Review
Clinical Neurology
Maria Teresa Perinan, Kajsa Brolin, Sara Bandres-Ciga, Cornelis Blauwendraat, Christine Klein, Ziv Gan-Or, Andrew Singleton, Pilar Gomez-Garre, Maria Swanberg, Pablo Mir, Alastair Noyce
Summary: Parkinson's disease is a complex neurodegenerative condition caused by interactions between genetic and environmental factors. This article provides insights into the environmental modifiers of Parkinson's disease, discusses precedents from other neurological conditions, outlines genetic and environmental factors contributing to the disease, and reviews potential environmental modifiers affecting its severity.
ANNALS OF NEUROLOGY
(2022)
Review
Medicine, General & Internal
Xiao-Yan Yao, Li-Na Guan, Qi Chen, Chao Ren
Summary: The pathogenesis of Parkinson's disease involves multiple factors such as heredity, environment, and ageing. Mutations in LRRK2 are recognized as risk factors and play a significant role in the degeneration of dopaminergic neurons in PD. Glial hyperactivation-mediated neuroinflammation is also involved in the development of PD.
POSTGRADUATE MEDICAL JOURNAL
(2023)
Article
Neurosciences
Marta Soto, Manel Fernandez, Paloma Bravo, Sara Lahoz, Alicia Garrido, Antonio Sanchez-Rodriguez, Maria Rivera-Sanchez, Maria Sierra, Paula Melon, Ana Roig-Garcia, Anna Naito, Bradford Casey, Jordi Camps, Eduardo Tolosa, Maria-Jose Marti, Jon Infante, Mario Ezquerra, Ruben Fernandez-Santiago
Summary: The LRRK2 G2019S mutation is associated with Parkinson's disease, but its penetrance is not complete. By longitudinally assessing miRNA expression in serum samples from individuals with the G2019S mutation who have not developed PD symptoms, the researchers identified potential biomarkers for premotor stages of PD. They also found miRNAs that have the potential to be early progression biomarkers for PD.
NPJ PARKINSONS DISEASE
(2023)
Article
Cell Biology
Jonas Walter, Silvia Bolognin, Suresh K. Poovathingal, Stefano Magni, Deborah Gerard, Paul M. A. Antony, Sarah L. Nickels, Luis Salamanca, Emanuel Berger, Lisa M. Smits, Kamil Grzyb, Rita Perfeito, Fredrik Hoel, Xiaobing Qing, Jochen Ohnmacht, Michele Bertacchi, Javier Jarazo, Tomasz Ignac, Anna S. Monzel, Laura Gonzalez-Cano, Rejko Krueger, Thomas Sauter, Michele Studer, Luis Pereira de Almeida, Karl J. Tronstad, Lasse Sinkkonen, Alexander Skupin, Jens C. Schwamborn
Summary: Research has shown that the LRRK2-G2019S mutation associated with Parkinson's disease accelerates the differentiation of dopaminergic neurons, leading to an increase in cell death. The key transcription factor NR2F1 plays a role in this pathogenic mechanism by regulating the dynamics of dopaminergic differentiation.
Article
Clinical Neurology
Antonio Sanchez-Rodriguez, Cristina Tirnauca, Diana Salas-Gomez, Mario Fernandez-Gorgojo, Isabel Martinez-Rodriguez, Maria Sierra, Isabel Gonzalez-Aramburu, Diana Stan, Angela Gutierrez-Gonzalez, Johannes M. Meissner, Javier Andres-Pacheco, Maria Rivera-Sanchez, Maria Victoria Sanchez-Pelaez, Pascual Sanchez-Juan, Jon Infante
Summary: This study examined early gait alterations in carriers of the LRRK2-G2019S mutation using an inertial sensor system. The results showed that significant and robust changes in gait were not detected in asymptomatic mutation carriers, but step or stride time during fast walking may serve as a potential biomarker.
PARKINSONISM & RELATED DISORDERS
(2022)
Article
Clinical Neurology
Jessica M. Bright, Holly J. Carlisle, Alyssa M. A. Toda, Molly Murphy, Tyler P. Molitor, Paul Wren, Kristin M. Andruska, Enchi Liu, Carrolee Barlow
Summary: The study found that a G2019S LRRK2 selective inhibitor can effectively reduce phosphorylated biomarkers of mutant G2019S LRRK2 while protecting the normal LRRK2. This precision medicine treatment paves the way for treating G2019S LRRK2 PD.
MOVEMENT DISORDERS
(2021)
Article
Clinical Neurology
Francesca Pischedda, Maria Daniela Cirnaru, Luisa Ponzoni, Michele Sandre, Alice Biosa, Maria Perez Carrion, Oriano Marin, Michele Morari, Lifeng Pan, Elisa Greggio, Rina Bandopadhyay, Mariaelvina Sala, Giovanni Piccoli
Summary: The study demonstrates that the LRRK2 G2019S mutation induces aggregation of NSF, leading to accumulation of protein inclusions in Parkinson's disease. It also shows that induction of autophagy can clear NSF aggregation and improve motor and cognitive impairment in aged G2019S mice.
Review
Clinical Neurology
Yuri L. Sosero, Ziv Gan-Or
Summary: LRRK2 variants are associated with both familial and sporadic PD. LRRK2-PD presents with benign clinical features and variable pathology, including inconsistent presence of Lewy bodies and significant Alzheimer's disease pathology. The mechanisms of LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested. Understanding the role and function of LRRK2 in PD is important as novel therapies targeting LRRK2 are being developed.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Article
Biology
Yu-En Lin, Chin-Hsien Lin, En-Peng Ho, Yi-Ci Ke, Stavroula Petridi, Christopher J. H. Elliott, Lee-Yan Sheen, Cheng-Ting Chien
Summary: The water extracts of Gastrodia elata Blume (GE) show neuroprotective effects in G2019S-induced Parkinson's disease fruit flies and transgenic mice by improving motor abilities and protecting dopaminergic neurons. The mechanism involves the activation of the Nrf2 protein in glial cells, which inhibits degenerative signaling pathways in neurons, ultimately preventing neuronal loss and maintaining coordination.
Article
Clinical Neurology
Alicia Garrido, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Marta Soto, Cristina Simonet, Manel Fernandez, Donina Obiang, Eduardo Tolosa, Maria-Jose Marti, Shalini Padmanabhan, Cristina Malagelada, Mario Ezquerra, Ruben Fernandez-Santiago
Summary: This study investigated protein and phospho-protein changes related to the G2019S mutant LRRK2 and identified specific phospho-protein changes associated with disease status. The findings can help distinguish different patient groups.
MOVEMENT DISORDERS
(2022)
Article
Neurosciences
Tanya Simuni, Kalpana Merchant, Michael C. Brumm, Hyunkeun Cho, Chelsea Caspell-Garcia, Christopher S. Coffey, Lana M. Chahine, Roy N. Alcalay, Kelly Nudelman, Tatiana Foroud, Brit Mollenhauer, Andrew Siderowf, Caroline Tanner, Hirotaka Iwaki, Todd Sherer, Kenneth Marek
Summary: This study examined the longitudinal changes in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs). The results showed that there were no significant changes in clinical measures or biomarkers over a 2-year period in LRRK2 NMCs, even in those with baseline dopamine transporter (DAT) deficit.
NPJ PARKINSONS DISEASE
(2022)
Article
Biology
Harry S. Xenias, Chuyu Chen, Shuo Kang, Suraj Cherian, Xiaolei Situ, Bharanidharan Shanmugasundaram, Guoxiang Liu, Giuseppe Scesa, C. Savio Chan, Loukia Parisiadou
Summary: Studies of mouse models with different mutations of the LRRK2 gene associated with Parkinson's disease reveal distinct alterations at multiple levels, including electrochemical, electrophysiological, molecular, and behavioral. The findings suggest that LRRK2 mutations affect striatal function, but the specific changes vary between different mutations. The results provide mechanistic insights for developing treatment strategies for Parkinson's disease patients.
COMMUNICATIONS BIOLOGY
(2022)
Article
Neurosciences
Ying Chen, Qing Yin, Xiao-Yu Cheng, Jin-Ru Zhang, Hong Jin, Kai Li, Cheng-Jie Mao, Fen Wang, Hong-Zhe Bei, Chun-Feng Liu
Summary: Induced pluripotent stem cells (iPSCs) can successfully mimic age-related diseases, such as Parkinson's disease (PD). In this study, we differentiated dopaminergic (DA) neurons from iPSCs of PD patients with the G2019S LRRK2 mutation and found morphological changes compared to control group. Furthermore, we observed that these mutated DA neurons were more vulnerable to damage, with higher rates of apoptosis and inflammatory response.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Chemistry, Physical
Avigyan Naskar, Kousik Kumar Bhanja, Rakesh Kumar Roy, Niladri Patra
Summary: This study investigates the effect of the G2019S mutation on the activity of LRRK2 kinase and finds that it leads to the formation of additional hydrogen bonds between S2019 and Q1919 and E1920, stabilizing the active state of the kinase and increasing its activity.
Review
Biochemistry & Molecular Biology
Genta Ito, Naoko Utsunomiya-Tate
Summary: Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase that phosphorylates and regulates Rab proteins. Genetic mutations in LRRK2 are implicated in both familial and sporadic Parkinson's disease (PD), but the mechanism is not well understood. PD patients with LRRK2 mutations show clinical symptoms similar to typical PD, but the pathological manifestations in their brains can vary greatly. Pathogenic mutations in LRRK2 affect its function and structure, which may contribute to the differences observed in patient pathology. This review summarizes the clinical and pathological manifestations caused by LRRK2 mutations, their impact on LRRK2's molecular function and structure, and their historical background, aiming to aid researchers in understanding LRRK2-associated PD pathogenesis.
Article
Neurosciences
Bruno Lopes Santos-Lobato, Artur F. Schumacher-Schuh, Carlos R. M. Rieder, Mara H. Hutz, Vanderci Borges, Henrique Ballalai Ferraz, Ignacio F. Mata, Cyrus P. Zabetian, Vitor Tumas
ARQUIVOS DE NEURO-PSIQUIATRIA
(2020)
Article
Neurosciences
Zachary D. Wallen, Mary Appah, Marissa N. Dean, Cheryl L. Sesler, Stewart A. Factor, Eric Molho, Cyrus P. Zabetian, David G. Standaert, Haydeh Payami
NPJ PARKINSONS DISEASE
(2020)
Article
Engineering, Biomedical
Nofar Schneider, Moria Dagan, Racheli Katz, Pablo Cornejo Thumm, Marina Brozgol, Nir Giladi, Brad Manor, Anat Mirelman, Jeffery M. Hausdorff
Summary: The study found that tDCS during challenging walking decreased the dual-task cost to walking in older adults. These results support the presence of a state-dependent impact of neuro-modulation.
JOURNAL OF NEUROENGINEERING AND REHABILITATION
(2021)
Article
Clinical Neurology
Anat Mirelman, Mor Ben Or Frank, Michal Melamed, Lena Granovsky, Alice Nieuwboer, Lynn Rochester, Silvia Del Din, Laura Avanzino, Elisa Pelosin, Bastiaan R. Bloem, Ugo Della Croce, Andrea Cereatti, Paolo Bonato, Richard Camicioli, Theresa Ellis, Jamie L. Hamilton, Chris J. Hass, Quincy J. Almeida, Maidan Inbal, Avner Thaler, Julia Shirvan, Jesse M. Cedarbaum, Nir Giladi, Jeffrey M. Hausdorff
Summary: This study utilized wearable sensors to record gait and mobility measures in PD patients and healthy controls, and applied machine-learning algorithms to distinguish between different stages of PD severity. The findings suggest that gait and mobility measures can reflect distinct PD stages with high discriminatory values.
MOVEMENT DISORDERS
(2021)
Article
Clinical Neurology
Brad Manor, Moria Dagan, Talia Herman, Natalia A. Gouskova, Veronique G. Vanderhorst, Nir Giladi, Thomas G. Travison, Alvaro Pascual-Leone, Lewis A. Lipsitz, Jeffrey M. Hausdorff
Summary: This study found that multi-session transcranial direct current stimulation targeting the left dorsolateral prefrontal cortex and primary motor cortex did not significantly improve laboratory-based FOG-provoking test performance, but showed some improvement in patients with mild-to-moderate FOG severity.
MOVEMENT DISORDERS
(2021)
Article
Geriatrics & Gerontology
Tamir Eisenstein, Nir Giladi, Talma Hendler, Ofer Havakuk, Yulia Lerner
Summary: The study found that aerobic activity and cardiorespiratory fitness in older adults are associated with neurocognitive abilities and identified potential neural pathways mediating this relationship. The results support a neuroprotective role of aerobic exercise on the aging brain.
NEUROBIOLOGY OF AGING
(2022)
Article
Clinical Neurology
Inbal Maidan, Noa Zifman, Jeffrey M. Hausdorff, Nir Giladi, Ofri Levy-Lamdan, Anat Mirelman
Summary: The study investigated specific changes in electrical brain activity in response to stimulation of four brain areas in patients with Parkinson's disease (PD) using a combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) assessment. Patients with PD showed lower waveform adherence, lower early phase deflection, lower inter-trial adherence, and lower connectivity between homologous brain areas compared to healthy controls. The findings suggest various alterations in neurophysiological measures in PD patients, indicating different aspects related to the pathophysiology of the disease.
PARKINSONISM & RELATED DISORDERS
(2021)
Article
Neurosciences
Zachary D. Wallen, William J. Stone, Stewart A. Factor, Eric Molho, Cyrus P. Zabetian, David G. Standaert, Haydeh Payami
Summary: Through research, it was found that there is dysbiosis in the gut microbiome of PD patients, with an overabundance of opportunistic pathogens influenced by the host genotype at the alpha-synuclein locus. These results suggest hypotheses on the pathogenesis of PD, incomplete penetrance of susceptibility genes, and potential triggers of gut pathology.
NPJ PARKINSONS DISEASE
(2021)
Article
Clinical Neurology
Nir Giladi, Tanya Gurevich, Ruth Djaldetti, Liat Adar, Ryan Case, Shelly Leibman-Barak, Nissim Sasson, Yoseph Caraco
Summary: ND0612, a continuous subcutaneous levodopa/carbidopa delivery system, was well-tolerated and resulted in reduced OFF time and decreased plasma levodopa fluctuations when used adjunctively in PD patients. Although most patients experienced infusion site nodules, they all resolved without sequelae.
PARKINSONISM & RELATED DISORDERS
(2021)
Article
Clinical Neurology
Mor Yam, Sigal Glatt, Shai Nosatzki, Anat Mirelman, Jeffrey M. Hausdorff, Lilach Goldstein, Nir Giladi, Firas Fahoum, Inbal Maidan
Summary: Juvenile myoclonic epilepsy (JME) is a common epileptic syndrome, and drug resistance is a significant issue. This study found that drug-resistant JME patients have altered brain activity during highly demanding tasks that combine cognitive and motor functions.
FRONTIERS IN NEUROLOGY
(2022)
Article
Neurosciences
Rosie Morris, Douglas N. Martini, Katrina Ramsey, Valerie E. Kelly, Katrijn Smulders, Amie Hiller, Kathryn A. Chung, Shu-Ching Hu, Cyrus P. Zabetian, Kathleen L. Poston, Ignacio F. Mata, Karen L. Edwards, Jodi Lapidus, Brenna Cholerton, Thomas J. Montine, Joseph F. Quinn, Fay Horak
Summary: The study aimed to investigate differences in gait and balance impairments in Parkinson's disease patients with and without GBA variants (mutation carriers and E326K polymorphism) and explore the direct and indirect effects of GBA status on gait, balance, and cognition. The results showed that the GBA variant group had more impaired gait and balance, and cognition mediated the impact of GBA status on gait and balance.
NPJ PARKINSONS DISEASE
(2022)
Article
Chemistry, Analytical
Dan Z. Milikovsky, Yotam Sharabi, Nir Giladi, Anat Mirelman, Ronen Sosnik, Firas Fahoum, Inbal Maidan
Summary: This study aimed to examine the presence of paroxysmal slow-wave events (PSWE) as a biomarker for cortical involvement in Parkinson's disease (PD). The results showed no significant differences in the number of PSWEs between PD patients and controls in all brain regions. However, the correlation between PSWEs and disease duration suggests early signs of cortical involvement in PD.
Letter
Clinical Neurology
Serdar Kazanci, Jennifer Witt, Kimmy Su, Oswaldo Lorenzo-Betancor, Dora Yearout, Cyrus P. Zabetian, Marie Y. Davis
MOVEMENT DISORDERS CLINICAL PRACTICE
(2023)
Article
Clinical Neurology
Shachar Shani, Orly Goldstein, Mali Gana-Weisz, Anat Bar-Shira, Avner Thaler, Tanya Gurevich, Anat Mirelman, Nir Giladi, Roy N. Alcalay, Avi Orr-Urtreger
Summary: Recent studies have found a link between Parkinson's disease (PD) and changes in the innate immune system. This study aimed to determine if genetic variations in innate immune genes are differentially associated with PD in different subgroups, including GBA-PD, LRRK2-PD, and non-carrier PD (NC-PD).
PARKINSONISM & RELATED DISORDERS
(2023)
Article
Chemistry, Analytical
Eden Shkury, Shani Danziger-Schragenheim, Zoya Katzir, Yael Ezra, Nir Giladi, Anat Mirelman, Inbal Maidan
Summary: This study investigated the neurophysiological changes in Parkinson's disease patients with and without the G2019S-LRRK2 gene mutation. The results showed that patients with the mutation performed better in cognitive tasks and exhibited more efficient early cognitive processes, which may contribute to their better cognitive performance.
