Podcasts about CADASIL

Adult‑onset leukodystrophies, though rare, can closely mimic MS on both clinical presentation and neuroimaging, posing a significant diagnostic challenge. This episode highlights key clinical and radiologic red flags that can help distinguish these disorders from MS, preventing misdiagnosis and avoiding inappropriate treatment while enabling timely genetic counseling and targeted therapies. In this episode, Teshamae Monteith, MD, FAAN, speaks with Roberta La Piana, MD, PhD, coauthor of the article "Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis" in the Continuum® April 2026 Multiple Sclerosis and Related Disorders issue. Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. La Piana is an associate professor in the Department of Neurology and Neurosurgery at the Montreal Neurological Institute, McGill University, and an associate member of the Department of Diagnostic Radiology at McGill University in Montreal, Quebec, Canada. Additional Resources Read the article: Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis 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 Host: @headacheMD Full episode transcript available here Dr Monteith: You just saw a patient in clinic. And you're clear, the diagnosis is multiple sclerosis. Not everything fits, but it kind of looks like multiple sclerosis. You see the patient back years later. There're some treatment issues, the patient's not responding to treatment, and things look different. Have you thought about a genetic inherited problem like leukodystrophy or a genetic white matter disorder? Listen to this podcast. We're going to help you figure it out. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Monteith: This is Dr Teshamae Monteith. Today I'm interviewing Dr Roberta La Piana about her article on adult-onset leukodystrophies mimicking multiple sclerosis, which she wrote with Dr Gabrielle Macaron. This article appears in the April 2026 Continuum issue on multiple sclerosis. Welcome to our podcast.  Dr La Piana: Thank you. Thank you for having me.  Dr Monteith: Absolutely. Why don't we start off with you introducing yourself? Dr La Piana: So, my name is Roberta La Piana. I'm a pediatric neurologist. I trained in Italy, I did my medical school, I did my residency in pediatric neurology there. And then I moved here to Montreal, to the Montreal Neurological Institute, to do a PhD in neuroscience. And that's where I specialized in adult-onset genetic white matter diseases. And after my PhD, I was recruited as an assistant professor here. So, that's where I got into this field.  Dr Monteith: This big field, highly specialized; lots of disorders, but highly specialized. And what got you into this? Neuroscience is huge. So, was it a mentor, or…?  Dr La Piana: No, actually, it was because of my background, because I trained as a pediatric neurologist and I loved the genetic white matter disorders in the pediatric population. So, when I came to the Montreal Neurological Institute, initially it was mainly to have a better expertise in imaging. And being at an adult neurology institute, I started seeing patients with adult genetic white matter diseases, and I was immediately fascinated by how different they were from their pediatric counterparts. Because in pediatric genetic white matter diseases, pediatric leukodystrophies look very diffuse, look very confluentous, so it's difficult to mistake them. But in adults, in the adult forms, I was initially driven by how often they can be misdiagnosed as multiple sclerosis or as other acquired white matter disorders. So that's why I got really interested in in this field.  Dr Monteith: You're, like, literally the perfect person for this discussion.  Dr La Piana: I'm not sure- *laughs* Dr Monteith: Why don't we start off with what your objectives were when writing this article? Dr La Piana: With writing this article, the goal is what I have been, actually, doing for the past ten years or so. So, really try to get more attention into the field because of the high rate of potential misdiagnosis of patients. So, that's exactly the reason why I really would like to raise the interest of neurologists for these disorders, because they are not considered enough in the differential diagnosis of patients, of adult patients presenting with white matter disorders. They are considered rare---which are, they are rare, definitely. But collectively, while each single form is rare, collectively they are not as rare. So- and thus, the risk of misdiagnosis and the potential impact of misdiagnosis on them with, you know, you can imagine giving patients inappropriate treatment or missing the possibility of a prenatal genetic diagnosis is so high that I really would like people to keep these disorders in the differential.  Dr Monteith: And it sounds like more than ever, this is really important because some of the newer developments in the field. Dr La Piana: Yes. Specifically, we have now tools that will allow to diagnose these patients quite quickly. All the genetic techniques that are available nowadays can really, with one single shot, we can now sequence hundreds of genes so we can have a quicker diagnosis. And this thing was impossible up until ten years ago. So that's definitely the first huge improvement that makes these disorders now easily diagnosed. Dr Monteith: Yeah. So why don't we talk a little bit about how common is this misdiagnosis for these rare subtypes? Dr La Piana: Yeah, the misdiagnosis, it depends on the cohorts. Generally speaking, I would say that the rate of that misdiagnosis for these forms is up to 25% or even more in some other cohorts. And it really depends on the forms. Like, there are clearly some forms, especially those that present with multifocal white matter diseases, that present with nonspecific clinical presentations like migraines, image---and especially for female patients, and for which migraine is so common, having multifocal with other abnormalities is so common, the rate of diagnosis increases even further. So, these are all things that we need to keep in mind. I know these are rare, but still, we need to always have them on the back of our minds.  Dr Monteith: Are there any particular disorders that are more often misdiagnosed? And you spoke about progressive forms of multiple sclerosis being a common kind of misdiagnosis.  Dr La Piana: Yeah. So, there are definitely forms that are more commonly misdiagnosed. And these are those that, as I probably repeated already too many times, is the word multifocal, which is key. So, all those genetic white matter disorders that present with multifocal white matter abnormalities are not initially considered as genetic. So, I'm thinking about all of the leukovasculopathies, so, the small vessel diseases which are genetic in origin. For example, CADASIL; for example, the disorders related to collagen-4; so, the COL4 A1 or A2-related disorders. Those are clearly more commonly misdiagnosed initially. Another big group, unfortunately, is the CSF1R-related disorders. I know I'm saying a lot of gene names, but due to the fact that they start with multifocal abnormalities and they start with quite nonspecific, slowly progressive symptoms, the rate of misdiagnosis is definitely higher. Dr Monteith: And can you discuss some of the clinical challenges when seeing patients that might lead to this misdiagnosis?  Dr La Piana: There are multiple clinical challenges. One is definitely the presence of nonspecific or initially mild clinical symptoms that sometimes don't raise initially the red flag of something, degenerative or progressive or genetic. One category that I would mention are psychiatric disturbances, especially in the form of depression, anxiety, or apathy. This is quite common in patients with some forms of genetic white matter disorders, and they are initially misdirected to psychiatrists and taken care in that domain. But it's only when some even mild neurological symptoms like a gait disturbance or hyperreflexia, or we had patients with, like, a urinary incontinence. It's only at that time, but maybe years have passed meanwhile, that these patients are finally referred to the neurologist Dr Monteith: You spoke about some of these clinical symptoms. Can you give us some other clinical red flags?  Dr La Piana: Well, some other clinical red flags can be, for example, the extraneurological involvement. So, we have patients where- and there's a reason immediately to some specific disorders. For example, infertility. The presence of infertility in a female patient with white matter disorders should immediately form the consideration of the specific genetic white matter diseases that are associated with these forms. And this is not something that neurologists tend to ask about in the collection of the clinical history. And this is something that can make the difference and can accelerate the diagnosis.  Dr Monteith: What are some other things? I mean, I know we can think about treatment, lack of a common treatment response, maybe, to steroids. You gave a great example of optic neuritis, for example. Give us some other things that we should say, hey, this doesn't fit the picture. Red flag.  Dr La Piana: In this case, I think we want to talk more about the specific misdiagnosis of MS. Because these patients are often misdiagnosed with MS, but they might sometimes be misdiagnosed with other forms of acquired white matter diseases. When we consider MS, definitely the presence of being treatment resistant: so, patients that are not responsive to the common MS-targeting treatment should be always a red flag. The evolution as well. So, for example, the presence of a more slowly progressive course is another red flag. The presence of optic neuritis. Sometimes it's tricky because it's not common in the genetic white matter disorders, it's used as a criterion to orient correctly towards a multiple sclerosis. But we need to keep in mind that there are forms, genetic forms, especially the mitochondrial forms, that can present with optic neuritis and are really at the overlap with the multiple sclerosis spectrum. Then, if we want to move forward beyond the clinical side and go into the laboratory, of course a negative lumbar puncture with no oligoclonal bands should be a major red flag. Dr Monteith: What about some of the radiographic features?  Dr La Piana: So, the radiographic features is something we are really working on in the field, especially with the new criteria used in MS. So, for example the paramagnetic rim lesions or the central vein sign, they are considered the specific forms. But it's true- and don't have an answer for that. I want to be clear, but it's true that they haven't been assessed yet extensively in patients with genetic white matter disorders. Anecdotally, I can say, because I have already reported this at conferences, that we have seen patients with genetic white matter conditions reaching a threshold for a central vein sign that can be considered diagnostic for MS. And we have seen that in some patients. Again, no study has been carried out extensively to date, but I think we should consider that with a grain of salt. But yeah, the paramagnetic rim in lesions is probably more accurate to distinguish between genetic and acquired white matter disorders.  Dr Monteith: And what about some of the genetic white matter disorders that mimic MS? You spoke about things like CADASIL; what are other things that we should keep in the back of our mind? And you have great charts, to our listeners, and they're going to have to review those charts, because they're excellent. I think maybe they need to find a way to make that a little bookmark you walk around with on the ward. But what are some other conditions that kind of commonly mischaracterized?  Dr La Piana: Two of the main groups are the one that you mentioned. So, leukovasculopathy is- so, CADASIL, is definitely one of the most common misdiagnoses of MS. And the presence, as we said, of some clinical features like migraine, especially when it's complicated migraine with visual aura, we all know that. But especially in the context of a positive family history for either a psychiatry condition or migraine as well, or strokes, these are all factors that should prompt the consideration of these disorders in the differential of a patient with white matter disorders. Another category are definitely mitochondrial disorders, which I think are more neglected than others because we don't think about mitochondrial disorders when we see white matter disease; we tend to consider that mitochondrial disorders are a problem of the gray matter, but they are not. There are white matter diseases that have definitely mitochondrial. And the third category are probably microgliocytes, which are represented by the CSF1R-related disorder. And this is also something that is clearly quite prevalent, relatively prevalent, in the field of genetic white matter disorders misdiagnosed as MS.  Dr Monteith: Yeah. Why don't we go through some of the, kind of, key history, you know, some of the key questions you would ask in the history to try and differentiate? You mentioned kind of subtle symptoms, longstanding progressive symptoms. I know things that we look at like relapsing/remitting and some trigger factors can actually be associated with some of these genetic disorders. So how do you approach a patient? What are some of the key questions? You talked about family history and you talked about medical history, but why don't you kind of give us a nice way to kind of hone in on to the patient? Dr La Piana: There are a couple of questions that we usually ask. I should make a disclaimer, though, that I work very closely with the MS clinics, so we are ready to receive patients that are prescreened. So, these are already patients that people working on acquired white matter disorders feel like they are atypical, so they want our opinion. But usually, there are two groups of questions that we always ask. One is about the family history. And by saying family history, I really dig into the family history. I don't just want to know whether there are family members with neurological disorders. I ask specifically about migraine. I ask specifically about infertility issues. I ask specifically about psychiatric issues. These three things are always on the top of my mind when asking about family history. The other thing is a family history for neurodevelopmental disorder, because you know that some people might not remember that some genetic white matter diseases can present at different ages. So, in the same family, there might be cases with a pediatric-onset leukodystrophy, and that can manifest at a later age in other family members. So, this is something that we always explore. In terms of the clinical history, one question that I recommend always to ask is really about more subtle symptoms. So, for example, many of our patients present with progressive balance problems or progressive mobility issues that have been going on for a while. So, we always ask how they were when they were in their teenage years, for instance. And it's frequent that they say, actually, I was a bit clumsy. Actually, I was not the first being picked in school at phys-ed sports. And these are all interesting aspects. Maybe they are totally incidental, and sometimes they suggest that there was probably something going on for a long time. The other thing is the presence, for example, of learning difficulties. Again, these are things that are subtle but testify that there was probably a process that was more longstanding. Dr Monteith:  You talked about things like rim lesions. Are there other types of sequences that might be useful to better characterize demyelinating diseases that are genetic in origin? I assume higher levels of MRI might be better at differentiating.  Dr La Piana: Yeah. So, in the clinical setting, there are a couple of sequences that are very useful. One is the diffusion, because as opposed to multiple sclerosis, the presence of persistently restricted areas of diffusion can point immediately towards some genetic white matter diseases. One is CSF1R-related disorders. But there are also some other, more rare tremor and ataxia syndrome that present with persistent areas of restricted diffusion as well as others. The presence of calcification. So, adding an SWI, susceptibility weighted imaging, to check not just for calcifications that can immediately orient towards some disorders, but can also identify areas of microhemorrhages that, if we are going back to the leukovasculopathies, to the genetic leukovasculopathies, can tell us that we are on the right track for excluding those type of diseases. Basically, these are the two that are available in every scanner without even going into fancy, more advanced techniques. Dr Monteith: I was going to ask you that question, how often should we think about this next-generation sequencing when you're kind of on the fence, allowing for some negative results to come back in the abundance of caution?  Dr La Piana: The problem with the panel, of course, is that you run a panel and you don't know what's coming back. So, then having to deal with variants of unknown significance in genes, then you have to deal with them, and then you have to deal with results that maybe are not as black or white as you would expect initially. So, I'll answer to your question when to do that, our recommendation would be to do that every time you are presented with a patient that presents those atypical features that we summarized in the paper, and that basically raise multiple red flags for an atypical white matter disease that is not multiple sclerosis. And then what to do when you have results? I still believe that having access, of course, to genetic counselors, to neurogeneticists, is critical, but also having access and being in contact with the network of people working on this. Because we are a network; we put the website address on the paper of the white matter rounds because this is an international network that we built over the years, and we connect monthly, on a monthly basis, with meetings to discuss exactly this type of patient. So, we are all learning together, and it's very frequent that people ask us to present cases at the white matter rounds because they have a presented with unusual or atypical genetic findings and they want the opinion of experts.  Dr Monteith: Great. Well, I'm really glad that resource is available. And I'm also really glad that you wrote that article with your colleague. Thank you so much. Dr La Piana: Thank you so much, Tesha.   Dr Monteith: Today I have been interviewing Dr Roberta La Piana about her article on adult-onset leukodystrophies mimicking multiple sclerosis, which she wrote with Dr Gabrielle Macaron. This article appears in the April 2026 Continuum issue on multiple sclerosis. 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 the 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.

This week we discuss about CADASIL, a hereditary small vessel disease and rare cause of stroke, it's clinical features, pathophysiology, diagnosis and management approach.

Moderator: Emanuele D'amico (Foggia, Italy) Guest: Anna Bersano (Milan, Italy) In this episode, Emanuele D'Amico speaks with Anna Bersano about red flags for rare and potentially treatable cerebral small vessel diseases. They discuss how early onset, family history, multisystem involvement, and characteristic MRI patterns can help distinguish monogenic and metabolic forms from sporadic disease, focusing on conditions such as CADASIL, Fabry disease, CARASIL, and COL4A1/2-related angiopathies, and emphasising the importance of structured diagnostic pathways and early recognition for appropriate management.

Los principales partidos de Extremadura ultiman su preparación para las elecciones del domingo. Feijóo no acompaña a Guardiola, quien enfatiza el enfoque regional de su campaña. Abascal asume protagonismo con VOX, mientras Sánchez apoya a Gallardo, aunque con cierta distancia. En Aragón, la precampaña electoral es tensa; el PSOE interpone recursos contra el gobierno, mientras el PP contraataca, logrando que la junta electoral obligue a Pilar Alegría a retirar un vídeo. A nivel internacional, Washington acusa a España de discriminar barcos estadounidenses por el transporte de carga con origen o destino a Israel, lo que podría acarrear sanciones económicas importantes, incluso el cierre de puertos. En deportes, el Valencia empata con el Mallorca y se prepara para el Real Madrid-Sevilla. El Baskonia logra una victoria en Euroliga. Se expone la problemática de la enfermedad rara CADASIL; Maricarmen Migueleth, paciente y presidenta de la asociación CADASIL España, trabaja incansablemente ...

En lyssnares familjemedlem är drabbad av den ovanliga demenssjukdomen CADASIL. Finns det forskning som kan ge nytt hopp om bot? Docent Helena Karlström, som forskar om sjukdomen, berättar vad vi vet idag.

This episode is with my friend Cassidy Olivia. I discovered her on TikTok while she was posting videos about her stay in the hospital, but I appreciated her honesty, and how real she was with her content. She is in the hospital due to a stroke that's related to a condition called Cadasil. This condition caused her to lose the ability to walk, though it seems to be temporary, this time around the effects from Cadasil has stayed with her for a much longer period of time. We go more in depth on what the condition is, her mindset while being in the hospital, and more. As this episode is coming out, she is still currently in the hospital, but has taken her first steps, and I know how much that means to her. Her TikTok @cassidyolivia

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.26.538393v1?rss=1 Authors: Zhang, W., Zhao, X., Qi, X., Kimber, S. J., Hooper, N., Wang, T. Abstract: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease caused by variants in the NOTCH3 gene. Patients with CADASIL experience recurrent strokes, developing into cognitive defect and vascular dementia. CADASIL is a late-onset vascular condition, but migraine and brain MRI lesions appear in CADASIL patients as early as their teens and twenties, suggesting an abnormal neurovascular interaction at the neurovascular unit (NVU) where microvessels meet the brain parenchyma. To understand the molecular mechanisms of CADASIL, we established induced pluripotent stem cell (iPSC) models from CADASIL patients and differentiated the iPSCs into the major NVU cell types including brain microvascular endothelial-like cells (BMECs), vascular mural cells (MCs), astrocytes and cortical projection neurons. We then built an in vitro NVU model by co-culturing different neurovascular cell types in Transwells and evaluated the blood brain barrier (BBB) function by measuring transendothelial electrical resistance (TEER). Results showed that, while the wild-type MCs, astrocytes and neurons could all independently and significantly enhance TEER values of the iPSC-BMECs, such capability of MCs from iPSCs of CADASIL patients was significantly impeded. Additionally, the barrier function of the BMECs from CADASIL iPSCs was significantly impaired, accompanied with disorganised tight junctions in iPSC-BMECs, which could not be effectively rescued by the wild-type MCs, astrocytes and neurons. Our findings provide new insight into early disease pathologies on the neurovascular interaction and BBB function at the molecular and cellular levels for CADASIL, which helps inform future therapeutic development. 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/2023.02.27.530286v1?rss=1 Authors: Barriere, D., Uszynski, I., Rajani, R., Gueniot, F., Domenga-Denier, V., Boumezbeur, F., Poupon, C., Joutel, A. Abstract: Background and purpose: Cerebral small vessel diseases (SVDs) are characterized by early white matter (WM) changes, whose pathological underpinnings are yet poorly understood. CADASIL is a monogenic and archetypal SVD, providing an ideal model for investigating these changes. Here, we used multicompartment microscopic diffusion imaging and relaxometry to elucidate microstructural changes underlying early WM abnormalities in CADASIL. Methods: We acquired diffusion MRI data with a multiple-shell Q-space sampling strategy, and relaxometry T1 and T2 data, with a 160 and 80-micrometers isotropic resolution respectively, ex vivo, in CADASIL and control mice. Diffusion datasets were computed with the Neurite Orientation Dispersion and Density Imaging model to extract the neurite density index, the extracellular free water and the orientation dispersion index. Relaxometry datasets were computed with a 3-compartment myelin water imaging model to extract the myelin content. MRI metrics were compared between CADASIL and control mice using voxel and WM tract-based analyses and with electron microscopy analysis. Results: WM in CADASIL mice displayed a widespread reduction in general fractional anisotropy, a large increase in extracellular free water, a reduction in the myelin content, but no reduction in neurite density. Electron microscopy analysis showed a ~2-fold increase in the extracellular spaces and an elevation of the g-ratio indicative of myelin sheath thinning in CADASIL WM. Conclusion: Our findings suggest that accumulation of interstitial fluid and myelin damage are 2 major factors underlying early WM changes in CADASIL. Advanced diffusion MRI and relaxometry are promising approaches to decipher the underpinnings of WM alterations in SVDs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Matthew Fink, M.D. discusses what patients should know about Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopath (CADASIL). He reviews the signs and symptoms of the rare disease and how it may cause strokes in younger adult patients. He goes over the risk of inheritance of the gene that may cause CADASIL and how parents who may carry it can still have healthy children through a coordinated collaborative care approach to treatment.To schedule with Matthew Fink, M.D

Welcome back to our weekend Cabral HouseCall shows! This is where we answer our community's wellness, weight loss, and anti-aging questions to help people get back on track! Check out today's questions:    Jessica: When I don't understand something I turn to Dr. Cabral! Thank you for being a trusting person to learn and seek information. My question is.. Is there a correlation to a rise in cholesterol and pregnancy? I haven't seen this asked before on the ask Cabral episodes… I recently got a lipid panel done and was completely shocked to see that my cholesterol went from 172 in April to 283 in October. I am 26 weeks pregnant with my third baby.   Brianna: Hi! I've been listening to your podcast for months now and I've learned so many helpful things not only for myself but for my family as well. I'm so incredibly grateful for the work you and your team do. A little background, I'm 25 and have had large kidney stones made up of calcium that have required surgery twice in the past 6 years and I just found out I have stones again. (Yay me) This time around, I was told I have medullary sponge kidneys which I've done some research about and the most I can find to help prevent the stones is to lower sodium intake. I already don't eat meat or dairy, drink 80-100oz of water a day and tend to stay away from processed foods as much as possible. Is there anything else that would be helpful? Maybe a calcium supplement? Thank you so much!   Heather: Hi Dr. Cabral! Can you please tell me what you know about CADASIL? I've looked in your podcast archives and couldn't find anything about it. It runs in my best friend's family (her mom, aunt, and uncle all had it and passed away from it), and now my friend started experiencing stroke-like symptoms and was admitted to the hospital where they said she had a stroke in her sleep. She's only 26 years old. Appreciate any insight/advise you can give me on this. Thanks so much for all you do. -Heather   Stephanie: Hi doctor Cabral, I absolutely love your podcast and had a quick question: they say that fasting can be stressful for your body- especially if you're a pre-menopausal woman. However, I've noticed that during a longer fast (20-24 hrs), my night-time HRV and deep sleep both double, which I thing means that I'm recovering and not stressing my body. Do you agree, or am I looking at this the wrong way? Thanks so much for your answer!   Whitney: Hello! I am a 35 y/o female and having a hard time making the decision to have a child/children or not. Fertility is likely not an issue for me but I have yet to get lab work to confirm. As my age is getting closer to the cutoff for child bearing my anxiety over this continues to increase, so I wanted to freeze my eggs to stop the clock on the decision. So my question to you is: 1) Is it better to freeze my eggs asap because of my age, or do you think I can hold off still and improve the quality of my eggs by diet/lifestyle inventions to freeze better quality eggs in the future ? And 2) What are your thoughts on egg freezing and IVF in general / might I be undervaluing the importance of getting pregnant naturally? I understand this is a nuanced convo & appreciate your thoughts!   Thank you for tuning into today's Cabral HouseCall and be sure to check back tomorrow where we answer more of our community's questions!    - - - Show Notes and Resources: StephenCabral.com/2542 - - - Get a FREE Copy of Dr. Cabral's Book: The Rain Barrel Effect - - - Join the Community & Get Your Questions Answered: CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels) - - - Get Your Question Answered On An Upcoming HouseCall: StephenCabral.com/askcabral - - - Would You Take 30 Seconds To Rate & Review The Cabral Concept? The best way to help me spread our mission of true natural health is to pass on the good word, and I read and appreciate every review!

A mysterious illness. A headstone for Karl Ludwig. An enigmatic inscription. In today's episode, we pose the question of why Nietzsche would memorialize his dead father, a Lutheran pastor, with a verse from Corinthians. This unusual event in Nietzsche's life intersects with both his lifelong ailment and his most ambitious philosophical ideas. In order to answer this question, we'll go on the podcast's first deep dive into Nietzsche's personal life - particularly his early life, his romantic period, and his ill-fated friendships with Richard Wagner, Paul Ree, and Lou Salome. This episode was partially inspired by an essay by Charlie Huennemann, a professor who has published many books worth checking out, including one on Nietzsche. You can find his blog here: https://huenemanniac.com/ Other sources utilized in the episode: Leonard Sax, What was the cause of Nietzsche's dementia? (pdf link: www.leonardsax.com/Nietzsche.pdf) Hemelsoet D1, Hemelsoet K, Devreese D., The neurological illness of Nietzsche (Abstract): https://www.ncbi.nlm.nih.gov/pubmed/18575181 Information on CADASIL: https://ghr.nlm.nih.gov/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy

Dr. Eric Goldstein discusses cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, also known as CADASIL.

It's been almost 9 years that I first heard of Cadasil. My now-husband told me that he was diagnosed with this very rare brain disorder within the first few days of our meeting, and I understand why he did. He's never been able to talk about it publicly until now and we decided to have a bit of a therapy session, as we always do on our show, to share a bit about it.

Michelle has as a long and successful history leading compliance, quality assurance, and regulatory affairs. She discusses the difference between QA and Regulatory Affairs and how they affect both clinical trials and commercialization. Michelle also shares part of the story about her father who suffered from CADASIL syndrome, a rare disease that has no treatment, and how that inspired her throughout her career to make key decisions in her life. She has worked for well both well-known generics companies such as Mylan and big pharma companies such as AstraZeneca and Sanofi. Join for the journey and to learn a few things on along the way!

This is a very emotional show as Gary speaks about his younger brother Scott and the battle to fight his rare brain disease, CADASIL. Gary also talks about the Breonna Taylor indictment, or lack thereof....Gary Garver- 'Controlled Chaos' Radio Show is broadcast live at 12AM ET Tuesday - Saturday on W4CY Radio (www.w4cy.com) part of Talk 4 Radio (www.talk4radio.com) on the Talk 4 Media Network (www.talk4media.com). This podcast is also available on Talk 4 Podcasting (www.talk4podcasting.com).

Gary has his younger brother Scott on the 'Controlled Chaos' radio show. They talk about his rare disease called 'CADASIL', growing up in Tarzana, and Gary taking care of him.

シリーズ脳卒中対策の最新情報㉕「その他の脳血管障害（６）MELAS CADASIL CARASIL」 （解説）三重大学脳神経内科教授　冨本秀和氏 （ききて）国際医療研究センター病院名誉院長　大西真氏

Author: Sam Killian, MD Educational Pearls: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) occurs in 1:100000 individuals The disease is caused by a defect in the NOTCH3 gene on chromosome 19 It is an important cause of stroke in young patients Features include ischemia, cognitive deficits, migraines, psychiatric disease, coma, and seizure, all of which is worse with pregnancy Migraine with aura is often the first presenting symptom with onset by age 30 Strokes typically can occur by age 50 Diagnosis is with MRI for characteristic lesions Unfortunately there is no cure, and treatment is focused on stroke prevention with aspirin and statins References: Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009 Jul;8(7):643-53. doi: 10.1016/S1474-4422(09)70127-9. Review. PubMed PMID: 19539236. Summarized by Will Dewispelaere, MS3 | Edited by Erik Verzemnieks, MD  

Gary has his younger brother Scott in studio as they talk about the battle Scott is going through with his rare condition called CADASIL and their childhood.This show is broadcast live Tuesday's at 12:00AM ET on W4CY Radio – (www.w4cy.com) part of Talk 4 Radio (http://www.talk4radio.com/) on the Talk 4 Media Network (http://www.talk4media.com/).

Gary has Dr. Janet Gunther, board member of the Cure Cadasil foundation to discuss the disease his younger brother Scott has and how it effets not only people who have the illness, but the caretakers who deal with their family members on a daily basis. Gary is his brother's caregiver and has been for the last 4 years. Please donate if you can to www.curecadasil.orgThis show is broadcast live Tuesday's at 12:00AM ET on W4CY Radio – (www.w4cy.com) part of Talk 4 Radio (http://www.talk4radio.com/) on the Talk 4 Media Network (http://www.talk4media.com/).

Gary has Dr. Michael Wang from the University of Michigan, who is leading the research in CADASIL, call in to discuss his younger brother's Scott's condition with this genetic illness. CADASIL causes the brain to manufacture white matter, which results in damage to the brain.This show is broadcast live Tuesday's at 12:00AM ET on W4CY Radio – (www.w4cy.com) part of Talk 4 Radio (http://www.talk4radio.com/) on the Talk 4 Media Network (http://www.talk4media.com/).

Gary discusses his trip ti Michigan with his younger brother Scott and their visit with Dr. Michael Wang at the University of Michigan. Scott has Cadasil, which is a rare genetic mutation that affects his brain function.This show is broadcast live Tuesday's at 12:00AM ET on W4CY Radio – (www.w4cy.com) part of Talk 4 Radio (http://www.talk4radio.com/) on the Talk 4 Media Network (http://www.talk4media.com/).

Gary dedicates this show to Rosie, the family cat who passed on this date.. He also talks about his daily life of care giving for his younger brother Scott, who has a rare genetic called CADASIL.This show is broadcast live on W4CY Radio – (www.w4cy.com) part of Talk 4 Radio (http://www.talk4radio.com/) on the Talk 4 Media Network (http://www.talk4media.com/).

Jigga and Gary christen the new studio in Burbank as sports guru Larry Burnett joins them at the new place. Lindsey Culcasi calls in to speak about her benefit run for Cadasil, an illness that Gary's brother Scott has.This show is broadcast live on W4CY Radio (www.w4cy.com) part of Talk 4 Radio (http://www.talk4radio.com/) on the Talk 4 Media Network (http://www.talk4media.com/).

1) PARK 10 locus being a major locus for sporadic, neuropathologically-confirmed Parkinson disease and 2) Topic of the month: Stroke in systemic disease. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Michelle Fullard interviews Dr. Jeffrey Vance about his paper on the PARK 10 locus being a major locus for sporadic, neuropathologically-confirmed Parkinson disease. Dr. James Addington is reading our e-Pearl of the week about a mnemonic for the clinical manifestations of CADASIL. In the next part of the podcast Dr. Michelle Johansen interviews Dr. Kevin Barrett about the topic of stroke in the setting of Renal disease. The participants had nothing to disclose except Drs. Vance, Addington, Johansen and Barrett.Dr. Vance serves as an editorial board member of American Journal of Neurodegenerative Diseases; speaker honoraria from Movement Disorders Society, Society of Neuroscience, Hussman Foundation, travel reimbursement for NIH for meeting on Parkinson Disease and NIH for study section; has patents for method of detecting Charcot-Marie-Tooth disease type 2A, TRPC6 involved in glomerulonephritis and methods for identifying an individual at increased risk of developing coronary artery disease; receives research support from NIH; receives royalties for invention from Duke University.Dr. Addington serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Johansen serves as a scientific advisory member of Stroke and as a contributor to Blogging Stroke.Dr. Kevin Barrett serves as an Associate Editor of Neurohospitalist; serves as an editorial board member of Neurology; and receives research support from the NIH.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) represents the most prevalent hereditary form of cerebral small vessel disease (SVD) resulting in early-onset stroke and vascular dementia. It is caused by stereotyped missense mutations in the transmembrane receptor Notch3, which alter the number of cysteine residues in the extracellular domain (ECD). This leads to the abnormal multimerization and extracellular deposition of mutant Notch3-ECD at the plasma membrane of smooth muscle cells in small blood vessels. Notch3-ECD-containing aggregates are the earliest manifestation of the disease and excess Notch3-ECD is believed to recruit functionally important extracellular matrix proteins resulting in brain vessel dysfunction. Biochemical and histological approaches on post-mortem brain tissue from CADASIL patients and control subjects as well as in vitro assays were used to study the consequences of Notch3-ECD deposition on the ECM components thrombospondin-2, fibrillin-1 and fibronectin and members of the latent transforming growth factor-β (TGF-β) binding protein (LTBP) family. It is demonstrated that the structural matrix components fibrillin-1 and fibronectin are enriched and contribute to the prominent thickening of CADASIL vessel walls without co-localizing with Notch3-ECD deposits, likely as a result of fibrotic adaptation secondary to aggregate formation. For LTBP-1, a key regulator of the TGF-β signaling pathway, an accumulation as well as a striking co-localization with Notch3-ECD deposits is shown suggesting specific recruitment into aggregates. Furthermore, increased levels of the TGF-β pro-domain (also known as latency-associated peptide, LAP) were found implying dysregulation of the TGF-β pathway in CADASIL development. Finally, a direct interaction of LTBP-1 with Notch3-ECD is demonstrated and evidence for a co aggregation with mutant Notch3 in vitro is provided. Conclusively, I propose LTBP-1 as a novel component of Notch3 deposits with a role in CADASIL pathogenesis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents the most common hereditary form of cerebral small vessel disease characterized by early-onset stroke and premature dementia. It is caused by mutations in the transmembrane receptor Notch3, which promote the aggregation and accumulation of the Notch3 extracellular domain (Notch3-ECD) within blood vessel walls. This process is believed to mediate the abnormal recruitment and dysregulation of additional factors including extracellular matrix (ECM) proteins resulting in brain vessel dysfunction. Based on recent evidence indicating a role for the transforming growth factor-β (TGF-β) pathway in sporadic and familial small vessel disease we studied fibronectin, fibrillin-1 and latent TGF-β binding protein 1 (LTBP-1), three ECM constituents involved in the regulation of TGF-β bioavailability, in post-mortem brain tissue from CADASIL patients and control subjects.

Das Thema dieser Arbeit ist kognitive Beeinträchtigung nach zerebrovaskulärer Schädigung. Aufgrund der Heterogenität des Krankheitsbildes der „vaskulären kognitiven Beeinträchtigung“ (Vascular Cognitive Impairment, VCI) und der häufigen Komorbidität mit Alzheimerdemenz wird eine monogen vererbte Mikroangiopathie (zerebrale autosomal dominante Angiopathie mit subkortikalen Infarkten und Leukenzephalopathie, CADASIL) als Modellerkrankung einer reinen VCI herangezogen. In der ersten der beiden Publikationen wurde mittels voxelbasiertem Läsions-Symptom-Mapping der Zusammenhang zwischen Läsionen in frontalen subkortikalen Arealen und CADASIL-typischen kognitiven Einschränkungen untersucht. Der stärkste Zusammenhang bestand zwischen kognitiver Bearbeitungsgeschwindigkeit und Läsionen in der anterioren Thalamusstrahlung sowie der Forceps Minor. Eine zusätzliche Regressionsanalyse konnte zeigen, dass nicht das Gesamtausmaß der Schädigung entscheidend ist für spezifische Funktionsbeeinträchtigung, sondern die Läsionslast in den zuvor identifzierten Lokalisationen. In der zweiten Publikation wurde ein Faktor untersucht, der diesen Zusammenhang zwischen Funktion und Struktur moderiert, die Kognitive Reserve. Ein häufig postuliertes Modell der kognitiven Reserve als aktiver Kompensationsmechanismus konnte in den CADASIL-Daten bestätigt werden. Patienten mit höherer Schulbildung (als Operationalisierung kognitiver Reserve) zeigten bei gleichem Ausmaß an Pathologie weniger Beeinträchtigung in Bearbeitungsgeschwindigkeit und Exekutivfunktionen als weniger Gebildete, jedoch nur bei geringem und mittlerem Ausmaß an Pathologie.

Thu, 2 Feb 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/13969/ https://edoc.ub.uni-muenchen.de/13969/1/Zechmeister_Martin.pdf Zechmeister, Martin

Migraine with aura is a hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In contrast with the majority of CADASIL patients, some affected subjects never experience visual symptoms during their attacks of migraine with aura. The aim of this study was to determine whether specific morphology of the primary visual cortex is associated with the absence of visual symptoms during migraine aura in CADASIL.

Background: The National Institutes of Health Stroke Scale (NIHSS) is widely used to measure neurological deficits, evaluate the effectiveness of treatment and predict outcome in acute ischemic stroke. It has also been used to measure the residual neurological deficit at the chronic stage after ischemic events. However, the value of NIHSS in ischemic cerebral small vessel disease has not been specifically evaluated. The purpose of this study was to investigate the link between the NIHSS score and clinical severity in a large population of subjects with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a unique model to investigate the pathophysiology and natural history of ischemic small vessel disease. Methods: Demographic and clinical data of 220 patients with one or more lacunar infarcts confirmed by MRI examination and enrolled from a prospective cohort study were analyzed. Detailed neurological examinations, including evaluation of the NIHSS and modified Rankin Scale score (mRS) for evaluating the clinical severity, were performed in all subjects. The sensitivity, specificity, positive and negative predictive values of various NIHSS thresholds to capture the absence of significant disability (mRS < 3) were calculated. General linear models, controlling for age, educational level and different clinical manifestations frequently observed in CADASIL, were used to evaluate the relationships between NIHSS and clinical severity. Results: In the whole cohort, 45 (20.5%) subjects presented with mRS >= 3, but only 16 (7.3%) had NIHSS >5. All but 1 subject with NIHSS >5 showed mRS >= 3. NIHSS

Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations of the NOTCH3 gene. Marked variations in disease severity have raised the hypothesis that non-genetic factors may modulate the expressivity of the phenotype. The aim of the current study was to evaluate whether atherosclerosis, assessed by carotid duplex ultrasonography, is associated with variations in the clinical and MRI phenotype of CADASIL. Methods: Data from 144 consecutive patients enrolled in an ongoing prospective cohort study were collected. Degree of disability was assessed by the modified Rankin Scale, that of cognitive impairment by the Mattis Dementia Rating Scale (MDRS). The total volume of the brain, of lacunar lesions and of white matter hyperintensities, the number of cerebral microhemorrhages, and parameters derived from histograms of apparent diffusion coefficient were measured on cerebral MRI. Atherosclerosis was evaluated by B-mode ultrasonography of carotid arteries. Both the carotid intima-media thickness cIMT) and the presence of carotid plaques or stenosis were recorded. Results: Higher cIMT was found to be independently associated with lower MDRS scores when this score was less than the quartile limit (p = 0.02). Only a trend for a positive association was detected between cIMT and the Rankin score (p = 0.06). There was no significant association between carotid markers and the occurrence of stroke or MRI parameters except for diffusion data. The mean and peak values of MRI diffusion histograms were found positively associated with the presence of plaques (p < 0.01). Conclusion: The results suggest that the severity of atherosclerosis may relate to cognitive decline in CADASIL and that this effect is possibly related to the degree of microstructural cerebral tissue lesions. Longitudinal studies are needed to confirm these results. Copyright (C) 2010 S. Karger AG, Basel

Background: CADASIL is responsible for diffuse hyperintensities in the white matter on FLAIR images. These lesions are often associated with focal lesions in the basal ganglia such as lacunar infarctions. The prevalence and significance of diffuse or confluent thalamic hyperintensities (CTH) remain unknown. Methods: The frequency of hyperintensities on FLAIR images in the thalamus was assessed in 147 CADASIL patients, and signal abnormalities on both FLAIR and T(1)-weighted images were categorized as focal/punctuate or diffuse/confluent by the same reader. The areas of increased diffusion were also analyzed on apparent diffusion coefficient maps. The association of CTH with vascular risk factors, the main clinical manifestations of the disease and MRI markers (brain parenchymal fraction, volume of white matter hyperintensities, volume of lacunar infarcts and number of microbleeds) was analyzed with generalized linear regression models. Results: CTH were detected in 12% of the CADASIL subjects in association with hypointensities on T(1)-weighted images. CTH corresponded to areas of increased diffusion apparent diffusion coefficient maps. CTH were found significantly associated with age and independently related to the volume of white matter hyperintensities but not to that of lacunar infarctions or to cerebral atrophy after adjustment for age and sex. No significant association was found between CTH and global cognitive performances. Conclusion: CTH are observed on FLAIR images in a sizeable proportion of CADASIL patients. They are mainly related to the extent of white matter hyperintensities and do not correlate with cognitive decline. Demyelination and/or loss of glial cells appear to be the most plausible cause of these confluent signal changes in the thalamus. Copyright (C) 2010 S. Karger AG, Basel

Thu, 18 Jun 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/10348/ https://edoc.ub.uni-muenchen.de/10348/1/Schneider_Elisabeth.pdf Schneider, Elisabeth ddc:610, ddc:600, Medizinische Faku

Alison Rowan discusses epilepsy services in the UK, and a review about CADASIL.

Thu, 19 Feb 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9759/ https://edoc.ub.uni-muenchen.de/9759/1/Karpinska_Anna.pdf Karpinska, Anna ddc:610, ddc:600, Medizinische Fakultät

Editor Helen Frankish discusses highlights from the April issue: including the EPITHET study of alteplase treatment 3-6 hours after a stroke, and donepezil treatment in patients with CADASIL, a genetic form of vascular dementia.

Die Diagnose der Multiplen Sklerose (MS) ist eine klinische Diagnose (65), die jedoch mit einer Zahl von paraklinischen Methoden erhärtet wird. Mit Einführung der MRT in die klinische bildgebende Diagnostik hat die MRT sehr schnell eine Schlüsselposition innerhalb der diagnostischen paraklinischen Methoden bei Patienten mit Verdacht auf MS erreicht. Die MRT ist die sensitivste Methode, pathologische Veränderungen in der weißen Substanz des Gehirns mit einer hohen örtlichen Auflösung darzustellen. Allerdings trifft dies auch auf ein breites Spektrum neurologischer Erkrankungen und Syndrome zu, weitgehend unabhängig von der zugrunde liegenden Pathologie; daher ist die hohe Sensitivität mit einer geringen Spezifität verbunden. Es wurden erhebliche Anstrengungen unternommen, möglichst verlässliche Kriterien für die MRT-Diagnostik für MS aufzustellen. (5, 25, 62) Die aktuell anerkannten MRT-Kriterien nach Barkhof et al. (5) wurden anhand eines präselektionierten Patientenkollektivs erstellt, bei welchem die Verdachtsdiagnose MS gestellt wurde. Auf der Grundlage der MRT-Untersuchungen wurden dann die Kriterien bestimmt, die am besten geeignet waren, eine Voraussage über die Entwicklung von möglicher MS zu klinisch sicherer MS zu treffen. Barkhof konnte mit diesen Kriterien eine Spezifität von 78%, eine Treffgenauigkeit von 80% und einen positiven Vorhersagewert von 75% erreichen (5). In dieser Studie wurde untersucht, wie verlässlich diese Kriterien bei der Differentialdiagnose in einem weniger selektierten Patientengut mit verschieden neurologischen Krankheitsbildern sind, die jedoch im MRT einer MS ähnlich sein können. So wurden Sensitivität, Spezifität und Treffsicherheit der Barkhof-Kriterien in unserem Patientenkollektiv untersucht. Das zweite Ziel dieser Studie war, zusätzliche MRT-Kriterien ergänzend auf das gleiche Kollektiv anzuwenden, und zu überprüfen, ob sich dadurch die Zahl der nach den Barkhof-Kriterien diagnostisch falsch klassifizierten Patienten vermindern und damit die differentialdiagnostische Sicherheit verbessern lässt. Die zusätzlichen Kriterien bestanden aus dem Magnetisierungstransferverhältnis des Zerebrums, des gemessenen Gesamtläsions-volumens T2-hyperintenser zerebraler Läsionen und dem Nachweis von T2 hyperintensen Läsionen in der MRT des Zervikalmarks im Hinblick auf deren Anzahl und Ausdehnung. Zwei Patientengruppen und eine Kontrollgruppe gesunder Probanden wurden in die Studie eingeschlossen. Die Kontrollgruppe war erforderlich, um einen Normalwert für die Beurteilung des Magnetisierungstransferverhältnisses zu erstellen. Die Analyse der Patientengruppen erfolgte retrospektiv. Die erste Gruppe setzte sich aus 64 Patienten zusammen, die an MS erkrankt waren. Die zweite Gruppe bestand aus 81 Patienten mit anderen Erkrankungen, die wie bei der MS ebenfalls zu Veränderungen der weißen Substanz des zentralen Nervensystems führen können. Die Gruppe untergliederte sich in Patienten mit systemischen Immunerkrankungen (SID; n=44), mit zerebral autosomal dominanter Arteriopathie mit subkortikalen Infarkten und Leukoencephalopathie (CADASIL; n=22) und Patienten mit Migräne (n=15). Die Kontrollgruppe bestand aus 20 gesunden Probanden. Von allen Patienten lagen eine kranielle MRT mit PD/T2-gewichteten Doppelechosequenzen und eine MRT des Halsmarks mit einer fast-STIR Sequenz vor. Die Magnetisierungstransfersequenzen des Gehirns wurden erst nach Abschluss der Untersuchungen der CADASIL-Patienten nachträglich dem Protokoll hinzugefügt und lagen daher bei Abschluss der Studie für diese Patientenuntergruppe nicht vor. Die Anzahl und Lokalisation der hyperintensen Läsionen in den T2-gewichteten Sequenzen des Gehirns und die Anzahl und Ausdehnung der Zervikalmarkläsionen wurden erfaßt. Die Sequenzen der kraniellen MRT wurden nachverarbeitet, um das komplette Läsionsvolumen des Zerebrums (TLV-total lesion volume) quantitativ zu erfassen, und um Histogramme des Magnetisationstransferverhältnisses (MTR – magnetisation transfer ratio) zu erstellen. Aufgrund des retrospektiven Charakters der Studie wurden die zusätzlichen Kriterien nur auf die nach den Barkhof-Kriterien falsch diagnostizierten Patienten angewandt, es wurde daher auch keine Analyse bezüglich Spezifität und Treffsicherheit durchgeführt. Pathologische Veränderungen in den T2-gewichteten MRT-Schichten des Hirns fanden sich bei allen MS-Patienten und bei 61,7% der Patienten mit anderen Erkrankungen. Hyperintense Läsionen des Zervikalmarks wurden nur bei MS-Patienten gefunden (84,4%). Kein Patient der zweiten Gruppe (0%) wies pathologische Veränderungen im Halsmark auf. Die statistische Auswertung der zusätzlichen potentiellen Kriterien definierte die Grenzwerte, die am besten geeignet sind, um MS von anderen Erkrankungen zu unterscheiden: 1. ein Gesamtläsionsvolumen über 1,83 ml 2. ein Magnetisierungstransferverhältnis des Gehirns kleiner als 40,2% und 3. der Nachweis von Halsmark-Läsionen. Anhand der anerkannten Barkhof-Kriterien wurden 108 von 145 Patienten richtig klassifiziert, diese zeigten somit eine Treffgenauigkeit von 74,5 %. Eine “falsch-negative“ Diagnose fand sich bei 13 Patienten. 2 Patienten mit systemischen Lupus Erythematodes mit neurologischer Symptomatik (NSLE) und 22 Patienten mit CADASIL wurden „falsch-positiv“ klassifiziert“. Wurden die Barkhof-Kriterien um das TLV mit einem Grenzwert größer als 1,83 ml ergänzt, konnten 9 „falsch-negative“ Patienten noch korrekt klassifiziert werden. Eine richtige Klassifizierung von 10 weiteren MS-Patienten und allen NSLE-, bzw. CADASIL-Patienten konnte aufgrund des Nachweises bzw. des Nichtvorhandenseins von Zervikalmarkläsionen durchgeführt werden. Zwei MS-Patienten mit negativen Barkhof-Kriterien und ohne Zervikalmarkläsionen im MRT konnten auf Grund des Hirn-MTR-Wertes richtig als MS-krank bestimmt werden. Letztendlich konnte nur ein Patient mit den verwendeten Kriterien nicht richtig diagnostiziert werden. Diese Daten rechtfertigen einen vermehrten Einsatz der zervikalen MRT als zusätzlichen differentialdiagnostischen Parameter bei Patienten mit Verdacht auf eine Erkrankung mit MS. Auch die Berechnung des Magnetisierungstransferverhältnisses ermöglichte eine verbesserte Differentialdiagnose. Die Berechnung des T2-Läsionsvolumens ist mit erheblichem Aufwand verbunden und hat zu keiner wesentlich verbesserten diagnostischen Sicherheit beigetragen.

Summary CADASIL (cerebral autosomal arteriopathy with subcortical infarcts and eukoencephalopathy) is a autosomal dominant disease,which lead among other things to migraen headache and early stroke. Shortly before beginning of this work Notch3 was identified as responsible gene. Notch3 coded for a large transmembranereceptor with 34 extracellularly located,epidermal growth factor (EGF) similar domains. In this work 70 related families (70 index patients and 13 relatives) with bioptisch secured diagnosis in substantial two Exons (3 and 4) were examined, since within this range the mutations accumulate. By sequencing of Exon 3 and Exon 4 mutations in 70 % of the cases were identified. Three types of mutations were found: Point mutations ((n = 50), Dinukleotid mutation (n = 1) and Deletionen (n= 2). In addition numerous Polymorphismen was identified (n =43). Seven of the mutated nucleotides mutations arose frequently, whereby transitions of cytosine to thymine occure. All mutations including the Deletionen led either to an acquisition or a loss of a Cystein. Therefore it is to be accepted obviously that the change of a Cystein in a EGF similar domain of Notch3 represents the crucial mutation mechanical which is responsible for CADASIL. With the Polymorphismen no changes of the Cystein arose. Genotyp/Phaenotyp correlations could not be proven. This stands in the agreement with the uniformity of the mutations. Due to the results of this work an improvement in the procedure results for the existing diagnostics. Scinbiopsie and MRT photographs can be supplemented by the sequencing of Exon 3 and 4. Thus 2/3 of the mutations are already discovered. If no mutations are found there, still the remaining 22 Exons of the extracellular domain can be sequenzed, whereby here first on Exon 6 (and 12) the emphasis should be put. This procedure is used meanwhile as standard technique for the diagnostics. In this work as the further supplementing diagnostic method the analysis with mutation-specific restriction enzymes was developed. Under consultation of the theoretically computed restriction enzymes of the 7 most frequent mutations one receives 52% (amount of = 37) of the mutations with 70 index patients (74% of the found mutations). In families, in which a mutation already admits is, further family members with this method let themselves be examined faster and more economically, than by sequencing. In this work it could be shown that forecasts of mutation effects make the development of protein models possible on the protein structure. As possible working hypothesis a Conformationchange ore a Surfacechange can be accepted, the one effect on the connection partner be had can and possibly the function affected. An incorrect dismantling of the Notch3 of receptor leads to the fact that truncated receptor fragments collect in the Media of the vessels in the proximity of osmiophilen deposits. Because of the stereotyped mutations with those frequently so-called CpG (modulators of the Epigenetic)is present further possible mutations can be predicted.

Mutations in Notch3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited small vessel disease leading to subcortical strokes and vascular dementia. The phenotypic presentation is variable but remarkable for a high frequency of migraine with aura. Magnetic resonance images show a microangiopathic pattern of lesions. Prominent involvement of the temporopolar white matter and involvement of the temporopolar arcuate fibers are conspicuous findings seen in many patients, The underlying angiopathy is characterized by a unique type of ultrastructural basal lamina deposits and by degeneration of vascular smooth muscle cells which are the major source of Notch3 expression. In line with these findings there is evidence for a functional impairment of vascular smooth muscle cells. CADASIL has opened a new perspective in studying basic mechanisms of vessel wall degeneration and ischemic tissue damage related to small vessel disease. Copyright (C) 2002 S. Karger AG, Basel.