Alexander Disease Research Update
Discussion of recent publications from the research literature on Alexander Disease, hosted by Albee Messing from the University of Wisconsin-Madison.
Alexander Disease Research Update
Alexander Disease Research Update - Episode #13: MRI diffusion tractography - what can it tell us?
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Albee Messing, Emi Takahashi, Arastoo Vossough, and Amy Waldman discuss the following recent publication:
Journal of Neuroimaging (in press)
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Hello and welcome to Alexander Disease Research Update, episode number 13, recorded on October 4th, 2022. I'm Alby Messing from the Wastement Center at the University of Wisconsin, and with me today are Amy Waldman and Arastu Fasot, both from the Children's Hospital of Philadelphia, as well as the senior author of the paper we're going to discuss, Emmy Takahashi from Boston Children's Hospital and Harvard Medical School. Amy is well known to all of you, but our other two guests are new to the podcast. So let me first ask Amy to say a bit more about your background and current position.
SPEAKER_03Yes. I got my PhD in neuroscience from Chibay University School of Medicine in Japan and did my postdoctoral studies at Boston University School of Medicine and MGH, Massachusetts General Hospital. And now I'm an assistant professor in the Department of Radiology at MGH.
SPEAKER_01And Arastu, can you tell us a bit more about yourself?
SPEAKER_00Yes, I am an adult and pediatric neuroradiologist. I did my radiology residency and fellowship at the University of Pennsylvania and Massachusetts General Hospital, respectively. And I do pediatric neuroradiology clinical and research work at the Chilman's Hospital of Philadelphia.
SPEAKER_01Again, thank you all for being here today. Before we get started, please send feedback and questions to AXDRU podcast at Waistman. That's W-A-I-S-M-A-N.edu.
Identification of association fibers using ex vivo diffusion tractography in Alexander disease brains
SPEAKER_01Today our topic is a paper just published by our guest, Emmy Takahashi and her colleagues, entitled Identification of Association Fibers Using X Vivo Diffusion Tractography in Alexander Disease Brains, which is in press in the Journal of Neuroimaging. Emmy, before we get into the paper itself, can you please tell us how you came to be interested in Alexander disease?
SPEAKER_03Yes, so for my research, I've been using a diffusion MRI technique, which measures the direction of water diffusivity in the brain. And with this technique, we can image fiber connections in the brain, but in complex brain diseases such as Alexander Disease, we still don't know how accurately we can image those connections. And I learned that Alexander disease has a problem with astrocytes, one of the components in the brain that support neuronal structures and functions. And I got interested to see if our technique is useful to image detailed fiber connections in brains with astrocytic problems and started working on Alexander disease.
SPEAKER_01So I found this paper very interesting because it's a very different type of imaging analysis than is typically done for Alexander disease. And so it will be very interesting to find out how much information, new information we get about the disease from this kind of study. I also will put in a plug for the value of brain banks, for the continued value of brain banks in Alexander disease research and why tissue donations will still be a valuable resource far into the future. So, Emmy, why don't you walk us through this paper, methods, results, and what you think the conclusions are?
SPEAKER_03So our goal in this study was to image unusual connections in the brain diagnosed with alexander disease, and to see if our imaging technique is useful to find if the fibers are decreased or connecting with unusual brain regions in Alexander disease. And we used diffusion MRI craptography technique in postmodern brains. And we found some specific connections being decreased or disconnected in the patient's brain. And we also found abnormal trajectories of those connections. We found abnormalities in both long-range white matter pathways and short-range subcortical pathways.
SPEAKER_01We should say that you used four Alexander disease brains. And I forget how many controls.
SPEAKER_02Yeah, for our audience, this study looked at four Alexander disease brains and compared that to three patients who did not suffer from Alexander disease. Yeah.
SPEAKER_01So this type of imaging you did on post-mortem brain samples, but can it be done in live patients?
SPEAKER_03Yes, of course, yes. So we used postmodern imaging to do long scans to get better images, but yes, similar protocols can be used in vivo.
SPEAKER_00Yeah, uh Amy, one question I had. Typically, the techniques that use there's wide variability in terms of their resolution and uh robustness. Uh, the particular one that you employed, sometimes uh some of these techniques are very long and may be difficult to uh implement for patients. I know I know there are newer methods to accelerate these types of sequences as well, but what would you say was the approximate time of acquiring these types of sequences? Well, to get a reasonable quality one for live patients, uh what would be the time that you would be happy with? Because obviously on MRI, the longer you scan, you get better images.
SPEAKER_03Right, right. So I think we are still exploring the best scan parameters for in vivo imaging for this kind of study. It depends on what we want to detect in vivo. So, for example, big changes can be detected in short time, maybe in five-minute scans or 10-minute scans, for example.
SPEAKER_02Is five to ten minutes what we're using in clinical patients that undergo these sequences? Is it typically a 10-minute? Is it longer? Is it shorter?
SPEAKER_00Again, as uh Emmy mentioned, that five minute, yes, you can get some data. And if there are uh uh large scale changes, uh you can detect them with shorter scans, but smaller changes would require uh longer scans, as Emmy had mentioned.
SPEAKER_01You know, most people don't know what you mean by the word sequences.
SPEAKER_03Right, right, right.
SPEAKER_01It's a scan, right?
SPEAKER_03Yes, scan.
SPEAKER_00Sequences are the different types of imaging that are acquired. So you can look at different ways of looking at the brain and come up with diagnoses, changes over time, so on and so forth.
SPEAKER_02Yeah, in general, when we do an MRI scan, it's not like an X-ray that you take one static image. When we do an MRI scan, we do a series of images, which is we're referring to different sequences. Um, and those sequences help us answer different questions within the brain. So some of those sequences tell us a little bit more, for example, about water flow, um, but some of them tell us a little bit more about structure or pathology or damage, and you get different information from each one of those sequences, which is a series of scans within that 45 minute to an hour window.
SPEAKER_00Yeah, and and the question that why how come it's so long is because there are multiple structural acquisitions in different planes and with and with contrast, without contrast, contrast as needed. So they they add up over time. So Emmy, I was very intrigued that that in addition to finding that some of the expected tracks were absent uh due to a variety of reasons damaged or edema or whatnot, uh, you found that uh there were some tracks that you detected that are not present in normal brains. Is that correct?
SPEAKER_03Uh yeah, not the entire fiber bundle, but we detected abnormal fiber trajectories.
SPEAKER_00Yeah, so these abnormal fiber trajectories are actually quite intriguing. I mean, I would be interested in what are your thoughts? Is this the brain trying to compensate? Is this an artifact of technique? Uh, is this related to something else about the pathophysiology of Alexander's disease in the brain? So, what's your hypothesis that you may have different trajectories that you would expect?
SPEAKER_03Yeah, so one thing is our sample size is really limited. So, this is kind of a combination of case study. So there are many potential reasons for these abnormal fiber trajectories found in Alexander disease brains. So, as you said, yeah, compensation is one of the potential reasons. I don't think artifact, those fibers are really clear, thick bundles.
SPEAKER_01So, Annie, what would you like to do next in this research?
SPEAKER_03So we definitely need more samples, and with with I'll be we can get more samples from the brain bank and then to correlate uh our tractography findings with genetics information.
SPEAKER_01Once again, what would you say is the key take-home message for patients and families?
SPEAKER_03Yeah, so in this study we use postmodern brain samples to do long MRI scans to see high-quality images, but and things are going on, we are still exploring what the best imaging techniques in in vivo studies. But if the changes we found in this study can be also seen in clinical and vivo MRI scans, those changes could be potential biomarkers for early diagnosed onset and potentially useful in finding treatment plans.
SPEAKER_01I think I'll add one more general comment, which is that the way Alexander disease was originally presented to the scientific community, it was described as a leucodystrophy, which is to say having white matter deficits, but it's not a pure leucodystrophy. And while the pathology was originally reported as defects in myelin with relative sparing of axons, that's not to say that there's no damage to axons. We're learning more and more about how the initial insult to the astrocyte creates a cascade of changes in all the other cell types in the central nervous system, and the kinds of tracts that you look at in this type of imaging is reflecting that damage to the axons as well as to the myelin. How do these results in Alexander disease relate to other disorders of the central nervous system?
SPEAKER_02Well, I can speak a little bit more broadly about the use of DTI, this particular technique in other leucodystrophies. For example, in Crab A, Maria Escalar and her team have actually looked at neonates or even prenatal changes on the MRI using this particular technique, using DTI. So in alive humans, not necessarily autopsy special, not in specimens, and have determined that DTI shows early signal change in those patients with crab A disease. So like an early biomarker, as Emmy was just describing. The challenge is that biomarkers is a very complicated field. And where DTI seems to be a little bit more useful clinically is in diseases that actually have a structural lesion or a tumor, not so much just some of these association studies. Arasu, would you agree with that?
SPEAKER_00Yes, so uh DTI is used widely clinically in, for example, pre-surgical planning in resection of parts of the brain. So white matter tracts that are mapped out are preserved or preserved as much as they can be. But then there's a whole different side to DTI, which is quantitative DTI, to potential use as biomarkers. Uh, that's a more much more complicated uh application. Certainly, even theoretically, DTI should be able to pick up earlier changes before the regular MRI shows abnormalities, although uh that might be challenging because uh you know uh one has to consider the robustness of DTI across different scanners, different time points, different institutions as well. So if those problems can be solved across the board, certainly for early biomarkers has potential, although I would say the potential has not been fully materialized yet because of the issues that surround these.
SPEAKER_03I know you've worked on standardization as well, so we've done large-scale retrospective studies, uh MRI studies, not Alexander disease, but other autism spectrum disorders or other diseases, and found you know, we studied 10 year, 15 years period, and scanners were changed, and even in the same scanner, people changed the protocols. So it's even in the same institution, it's not super straightforward to you know compare.
SPEAKER_01That's all for today's episode of Alexander Disease Research Update. Thanks for listening, and thank you to Amy, Emmy, and Arastu for joining me today. Our theme song was written by Charlie Allenson, special technical assistance from my daughters Zoe and Rebecca, and from Clark Kellogg at the UW's Wastement Center. And thanks to our donors for these podcasts, the Barrent Riddle family. I'm Albie Messing. See you next time.
