Can we measure Parkinson disease severity with levodopa and MRI?

What is it about?

Levodopa (L-DOPA) is the most effective medication for treating Parkinson disease (PD) symptoms. Other scientists, like Maria Contin, showed that the timing of a PD patient's response to a single dose of levodopa provided a good indicator of how severe the disease was: namely, people with mild disease have improved symptoms for many hours after the levodopa has disappeared from of the bloodstream, whereas in severe disease, the benefit wanes quickly. We and others had shown that levodopa produced robust brain effects that we could measure using a special form of MRI, and hypothesized that we could measure the timing of levodopa's effect--and hence disease severity--using MRI rather than clinical measures. We predicted that such a measurement might be more reliable and that it might also allow measurement of disease progression in different parts of the midbrain (through their effects on different parts of the rest of the brain). So this study is only a first step, using mathematical modeling. We combined published data on clinical responses to levodopa, information about brain blood flow responses to levodopa, and the pharmacological mathematical models others had developed, to test whether people with milder and more severe degrees of PD are expected to have different enough MRI response timing to allow accurate measurements of disease severity. Short answer, it's not perfect, but it looks like there should be a clear difference in the timing of MRI response to levodopa across a range of PD severity, especially in people with moderate to severe disease (see Figure 6 here: https://www.frontiersin.org/articles/10.3389/fneur.2020.00370/full#F6).

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Why is it important?

Measuring the severity of PD is important for several reasons. The most important may be for studies of treatments proposed for slowing the progression of the illness: to know if the treatment is working, you have to have a way of quantifying disease severity. The obvious way of doing that is to measure symptom severity, but it turns out that doesn't work unless you take people off effective medications for at least several weeks. Alternatively, you can conduct a very long, very expensive clinical trial, delaying treatment initially for many months in one group. Neither of these is an appealing option. Autopsies can quantify disease severity, but waiting until people die is not a useful approach for treatment development. For years, people have tried to measure disease severity based on PET or SPECT imaging in the putamen (or striatum). However, a few years ago my colleague Joel Perlmutter showed that this approach failed after about half the dopamine-producing cells in the midbrain had disappeared--and symptoms come mostly after more than half of those cells have died. He and his colleagues then showed that PET imaging of the midbrain does accurately measure midbrain dopaminergic cell death during life, but there is not a great deal of published data yet with that approach. A few other methods have been proposed or tested, including measuring brain structure in various ways with MRI. None has yet become well accepted. So if this method works, it will provide an alternative to the approaches mentioned above.

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