Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study

Simuni, Tanya; Uribe, Liz; Cho, Hyunkeun Ryan; Caspell‐Garcia, Chelsea; Coffey, Christopher S.; Siderowf, Andrew; Trojanowski, John Q.; Shaw, Leslie M.; Seibyl, John; Singleton, Andrew B.; Toga, Arthur W.; Galasko, Doug; Foroud, Tatiana; Tosun, Duygu; Poston, Kathleen L.; Weintraub, Daniel; Mollenhauer, Brit; Tanner, Caroline M.; Kieburtz, Karl; Chahine, Lana M.; Reimer, Alyssa; Hutten, Samantha J.; Bressman, Susan; Marek, Kenneth; Arnedo, Vanessa; Clark, Adrienne; Fraiser, Mark; Kopil, Catherine; Chowdhury, Sohini; Sherer, Todd; Daegele, Nichole; Casaceli, Cynthia; Dorsey, Ray; Wilson, Renée; Mahes, Sugi; Salerno, Christina M.; Crawford, Karen; Casalin, Paola; Malferrari, Giulia; Weisz, Mali Gani; Orr‐Urtreger, Avi; Montine, Thomas J.; Baglieri, Chris; Christini, Amanda; Russell, David; Dahodwala, Nabila; Giladi, Nir; Factor, Stewart A.; Hogarth, Penelope; Standaert, David G.; Hauser, Robert A.; Jankovic, Joseph; Saint‐Hilaire, Marie; Richard, Irene Hegeman; Shprecher, David; Fernandez, Hubert; Brockmann, Katrina; Rosenthal, Liana S.; Barone, Paolo; Espay, Alberto J.; Rowe, Dominic B.; Marder, Karen; Santiago, A. Parra; Hu, Shu‐Ching; Isaacson, Stuart; Corvol, Jean‐Christophe; Martinez, Javiar Ruiz; Tolosa, Eduardo; Tai, Yen; Politis, Marios; Smejdir, Debra; Rees, Linda; Williams, Karen; Kausar, Farah; Richardson, Whitney; Willeke, Diana; Peacock, Shawnees; Sommerfeld, Barbara; Freed, Alison; Wakeman, Katrina; Blair, Courtney; Guthrie, Stephanie; Harrell, Leigh; Hunter, Christine; Thomas, Cathi‐Ann; James, Raymond; Zimmerman, Grace; Brown, Victoria; Mule, Jennifer; Hilt, Ella; Ribb, Kori; Ainscough, Susan; Wethington, Misty; Ranola, Madelaine; Santana, Helen Mejia; Moreno, J.M.; Raymond, Deborah; Speketer, Krista; Carvajal, Lisbeth; Carvalo, Stephanie; Croitoru, Ioana; Garrido, Alícia; Payne, Laura Marie; Viswanth, Veena; Severt, Lawrence; Facheris, Maurizio; Soares, Holly; Mintun, Mark A.; Cedarbaum, Jesse M.; Taylor, Peggy; Biglan, Kevin; Vandenbroucke, Emily; Sheikh, Zulfiqar Haider; Bingol, Baris; Fischer, Tanya; Sardi, Pablo; Forrat, Rémi; Reith, Alastair D.; Egebjerg, Jan; Hillert, Gabrielle Ahlberg; Saba, Barbara; Min, Chris; Umek, Robert M.; Mather, Joe; Santi, Susan De; Post, Anke; Boess, Frank; Taylor, Kirsten I.; Grachev, Igor D.; Avberšek, Andreja; Muglia, Pierandrea; Merchant, Kaplana; Tauscher, Johannes

doi:10.1016/s1474-4422(19)30319-9

Cited by 97 publications

(103 citation statements)

References 30 publications

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“…A more pronounced DAT deficit has been reported in GBA PD, but that was driven by severe (L444P) mutation and not observed in N370s participants . Interestingly, we have demonstrated increased SBR DAT binding in all striatal regions in GBA but not LRRK2 nonmanifest mutation carriers compared with healthy controls . Longitudinal follow‐up of both at‐risk and PD‐manifest genetic cohorts will be essential to further elucidate the progression of DAT deficit in these cohorts.…”

Section: Discussionsupporting

confidence: 43%

Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross‐Sectional Study

et al. 2020

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Background There are limited data on the phenotypic and dopamine transporter (DAT) imaging characterization of the Parkinson's disease (PD) patients with leucine rich kinase 2 (LRRK2) and glucosylceramidase beta (GBA) mutations. Objective The objective of this study was to examine baseline clinical and DAT imaging characteristics in GBA and LRRK2 mutation carriers with early PD compared with sporadic PD. Methods The Parkinson's Progression Markers Initiative is an ongoing observational longitudinal study that enrolled participants with sporadic PD, LRRK2 and GBA PD carriers from 33 sites worldwide. All participants are assessed annually with a battery of motor and nonmotor scales, 123‐I Ioflupane DAT imaging, and biologic variables. Results We assessed 158 LRRK2 (89% G2019S), 80 GBA (89 %N370S), and 361 sporadic PD participants with the mean (standard deviation) disease duration of 2.9 (1.9), 3.1 (2.0), and 2.6 (0.6) years, respectively. When compared with sporadic PD, the GBA PD patients had no difference in any motor, cognitive, or autonomic features. The LRRK2 PD patients had less motor disability and lower rapid eye movement behavior disorder questionnaire scores, but no meaningful difference in cognitive or autonomic features. Both genetic cohorts had a higher score on the impulse control disorders scale when compared with sporadic PD, but no difference in other psychiatric features. Both genetic PD cohorts had less loss of dopamine transporter on DAT imaging when compared with sporadic PD. Conclusions We confirm previous reports of milder phenotype associated with LRRK2‐PD. A previously reported more aggressive phenotype in GBA‐PD is not evident early in the disease in N370s carriers. This observation identifies a window for potential disease‐modifying interventions. Longitudinal data will be essential to define the slope of progression for both genetic cohorts. Trial Registration http://clinicaltrials.gov (NCT01141023). © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionsupporting

confidence: 43%

Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross‐Sectional Study

et al. 2020

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“…Human asymptomatic LRRK2 mutation carriers represent an appropriate population to define these preclinical symptoms. Indeed, emerging evidence suggests that asymptomatic LRRK2 mutation carriers do show subtle motor and non-motor symptoms, including alterations of corticostriatal circuit organization, in comparison to asymptomatic non-carriers ( PPMI Investigators et al, 2020 ; LRRK2 Ashkenazi Jewish Consortium et al, 2015 ). Accordingly, cellular and synaptic dysfunctions in etiologically relevant LRRK2 mutant KI mice allow investigations of the early events that precede neuronal death and may be predictive of future dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations

Chen

Soto

Dumrongprechachan

et al. 2020

eLife

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LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson’s disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose towards disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of miniature excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using 2-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset.

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“…More recently, a large cohort study conducted within the Parkinson's Progression Markers Initiative of the Michael J. Fox Foundation reported increased DAT striatal binding ratios in GBA asymptomatic carriers, compared with healthy controls (Simuni et al, 2020).…”

Section: Neuroimagingmentioning

confidence: 99%

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Avenali

Blandini

Cerri³

2020

Front. Aging Neurosci.

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Heterozygous mutations of the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), occur in a considerable percentage of all patients with sporadic Parkinson's disease (PD), varying between 8% and 12% across the world. Genome wide association studies have confirmed the strong correlation between PD and GBA1 mutations, pointing to this element as a major risk factor for PD, possibly the most important one after age. The pathobiological mechanisms underlying the link between a defective function of GCase and the development of PD are still unknown and are currently the focus of intense investigation in the community of pre-clinical and clinical researchers in the PD field. A major controversy regards the fact that, despite the unequivocal correlation between the presence of GBA1 mutations and the risk of developing PD, only a minority of asymptomatic carriers with GBA1 mutations convert to PD in their lifetime. GBA1 mutations reduce the enzymatic function of GCase, impairing lysosomal efficiency and the cellular ability to dispose of pathological alpha-synuclein. Changes in the cellular lipidic content resulting from the accumulation of glycosphingolipids, triggered by lysosomal dysfunction, may contribute to the pathological modification of alpha-synuclein, due to its ability to interact with cell membrane lipids. Mutant GCase can impair mitochondrial function and cause endoplasmic reticulum stress, thereby impacting on cellular energy production and proteostasis. Importantly, reduced GCase activity is associated with clear activation of microglia, a major mediator of neuroinflammatory response within the brain parenchyma, which points to neuroinflammation as a major consequence of GCase dysfunction. In this present review article, we summarize the current knowledge on the role of GBA1 mutations in PD development and their phenotypic correlations. We also discuss the potential role of the GCase pathway in the search for PD biomarkers that may enable the development of disease modifying therapies. Answering these questions will aid clinicians in offering more appropriate counseling to the patients and their caregivers and provide future directions for PD preclinical research.

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Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study

Cited by 97 publications

References 30 publications

Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross‐Sectional Study

Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross‐Sectional Study

Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

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