New diagnostic and staging framework applied to established PD in the BioFIND cohort

Abstract

The proposed Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS) was recently applied to early Parkinson's disease (PD) cohorts. We applied this research framework to the BioFIND study cohort, which includes more moderately advanced PD participants with clinically established PD. Disease durations within each ISS stage were highly variable. Cognitive and non-motor anchors had little weight in determining staging. The analysis highlights strengths and limitations of NSD-ISS to guide further refinement of an integrated staging system.

Fig. 1. NSD-ISS Applied to BioFIND.

A Selection of BioFIND participants with evidence of α-synuclein as biological anchor through CSF α-synuclein seed amplification assay (αSyn-SAA). These 104 S+ participants were stageable by NSD-ISS criteria. A single bar plot shows the number and percentage of S+ participants within each clinical stage. Again, no dopamine imaging is available within BioFIND, so these participants are minimally stage 2 A and likely stage 2B, but we did not make this distinction. B Duration of disease, defined as time since diagnosis, for all participants, within each clinical stage. Each marker is a single participant. Black bars represent median, and colored blocks indicate interquartile range (stage 2: 5.4 [2.3]; stage 3: 5.8 [4.9]; stage 4: 6.5 [4.1]; stage 5: 10.8 [4.5]; median [IQR], non-parametric Kruskal-Wallis H-statistic 87.5, p = 0.44). C MDS-UPDRS Part III score when off of motor medications (OFF) is plotted versus MDS-UPDRS Part II scores for each S+ participant – each point represents single participant. NSD-ISS stages are represented by color with key provided in legend. Note the variability of MDS-UPDRS Part III OFF scores within each stage, and overlap across stages. Dotted lines indicate the 25th, 50th (median), and 75th percentiles of UPDRS Part III OFF scores. D Bar plots indicating distributions of NSD-ISS stages within each Hoehn & Yahr (HY) stage within BioFIND (percentages indicate fraction of each NSD-ISS stage within each HY stage). E Fraction of tremor-dominant (TD) and postural instability & gait difficulty (PIGD) motor phenotypes within each NSD-ISS stage within BioFIND. F Plot of Montreal Cognitive Assessment (MoCA) score versus MDS-UPDRS Part I Question 1.1 score (Q1.1) for each BioFIND participant, with stages indicated by color. Dotted line indicates MoCA score = 25, which is the typical delineation of mild cognitive impairment and is the demarcation of cognitive progression in the NDS-ISS. Points are ‘jittered’ from the integral abscissa for visibility.