Alan Wein: Hello, again. I'm Alan Wein from UroToday, and today we have the great pleasure of speaking to Dr. Henry Lai, who has done so many things to advance lower urinary tract research. He is the Gerry Andriole Professor of Urology at the Washington University School of Medicine, and chaired this committee basically called LURN, the Symptoms of Lower Urinary Tract Dysfunction Research Network. And today, we're going to have a discussion about what we've learned so far. Henry, take it away.

Henry Lai: Thank you, thank you, everybody, for giving me the opportunity to talk about the LURN study. So the LURN study is actually funded by the NIH and the NIDDK to look at lower urinary tract symptoms. So there are really two LURN studies. The first phase of the LURN study, you look at LUTS in men or women. But the second phase of the study that I'm going to talk about mostly today is also to look at urinary urgency or overactive bladder symptoms in men or women. Now LURN is a phenotyping study. Basically what that means is that we try to understand better subtypes of phenotypes of patients who present with the symptoms of urinary urgency in the second phase of the LURN study. Now what we have adopted is a multimodal deep phenotyping approach to better understand this patient beyond the typical urologic factors. You look at pelvic floor factors, psychosocial factors, metabolic factors, how sleep disturbances, lack of physical activity, decline of cognition, presence of pain contribute to urinary urgency.

We also have studies that look at central sensitization or sensory abnormalities in these patients. We conduct the largest neuroimaging brain MRI study on urgency patients. We look at the physiology looking at urethral and bladder sensation. We also have focus group talk to our patients for treatment expectation and satisfaction and predictors of that. We use a lot of novel technologies to phenotype our participant. We do experimental pain testing, which is QST. We put a wearable tracker on them so we could keep track of the physical activity, sleep disturbances, and the number of times they wake up at night to urinate. We use taxing, we use neuroimaging and other sophisticated physiologic testing. I'm going to summarize in a few what we have achieved and learned. I think one of the most important things is that we collected a huge biospecimen of patients with urinary urgency.

We collect over 47,000 biospecimen plasma, serum, and urine, currently banked the NIDDK biorepository ready for any researchers to use for the future studies. And these biomarkers, these biospecimens are actually associated with a lot of rich phenotyping data from our participants. We have also developed questionnaires that are better, we think, than the existing questionnaire to assess LUTS. For example, we developed this called LURN SI, the LURN Symptom Index 10-item Questionnaire to assess these unique symptoms that you see on the screen. Now this is specifically developed to measure LUTS in both men and women. For example, for men, in addition to the typical storage symptoms and the voiding symptoms, the LURN SI-10 also asks about urgency incontinence, stress incontinence, pain with bladder filling, and post-void dribble. So I think we have developed a comprehensive LUTS questionnaire that is better than the existing questionnaire such as the AUA Symptom Index.

We also spend a lot of time looking at non-urologic factors in LUTS, for example, we have shown that central obesity or high BMI is associated with worse incontinence, both stress incontinence, urgency incontinence, and overactive bladder. We show that depression, anxiety, sleep disturbances, and poor physical function can be associated with worse LUTS in men or women. We also show that childhood sexual trauma is common in men or women with LUTS and they are associated with worse urinary symptoms. Another thing that we have done is LURN has done the largest neuroimaging study, brain MRI study on patients with LUTS and urinary urgency.

For example, we have done resting-state functional MRI studies and show that increased connectivity between brain regions may be associated with higher urgency. A connection between a prefrontal cortex and your somatosensory region in the brain may play a key why patients are having urgency. The structural imaging of the brain actually shows that disruption of white matter tracts in the brain might be associated with lower urinary tract symptoms and overactive bladder symptoms.

Finally, we developed tools for us to better understand phenotype patients. We have developed clustering tools so that we could put patient into different subgroups of bins based on the objective data without biasing it without clinical diagnosis and we are going to use this phenotyping and clustering tools to better understand overactive bladder patients and our goal is to identify several subtypes of overactive bladder patients so in the future we could individualize the treatment to them. So in a nutshell, those are some of the things that we have achieved and learned. I'll be happy to answer any questions, Alan, you have about the LURN study.

Alan Wein: That's fascinating. Thank you. Thank you so much. So from what you've learned so far, are there any phenotypes that you can glean just from the questionnaire that would serve as a guide for maybe the type of diagnostic modalities you should use and or also the types of treatment that you should go right to? In other words, not start with the usual sequence, which is sometimes time-consuming, but maybe there's a specific phenotype that would lead you to go right to a specific type of treatment.

Henry Lai: That's a wonderful question. This is what everybody wants to get to, right? Using the phenotyping information so you could individualize the treatment for this, for the patient, there are a couple of phenotype that is emerging. Of course, we're still analyzing our data. There appears to be a subgroup of patient where their urgency and frequency is related to behavior. High fluid intake problem with sleep disturbances. Some of those could be related to behavior that we can address it in that manner. There appears to be a subgroup of patients that have more of a pelvic disorder, a pelvic floor disorder issue leading to urinary urgency. So maybe we could target the physical therapy. We don't have evidence, but that seems to make logical sense. There appears to be two further groups. There appears to be a pelvic group where the urology arises from the bladder as you would expect to resolve activities, small bladder capacity, but is urology of pelvic.

But there also appears to be a subgroup where we are seeing changes more systemically. They appears to have brain changes, changes in the sensory threshold, et cetera, that we need to explore further. So these are what we call perhaps systemic patients that we need to better understand because there are therapies that are directed at the pelvic floor. There are therapies directed at behavioral modification. There are therapies directed at the bladder for detrusor activity. For example, Botox injections into the bladder, or there are therapies that involve the brain circuit, for example, neuromodulation. So we are going to see if this will map to better outcome for these patients, but we don't know the answer to that yet. We don't know if the phenotype will map to differentially better treatment with certain modality at this point, but that's where we wanted to go.

Alan Wein: Great. Is there a specific relationship between... or have you been able to look at these MRIs before and after any treatments to see what changes?

Henry Lai: Mm-hmm.

Alan Wein: At least in terms of the MRI, let's say above the neck and maybe even in the spinal cord as well. For instance, neuromodulation, no one knows how it works. It seems to work for storage. It seems to work for emptying, but nobody really knows how it works, have you been able to do any CNS MRI studies before and after any kind of management, drugs, Botox, anything, to see what actually changes in the central nervous system?

Henry Lai: I think that was a wonderful question. We did this as the baseline before treatment. We did not do a follow-up study after treatment and see whether or not the brain changes that we saw were correct. And we don't know if any brain signatures that will predict response to treatment. Those could be really great idea for future studies because if you have a certain brain signatures that will tell you that maybe you will respond to treatment or not, or maybe you respond to certain type of treatment, like you said, sacral neuromodulation versus some other treatment, I think that would be wonderful contribution to our field. But we haven't got to that point yet.

Alan Wein: I'm intrigued by the development of the questionnaires because I've always thought that the AUA Symptom Score, it was like a very blunt tool. It was designed really to follow patients that pretty much had a diagnosis of outlet obstruction secondary to static enlargement-

Henry Lai: Yeah.

Alan Wein: ... but not to give you a full look at the urinary tract. So with these, first of all, is there any possibility that these symptoms or scores or something like them will replace that? And is there a possibility that if the patient fills these out before they come to the office, that you could use artificial intelligence to point you like what you really should be looking at further asking the patient and which diagnostic studies you might use or even which management strategy you might start with without any diagnostic studies at all?

Henry Lai: Yeah, absolutely. These are all the possibilities, you could see the LURN SI-10 over here. As you said, the AUA Symptom Index was developed specifically for men with BPH. It's never really meant to be developed for women, but this LURN SI-10 is developed for both men and women. And it also, I think the most important thing is it has incontinence questions, right? Because overactive bladder is-

Alan Wein: Yes-

Henry Lai: ... dominant in men and women and so is post-prostatectomy stress incontinence and those kind of things. I think the LURN SI-10, hopefully we will replace the AUA Symptom Index where people find it useful. I incorporate this into my clinical practice for the last year or two, I have so many patients fill it up. It's so useful just to get a sense of screening for the urinary symptoms, what bothers them the most. And like you said, I think this is extremely useful to track response to treatment. I use this all the time, actually.

Alan Wein: Yeah, that I think has amazing potential. So hopefully the funding for this study is ongoing and will keep going because of all the NIH-funded sort of global studies that I've seen. I think this one has the most potential for really making it easier for clinicians to diagnose and management and manage lower urinary tract symptoms in both men and women.

Henry Lai: Absolutely. Yes.

Alan Wein: Well, listen, thank you so much for speaking to us. Really appreciate-

Henry Lai: Thank you.

Alan Wein: ... the information, I think that you and your committee are going to accumulate, I think that's really going to be invaluable. And I think that the funding agency in 10 years will be very happy that they expended the money to do this.

Henry Lai: Thank you. Thank you for the opportunity. Thank you.

Alan Wein: Listen, take care. Hope to see you sometime in the near future.

Henry Lai: Okay. Take care. Thank you. Bye-bye.