Progression in the <i>LRRK2</i>-Associated Parkinson Disease Population

Saunders‐Pullman, Rachel; Mirelman, Anat; Alcalay, Roy N.; Wang, Cuiling; Ortega, Roberto A.; Raymond, Deborah; Mejia‐Santana, Helen; Orbe-Reilly, Martha; Johannes, Brooke; Thaler, Avner; Ozelius, Laurie J.; Orr-Urtreger, Avi; Marder, Karen; Giladi, Nir; Bressman, Susan

doi:10.1001/jamaneurol.2017.4019

Cited by 124 publications

(134 citation statements)

References 47 publications

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“…suggested slower progression of PD among patients with LRRK2 G2019S mutation compared with patients without the mutation. These findings were confirmed by Saunders et al . in a longitudinal follow‐up of a large cohort of PD patients.…”

supporting

confidence: 76%

“…Subjects with LRRK2 mutations were found to progress at a slower rate (~ −27%) compared with subjects without LRRK2 mutations ( Figure a ). A slower progression rate of UPDRS Part III motor score for subjects with LRRK2 G2019S mutation compared with subjects without LRRK2 G2019S mutations was reported by Rachel Saunders‐Pullman et al . Additional details on covariate analysis are presented in .…”

Section: Resultsmentioning

confidence: 94%

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Development of a Disease Progression Model for Leucine‐Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs

Ahamadi

Conrado

Macha

et al. 2019

Clin Pharma and Therapeutics

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A quantitative assessment of Parkinson's disease (PD) progression is critical for optimizing clinical trials design. Disease progression model was developed using pooled data from the Progression Marker Initiative study and the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease study. Age, gender, concomitant medication, and study arms were predictors of baseline. A mutation in the leucine‐rich repeat kinase 2 (LRRK2) encoding gene was associated with the disease progression rate. The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month). For a nonenriched placebo‐controlled clinical trial, approximately 70 subjects/arm would be required to detect a drug effect of 50% reduction in the progression rate with 80% probability, whereas 85, 93, and 100 subjects/arm would be required for an enriched clinical trial with 30%, 50%, and 70% subjects with LRRK2 mutations, respectively.

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supporting

confidence: 76%

Section: Resultsmentioning

confidence: 94%

Development of a Disease Progression Model for Leucine‐Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs

Ahamadi

Conrado

Macha

et al. 2019

Clin Pharma and Therapeutics

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“…Notably, although TMEM106B variants do not associate with risk for developing the TDP-43 proteinopathy ALS, they do associate with cognitive impairment among individuals with manifest ALS. In this context, we point out that other genetic variants associated with increased risk for developing a disease have been associated with both faster progression of that disease (eg, APOE4 alleles in AD) 26 and slower progression (eg, LRRK2 G2019S in PD), 27 underlining the importance of formal evaluation in longitudinal studies. 3,25 We find here that TMEM106B variants that increase risk for FTLD-TDP may also associate with a faster rate of cognitive decline in clinically diagnosed FTD patients, with positive findings in the bvFTD subgroup as well.…”

Section: Discussionmentioning

confidence: 97%

TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia

Tropea

Mak

Guo

et al. 2019

Annals of Neurology

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Objective: Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases. Methods: We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371).Results: The TMEM106B rs1990622 T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622 T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622 C , dominant model. Among PD patients, rs1990622 T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores. Interpretation: Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies.

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“…The sample comprised participants from the Ashkenazi Jewish LRRK2 Consortium study sites in Tel Aviv (Tel Aviv Medical Center) and New York (Columbia University Irving Medical Center and Mount Sinai Beth Israel) 2. PD probands were screened for the LRRK2 G2019S mutation 3.…”

Section: Methodsmentioning

confidence: 99%