Review
Biochemistry & Molecular Biology
Maria Dolores Perez-Carrion, Inmaculada Posadas, Javier Solera, Valentin Cena
Summary: This review summarizes the main pathological mutations in LRRK2 that contribute to Parkinson's disease and discusses the different cellular and therapeutic strategies to correct LRRK2 homeostasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Psychology, Multidisciplinary
Antonia Siquier, Pilar Andres
Summary: The aim of this study was to describe memory deficits in Parkinson's disease (PD) by combining objective and subjective memory measures. The study found that PD patients had more memory complaints and performed worse in associative memory tasks compared to controls. Furthermore, associative memory impairment was correlated with subjective memory complaints.
FRONTIERS IN PSYCHOLOGY
(2022)
Article
Neurosciences
Diana C. Oviedo, Ambar R. Perez-Lao, Julio A. Flores-Cuadra, Alcibiades E. Villarreal, Maria B. Carreira, Shantal A. Grajales, Gabrielle B. Britton
Summary: This study investigated the relationship between APOE ε4 expression and cognitive function in Panamanian older adults, revealing that individuals with at least one copy of APOE ε4 performed significantly lower in various cognitive domains, regardless of diagnosis. This contributes to a better understanding of the impact of APOE ε4 on specific cognitive functions in elderly Hispanics.
JOURNAL OF ALZHEIMERS DISEASE
(2021)
Article
Multidisciplinary Sciences
Ranjan K. Singh, Ahmed Soliman, Giambattista Guaitoli, Eliza Stoermer, Felix von Zweydorf, Thomas Dal Maso, Asmaa Oun, Laura Van Rillaer, Sven H. Schmidt, Deep Chatterjee, Joshua A. David, Els Pardon, Thomas U. Schwartz, Stefan Knapp, Eileen J. Kennedy, Jan Steyaert, Friedrich W. Herberg, Arjan Kortholt, Christian Johannes Gloeckner, Wim Versees
Summary: Mutations in the LRRK2 gene are a leading cause of Parkinson's disease, while overactivation of LRRK2 is associated with idiopathic form of the disease. Researchers have identified and characterized nanobodies that can bind to different domains of LRRK2 and inhibit or activate its activity. These nanobodies act through an allosteric inhibitor mechanism and provide potential therapeutic strategies for Parkinson's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Jasmin Galper, Woojin S. Kim, Nicolas Dzamko
Summary: Genetic alterations in the LRRK2 gene are a common risk factor for Parkinson's disease. LRRK2 alterations are associated with changes in lipid pathways, which can lead to cellular pathology.
Article
Clinical Neurology
Mallory L. Hacker, Michael G. Tramontana, Kian Pazira, Jacqueline C. Meystedt, Maxim Turchan, Kelly A. Harper, Run Fan, Fei Ye, Thomas L. Davis, Peter E. Konrad, David Charles
Summary: This study examined the long-term neuropsychological outcomes of deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) patients. The results showed no significant differences between DBS plus optimal drug therapy (DBS + ODT) and optimal drug therapy alone (ODT) groups after five and eleven years. However, there was a significant decline in cognitive processing speed and motor control for all PD patients. More research is needed to understand the long-term effects of early DBS on neuropsychological outcomes in PD.
PARKINSONISM & RELATED DISORDERS
(2023)
Article
Psychology, Multidisciplinary
Lois Walton, Magdalena Eriksson Domellof, Carl-Johan Boraxbekk, Erik Domellof, Louise Ronnqvist, David Backstrom, Lars Forsgren, Anna Stigsdotter Neely
Summary: This study demonstrated the feasibility of working memory updating training for Parkinson's disease patients and showed that changes occurred in cognition, movement, and functional brain response in FL at post-test.
FRONTIERS IN PSYCHOLOGY
(2021)
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
Jasmine Carcamo, Anton J. Kociolek, Kayri K. Fernandez, Yian Gu, Carolyn W. Zhu, Yaakov Stern, Stephanie Cosentino
Summary: This study assessed the predictive value of neuropsychological tests for severe dependency in Alzheimer's disease. Findings indicated that higher semantic processing and memory test scores at baseline were associated with lower risk of severe dependency. This suggests that the integrity of semantic processing and memory abilities in dementia can predict time to severe functional dependency.
JOURNAL OF ALZHEIMERS DISEASE
(2021)
Article
Cell Biology
Sara R. Oliveira, Pedro A. Dionisio, Maria M. Gaspar, Leonor Correia Guedes, Miguel Coelho, Mario M. Rosa, Joaquim J. Ferreira, Joana D. Amaral, Cecilia M. P. Rodrigues
Summary: The study reveals a protective role of miR-335 in experimental models of Parkinson's disease, showing its ability to combat inflammation and neurodegenerative events.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Dominika Natalia Wojewska, Arjan Kortholt
Summary: This review provides a comprehensive overview of the current state of the art, presenting recent developments and challenges in developing LRRK2 inhibitors, and discussing extensively the potential targeting strategies from the protein perspective. As currently there are three LRRK2-targeting agents in clinical trials, more developments are predicted in the upcoming years.
Review
Biochemistry & Molecular Biology
Ailyn Irvita Ravinther, Hemaniswarri Dewi Dewadas, Shi Ruo Tong, Chai Nien Foo, Yu-En Lin, Cheng-Ting Chien, Yang Mooi Lim
Summary: Parkinson's disease is a common neurodegenerative disease affecting the ageing population, and its prevalence has increased in recent years. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease, and aberrant LRRK2 kinase activity is also associated with idiopathic Parkinson's disease. This review aims to categorize and synthesize current information on LRRK2-linked Parkinson's disease and identify potential therapeutic targets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Ahsan Usmani, Farbod Shavarebi, Annie Hiniker
Summary: Point mutations in LRRK2 are common causes of familial and apparent sporadic Parkinson's disease. LRRK2-driven PD is clinically indistinguishable from sporadic PD, making it a valuable genetic model. Recent research highlights LRRK2's functions in the endolysosomal system and regulation by Rab GTPases, as well as its interaction with the cytoskeleton for protein degradation and inhibitor therapies. Interactions between LRRK2 and other PD-driving genes may illuminate broader cellular pathways disrupted in PD.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
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.
News Item
Biochemistry & Molecular Biology
Surya K. De
Summary: This patent describes the use of novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors for the treatment or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).
CURRENT MEDICINAL CHEMISTRY
(2023)
Editorial Material
Clinical Neurology
Merida Teran Jimenez, Philippe Salles Gandara, Alberto J. Espay
Article
Clinical Neurology
Thanaphong Phongpreecha, Brenna Cholerton, Syed Bhukari, Alan L. L. Chang, Davide De Francesco, Melan Thuraiappah, Dana Godrich, Amalia Perna, Martin G. Becker, Neal G. Ravindra, Camilo Espinosa, Yeasul Kim, Eloise Berson, Samson Mataraso, Sharon J. J. Sha, Edward J. Fox, Kathleen S. Montine, Laura D. Baker, Suzanne Craft, Lon White, Kathleen L. Poston, Gary Beecham, Nima Aghaeepour, Thomas J. Montine
Summary: This study used statistical tools and machine learning to predict 17 neuropathologic lesions based on 381 clinical features of 6518 individuals. The results showed high prediction performance for certain lesions. Some clinical features were strongly associated with multiple neurodegenerative diseases, while others were specific to certain lesions.
ALZHEIMERS & DEMENTIA
(2023)
Article
Clinical Neurology
Luca Marsili, Kevin R. Duque, Nathan Gregor, Elhusseini Abdelghany, Jesus Abanto, Andrew P. Duker, Matthew C. Hagen, Alberto J. Espay, Matteo Bologna
Summary: This study found no significant differences in the features of bradykinesia between patients with synucleinopathies and tauopathies.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Alonso Zea Vera, Adrienne Bruce, Travis R. Larsh, Zachary Jordan, Norbert Bruggemann, Ana Westenberger, Alberto J. Espay, Donald L. Gilbert, Steve W. Wu
Summary: POLR3A-related disorders exhibit significant phenotypic pleomorphism, including a range of movement disorders such as parkinsonism, dystonia, ataxia, and spasticity. Vertical gaze dysfunction and T2-weighted/FLAIR hyperintensity of the superior cerebellar peduncles and midbrain may be useful signs suggestive of this condition.
MOVEMENT DISORDERS CLINICAL PRACTICE
(2023)
Article
Clinical Neurology
John L. Robinson, Sharon X. Xie, Daniel R. Baer, EunRan Suh, Vivianna M. Van Deerlin, Nicholas J. Loh, David J. Irwin, Corey T. McMillan, David A. Wolk, Alice Chen-Plotkin, Daniel Weintraub, Theresa Schuck, Virginia M. Y. Lee, John Q. Trojanowski, Edward B. Lee
Summary: In this retrospective study, the incidence of 10 pathologies in neurodegenerative disease (ND) and normal aging was examined, with up to seven pathologies observed concurrently resulting in 161 different combinations. The presence of multiple additive pathologies was associated with factors such as longer disease duration, clinical dementia, older age, and APOE e4 status.
Article
Clinical Neurology
Matteo Bologna, Alberto J. Espay, Alfonso Fasano, Giulia Paparella, Mark Hallett, Alfredo Berardelli
MOVEMENT DISORDERS
(2023)
Editorial Material
Clinical Neurology
Alberto J. Espay, Kevin McFarthing
Summary: The process of protein aggregation involves the transformation of soluble peptides into insoluble cross-beta amyloids. In Parkinson's disease, soluble monomeric a-synuclein transforms into the amyloid state known as Lewy pathology. Most disease-modifying projects in the therapeutic pipeline for Parkinson's disease aim to reduce the insoluble a-synuclein fraction, while none aim to increase soluble a-synuclein levels. We propose rebalancing the therapeutic pipeline to include treatments that restore soluble a-synuclein within a normal range.
PARKINSONISM & RELATED DISORDERS
(2023)
Article
Multidisciplinary Sciences
Zhi Huang, Gennifer E. Merrihew, Eric B. Larson, Jea Park, Deanna Plubell, Edward J. Fox, Kathleen S. Montine, Caitlin S. Latimer, C. Dirk Keene, James Y. Zou, Michael J. MacCoss, Thomas J. Montine
Summary: Resilience to Alzheimer's disease is a rare combination of high disease burden without dementia, which provides valuable insights into limiting clinical impact. Lowering soluble A beta concentration may suppress severe cognitive impairment along the Alzheimer's disease continuum.
NATURE COMMUNICATIONS
(2023)
Article
Clinical Neurology
Ashwani Jha, Alberto J. Espay, Andrew J. Lees
MOVEMENT DISORDERS CLINICAL PRACTICE
(2023)
Article
Clinical Neurology
Daniel Weintraub
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Amalia Perna, Kathleen S. Montine, Lon R. White, Thomas J. Montine, Brenna A. Cholerton
Summary: Neurodegenerative dementia arises from various abnormalities and the co-occurrence of multiple processes complicates identifying effective treatment targets. Current treatments mainly focus on symptoms and recently approved drugs for disease structures only have moderate benefit on symptom progression. Ongoing trials explore cognition enhancers, new drug combinations, less toxic prodrugs, and drugs targeting neuroinflammation or microbiome. A paradigm shift towards individualized and multimodal treatments is necessary to advance dementia therapeutics effectively.
Article
Multidisciplinary Sciences
Eloise Berson, Anjali Sreenivas, Thanaphong Phongpreecha, Amalia Perna, Fiorella C. Grandi, Lei Xue, Neal G. Ravindra, Neelufar Payrovnaziri, Samson Mataraso, Yeasul Kim, Camilo Espinosa, Alan L. Chang, Martin Becker, Kathleen S. Montine, Edward J. Fox, Howard Y. Chang, M. Ryan Corces, Nima Aghaeepour, Thomas J. Montine
Summary: The authors developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression, allowing cost-effective cell type-specific open chromatin profiling. Applied to bulk samples from three brain regions, Cellformer identified cell type-specific gene regulatory mechanisms underlying resilience to Alzheimer's disease and suggested potential epigenetic mediators. The Cellformer tool is now freely available for future investigations using high-throughput bulk ATAC-seq data.
NATURE COMMUNICATIONS
(2023)
Article
Clinical Neurology
Vindhya Koneru, Alberto J. Espay, Allan J. Cole, Daniel Weintraub, Kathleen Crist, Maria B. Pascual, William G. Ondo
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Daniel Weintraub
MOVEMENT DISORDERS
(2023)