Progression in the LRRK2-Asssociated Parkinson Disease Population.

I think this is a really important study.

We have long suspected that patients with LRRK2-associated PD manifest Parkinson's in a different way to those that don't carry LRRK2 mutations. Here the authors show differences in the rate of progression of motor features – those with LRRK2-associated PD progress at a slower rate. This fits somewhat with notion that LRRK2 patients run a more benign course than 'regular PD' but what is at odds with this is that more of them had the postural instability gait disorder (PIGD) type of PD which is usually associated with a poor prognosis. The authors don't mention it much in the discussion but what is interesting to me is that the increase in PIGD type cases is not the result of a reduction in tremor-dominant cases, so much as a reduction in the indeterminate type. To me these observations lead to interesting questions:

1) Do LRRK2 patients fit into these two subtypes of PD better than those without LRRK2 mutations?? This is plausible because one would expect the pathology of LRRK2 to perhaps be less heterogeneous (even though a range of pathologies have been reported). 

2) Is there an imaging correlate for these different types in LRRK2 cases?

3) Does this tells us about the outcome measures we should be selecting for clinical trials in LRRK2 patients? And indeed,

4) Does it give us increased confidence that as a result of less heterogeneity (whether clinical or pathological) we would be more likely to detect an effect of a disease modifying therapy?

I was interested in the cognitive progression too. It fell short of nominal statistical significance but the MoCA is a relatively blunt tool for testing cognition and I expect that there would be differences in favour of slower progression in LRRK2 carriers if domains were studied more fully.

Important to exclude the GBA carriers in this work because they could bias the results, but there are other genetic factors that can influence seemingly monogenic forms of PD and should be kept in mind in future work.

- Alastair Noyce

JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4019. [Epub ahead of print]

Saunders-Pullman R, Mirelman A, Alcalay RN, Wang C, Ortega RA, Raymond D, Mejia-Santana H, Orbe-Reilly M, Johannes BA, Thaler A, Ozelius L, Orr-Urtreger A, Marder KS, Giladi N, Bressman SB; LRRK2 Ashkenazi Jewish Consortium.

https://jamanetwork.com/journals/jamaneurology/article-abstract/2668463?redirect=true

IMPORTANCE: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials.

OBJECTIVE: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.

DESIGN, SETTING, AND PARTICIPANTS: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.

MAIN OUTCOMES AND MEASURES: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.

RESULTS: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08).

CONCLUSIONS AND RELEVANCE: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.