EP 26 - Article Of The Week: Clinical severity in Parkinson's disease is determined by decline in cortical compensation

🎙️ We’re back with the twenty-sixth episode of Parkinson Weekly, hosted by Prof. Bas Bloem.

In Episode 26, Prof. Bloem explores a thought-provoking shift in how we understand Parkinson’s disease progression.

Inspired by a 2024 study published in Brain by Martin Johansson and colleagues, the episode examines whether we may have been focusing too heavily on the substantia nigra — and overlooking the crucial role of the brain’s cortex.

Drawing on data from the Parkinson Precision Project, the study suggests that faster disease progression may be driven more by a breakdown in cortical compensation than by continued degeneration in the basal ganglia.

Prof. Bloem discusses what this could mean for future disease-modifying strategies, and why approaches that support or protect cortical function — including exercise — may become increasingly important.

A short but impactful episode that challenges conventional thinking and opens new directions for Parkinson’s research.

Article can be found here: https://pubmed.ncbi.nlm.nih.gov/37757883/

Have a question you’d like Bas to answer in a future episode? Email us at parkinsonweekly@gmail.com – we’d love to hear from you.

Transcript

SPEAKER_00 0:01

Everybody in the Parkinson field is interested in developing new treatments that can slow down the progression of Parkinson's disease. The dopamine-producing factory in our brain. But a study published in 2024 suggests that maybe, maybe we are barking up the wrong tree. Do you want to understand why this is the case? Listen to episode 26 of Parkinson Weekly. So, a brand new episode of Parkinson Weekly, and although I promised you that I wouldn't bore you too much with studies that were produced by colleagues in my own group, I am discussing a paper today that was produced by Rick Hellmich as a supervisor and his team at the Rottboute University Medical Center, which I think is just a lovely study that should hopefully change our thinking, make us rethink how we should look at disease-modifying strategies in people with Parkinson's disease. It's a paper called Clinical Severity in Parkinson's Disease is determined by decline in cortical compensation, published in Brain, which is one of our leading journals in the field. First author's Martin Johansson, who defended his PhD thesis successfully in Rick Helmick's group not too long ago. So the topic of the study was to try and find out what exactly determines disease progression in Parkinson's disease. Because if we understand the determinants of disease progression, we can develop better-tailored disease modifying strategies that tackle the underlying disease processes. And very specifically, what Martin and Rick were interested in is what really determines disease progression most. Is it further degeneration of the substantia nigra, the area in the brain that has received by far most attention in our field? It is the area that produces dopamine, where a lot of the lesions are happening, where we can find the Lewy bodies, which is associated with the loss of dopamine, and of course dopamine replacement therapy is leading to significant clinical improvements. But Rick was wondering with his group whether perhaps at least part of the progression was also caused by a collapse of cortical compensation. And the reason why there is so much interest in cortical compensation is that there is very interesting work to suggest that a lot of the functions of the basal ganglia, which are damaged in early stages of Parkinson's disease, can be taken over by healthy brain areas, for example, in the brain's cortex, the outer area of the brain, in order to compensate for the loss and the damage in the deeper structures in the basal ganglia. And there is good work, in particular from functional neuroimaging, to suggest that this is the case and that people with Parkinson's disease can still perform a task reasonably well, even in the face of a severe lesion in substantia nigra, because the task is now subserved by other areas in the brain, which in many ways is a really cool way of thinking about how the brain functions. It's a wonderful idea that healthy brain areas can take over functions of diseased brain areas. And this is also known from the field of stroke, where healthy brain areas can also take over functions of damaged brain areas. And what we know is that there are people with Parkinson's disease with a relatively fast progression, and there are people with Parkinson's disease with a relatively mild progression. And Martin and Rick were wondering what makes the difference between a fast progressor and a slow progressor? Is it the decline in the substantia nigra? Or is it because the cortex starts to collapse, depriving people of their ability to compensate for the lesions in the basoganglia? And they went to take on this hypothesis to the test in the PPP project. This is the Parkinson Precision Project, the personalized Parkinson Precision Project, executed at my own center at the Rudbaud University Medical Center, which is a longitudinal cohort study in a deeply phenotyped group of, in total, over 600 individuals who all received extreme deep phenotyping, including structural and functional MRI, all within the same center on the same scanner. Everybody had the same structural MRI, but Rick and his team also deployed three different tasks in subgroups. So for a particular task, a so-called visual motor task, they had 353 persons with Parkinson's disease and 60 matched healthy controls. I mean, imagine for a neuroimaging study, over 350 participants with Parkinson's is an insane number. All on the same scanner. So that's rather unique and special. And the main findings to my mind are really interesting. And in the show notes, I'm giving you two graphs to show you on the left side in the graph, you see disease progression in this large cohort related to decline in the putamine, and the putamin is a part of the basal ganglia, and the correlation between progression of the disease, in other words, differences between fast and slow progressors, and the relationship to further degeneration of the putamin is a flat line. The basal ganglia could not explain why fast progressors were different from slow progressors, but instead, a particular area in the brain's cortex, in this case the superior parietal lobule, which the investigators studied on purpose because it was in prior work associated with taking over functions of the basoganglia. When that area started to collapse, then this did correlate with progression of bradykinesia, disease severity. So it was the collapse of the cortex and not collapse of the basal ganglia that explained a faster progression in motor disability. And similarly, and this is a second figure that I'm showing in the show notes, the same applied to the decline in cortical and cognitive functioning. Again, if you looked at fast progressors, slow progressors for cognitive functioning, and if you correlate that to degeneration in the putamen, in the basoganglia, it was a flat line. But if they correlated this in this instance to the premotor cortex, another part of the brain's cortex, there was a very strong correlation. In other words, the more the premotor cortex declined, the faster people's cognitive function went down. And I think this is a really important finding. First of all, the strength of the study is that this is a unique cohort. The personalized Parkinson Project is a rather unique study because it included a highly representative real-life population. The inclusion criteria was deliberately very liberal. The inclusion criteria were also stratified so that if there were enough men, they stopped including men, so that, for example, gender was having a fair representation. They had a fair reputation of younger and older people, high and low education, etc. And it did, and again, this was a single-center study. All people were tested in the same center and the same scanner. So that is a unique and particular strength of the study. Of course, no study is without any flaws. An area for improvement is that this study only used clinical measures as indicators for disease progression. We know that the clinical scales are highly variable. They are subject to intra and intra-rater variability. What is really interesting is that this personalized Parkinson project also included wearable sensors from which we are now deriving digital progression biomarkers. That is not part of the present analysis, but I think that should be done because ultimately I think that a digital biomarker gives you an objective quantitative measure for disease progression 24-7 in the person's own home situation, as opposed to the rating scales which we take once every year in the clinic, which is a highly biased situation. Another drawback of the study is they looked at one specific functional task, but there are obviously many other imaging modalities that can be tested: neuromelanin scans, structural imaging, other functional tasks. So this is all work that needs to be done. And another drawback is that the follow-up in the present study was only short. People were followed for up to two years. But what is really interesting is that this cohort will now receive a new assessment eight years after the baseline assessment. So some of this work can now be repeated and look at long-term progression because one would expect that as the disease progresses, the pathology might reach the cortex of the brain in a greater number of cases or to a greater extent. So one would expect a further decline of the cortex and thereby an even better correlation with disease progression. The reason I am personally so excited about this finding is that, as I indicated in the beginning of this Parkinson Weekly, is that most attempts to build and evaluate disease modifying strategies is that these efforts are focused on protecting the substantia nigra. And I'm not saying that this is wrong, but what we know from several studies is that by the time we diagnose Parkinson's, the substantia nigra is already, by and large, kaput, damaged. And after several years of the disease, there are hardly any living neurons left in the substantia nigra. So what is there left to protect? This is exactly why many international efforts focused on designing and evaluating disease-modifying strategies are moving a phase earlier to the prodromal phase, to the lead-up phase of Parkinson's. But if you want to develop a strategy that slows progression in clinically manifesting people, maybe we are barking up the wrong tree if we focus only on the substantia nigra, and maybe we should focus on protecting the cortex. And one way to protect the cortex, and apologies for quoting yet another study by my own group, is exercise. One of the more interesting studies that I was personally involved in was the study by Nicoline van der Koolk. I'm showing the reference in the show notes, published in Lancet Neurology, which was an exercise study where people were asked to exercise three times a week on a stationary bicycle at home for about 30 minutes. And the results were evaluated both clinically and using neuroimaging. The clinical results showed that there was a more stable disease course in exercising people compared to a control group only doing stretching exercises. But importantly, when we looked at the neuroimaging findings in a subgroup of participants, this was work separately published in the Annals of Neurology. Again, the reference can be found in the show notes. Again, Rick Helmick and the same Martin Johansson found in a beautiful analysis that the exercising group made new or better connections between the diseased basoganglia and the cortex, suggesting that through exercise people were better able to engage the cortex. Whether it protected the cortex from degeneration was not shown by this study. One can only speculate about this, but certainly the compensatory activity of the cortex could perhaps be better recruited through exercise. And I think it is really interesting to speculate with colleagues in the field what attempts we can make to better protect the cortex. Is it strategies aimed at preventing alpha-synuclein pathology from spreading? Or could there be other ways of keeping the cortex fit and healthy, perhaps using stimulating neurophysiological stimulation techniques to stimulate cortical neurons? So I think this is all really interesting and encouraging. How will this affect clinical practice tomorrow? Well, I think for researchers, this should be a motivation to not just look at the NIGRA, but to also think strongly about how to protect the cortex. And I think for anybody affected by Parkinson's, or if you have a near one in your vicinity who is affected by Parkinson's, I think this is a powerful incentive. For example, to keep exercising, because we know exercise is one of the possible mechanisms to protect the brain's cortex or to engage the cortex and thereby ascertain a better future, perhaps slow down disease progression. It's work in progress. This is far from definitive. It's early days, but I think it's a provocative study, interesting study that really shaped my thinking about how to look at disease progression in Parkinson's. I hope it will affect your line of thinking as we move on in this very important field. Thank you for listening. This was episode 26 of Parkinson Weekly. Look forward to seeing you again next week.

SPEAKER_01 15:54

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