Age-specific penetrance of
            <i>LRRK2</i>
            G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Marder, Karen; Wang, Yuanjia; Alcalay, Roy N.; Mejia‐Santana, Helen; Tang, Ming; Lee, Annie; Raymond, Deborah; Mirelman, Anat; Saunders‐Pullman, Rachel; Clark, Lorraine N.; Ozelius, Laurie J.; Orr-Urtreger, Avi; Giladi, Nir; Bressman, Susan

doi:10.1212/wnl.0000000000001708

Cited by 132 publications

(164 citation statements)

References 35 publications

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“…A higher relative proportion of LRRK2 carriers among women (45 vs. 55%) vs. men (40 vs. 60%) was observed 25, 26. However, we did not demonstrate a difference between the rates of PD in male and female LRRK2 mutation carrier PD (52 vs. 48%).…”

Section: Discussioncontrasting

confidence: 82%

“…Although genetic determinants may be sexually dimorphic,21, 22 and a specific LRRK2 gender effect has been postulated,23 we confirm that the male predominance observed in Western populations with PD is not present in the G2019S mutation in LRRK2 PD 23, 24, 25. A higher relative proportion of LRRK2 carriers among women (45 vs. 55%) vs. men (40 vs. 60%) was observed 25, 26.…”

Section: Discussionsupporting

confidence: 71%

“…Epigenetic factors may also play a role as transcriptomic reports demonstrate downregulation of B‐cell‐related genes in women with PD compared to those without, as well as men with PD 31. Differential effects of deleterious factors may play less of a role in LRRK2 PD, since similar penetrance has been reported in male and female carriers,25 suggesting that modifiers of penetrance of LRRK2 PD are not sex‐specific, or if they are, are balanced between the sexes.…”

Section: Discussionmentioning

confidence: 85%

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Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD).Methods530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women.Results Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS‐IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS‐IV but better olfaction. Among same sex:LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS‐IV and rates of dyskinesia.InterpretationThere were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 85%

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Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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“…Penetrance increases with age until 25%-75% at 80 years according to different studies. 2,19,20 As expected, PD converters in our study were older (an average of 10 years) than nonconverters, with statistical nonsignificance probably just because of the small number of cases. One of the patients was younger than 60 years when he developed PD motor symptoms.…”

Section: Resultssupporting

confidence: 73%

Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease

et al. 2017

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Objective: To assess the value of baseline clinical and imaging biomarkers in a cohort of asymptomatic LRRK2 G2019S carriers for predicting conversion to Parkinson disease (PD) at 4 years.Methods: Thirty-two asymptomatic carriers of LRRK2 G2019S mutation underwent baseline and Results: Three carriers, asymptomatic at baseline, had converted to PD at 4-year evaluation.Twenty-three participants were fully evaluated. PD converters had lower striatal DaT binding at baseline than nonconverters (p 5 0.002). A baseline scan with a ratio of bilateral striatal uptake below 1 predicted conversion to PD within the 4-year period with high sensitivity and specificity (area under the curve 1; p 5 0.006). The slope of DaT binding decline between the 2 scans was similar in PD converters and nonconverters. Age-adjusted UPSIT score at baseline and at 4 years was similar in both groups.Conclusions: Semiquantitative DaT-SPECT could be used to predict early conversion to PD in asymptomatic carriers of the LRRK2 G2019S mutation. Rate of conversion to PD at 4 years in this cohort aged ;64 years was 12%. The slope of DaT binding decline on DaT-SPECT imaging seems to be similar across different stages of the premotor period. The G2019S mutation of the LRRK2 gene is the commonest known cause of Parkinson disease (PD). 1 Clinically and pathologically, this form of the disease is indistinguishable from idiopathic PD, and therefore it constitutes an ideal scenario in which to deepen our knowledge about the disease. The identification and follow-up of carriers of the LRRK2 G2019S mutation who still have not developed motor symptoms of PD represents a unique opportunity for studying the prodromal stage of PD. We lack information on the timing between the beginning of the neurodegenerative process and the appearance of the motor symptoms of PD and the pace of cell loss at the substantia nigra (SN) at the premotor stage. Shedding light into the prodromal stages of the disease is going to be crucial for planning drug trials aiming to modify the disease process early, before most of the damage is already done. The penetrance of the LRRK2 G2019S mutation is age-dependent and only a proportion of LRRK2 G2019S mutation carriers will develop motor symptoms of PD. 2 Besides age, no other clinical marker has been proven to be useful to predict conversion to manifest PD in asymptomatic carriers. In a previous study by our group, we characterized a cohort of 32 asymptomatic carriers of the LRRK2 G2019S mutation with brain imaging ( 123 I-ioflupane SPECT and transcranial sonography) and olfaction tests. 3

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“…7,8 Healthy carriers of the LRRK2 G2019S mutation therefore form a unique population at risk of PD. 9,10 Penetrance estimations range from 10%-17% at the age 50 years to 25%-85% at the age of 70 years, 7,[11][12][13] suggesting that the risk of developing PD is age-dependent. 7 Thus, we investigated age-related changes in corticostriatal connectivity in healthy LRRK2 G2019S mutation carriers.…”

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confidence: 99%

Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers

et al. 2015

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Objective: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.Methods: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen. Results:The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.Conclusions: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes. Parkinson disease (PD) is a progressive, neurodegenerative disorder characterized by nigrostriatal dopamine depletion. The motor symptoms of PD appear only when dopaminergic cell death reaches a critical threshold of 50% to 80%.1 This suggests that the nervous system has a marked potential to compensate for these changes.2 However, human studies of cerebral compensation in premotor PD are lacking, given the difficulty of predicting who will develop PD in the future.Previous work has shown that compensatory mechanisms in idiopathic PD depend on brain regions relatively unaffected by dopamine depletion, such as the anterior striatum.3,4 Using fMRI in early-stage PD, we recently showed a shift in corticostriatal connectivity from severely affected striatal regions (posterior putamen) to less affected striatal regions (anterior putamen). 5If these changes reflect compensation, they should also occur in the premotor phase of PD, when functional reorganization of cerebral circuits prevents overt clinical symptoms. 2 *These authors contributed equally to this work.

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Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Cited by 132 publications

References 35 publications

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease

Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers

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