Application of the Movement Disorder Society prodromal criteria in healthy G2019S-LRRK2 carriers

This is an interesting application of the MDS Task Force criteria for prodromal PD. Here the Ashkenazi Jewish consortium applied the MDS criteria to non-manifesting carriers and non-carriers of the G2019S-LRRK2 mutation. 

Despite relatively small numbers of participants being diagnosed with PD during the follow-up period, they report impressive specificity of the criteria for idenitfying those in the pre-diagnostic (prodromal) phase of PD. 8 of the 10 patients (80%) that were diagnosed during follow-up were in the highest probability group at baseline. Unfortunately I could not find the raw data in the manuscript to determine how they arrived at 91.8 % specificity but working backwards from the reported specificity and positive predictive value I think there must have 9 out of 110 (8.2%) who were in the high probability group  at baseline, but did not subsequently get diagnosed with PD during follow-up. It will be interesting to see what happens to those participants with more time.

The positive predictive value (PPV) tells us about the probability of getting a diagnosis of PD over time if you are in the highest risk group at baseline. Based on the follow-up so far, 47% of people that screened positive at baseline have been diagnosed with PD. Whilst that's approximately 50:50 - if you imagine a scenario where a preventive treatment were available and the toxicity or side effects of that treatment were low then perhaps 50% PPV for a screening test is not widely inappropriate. Of course these data only apply to carriers of the G2019S LRRK2 mutation which in itself puts people at significantly higher risk of PD. The MDS Task Force criteria have been applied to other at risk cohorts, but we are in the final stages of applying them to the PREDICT-PD population-based cohort... watch this space.

- Alastair Noyce

Mov Disord. 2018 Mar 30. doi: 10.1002/mds.27342. [Epub ahead of print]
Mirelman A, Saunders-Pullman R, Alcalay RN, Shustak S, Thaler A, Gurevich T, Raymond D, Mejia-Santana H, Orbe Reilly M, Ozelius L, Clark L, Gana-Weisz M, Bar-Shira A, Orr-Utreger A, Bressman SB, Marder K, Giladi N; AJ LRRK2 Consortium.

https://onlinelibrary.wiley.com/doi/full/10.1002/mds.27342

BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD.

OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters.

METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point.

RESULTS: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers.

CONCLUSIONS: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society.

 © 2018 International Parkinson and Movement Disorder Society.