NEW: “When does postural instability appear in monogenic parkinsonisms? An individual-patient meta-analysis” in The Journal of Neurology.
A 2-year effort with @LucaMarsili1 @andrea_sturchio @Dr_Murli_Mishra @DrAlfonsoFasano @nachogenePD @Marcelokauffman @AlbertoEspay
THREAD 🧵
A 2-year effort with @LucaMarsili1 @andrea_sturchio @Dr_Murli_Mishra @DrAlfonsoFasano @nachogenePD @Marcelokauffman @AlbertoEspay
THREAD 🧵
LINK: link.springer.com/article/10.100…
Monogenic parkinsonisms are very different from one another. Not only on the severity of parkinsonism, but also on cognition, behavioral, and autonomic function.
(See a nice review ⬇️ sciencedirect.com/science/articl…)
Monogenic parkinsonisms are very different from one another. Not only on the severity of parkinsonism, but also on cognition, behavioral, and autonomic function.
(See a nice review ⬇️ sciencedirect.com/science/articl…)
A critical marker of disability is postural instability🚶➡️🧑🦯➡️🧑🦽, which leads to falls, and increased morbidity and mortality. The frequency and time-to postural instability in different monogenic parkinsonisms remained unknown.
We reviewed studies in SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, FBXO7, VPS35, DNAJC6, or SYNJ1-related monogenic parkinsonisms and postural instability. We included genes with ≥ 15 patients in an individual-patient meta-analysis and compared to a Parkinson’s disease (PD) cohort.
The primary outcome measure was the progression-free survival from postural instability using Kaplan–Meier survival curves. Cox proportional hazards analyses were summarized using hazards ratio (HR). We defined postural instability as Hoehn and Yahr (H&Y) staging ≥ 3.
Of 2085 eligible studies, 124 met full criteria (636 patients) for the systematic review, and 871 subjects (270 from PD cohort, 601 monogenic parkinsonisms) were included in the individual-patient meta-analysis.
Postural instability was reported in 80% of DJ-1, 40% of PRKN, 39% of PINK1, 34% of ATP13A2, 31% of LRRK2, and 29% of SNCA patients.
Progression-free survival from postural instability at 10 years after disease onset was longest in ATP13A2 (97%) and shortest in SNCA (50%). Halfway between these two extremes were PRKN (88%), PINK1 (87%), and LRRK2 (81%), similar to sporadic Parkinson’s disease (72%).
Higher risk of postural instability was observed in SNCA (HR = 3.2, p = 0.007) and DJ-1 (HR = 3.96, p = 0.001) compared to sporadic PD. Young age at onset in PINK1 and female sex in LRRK2 were associated with a decreased risk of postural instability.
Our results are comparable with two other studies with similar design in sporadic PD, with differences likely explained by longer disease duration at analysis. We speculate that each monogenic parkinsonism may be associated with unique biological and neuroanatomical profiles.
As postural instability may occur due to dysfunction of the brainstem and cerebellum🧠, different neurodegenerative involvement in these structures may explain the differential timelines to postural instability.
🚨Limitations:
-Retrospective and cross-sectional nature, cannot exclude length-time bias
-True time-to-event (postural instability) is unknown
-Highly heterogeneous studies ➡️ variable sample sizes
We selected 10 and 15 years as the event horizons and adjusted for variability✔️
-Retrospective and cross-sectional nature, cannot exclude length-time bias
-True time-to-event (postural instability) is unknown
-Highly heterogeneous studies ➡️ variable sample sizes
We selected 10 and 15 years as the event horizons and adjusted for variability✔️
Conclusions:
-Monogenic parkinsonisms were associated with unique timelines to postural instability compared to sporadic PD.
-LRRK2 was closest to sporadic PD; ATP13A2, PINK1, and PRKN had the longest latency to postural instability; and DJ-1 and SNCA, the shortest.
-Monogenic parkinsonisms were associated with unique timelines to postural instability compared to sporadic PD.
-LRRK2 was closest to sporadic PD; ATP13A2, PINK1, and PRKN had the longest latency to postural instability; and DJ-1 and SNCA, the shortest.
This study may serve to counsel patients and families and inform the outcomes of future studies on disease-modifying interventions for monogenic parkinsonisms.
We need prospective cohorts to replicate findings!
We need prospective cohorts to replicate findings!
