Looking for a relevant clinical milestone to study in your next research? You've come to the right topic

Analyzing and Reusing Data
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I was recently tasked with creating a short presentation for the Global Parkinson’s Genetics Program pertaining to the usage of motor progression scores. This topic is very interesting to me, as I’m also required as per my PhD to evaluate the best ways possible we can understand motor and non-motor progression.

The idea of this topic is to briefly present to you some key aspects of the MDS-UPDRS and Hoehn & Yahr scales and to bring to you relevant milestones that were utilized in previous research. I hope this knowledge gives you inspiration for future research.

The importance of motor progression in PD

As most (if not all) of you know, PD is a neurodegenerative disease with motor and non-motor manifestations, with symptoms gradually increasing over time, as displayed by the graph below.

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Reference: Poewe W et al. Parkinson disease. Nat Rev Dis Primers. 2017.

Measuring how these symptoms progress is critical to discover new treatments, and most clinical trials and observational studies rely on clinical measures obtained by standardized rating scales to do so.

Here, I will show you one example. Below is a graph of a post-hoc analysis of a recent clinical trial involving a monoclonal antibody that binds aggregated α-synuclein. In this study, the authors demonstrated a possible neuroprotection effect of the drug (prasinezumab) as measured by the composite score of MDS-UPDRS Part I, II and III scale.

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Reference: Pagano, G et al. Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Nat Med 2024.
Legend: Blue lines represent patients that received the treatment, while the black line are the controls

The MDS-UPDRS and Hoehn & Yahr scales

So, what is this MDS-UPDRS we so often talk about? It is a clinical scale that evaluates non-motor and motor symptoms of PD It does so through the examination of 65 clinical features, which are individually measured in a scale from 0 to 4, with highest values indicating more impairment.

It is divided in 4 sections: Part I evaluates non-motor symptoms. Part II quantifies motor impairments in activities of daily living. Part III evaluates motor symptoms through a standardized neurological examination. Lastly, Part IV grades motor complications, such as dyskinesias and OFF periods.

Here is an example of a feature evaluated in Part III of the scale. Each side (R or L) is evaluated separately:

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As of the Hoehn & Yahr scale, it is a lot simpler. In this scale, patients are rated from stages 1 to 5 based on an overall impression of the physician of its motor capacity. It is formally present inside the MDS-UPDRS

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Selected MDS-UPDRS outcomes of interest

There are many different ways in which we could define outcomes in the MDS-UPDRS, but broadly, they are separated in a global composite, subscores and individual features usage. I will provide you with some examples for each category, most of which comes from high quality published research.

Global composite scores - one of the most utilized

  • Part II Sum

  • Part III Sum

  • Part I and II Sum

  • Part II and III Sum

  • Part I, II and III Sum

References:

Subscores - useful for detailed and specific phenotyping

Concept Variables(Items) PPMI Code
Speech 2.1 + 3.1 [“NP2SPCH”, “NP3SPCH”]
Tremor 3.15 + 3.16 + 3.17 + 3.18 [“NP3KTRML”, “NP3KTRMR”, “NP3PTRML”, “NP3PTRMR”, “NP3RTALJ”, “NP3RTALL”, “NP3RTALU”, “NP3RTARL”, “NP3RTARU”, “NP3RTCON”]
Gait and Postural Stability 2.12 + 2.13 + 3.9 + 3.10 + 3.11 + 3.12 + 3.13 [“NP2WALK”, “NP2FREZ”, “NP3RISNG”, “NP3GAIT”, “NP3FRZGT”, “NP3PSTBL”, “NP3POSTR”]
Bradykinesia 3.4 + 3.5 + 3.6 + 3.7 + 3.8 + 3.14 [“NP3FTAPR”, “NP3FTAPL”, “NP3HMOVR”, “NP3HMOVL”, “NP3PRSPR”, “NP3PRSPL”, “NP3TTAPR”, “NP3TTAPL”, “NP3LGAGR”, “NP3LGAGL”, “NP3BRADY”]
Axial scores 3.1 + 3.2 + 3.9 + 3.10 + 3.11 + 3.12 + 3.13 [“NP3SPCH”,“NP3FACXP”,“NP3RISNG”, “NP3GAIT”, “NP3FRZGT”, “NP3PSTBL”, “NP3POSTR]”
Left sided symptoms 3.3c + 3.3e + 3.4b + 3.5b + 3.6b + 3.7b + 3.8b + 3.15b + 3.16b + 3.17b + 3.17d [“NP3FTAPL”, “NP3HMOVL”, “NP3KTRML”, “NP3LGAGL”, “NP3PRSPL”, “NP3PTRML”, “NP3RIGLL”, “NP3RIGLU”, “NP3RTALL”, “NP3RTALU”, “NP3TTAPL”]"
Right sided symptoms 3.3b + 3.3d + 3.4a + 3.5a + 3.6a + 3.7a + 3.8a + 3.15a + 3.16a + 3.17a + 3.17c [“NP3FTAPR”, “NP3HMOVR”, “NP3KTRMR”, “NP3LGAGR”, “NP3PRSPR”, “NP3PTRMR”, “NP3RIGRL”, “NP3RIGRU”, “NP3RTARL”, “NP3RTARU”, “NP3TTAPR”]"

This list is not exaustive, however. Most of the concepts present here are described in the literature, although some were proposed by me. There is also the Tremor Dominant (TD) and Postural Instability and Gait Disorder (PIGD) classification, and I will leave a link in the reference part

References:

Individual features - relevant for specific investigations

A milestone based-strategy - suggestion of an article

I would also like to suggest everyone visiting this article (Parkinson's Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson's Disease Progression - PubMed). In this article, the authors propose clinically significant outcomes across six different domains. The authors postulate that an early-stage PD patient needs to present one of the selected features in one domain within 5 years to be considered as having achieved this outcome. I believe that, even though this analysis is centered on PPMI data, the definitions proposed here could be applied to other research settings.

Pitfalls in dealing with motor progression scores

I would like to highlight some possible pitfalls you might face when dealing with motor progression scores. First, symptom’s intensity depend on diverse clinical conditions, and situations as the patient being examined in the OFF or ON state, being insuficiently treated, and being treated with Deep Brain Stimulation can impact the measures.

Also, the MDS-UPDRS is affected by measurement error and previous studies have shown that this scale, even though validated, can present poor longitudinal within-subject reliability (Measuring Parkinson's disease over time: The real-world within-subject reliability of the MDS-UPDRS - PubMed) and limited inter-rater reliability in mild symptoms (Assuring interrater reliability for the UPDRS motor section: utility of the UPDRS teaching tape - PubMed).

Lastly, we might ask ourselves: what is clinically significant? If I tell you that a patient presented a 2 point decrease in the total MDS-UPDRS since his last evaluation, is that meaningful? So keep this in mind!

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Thank you for the insightful overview, @danieltds! I agree that using milestones is a useful approach to navigating the clinical progression of Parkinson’s Disease. The binary outcomes (whether or not the milestone is reached) are straightforward, yet the robustness of this method is critical.

One of the primary sources of variability in measuring PD outcomes is the On/Off status. The PPMI includes the MDS-UPDRS for both On/Off statuses. @danieltds, exploring how medications affect the subscores could be intresting. Although axial scores are generally considered less responsive to medication, my preliminary comparisons between On vs. Off statuses and visits before vs. after medication initiation showed significant variability in HY scales and axial-related items.

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Hey Daniel. I think the tittle you used is very appealing, and a nice way to engage in reading the new posts, so I will definitely adopt this way of posting!!! Super engaging!

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