Tracking LRRK2-Parkinson’s Progression for Better Trial Design

Parkinson’s disease comes in many flavors, posing a challenge for researchers who design clinical trials in their search for treatments. Knowing how the disease progresses naturally may better their chance of success. A longitudinal study from the LRRK2 Ashkenazi Jewish Consortium provides just such data. Researchers led by Rachel Saunders-Pullman, Mount Sinai Beth Israel Medical Center in New York, compared how PD progressed in patients who carry the G2019S LRRK2 mutation and people with sporadic disease. Confirming previous studies, they found that motor symptoms advanced more slowly in mutation carriers. The results appear in the March 1 JAMA Neurology.

  • The study maps progression in people with and without the G2019S LRRK2 mutation.
  • Motor symptoms worsen more slowly in G2019S-PD.
  • The data may help clinicians better design clinical trials.

The size of the new data set and the length of follow-up supersede similar studies. “It is a substantive and important study, one of the biggest involving LRRK2 patients,” noted Mark Cookson at the National Institutes of Health, Bethesda, Maryland. Carole Ho of Denali Therapeutics in South San Francisco was encouraged by the quality of the study. “We are using the new data to design trials to test LRRK2 inhibitors,” she told Alzforum. “Knowing the natural course of disease is very important.”

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial PD, but their penetrance and prevalence varies greatly between populations. Also, while some LRRK2 variants slow down disease progression, others speed it up (Oosterveld et al., 2015). Because LRRK2-PD shares symptoms and pathology with the sporadic form, researchers believe that drugs targeting the kinase may help most PD patients. Moreover, because the kinase is overactive in disease, it is a tractable target for drug development. Pfizer, Merck, Glaxo-SmithKline, Denali, and Genentech have created an array of LRRK2 inhibitors. As they begin testing them in clinical trials, the need to understand how PD progresses in LRRK2-PD patients has become urgent.

PD Trajectories. Motor symptoms develop more slowly in G2019S-LRRK2 (orange) than in idiopathic PD (blue). [Courtesy of Saunders-Pullman et al., JAMA Neurology, © (2018) American Medical Association. All rights reserved.]

Most studies following progression of PD caused by G2019S LRRK2 have been sparse, small, or cross-sectional (Healy et al., 2008; Alcalay et al., 2013; Yahalom et al., 2014). The Parkinson’s Progression Markers Initiative (Oct 2013 news) tracks data from LRRK2-PD patients, but until recently, was limited to a single follow-up visit at one year.

To chart progression specifically in G2019S LRRK2 PD, Saunders-Pullman analyzed data from 144 patients with the mutation and 401 with sporadic PD. The patients were recruited from the LRRK2 Ashkenazi Jewish Consortium. In this population, the G2019S mutation causes up to 15 percent of PD cases, compared to 1 to 2 percent worldwide, said Saunders-Pullman. Participants had undergone up to six extensive evaluations over six years. Using the Unified Parkinson’s Disease Rating Scale III, clinicians scored them on motor skills such as talking, finger tapping, walking, and standing up. The scale also measured tremor, rigidity, and slowness. Participants took the Montreal Cognitive Assessment, which tests memory, attention, concentration, language, and awareness of time and place. All examinations were done when patients were in the “on” state, meaning when they had maximum benefit from their PD medication.

After adjusting for sex, age, disease duration, and PD medication dosing at baseline, G2019S LRRK2 mutation carriers declined some 30 percent slower on the UPDRS than did those with sporadic PD (image above). The milder motor course is consistent with other studies.

Cognitive impairment followed a similar trend, though the difference was not statistically significant. “The cognitive phenotype is so variable that it’s not surprising it didn’t reach significance,” said Cookson. Nonetheless, Saunders-Pullman believes the trend reflects a real difference, and added that full neuropsychological assessments in a subgroup of patients should help resolve the issue.

Why the difference in progression? There is no easy answer, said Cookson, noting that PD pathology is very variable. “Sometimes you see different pathology even in the same family with the same mutation,” he said. Indeed, Lewy body pathology, a hallmark of idiopathic PD, surfaces in only some patients with the G2019S mutation (Kalia et al., 2015). It is still unclear whether the milder G2019S disease course is due to a subgroup of patients with more benign pathology bringing down the average, or if most mutation carriers have less aggressive pathology, noted the authors.

Matthew Farrer, University of British Columbia, Vancouver, Canada, welcomed the new findings, but said that future studies would benefit from longer follow-up. He noted that results for 62 of the patients were limited to a single time point, and only seven patients had five or more years of follow-up. Adding more patients with more data points should refine the progression model and help scientists address the question of how a person’s age of onset correlates with disease severity across different forms of PD (Trinh et al., 2014). 

Will the new data improve the design of LRRK2 inhibitor trials? Ho said it is helping to calculate the number of patients needed for a Phase 2 study.

“I think it’s a very exciting time in the PD world,” said Saunders-Pullman. “The hope is that with more homogenous cohorts, we’ll find signals more easily.”—Marina Chicurel

Comments

  1. This study by Saunders-Pullman et al. and the LRRK2 Ashkenazi Jewish Consortium further confirms previous cross-sectional/retrospective findings that LRRK2 mutation carriers have a milder motor course (Fernandez-Santiago et al., 2016; Kestenbaum and Alcalay, 2017; Nishioka et al., 2010; Saunders-Pullman et al., 2015; Trinh et al., 2014), and it provides valuable information and resources for future clinical trials. As more and more disease-modifying therapies and genetic modifiers for LRRK2 are found, it would be important to characterize their effect in this homogeneous PD group. It would also be important to not only characterize the motor progression but also the non-motor symptoms such as autonomic dysfunction, sleep patterns, and olfactory dysfunction, as these symptoms also progress during the course of PD. The phenomena can be specific to the p.G2019S mutation because different LRRK2 mutations (e.g. p.G2385R, p.R1441G) have more progressive clinical courses, which may depend on different biological effects of the mutation, on the ethnic background, and on the environment. Lastly, unlike idiopathic PD, the authors find that postural instability and gait disorder does not correlate with a more rapid progression in LRRK2 mutation carriers. This also confirms previous findings that show PIGD and tremor do not predict the clinical course of LRRK2 PD as it does for idiopathic PD (Trinh et al., 2014). 

    LRRK2 mutation carriers are known for their pleomorphic pathology (Lewy body inclusions, TDP43 proteinopathies) and even the absence of Lewy bodies (Kalia et al., 2015). As Lewy body pathology correlates with non-motor features (olfactory dysfunction, gastrointestinal dysfunction, REM sleep behavior disorder) and these are also less frequently seen in LRRK2, as shown from previous cross-sectional studies, perhaps the pathology spread and disease vulnerability patterns are different from idiopathic PD. Idiopathic PD may arise from exogenous exposures through the enteric nervous system and proceeding through the vagus and medulla, which correlates with the “spread of LB pathology” while LRRK2 PD pathophysiology could be more driven by endogenous factors allowing for selective vulnerability patterns that differ from idiopathic PD.

    References:

    Fernández-Santiago R, Iranzo A, Gaig C, Serradell M, Fernández M, Tolosa E, Santamaría J, Ezquerra M. Absence of LRRK2 mutations in a cohort of patients with idiopathic REM sleep behavior disorder. Neurology. 2016 Mar 15;86(11):1072-3. Epub 2016 Jan 8 PubMed.

    Kestenbaum M, Alcalay RN. Clinical Features of LRRK2 Carriers with Parkinson's Disease. Adv Neurobiol. 2017;14:31-48. PubMed.

    Nishioka K, Kefi M, Jasinska-Myga B, Wider C, Vilariño-Güell C, Ross OA, Heckman MG, Middleton LT, Ishihara-Paul L, Gibson RA, Amouri R, Ben Yahmed S, Ben Sassi S, Zouari M, El Euch G, Farrer MJ, Hentati F. A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):391-5. PubMed.

    Saunders-Pullman R, Alcalay RN, Mirelman A, Wang C, Luciano MS, Ortega RA, Glickman A, Raymond D, Mejia-Santana H, Doan N, Johannes B, Yasinovsky K, Ozelius L, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB, AJ LRRK2 Consortium. REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers. Mov Disord. 2015 Nov;30(13):1834-9. Epub 2015 Sep 14 PubMed.

    Trinh J, Amouri R, Duda JE, Morley JF, Read M, Donald A, Vilariño-Güell C, Thompson C, Szu Tu C, Gustavsson EK, Ben Sassi S, Hentati E, Zouari M, Farhat E, Nabli F, Hentati F, Farrer MJ. Comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism. Neurobiol Aging. 2014 May;35(5):1125-31. Epub 2013 Nov 22 PubMed.

    Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW, Ross OA, Van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martínez J, Marti-Masso JF, Ferrer I, López de Munain A, Goldman SM, Schüle B, Langston JW, Aasly JO, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, Maues De Paula A, Hasegawa K, Duyckaerts C, Brice A, Stoessl AJ, Marras C. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015 Jan;72(1):100-5. PubMed.

    View all comments by Joanne Trinh

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References

Alzpedia Citations

  1. Leucine-rich repeat kinase 2 (LRRK2)

News Citations

  1. Parkinson’s Foundation Encourages Data Mining

Paper Citations

  1. Oosterveld LP, Allen JC Jr, Ng EY, Seah SH, Tay KY, Au WL, Tan EK, Tan LC. Greater motor progression in patients with Parkinson disease who carry LRRK2 risk variants. Neurology. 2015 Sep 22;85(12):1039-42. Epub 2015 Aug 26 PubMed.
  2. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW, . Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 2008 Jul;7(7):583-90. PubMed.
  3. Alcalay RN, Mirelman A, Saunders-Pullman R, Tang MX, Mejia Santana H, Raymond D, Roos E, Orbe-Reilly M, Gurevich T, Bar Shira A, Gana Weisz M, Yasinovsky K, Zalis M, Thaler A, Deik A, Barrett MJ, Cabassa J, Groves M, Hunt AL, Lubarr N, San Luciano M, Miravite J, Palmese C, Sachdev R, Sarva H, Severt L, Shanker V, Swan MC, Soto-Valencia J, Johannes B, Ortega R, Fahn S, Cote L, Waters C, Mazzoni P, Ford B, Louis E, Levy O, Rosado L, Ruiz D, Dorovski T, Pauciulo M, Nichols W, Orr-Urtreger A, Ozelius L, Clark L, Giladi N, Bressman S, Marder KS. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov Disord. 2013 Dec;28(14):1966-71. Epub 2013 Oct 15 PubMed.
  4. Yahalom G, Orlev Y, Cohen OS, Kozlova E, Friedman E, Inzelberg R, Hassin-Baer S. Motor progression of Parkinson's disease with the leucine-rich repeat kinase 2 G2019S mutation. Mov Disord. 2014 Jul;29(8):1057-60. Epub 2014 Jun 5 PubMed.
  5. Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW, Ross OA, Van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martínez J, Marti-Masso JF, Ferrer I, López de Munain A, Goldman SM, Schüle B, Langston JW, Aasly JO, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, Maues De Paula A, Hasegawa K, Duyckaerts C, Brice A, Stoessl AJ, Marras C. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015 Jan;72(1):100-5. PubMed.
  6. Trinh J, Amouri R, Duda JE, Morley JF, Read M, Donald A, Vilariño-Güell C, Thompson C, Szu Tu C, Gustavsson EK, Ben Sassi S, Hentati E, Zouari M, Farhat E, Nabli F, Hentati F, Farrer MJ. Comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism. Neurobiol Aging. 2014 May;35(5):1125-31. Epub 2013 Nov 22 PubMed.

Further Reading

News

  1. The Many Faces of LRRK2

Primary Papers

  1. 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. Progression in the LRRK2-Asssociated Parkinson Disease Population. JAMA Neurol. 2018 Mar 1;75(3):312-319. PubMed.

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