PET to image onset of Alzheimer's

How can PET imaging be used to look at protein build ups in the brain?
26 January 2021

Interview with 

Justin Sanchez, Massachusetts General Hospital and Harvard Medical School


Alzheimer's Disease is thought to be caused by the abnormal build up of proteins in and around brain cells. A key priority in Alzhimers research is finding ways to get vulnerable people treated earlier, when interventions are more likely to be effective. And so understanding what happens in these protein build ups early on in the brain is a crucial question to answer. So could imaging where the protein build ups are happening early on in someone’s journey to Alzhiemers help with drug trials to treat these build ups, or potentially even diagnose people earlier? This is the hope of scientists from Harvard, including Justin Sanchez, who, having laid the groundwork with MRI has just published a paper about a new way of using PET to do exactly this. Adam Murphy spoke to Justin, asking first how the use of PET in this context compares to the use of PET to look at cancer cells...

Justin - The idea is basically the same: that you're injecting a radiotracer into the body, and then tracking it within the PET camera. But the difference here with Alzheimer's imaging is that we've designed these tracers to bind specifically to the proteins that we know build up in the brains of people with Alzheimer's, namely amyloid beta and tau. So by using these advanced PET imaging methods, we're able to now detect the early stages of Alzheimer's pathology, and also track changes over time.

Adam - Where exactly in the brain does this tend to show up? Is there anywhere in particular you're looking?

Justin - Yeah, so we know from autopsy studies of Alzheimer's disease that tau accumulation tends to follow a pretty stereotyped pattern; namely, it begins in this very specific area of the brain's medial temporal lobe that we call the transentorhinal cortex. And from there, as amyloid is also accumulating, it spreads to other regions of the brain and what we call the neocortex. And we really think it's this neocortical tau accumulation that is the bullet that really injures brains in Alzheimer's disease.

Adam - Now you looked at about 400 odd people from a huge range of ages. So what is it that you actually found out about tau?

Justin - What we applied here was a sort of automated method for identifying, in each individual person, this region of earliest vulnerability to tau accumulation. So we know to look in the transentorhinal region for the initial stages of tau, but the challenge that we face is that each person's brain anatomy is slightly different. And so what we did was basically modelled the surface anatomy of each person's brain as a kind of map; you can think of like a map of hiking trails, where you have the mountains and the valleys, and those corresponded in our data to the gyri and the sulci - the hills and valleys of the brain. And then we implemented an algorithm that would automatically identify the valley in which the transentorhinal region is found, accounting for individual differences in surface anatomy. And so we looked, as you say, across about 450 people, spanning the whole range from 20 year old healthy people to older folks with a diagnosis of dementia; and we looked along there to see at what point we observed the initial accumulation of tau. And what we found was that, even as early as 58 years old in patients without dementia or without even significant amyloid accumulation, we were already able to detect these very earliest signs of tau pathology.

Katie - Justin, what does this mean for people who go on to develop Alzheimer's? Because these buildups can occur, but it doesn't necessarily mean someone's going to get Alzheimer's.

Justin - That's exactly right, yeah. So it's still kind of an open question for us what level of tau is really dangerous. Because the autopsy data would suggest that about half of people, by the time they're 50 years old, have some degree of tau accumulating in their brain; but obviously not everyone is going to go on to develop Alzheimer's. So we wanted to know in this study - and we followed people over over two years to track the changes longitudinally - we wanted to know what basically were the best predictors, at baseline, of your going on to accumulate this neocortical tau pathology that really does the damage in Alzheimer's. And what we found was that applying this method that we developed to identify this transentorhinal region, and measuring tau there, in combination with amyloid beta, did the best job of predicting who would go on to accumulate tau in additional brain regions onto your followup. So this really has implications for ongoing work in clinical trials, for these drugs that we're trying to treat Alzheimer's; we really want to get in at the earliest stages in order to hopefully prevent the catastrophic tau spread before it really becomes a problem for people.

Katie - Do you think this technique is about applying this to research methods, like you said, or do you think it could be used to actually diagnose people really early on?

Justin - At this stage our work is sort of translational in between the basic science, because there's still a lot that we don't know about Alzheimer's, its natural history and progression. But yeah, we're hopeful that in the long run this will be a very useful diagnostic tool for neurologists in the clinic; and hopefully catching it early on and being able to provide effective treatment strategies.


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