I’m Jürgen Götz, neuroscientist. My lab has reversed Alzheimer’s symptoms in animal models. AMA.

Have you been able to reverse the symptoms in unattractive or homely animals as well, or just the models?

The treatment doesn't discriminate!

Thank you for your hard work. Is the time from testing to market frustrating for you as someone who clearly sees the potential your work has?

It is frustrating but it's inevitable because we don't want to make any mistakes on our journey. We don't want to ruin the potential applications of this fascinating technique by rushing the process. Especially in terms of safety, we are running a lot of studies; the medical device needs to have an online monitoring system to ensure safety – this requires some further work and time, but we're working with an engineering company to streamline the process as quickly as we can.

I must say that I'm a huge fan of your work. SUS is probably the coolest development in neuroscience in the last 15 years. I’ve been waiting for the opportunity to ask you these questions for a long time now. Hopefully you can answer them:

1) How do you expect SUS coupled with microbubbles therapy to translate into humans? How do you plan to overcome differences in skull thickness and overall head size?

2) In your paper titled "Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer's disease mouse model", you find that microglia is activated by SUS. How can you see a 5-fold increase in the area of CD68 immunoreactivity without alteration in the size of microglia cell bodies?

3) In all your studies (that my university's library grants me access to read), you employ microbubbles without SUS as control, but not SUS without microbubbles. Why not test the effects of SUS on its own?

4) What's the point of focused ultrasound beam if you're going to move it in 1.5 mm increments to cover the entire forebrain? Why not use a more diffuse beam and then move it in larger increments?

5) If you hypothesize that SUS coupled with microbubbles works by opening the BBB, why do you need to sonicate the entire forebrain with SUS and not just the areas adjacent to the BBB?

6) When I was reading your papers, I was visualizing a plumber who was using a big vibrator to shake a partial blockage through a pipe as water is flowing through it, and using the content inside the pipe to remove the soft sticky goo that's blocking the pipe. Is it possible that SUS coupled with microbubbles doesn't actually work by opening the BBB, but rather, that it works by using those non-sticky microbubbles as the content inside the pipes that's vibrating and causes amyloid plaques to lose their grip on blood vessels? If my hypothesis is correct, you would find a milder (but still significant) reduction in amyloid plaques with SUS without microbubbles, and you would also find a reduction in amyloid plaques if you had sonicated the entire forebrain with SUS after microbubbles injection, but prevented the vibration within the BBB. Basically, what I'm saying is that opening the BBB isn't a requirement for SUS coupled with microbubbles to work, it's just a nice bonus.

7) Are you looking for new research assistants or graduate students? Asking for a friend ;)

Thank you for your interest in our work.

1) One option we are exploring is phased-array systems in order to avoid heating of the human skull and inefficient delivery of energy to the target area. 2) CD68 is a lysosomal marker. We see a massive uptake of amyloid into microglial lysosomes. We don't see increases in microglia numbers, but changes in their morphology, which is more important than a change in size and is indicative of activation state. 3) Without microbubbles, we would need much higher SUS energy, which could be damaging to the brain tissue. 4) Our experiment was dictated by the availability of the transducer system and we have since also used more diffuse transducers which have achieved similar outcomes. However, having a more focused transducer allows a more targeted approach. 5) Each neuron is in close proximity to capillaries (ie the BBB is present all throughout the brain), and Alzheimer's disease pathology is found throughout most of the brain. 6) We believe that mechanisms in addition to microglial activation act to remove toxic amyloid. 7) Always looking for capable hands (and brains)! You can contact the team if interested.

What is the mechanism of removal of the proteins associated with Alzeheimer's?

I know there's been work with ultrasound that helps therapeutic drugs cross the blood-brain barrier - Is your work related to this or something else entirely?

Thanks!

What we found was that ultrasound works together with microbubbles, which are commonly used as a contrast agent in imaging. What the ultrasound does is interact with the microbubbles, causing them to oscillate and open the blood-brain barrier by exerting a mechanical force onto the blood vessels. What's then happening is that blood-borne factors enter the brain and stimulate microglia cells to take up and digest toxic amyloid protein. As a consequence, cognitive functions including memory and learning is restored.

We have also shown that ultrasound helps to deliver therapeutic antibodies across the blood-brain barrier. There's huge potential in this approach, because this method dramatically increases how much drug reaches the brain – current studies have shown that only 1–2% of brain drugs actually reach the brain.

That's really fascinating, thanks!

Are there any potential complications associated with the ultrasound process? From how you described it (exerting a mechanical force onto the blood vessels), it sounds like there's potential for damage to the blood-brain barrier or brain tissue itself.

That's a good question. The potential damage lies in microbubbles bursting (the technical term is inertial cavitation) rather than the very subtle mechanical forces exerted onto blood vessels. We are working on ways to monitor microbubbles to prevent inertial cavitation from happening and any device would have in-built safety feedback mechanisms.

Also, ultrasound has previously been proven to be safe in various animal and human studies, which includes a clinical trial to treat brain tumours with ultrasound (SonoCloud trial).

Did you encounter any notable side effects so far? Ultrasound treatment sounds too good to be true IMHO.

Vielen Dank für eure Arbeit. Alzheimer ist eine grausame Krankheit.

Ultrasound is highly tuneable and with too much pressure it's possible to cause damage such as bleeding, which we have avoided in the animal experiments and which we obviously want to avoid in any human trials.

Es ist absolut richtig. Alzheimer's ist eine grausame Erkrankung!

Could this ultrasound mechanism be used to treat other neurodegenerative diseases?

Thank you for your time and dedication to your helpful work.

Absolutely. The underlying principle of neurodegenerative diseases is the aggregation of insoluble proteins. These diseases have been termed 'proteinopathies', and include conditions such as Parkinson's disease, motor neurone disease, Huntington's disease and dementia with Lewy bodies.

Ultrasound should assist in clearing any of these protein aggregates from the brain. We have now shown the underlying principle of the ultrasound to be successful in targeting tau and amyloid-beta proteins, and more work is currently being done in our lab looking at other protein aggregates. Watch this space!

How long before this research will be ready to treat humans?

We have already promising results in larger animal models using a simple ultrasound transducer. This is encouraging but we are doing much more work with multiple transducer elements, which need to be integrated into a device for humans, and this will take a couple of years.

Do you like cheeseburgers?

I'm more partial to a home-cooked meal, tbh.

Does your experience lend to the notion that Alzheimer's is likened to "type III diabetes" ? Multiple family members passed while diagnosed with this, including one recently from suicide who was affected by symptoms recognized in others. All of them were keen on sweets.

Alzheimer's has been labelled 'type III diabetes" for good reason. A lot of work nowadays goes into looking at co-morbidity. It's very rare that a person suffers only from Alzheimer's disease in the absence of any other conditions including cardiovascular disease or movement disorders.

are there other theoretical therapeutic applications of this technique being discussed?

Excitingly, yes. In principle, the technology can be used for any brain disease in which a therapeutic drug needs to be delivered. A current major obstacle for developing drugs to treat neurological diseases is the blood-brain barrier, which exists to keep out bacteria and toxins, but which unfortunately also keeps out most drugs that have been developed. What we've found is that using ultrasound transiently opens the blood-brain barrier, but without allowing bacteria and other nasty agents to enter. The benefit of this is that the ultrasound technique could vastly improve the spectrum of drugs that are available for neurological diseases.

Ultrasound is also highly tuneable so it's possible to target it to a specific brain area, for example, the substantia nigra, which degenerates in Parkinson's disease, or to the entire brain, to target the many brain areas that are affected in Alzheimer's disease or frontotemporal dementia.

Do mouse rights activists protest your research?

Fortunately not, partly because the studies we are doing are not invasive. Our work is overseen by many ethics committees to ensure that we're complying with animal welfare standards.

How is the study done? Don't you have to dissect the mouse afterwards to see if it worked? How will testing in humans work?

In humans, a PET scan before treatment would identify the amount of amyloid in patients' brains. After the treatment, a follow-up scan would determine how effective the treatment has been.

Are you familiar with the work of David Perlmutter? What is your opinion of a high 'good' fat diet, moderate protein and low carb diet to help stave off Alzheimer's?

I think a balanced diet is important – I would suggest avoiding processed foods as much as possible.

I watched a TED talk discussing the role of dietary iron and copper in AD, as well as animal fat. Is there any truth to the idea that a plant based diet delays or prevents AD?

There are many ways to delay the onset of Alzheimer's and in some countries incidence is actually decreasing, possibly owing to better nutrition. You can find some information about delaying or reducing the risk of getting Alzheimer's here: https://qbi.uq.edu.au/dementia/how-delay-dementia-and-reduce-your-risk

How far are you from human trials.

We're you able to see repair of the damage caused by the oxidative stress in the mitochondria?

We envisage that human clinical trials will be underway in a few years. We have worked a lot on oxidative stress and shown that amyloid beta causes oxidative stress, and removing amyloid beta reduces it. We have not shown specifically whether the ultrasound that removes amyloid also restores mitochondrial function, but we assume it does so.

In theory would this be utilized in early or late stage Alzheimer's?

The method would be used at a relatively early stage, before the build-up of too much toxic amyloid protein has started to destroy nerve cells. However, having said that, ultrasound as a general tool to open the blood-brain barrier could also be a strategy that could eventually be applied to different stages of Alzheimer's.

My impression was that antibodies targeted against amyloid failed in clinical trials largely because they were tested in patients already with enough amyloid burden such that neuronal toxicity had already been achieved.

Do you expect that your treatment would work better than these antibodies, in a comparable test subject population?

I share this view that too little had been given too late in these failed clinical trials. Another issue is the definition of primary endpoints – how you monitor efficacy over short periods of treatments. We expect that ultrasound would better facilitate antibody uptake but even with ultrasound treatment, treatment would have to be administered early, before the point of no return, so to speak, when too much amyloid has already caused irreversible damage.

I used to work at QBI under Burne Eyles and McGrath!

Do they still do wednesday free seminars and subway?

Hello! Seminars yes, but unfortunately no Subway!

Do you have a paper of your study? If so, where can I find it..?

The abstract is here: https://www.ncbi.nlm.nih.gov/pubmed/25761889

Your doing the lords work!

What has been the hardest part of doing this?

What has surprised you to be easy?

The clear outcome of the initial breakthrough was surprising. The challenge now for us is to move into an unfamiliar space of engineering and simulations. Being trained as a biochemist, that's often outside of my comfort zone. However, it's also really exciting and rewarding.

Is your research applicable also to other types of dementias?

Yes, absolutely – it would in theory be able to be applied to all types of dementia involving protein aggregation.

Thank you for this potentially grounbreaking study!

I am wondering about the potential of blood-borne infections though and cerebrosponal fluid contamination.

Aren't bactererias, viruses and funghi susceptible to crossing the blood-brain barrier during inertial cavitation?

We have not seen any adverse side-effects in animal studies, nor have other researchers using a wide range of animal species. Bacteria and fungi are too large to enter the brain through the opening generated by ultrasound, and even for viruses there is a size limit. In addition, the brain has also developed efficient protective mechanisms to shuttle out toxic agents if they do enter the brain.

Do you think such treatments would also be adaptable to other forms of dementia, such Lewy Body Dementia?

Yes, absolutely – it would in theory be able to be applied to all types of dementia involving protein aggregation.

What similarities of the disease forming and removing have you found between mice and humans?

Biochemically, the disease in mice is very similar to that in humans – we see the same types of toxic protein buildup. However, mice are obviously less complex than humans in terms of their cognitive functions. The challenge for us as researchers is to translate the findings from animal models into human clinical trials.