Open Blood-Brain Barrier for Alzheimer’s Treatment?; Managing TMD

Derick Alison
Derick Alison
18 Min Read

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include a new medication for atrial fibrillation, a comprehensive approach to pre-pregnancy through early childhood, opening the blood-brain barrier for an Alzheimer’s’s antibody treatment, and management of temporomandibular disorders.

Program notes:

0:47 Temporomandibular disorders and management

1:47 10-cm visual analog scale

2:47 In subtypes expect some variation

3:36 Which relieves pain and which improves function

4:27 Opening the blood-brain barrier and using an antibody for Alzheimer’s

5:27 Applied on one side of brain

6:27 Does it reverse or halt dementia?

7:00 A multidomain intervention in preconception through early childhood

8:00 Was helpful in childhood outcomes

9:00 Don’t know which factor was most effective

10:00 How to assess factors separately

10:15 IV drug for early atrial fibrillation

11:15 Phase II study

12:43 End

Transcript:

Elizabeth: Does intervening from conception through early childhood help childhood outcomes?

Rick: Opening the blood-brain barrier to improve Alzheimer’s treatment.

Elizabeth: What’s the best way to manage TMD?

Rick: And finding new ways to stop atrial fibrillation.

Elizabeth: That’s what we’re talking about this week on TT HealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Happy New Year to you and to everybody who is listening.

Rick: Happy New Year to you, Elizabeth. I believe this is going on our 20th year of recording.

Elizabeth: Isn’t that the craziest thing? I would like to turn to the BMJ and talk about TMD, temporomandibular disorders. The reason I want to do that is because we have never talked about this in 20 years of recording. I’m kind of astonished by that. What these authors point out is that TMD is the second most common group of musculoskeletal chronic pain disorders after low back pain, which I had no notion of that. They say that at any one time chronic TMD pain persisting for more than 3 months affects 6% to 9% of adults globally, with women reporting a higher prevalence than men.

This is a meta-analysis. They looked at 153 trials that they decided to use, enrolling 8,700+ participants and 59 interventions or combinations of interventions. They come up with a metric that they call the risk difference, which is the minimally important difference in pain relief of 1 cm on a 10-cm visual analogue scale.

What they were able to discern from looking at all of this data was that there were some things that really seemed to help. Those included therapist-assisted jaw mobilization, manual trigger point therapy, and five interventions that were somewhat less effective but more effective than placebo. Those were supervised postural exercise, supervised jaw exercise and stretching, supervised jaw exercising and stretching with manual trigger point therapy, and usual care such as home exercises, self-stretching, and reassurance.

They say that basically any of these more dramatic and permanent interventions really aren’t very helpful. The way to approach this is really with some of these strategies.

Rick: When it talks about temporomandibular disorders, there are 12 different subtypes. You’d think that among those subtypes there would be some that would be more responsive to invasive therapies or irreversible therapies like joint surgery, or prosthodontics, or orthodontics, oral splints, injections. But, in fact, in none of these subtypes was the more invasive therapy the preferred therapy. The more conservative therapy or the self-management — jaw exercises, cognitive behavioral therapy, relaxation strategies — were much more effective than the invasive, irreversible strategies. That’s very nice to know.

Elizabeth: I thought one of the things disconcerting about this study was that they report the mean age among their participants was 35 years. Their median average pain score at baseline was 5.4 cm on a 10-cm visual analogue scale. That’s a really pretty significant amount of pain and their average pain duration was 44 months, so significant pain over a long period of time at a very young age. This is concerning, I think.

Rick: It is, Elizabeth, and as you mentioned, I didn’t realize behind low back pain it was one of the more common disorders. You did mention something that I should have made our listeners aware of. They looked at which of these therapies could actually relieve the pain, and then secondly is which improved function. In both of those circumstances, whether one was looking for pain relief or improvement in function, the more conservative therapies were the most effective.

Elizabeth: The editorialist points out, of course — and this is something that’s pretty glaring also — these more comprehensive strategies for trying to help somebody manage their pain require training and they require supervision, and we have a shortage of those kinds of folks to deliver this kind of care.

Rick: Not only that, but sometimes the public healthcare systems don’t even fund some of these things. I hope that this information brings this to light so that we do use the most effective therapies, and we actually increase availability of them as well.

Elizabeth: Why don’t we turn now to the New England Journal of Medicine, something I thought was really fascinating: should we use ultrasound to open the blood-brain barrier with a monoclonal antibody for Alzheimer’s?

Rick: This is a study with just three individuals. These are all three individuals who had early Alzheimer’s. They had mild cognitive dysfunction, but on MRI scanning they had clear evidence of amyloidosis, these plaques in the brain. We know that there are antibodies to these plaques. These antibodies are usually given by an infusion, but that means they have to get from the blood into the brain. That’s called the blood-brain barrier, and it oftentimes prevents most of these antibodies from getting in.

What these investigators did is they said, “Listen, we know that you can use ultrasound to briefly increase access across the blood-brain barrier. I wonder if we combine this with the antibodies whether we can be more effective in removing the plaque?”

They took these three individuals that had amyloidosis — by the way, these plaques were on both sides of the brain — and they localized just one side of the brain. They applied this ultrasound and then they gave the antibodies, and then they followed the plaques over the course of the next 26 weeks with multiple imaging.

What they discovered was, in the areas where the ultrasound was applied and then the antibodies were given, there was a marked increase in resolution of the amyloid plaques as opposed to the other side of the brain where they didn’t use ultrasound. They were able to use the patient as their own control. There was a significant decrease in amyloid plaques when they combined ultrasound with antibodies. In fact, in animal studies that technique increases the antibodies in the brain by about 6- to 8-fold.

Elizabeth: Of course, this sounds like a very attractive idea, and we have heard and reported many times that depletion of the amyloid plaques doesn’t necessarily translate into a clinical benefit.

Rick: In fact, Elizabeth, they measured neurocognitive function of these individuals and there wasn’t a significant change, but it’s only three patients. It’s one thing to decrease amyloid protein in the brain. It’s another thing to say, “Gosh, does that actually reverse or halt the dementia?” That will be the next studies that are done.

Elizabeth: Of course, we have talked many times about these strategies for Alzheimer’s and other forms of dementia where they would initiate them much sooner in the course of the disease to see if early depletion would result in a better clinical outcome.

Rick: Right, and we’re presuming that it will make the neurocognitive dysfunction less severe, or it will decrease the progression. It could be positive, it could be negative. You have to approach it in a randomized way.

Elizabeth: Let’s move on, then, to JAMA. This is a look at a multidomain intervention in pregnancy at early childhood, but also in preconception. This is a multifaceted approach that includes health, nutrition, water, sanitation, and hygiene — so-called WASH — and psychosocial support interventions from the preconception period and during pregnancy and early childhood, and how does that impact child development.

This randomized trial in low- and middle-income neighborhoods in Delhi, India enrolled 13,000+ participants. They either got this preconception intervention or routine care for the primary outcome of preterm birth and childhood growth. Those participants who became pregnant were randomized into these pregnancy and early childhood interventions or routine care groups. Then they looked at neurodevelopmental assessments in a subsample of children at age 24 months. There were 509 who were in that arm that had preconception, pregnancy, and early childhood interventions.

Sure enough, it was helpful to enroll these moms who intended to become pregnant to intervene during preconception, manage them pretty intensively, I have to say, during pregnancy and in the postpartum period for outcomes for these kids, suggesting that this is a strategy that could be helpful for all these kids who experience failure to thrive, which is a large number of kids worldwide.

Rick: But when you say a large number, Elizabeth, the editorialist mentions that about 43% of children younger than 5 years old in low- and middle-income countries remain at risk of either poorly developing due to poverty and stunting. In Sub-Saharan Africa, that number is 66%. This multifaceted approach where they looked at nutrition, health, psychosocial well being, and hygiene, both preconception — and that was about 4 months before conception — or during pregnancy and early childhood, or both, ends up being a pretty remarkable study.

We don’t know which of those things, whether looking at nutrition health or hygiene, was most effective, but the most effective way to apply it was to do it preconception. If you stopped there, it didn’t really help enough. You need to do it also in early pregnancy and early childhood.

Elizabeth: Yeah. I’m really interested in this also from the perspective of here domestically. There is this whole notion of preconception health. Women really need to get themselves into optimal health and habits before they even become pregnant in order to have the best outcomes.

Rick: This gets women basically on track to take care of themselves before the child is born. These mechanisms could be physiologic. It could be epigenetic. There is a lot of different ways where it can be beneficial.

Elizabeth: I just have to say one thing about the point you made about we’re not sure which of these specific interventions were the ones that gave us the most bang for our buck. I’m a little troubled by that just because this strategy was so comprehensive that it’s hard for me to imagine picking out individual things out of that and trying to assess them separately. I think that this comprehensive approach really is the thing that needs to be taken.

Rick: You may be right. Again, we need to study that because we want to use the things that are most effective. What can we do to further enhance those?

Elizabeth: Finally, let’s turn to Nature Medicine and another very high-tech study. That’s all yours.

Rick: We have talked many times about atrial fibrillation. It’s the most common cardiac arrhythmia, associated with reduced quality of life and increased risk of stroke, heart failure, and death. Currently, the treatments are either pharmacologic or doing electrical cardioversion. The trouble with the current medication treatments is they have limited efficacy. The risk is increased in people that have a thick heart, blockage in one or more of the arteries, or heart failure.

We’re looking for new medications that can be effective in stopping atrial fibrillation without increasing the risk. This is a new group of medications. It’s a calcium-activated potassium channel blocker and it’s the first [of] its kind. They took individuals that had new-onset atrial fibrillation; they had it for less than a week. This is a phase II trial where they try to see if it’s effective, and if so, what the doses might be.

They took about 60 individuals. They randomized them to receive either 3 or 5 mg of this IV medication. It goes, by the way, just by a number. It’s called AP30663. We’re going to call it the new medication. Or they gave a placebo. Over the next 90 minutes, about half the individuals that received the new medication converted from atrial fibrillation to a regular rhythm and 0% of the individuals that received placebo. There were no ill side effects, but it’s a fairly small study. From here on out, we’ll be seeing this tested in a larger number of individuals.

Elizabeth: Probably a lot less onerous for the patient, too, than the cardioversion, I suspect.

Rick: It is. I mean, if you can get an IV infusion and then wait — by the way, the average time it took to convert them was about 40 to 45 minutes. If you have new-onset atrial fibrillation, you can go in there and get this medication and do so safely, knowing that about 50% of the time it will convert you into a regular rhythm. It will save you from having cardioversion. I suspect we’ll be reporting on this in the future when there are a larger number of patients.

Elizabeth: One of the questions I have, of course, is what’s the durability of this? Because we know that there is a high rate of recurrence among people even who have cardioversion.

Rick: That’s a great question; 90% of the individuals remain in sinus rhythm afterwards.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.

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