AAN 2024 | Quantifying cutaneous alpha-synuclein to diagnose and differentiate synucleinopathies

Well, synucleinopathies in general are challenging disorders to diagnose. They come in a variety of flavors; things like Parkinson’s disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure. Even though they have the same underlying pathology – a misfolded protein – they are very clinically different disorders and have different natural histories, outcomes, mortality, morbidity. As a consequence, these can be challenging to diagnose accurately. The need to help both physicians and patients come to a more accurate and rapid diagnosis has been a critical need for decades. The goal of trying to find a biomarker that can help accelerate this process has been work we’ve been interested in for many years.

One of the things that we’ve been particularly interested in is the use of skin biopsy to detect this misfolded, phosphorylated alpha-synuclein. The protein itself, when it’s misfolded, may deposit in the central nervous system, so typically we think of autopsies as the kind of diagnosis. This, of course, does not help patients at the time. What we’re looking for is a very simple way to achieve samples of skin that contain nerves and detect this protein within these nerves. But even that requires a pathologist to spend a lot of time looking at skin samples to identify this. So, what we’ve been able to do is use high-resolution image scanners to detect the whole piece of tissue and digitize it, and then allow artificial intelligence-supported computer algorithms to really recognize these proteins in the skin, measure them, quantify them, and then display them back to the pathologist and say, look here, this is where it’s located. This can be much more efficient for the pathologist, much more accurate, and allow us what we call a continuous, quantifiable measure, which really means that we can tell someone exactly how much protein they have there. Ultimately, if we can develop a drug that can reduce that protein, that’s really what we’re all waiting for, which is a treatment

So, what we can find now is that in general, skin has always been very sensitive and specific for detection of this protein. But now we actually increase that sensitivity and specificity further. It allows us to be more sensitive and specific; it allows us to categorize where the protein is deposited. If it’s deposited within certain regions of the skin, such as sweat glands or just below the epidermis (the very superficial layer of the skin), these may indicate different types of disease. So for example, multiple system atrophy, which is unfortunately a very aggressive synucleinopathy, may be deposited right below the skin. The computer can now tell us that’s where it’s located and may indicate very quickly that this is the underlying diagnosis. So, this has improved how fast we can make the diagnosis and allowed an improvement in accuracy.