachweisbar ist. In der histologischen Betrachtung finden sich in der HE Färbung keine pathologischen Veränderungen der Hirnarchitektur und in einer immunhistologischen Färbung mit CD 11b und GFAP bindenden Antikörpern keine Unterschiede zwischen den CpG-ODN, NaCl oder Neg-ODN behandelten Tieren. In der Leber findet sich eine signifikante Hochregulierung von IL-12p40 über mindestens drei Wochen und eine C1q, TNFα und IFNg Hochregulierung von mindestens einer Woche. Histologisch finden sich in der HE Färbung massive Leukozyteninfiltrate über mindestens zwei Tage. In der Immunhistologie sieht man an den Infiltraten beteiligte aktivierte Makrophagen, T und B-Lymphozyten, jeweils dargestellt mit CD 11b, CD 8 und B220 bindenden Antikörpern. Es zeigte sich, dass eine repetitive CpG-ODN-Gabe eine verlängerte stimulatorische Wirkung auf das Immunsystem ausübt, was Voraussetzung für den Einsatz als Therapeutikum ist. Besonders bemerkenswert ist die Tatsache, dass man durch periphere Gabe von CpG-ODN im Gehirn eine Immunstimulierung erreichen kann. Diese könnte im Rahmen einer Therapie von Prionerkrankungen, anderen Gehirninfektionen, Morbus Alzheimer oder Gehirntumoren Anwendung finden. Allerdings sind noch weitere Studien nötig, um Risiken wie Hepatotoxizität oder Autoimmunität besser abschätzen zu können und den Mechanismus zu erforschen, wie durch periphere Gabe von CpG-ODN eine immunologische Gehirnaktivierung erreichen wird. Eine wichtige Frage für die Zukunft ist hierbei, ob die Wirkung von CpG-ODN direkt auf die Gehirnzellen wirkt oder ob es einen second messenger gibt, der die Blut-Hirn-Schranke überwindet.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 02/19
Seit Jahrzehnten wird versucht, spezifische Proteine oder Peptide zu bestimmen, deren Konzentrationsänderungen im Liquor und oder im Blut eine diagnostische Aussage über den Zustand des ZNS bzw. über das quantitative Ausmaß des Schadens im Gehirn und Rückenmark zulassen. Der Wert eines biochemischen Markers insbesondere bei akuten Ereignissen, ähnlich wie die Herzenzymdiagnostik in der Kardiologie, erscheint hoch. GFAP wurde 1971 von Eng erstmalig aus Multiple Sklerose Plaques isoliert. GFAP ist ein 50 ± 1 kDa großes Protein, welches in einer wasserlöslichen und wasserunlöslichen Form existiert. GFAP gehört zu der Gruppe der Intermediärfilament-Proteine, die am Aufbau des Zytoskeletts beteiligt sind. GFAP konnte bisher nur in Gliazellen und Zellen glialen Ursprungs gefunden werden. Fast jede Reaktion von Astrozyten geht mit einer morphologisch sichtbaren Veränderung einher. Die Zellform verändert sich von einer runden protoplasmatischen Zelle mit wenigen Zellfortsätzen in eine verzweigte Zelle mit zahlreichen Zellfortsätzen. Diese Vorgänge sind immer mit einer Vermehrung zytoplasmatischer Filamente und einer Veränderung des GFAP Gehaltes verknüpft. Deshalb ist GFAP ein wichtiger Funktionsmarker. Bisher konnte GFAP in wäßrigen Gewebsextrakten mittels Immundiffusion und Elektrophorese, Immunradiometrie, Immunelektrophorese und Radioimmunoassays nachgewiesen werden. Die hauptsächlich angewendeten Nachweise beruhen auf immunhistochemischen Verfahren. Es gelang auch GFAP im Liquor mittels Radioimmunoassay und Enzyme Linked Immunosorbent Assay nachzuweisen und bei Erkrankungen, die mit einer Gliose einhergehen, erhöhte GFAP-Konzentrationen nachzuweisen. Der in dieser Arbeit vorgestellte Nachweis von GFAP in humanem Serum basiert auf der Messung von GFAP in humanem Blut mit Hilfe eines zerfallsunterstützten Lanthanide Immunfluoresenzassays (Dissociation Enhanced Lanthanide Fluorescence Immunoassay = DELFIA). Die Messung beruht auf der Bindung von in Standardlösungen und Proben enthaltenem GFAP an Festphasen-Anti-GFAP. Anschließend wird das gebundene GFAP in mehreren Schritten mittels eines anti-GFAP Antikörpers und Europium detektiert. Die Fluoreszenz des gebundenen Europiums wird nach Anregung durch einen Lichtimpuls gemessen und so die in der Probe enthaltene Menge GFAP quantifiziert, die der Menge des gebundenen GFAP proportional ist. In dieser Arbeit konnte erstmalig GFAP zuverlässig, empfindlich und quantitativ bestimmt werden. Damit wird es erstmalig möglich ein für das Zentralnervensystem spezifisches Protein im Blut zu messen. Uns gelang es mit einem Kollektiv von Schädel-Hirn-Trauma Patienten eine Korrelation zwischen klinisch gesicherten Affektionen des Zentralnervensystems und dem Ansteigen des GFAP-Spiegels im Blut nachzuweisen.
© 2020-2025 Ivy Podcast Discovery LLC
