Pulse pressure and Alzheimer's, mapping genomes to catch infectious diseases and the global burden of disease

Norman Swan: Hello, and welcome to this week's Health Report with me, Norman Swan.

Today, chasing resistant bugs, especially those from overseas, by watching their genes.

Surprises when you look globally at the patterns and burden of disease.

And the first optimistic findings for a long while on dementia and the promise of a simple solution. Worldwide research into Alzheimer's disease is in a deep rut. We've covered this research before on the Health Report, dementia researchers have been obsessed with a substance called amyloid which collects in the brains of people with Alzheimer's. Trouble is that repeated trials of medications that are supposed to reduce amyloid have failed or even made people a bit worse. The so-called amyloid hypothesis is now being seriously questioned and it's time for some new thinking, and that has perhaps arrived in the last couple of years with what looks like confirmation from a new study published last week.

The theory is that as arteries stiffen as we age, the carotid arteries in the neck are less able to expand to absorb the shock wave from the heart as each beat pushes blood to the brain. That shockwave in stiffened arteries is then transmitted forward to the blood vessels in the brain, causing damage which might lead to dementia. And the solution may be quite simple. One of the authors and the person who thinks he may have the solution is academic cardiologist Professor David Celermajer. Welcome to the Health Report, David.

David Celermajer: Good afternoon Norman.

Norman Swan: We should just have a declaration of interest first because you're the founder of a company which has developed what you think might be the solution.

David Celermajer: Well, that's a little immodest I guess, to say we think we've developed a solution yet, but we are working towards one. So although, as you said, I am an academic cardiologist based here in Sydney, a number of years ago I did start up a company called the Brain Protection Company to try and develop some of these exciting diagnostic and therapeutic possibilities based on arterial abnormalities.

Norman Swan: So where did the idea come from, that stiffness of the carotid artery might be an issue?

David Celermajer: So where it came from was the observation, I guess a confluence of observations…the most important is that high blood pressure in midlife seems to be an extremely important risk factor for dementia in late life. And people started to ask the question…

Norman Swan: This is untreated hypertension?

David Celermajer: Untreated hypertension. So people started to ask the question; why would high blood pressure in midlife predict dementia in late life? And that led to a series of molecular, animal and now human experiments that suggest that the mechanism is the pounding of the pulse inside the brain leading to a leak of proteins or cells that can set up a cascade that leads to dementia.

Norman Swan: So they've shown that in animals?

David Celermajer: So in animals an extraordinary experiment which was done in Montréal a couple of years ago where the authors put a band around the main blood vessel to the body called the aorta and they did that between the blood vessel to the right side of the brain and the blood vessel to the left side of the brain. So they created a condition of very high intensity on the right side, but normal pulse intensity on the left side. And when they looked at these mice that were Alzheimer's prone, the right side of the brain had turned into Alzheimer's brain, and the left side was protected.

Norman Swan: So the amyloid then is a reaction to the protein and blood that's leaking out.

David Celermajer: Yes, there's a whole cascade of events. I think amyloid is obviously an oversimplification. It's a marker. So what happens is that there is oxidation, inflammation, loss of neurons, loss of synapses, and there are a number of proteins that you see when you look at the brain of Alzheimer sufferers, amyloid is one of them, tau is another, but whether it's a cause, an innocent bystander, or something protective, the jury is certainly out on that.

Norman Swan: So tell me about this study that you and colleagues published last week.

David Celermajer: So this study asked the question; when you are 60 years old, what is the single best predictor of cognitive decline over the next decade? Is it your age, is it your genes, is it the intensity of the pulse to the brain, is it your education level? And the answer was resoundingly that the single most important risk factor for cognitive decline when you're a 60-year-old man or woman is the intensity of the pulse to the brain, so how strong is the pulsation in the carotid arteries, which are the vessels that carry blood to the brain.

Norman Swan: How do you diagnose that?

David Celermajer: It's a simple scan, it takes five minutes, you do it in the neck. It's based on a very high rate of acceleration of the pulse wave velocity that comes out of the heart that goes to the brain.

Norman Swan: And was it so-called linear? In other words, it started at a low level and then just progressively went up?

David Celermajer: No, there was a threshold. So if you were in the top one-quarter of the population for this parameter, the pulse wave intensity, if you like, you had a 50% higher chance of cognitive decline. So the bottom three-quarters were okay. The top quarter really had a major problem develop over the duration of the study.

Norman Swan: And how predictive was that cognitive decline of Alzheimer's disease?

David Celermajer: This was a study of 3,200 well people, so very few well 60-year-olds get dementia itself, but what they get is a decline in their cognitive abilities, like fluency, memory, executive function. So we didn't have enough cases to look at whether dementia was predicted, but we did to show cognitive decline. And there's a well-worn literature that shows that cognitive decline in turn causes dementia.

Norman Swan: And what predicts the stiffness in the artery?

David Celermajer: So it's an age related phenomenon. When you're young and your heart beats, the central vessels like the aorta and the carotid are very elastic and they absorb the energy. But as you get older, those central vessels stiffen up. But that's not a uniform process. The stiffening is something that varies from person to person.

Norman Swan: We haven't got cause and effect yet, this is still an association…

David Celermajer: It's pretty close to cause and effect because this was a prospective study. So just to clarify, the people were studied in 2003 for their carotid wave intensity, and then they were followed four times between that and 2015, and it was shown that it was a predictive factor.

Norman Swan: Before you get to the solution that you're coming up with, is there a way of preventing the stiffening of the artery? Is it smoking, exercise, that sort of thing?

David Celermajer: It seems that stiffening can definitely be worse in the presence of traditional vascular risk factors like diabetes and ageing. But the correlation coefficients are not very high. It seems to be that there is a genetic component as well. And there has been one study that was published last year that gave a clue to what the answer might be. That was a study called the SPRINT MIND Study in the Journal of the American Medical Association, and they showed that if you reduce the pulse pressure, you can reduce the rate of cognitive decline. That wasn't the main aim of the study, but it was a finding that gave a clue.

Norman Swan: That was through the control of blood pressure.

David Celermajer: It was. Unfortunately the people who had the blood pressure control also had side-effects from that, so I don't know that drugs are the answer, but it's a clue to the answer.

Norman Swan: And of all the people who develop Alzheimer's disease, what proportion could be ascribed to this pulse pressure problem?

David Celermajer: So my own view is probably a fifth to a quarter of Alzheimer's might be due to this problem, but I think in almost anyone who is destined to get Alzheimer's for whatever cause, genetic or otherwise, a high pulse pressure is an accelerant.

Norman Swan: So what's your device?

David Celermajer: I can't say too much about it, I don't want to be cute here, but it is a device that we believe can be placed very simply in relationship to the carotid artery and restores the shock absorber function, if you like, so it can restore elasticity to the carotid arteries. I should emphasise we haven't done this in humans yet, we've done it in experimental animals where it appears a very promising, and we are hoping to do our first in-human experiments later this year.

Norman Swan: And what do the Alzheimer's disease community, the people who are obsessed with amyloid, think about all this?

David Celermajer: Well, I think the Alzheimer's disease community has had a lot of disappointments lately and so they look at any new development with a little bit of scepticism, as they should. I don't know that the amyloid community are very happy about anything at the moment. That's a big shame, that recent development.

Norman Swan: David, thanks for joining us.

David Celermajer: Thank you Norman.

Norman Swan: Founder of the Brain Protection Company and academic cardiologist Professor David Celermajer. Watch this space.

You're listening to ABC RN's Health Report, I'm Norman Swan.

The United States and other countries have been reporting a very scary fungal outbreak in hospitals. It's called Candida auris. It's hard to diagnose, is resistant to all known medications and some routine antiseptics and is travelling around the world. Australia seems to have escaped with only a couple of cases. It's just one example of potentially dangerous microorganisms which can land in our airports or even spread through the food supply causing food poisoning and even deaths.

Controlling such infections, including antibiotic resistant bacteria, requires them to be tracked. But they can be hard to do because they can be hidden in a population of other germs that looks superficially the same. One solution is sequencing the genetic fingerprint of these bugs which is why a group of researchers has called for a microbial genomics capacity to be built in Australia. One of these researchers is Associate Professor Deborah Williamson of the Doherty Institute in Melbourne. Thanks for joining us on the Health Report.

Deborah Williamson: Good evening Norman, thanks for having me.

Norman Swan: So you've heard me define the problem, is that how you define the problem we're trying to solve?

Deborah Williamson: I think that's spot-on, Norman, I think you've hit the nail on the head there.

Norman Swan: So why can't we do this now? It's not as if we are new to genomics, there are lots of genomics facilities in Australia, there's lots of good microbiologists, so why aren't we doing it now?

Deborah Williamson: Well, actually we are doing it now around the different states have this capacity, but what we are not doing at the moment is joining the dots up, so joining this up nationally. And I guess what we are talking about in this article is really improved national coordination and resource for this technology to make sure that it's not just confined to two or three different states, it's really equitable across the country. And we really believe that that's in the national interest and that it would significantly improve Australia's capacity to detect and to respond to infectious diseases.

Norman Swan: So what's the burden of the problem? What's the dimension of the problem in Australia in terms of number of people affected, number of people dying? We are broadcasting, we might as well be sensationalist about it.

Deborah Williamson: That's a curveball, Norman. Well, look, it depends I guess…

Norman Swan: It's a career ending question really, isn't it.

Deborah Williamson: Thank you for that, yep. So I guess it depends on what pathogen, what infections you're talking about…

Norman Swan: To be serious, give me an example of a problem that they've got in Australia that has not been solved because bugs don't respect state borders.

Deborah Williamson: Okay, well, the question of antimicrobial resistance would be I guess an exemplar are of that. So at the moment there's no formal capacity to link the genetic sequences of antimicrobial resistant bugs in one state with another, or indeed internationally. And I guess the technology that we are talking about, whole genome sequencing, which is where you look at the entire genetic sequence of an organism, the technology is a kind of unifying technology in so much as we can compare sequences very rapidly across state and territory borders and across international borders. If you think about the way that bacteria evolve and have emerged and become resistant, they are really smart, they've got billions of years of evolution on their side and we really need to pull out everything that we can to combat that and be much more sophisticated in our approach to preventing and controlling these outbreaks. So antimicrobial resistance would be an exemplar are of that.

Norman Swan: Food poisoning organisms being another. Is it because we lack genome sequencing facilities or are there legal barriers? What's the story here in terms of stopping us cooperating as a state? Are we talking about the railway gauge again or what?

Deborah Williamson: Partly, yes. So there are a number of barriers I guess to this. Some are real, some are perceived, but I should say that none of them are insurmountable. So I guess some of the real barriers, one of the ones that you've mentioned, is that some states and territories simply do not have the hardware or the workforce capacity to do that, and that's what we would like to change, either some barriers around sharing of data…

Norman Swan: They can always put a swab in the mail, by courier, and send it to Melbourne or Sydney or Brisbane, couldn't they?

Deborah Williamson: That's not the model that we would like, we would like to build capacity across the country. And the reason is that it would be great for different states and territories to be able to use this for their own local purposes in real time. So sending isolates across the country takes time, it can take days, sometimes it can take weeks, but this information can be generated very quickly and used very quickly. So that's some of the real barriers. Some of the perceived barriers are around some threats to privacy, for example from industry, and indeed actually from the research community itself around sharing data.

Norman Swan: You're kidding? When people's lives are at stake?

Deborah Williamson: Well, actually interestingly the WHO have just put out a code of conduct for open and timely sharing of genetic sequence data from pathogens during outbreaks. So there's a recognition now that if you are involved in an outbreak, it's good practice, it's simply the right thing to do to share data very quickly with public health agencies, not just in your own country but around the world.

Norman Swan: The UK and the US are doing this.

Deborah Williamson: They are doing it, yes, they've been doing it for a number of years now. I don't think it has been entirely straightforward for them but it has led to certainly some reductions in outbreaks in the US and they've published on this, and…

Norman Swan: So how does it lead to controlling outbreaks faster?

Deborah Williamson: Okay, if we go back to the foodborne disease example, so if you're able to link a company and an outbreak earlier, what that can mean is that…so a contaminated facility, for example, can be closed quicker, it can lead to more specificity and food safety recalls which ultimately I guess prevents food wastage.

Norman Swan: Traditionally farmers have resisted this because they say they don't want it to be traced back to the original farm, for example, and food poisoning.

Deborah Williamson: Look, I think that's an important point, but it is something that is actively being worked through, not just in Australia but internationally as well.

Norman Swan: Consumers would like to know which farm it came from.

Deborah Williamson: Absolutely, yes. Again, if you think about…

Norman Swan: So is the farming community part of the resistance here?

Deborah Williamson: I couldn't comment specifically on the farming community but I think certainly from the food industry as a whole, efforts are being made to work through this process with a number of industries as well. But if you think about some of the benefits that could actually I guess befall the industries rather than some of the negative aspects, so they could rapidly say that they were not part of an outbreak, for example, and certainly some pathogens they could say look at different virulence characteristics and pathogens and know that if something that was contaminated it may not be particularly virulent.

Norman Swan: So just finally, in whose court is it to actually do something about this, because I think most people listening to this would be fairly shocked.

Deborah Williamson: As I say, what we are advocating for is sustainable national resourcing and coordination for this, and equity across jurisdictions. There are a number of ways that that could happen. One of them is through I guess some translational research funding, but that's not I guess a particularly sustainable model, and I guess the impetus for this to happen has to come centrally.

Norman Swan: Thanks for joining us.

Deborah Williamson: Thanks for having me.

Norman Swan: Associate Professor Deborah Williamson is at the Doherty Institute at the University of Melbourne.

Well, on today's Health Report we've already covered to problems—dementia and infections—which contributes significantly to the global burden of disease. If you are a regular Health Report listener you will have heard that phrase a lot. It describes how many years of disability-free life are lost as well as actual years lost due to premature death caused by disease, diseases' risk factors and injury. The measure is called a disability adjusted life year or DALY.

By creating a tangible and reproducible measure, the DALY and the burden of disease concepts have transformed thinking and planning of public health and health research around the world. They were created in the early 1980s by Chris Murray whose life started as a New Zealander, and a Western Australian, Alan Lopez. Chris is now director of the Institute for Health Metrics and Evaluation at the University of Washington in Seattle, and Alan is Laureate Professor in the School of Population and Global Health at the University of Melbourne. They're both in our Melbourne studio as Chris is on a lightning visit to Australia. Welcome back to the Health Report, both of you.

So Chris, from small beginnings, I think just your institute has got hundreds of people working for it.

Chris Murray: Yes, the institute is now 450 people focused on measuring health and health expenditure and impact of interventions around the world.

Norman Swan: So how granular have the causes of lost disability adjusted life years become?

Chris Murray: We now track about 360 diseases and injuries and we track about 84 risk factors that account for the patterns that we see around the world.

Norman Swan: When you developed this in the early '80s there was a league table of loss of DALYs, and one of the surprises globally was how high mental health issues were, I think it was number three at one point. When you look at the league table now, let's look at the league table of diseases, league table of risk factors, what's shaking out globally?

Chris Murray: Well, I think the world is tracking on different trajectories. Outside of Sub-Saharan Africa we are seeing this incredible success story, longer lifespans, a big shift from communicable diseases to the non-communicable causes, you know, with heart disease and cancer at the top and, soon after, many of the conditions that cause disability, like mental health or musculoskeletal disorders, drug abuse, vision loss, hearing loss. And while the consequences of progress are being seen in most parts of the world, in Sub-Saharan Africa we still have a profile of burden that is really dominated by the big infections; HIV, TB, malaria, diarrhoea, pneumonia.

Norman Swan: I thought there was convergence, I thought that was one of the surprises, that there was more non-communicable disease in Sub-Saharan Africa then we thought, but there has not been as much as you originally predicted?

Chris Murray: Oh there is more than people think, it's that…and the rates in any particular age group are higher in Sub-Saharan Africa for NCDs than they are in middle income and higher income countries. But it's the very young that population age structure in Africa that means in terms of the actual counts of burden, the communicable causes still are more than 50%, they are still the majority.

Norman Swan: One of the issues globally, it's an issue in your home country of the United States but globally as well, is universal healthcare and the ability to influence the global burden of disease with universal healthcare. Is your research illuminating that?

Chris Murray: Yes, we've been working very closely with Dr Tedros, the new director-general of the World Health Organisation, and part of that work has been to try to revamp the measurement of universal health coverage by focusing in on outcomes that are very healthcare sensitive, and looking at variation in the case fatality rates. You know, one measure of how well the health system is doing is what fraction of people with pneumonia die, even though they get treatment, or what fraction of people survive with some of the treatable cancers. And so by focusing in on those healthcare sensitive outcomes, I think we've got a much better handle on where people are getting needed care with high quality. And then there's a whole series of really interesting questions that that is framing, about how likely is it that we can achieve the ambitious sustainable development goals for UHC.

Norman Swan: So we are in the middle of an election campaign, which wouldn't have escaped you, in Australia, and the structure of our universal healthcare system is under examination. Are there features of universal healthcare that you've noticed which reduce the burden of disease effectively and cost effectively?

Chris Murray: I think as we look across countries, it's not just how much money you spend. The US is the sad example of that where spending is one of the first or second in the world per capita in terms of healthcare, but by any of these measures of access and quality of care, the US compared to its peers in the high income world doesn't fare so well. Australia has done remarkably well in terms of comparison in the horserace of health outcomes. It has really caught up very close to Japan in terms of things like life expectancy, and it has…you know, it's really something that other countries are interested in the Australian experience.

Norman Swan: Alan Lopez, when you started this work on global emergencies your interest was tobacco and tobacco control, that's where you started off. When you look at tobacco, when you look at obesity, you look at alcohol and you look at the global burden of disease, what's the picture that is emerging and the trends?

Alan Lopez: Well, tobacco was a major cause of disease burden 25 years ago when Chris and I first started doing this study, it still is, Norman, it's still a major cause of disease burden, including in countries like Australia, it's responsible for about 10% of healthy years of life lost. So it hasn't gone away, even though we've been successful in bringing down prevalence. About 15% of Australian adults still smoke every day and they run a threefold excess risk of dying at any time from tobacco. But tobacco is not the only issue. In the last three decades things like obesity, body mass index have increased dramatically. In countries like Australia it's probably the second or third fattest country on the planet now. And being overweight and obese, particularly obese, carries with it extreme health risks. So we are seeing emergence of risk factors such as obesity that have been very hard to control. No country on the planet seems to have had any success in bringing down the fraction of the population that's overweight and obese.

Norman Swan: And where does obesity sit in the league table?

Alan Lopez: It sits about third or fourth, it's depends on how you break it up. But the main ones globally are things like suboptimal or high blood pressure. We take for granted that populations like Australia and the United Kingdom and the US have a significant fraction of the population with high blood pressure. But it's actually prevalent in large populations in the developing world, places like China and particularly Sub-Saharan Africa. So high blood pressure is a major issue. So is tobacco, so is poor diet. And we've seen several aspects of poor diet that have contributed to disease burden in a significant way. Alcohol use causes a lot of disease and injury, not only fatal outcomes but a lot of non-fatal disease burden as well.

Norman Swan: Alan, you've spent…Chris has tended to focus more on the global picture and mathematical modelling, which we'll come back to in a moment, you've tended to focus more on looking at countries and the burden of disease locally and getting accurate measurement and you've been funded by Bloomberg to do this. Just tell us about some of the work you've been doing because you've got this interesting concept called verbal autopsies.

Alan Lopez: That's right Norman. One of the fundamental things Chris and I discovered a couple of decades ago was that to really reduce uncertainty in what we are measuring in terms of disease burden we need to focus on what people are dying from. If we don't have some handle with some reliability on the major causes of death in populations, then we're going to have significant uncertainty in our estimates. And one way to reduce that is to work with countries to improve the quality of their cause of death systems. We take it for granted in Australia or the US when someone dies that a doctor will reliably certify what they died from, and that by aggregating those data, governments in these countries have reliable information on which to act. And by and large they do.

But in many developing countries in the region here—Indonesia, Philippines, Sri Lanka, even China—those data are not readily available. And so one needs to think creatively about how can we cost effectively help these countries to leapfrog the 100 years of investment that countries like Australia put in, in order for them to get reasonably reliable information on leading causes of death today. And one of the most promising techniques to do that is a thing called verbal autopsy where trained interviewers…and they do not need to be doctors, but community health workers who are well trained interview a family for 20 minutes, and using algorithms that Chris and I and others have developed you can then reasonably reliably predict the cause of death in those communities.

Norman Swan: Any surprises there?

Alan Lopez: Big surprises. For example, in the Solomon Islands where we've done this we have now collected over 500 verbal autopsies and it made the front page of the Solomon Islands Times where they said 'We are all dying from heart disease and stroke, or at least in much greater fractions, than we had predicted. We thought we were still dying from measles, malaria and TB.'

Norman Swan: So it's reprising the early '80s, an intensive global burden of disease study.

Alan Lopez: Exactly, exactly.

Norman Swan: So when you both look at the future based on what you know now and the trends, Chris, what does your modelling tell you about health systems, where we're going and what we can do about it?

Chris Murray: So years ago, 20+ years ago, Alan and I had developed some very simplistic forecasts, and then this last fall we've actually launched a much more sophisticated future scenario platform which allows us to think both what's likely to occur, and then what are the ways we can change the trajectory. And that analysis says that this transition towards NCDs is likely to continue. Life expectancy is likely to continue to grow, but probably at a slower pace because of some of the factors like obesity that are coming down on the trajectory for many countries. And the sort of slowdown in the decline in cardiovascular disease that we've observed in places like Australia or the US or the UK, those combined say that the future looks positive but some of that progress is at risk. We also frame a better/worse scenario, and the range between better and worse, which is really driven by how well we manage the big risk factors and manage the growth of healthcare systems, is really quite a large.

Norman Swan: And briefly, Alan, one of the concepts 20-odd years ago was 'best buy'. What's the best buy at the moment in prevention around the world?

Alan Lopez: Well, I'd be looking at the main causes of health loss in populations, Norman, things like high blood pressure; what can you do about it that would bring down levels of blood pressure in population? Even a small change in a larger risk like high blood pressure would yield significant population health benefits. So we know we have established treatments for bringing down the blood pressure. Why are we not getting these treatments to the population in need? They are off patent, so the cost of these treatments is not great. So something in our health system that is not functioning in order to bring down these disease burdens through more effective treatments, same with tobacco. We know what to do.

Norman Swan: Thank you very much to you both.

Professor Chris Murray is director of the Institute for Health Metrics and Evaluation at the University of Washington, Seattle. And Professor Alan Lopez is in the School of Population and Global Health at the University of Melbourne.

That's the Health Report for this week, hope you can join me next time.