Article
Neurosciences
Konstantin Senkevich, Uladzislau Rudakou, Ziv Gan-Or
Summary: Parkinson's disease is a complex disorder that may be a mixture of different diseases, with genes playing an important role in patient classification and drug development. GBA, LRRK2, and PRKN are key genes associated with PD, and targeting these genes could lead to novel therapeutic approaches.
Article
Geriatrics & Gerontology
Yuri L. Sosero, Eric Yu, Lynne Krohn, Uladzislau Rudakou, Kheireddin Mufti, Jennifer A. Ruskey, Farnaz Asayesh, Sandra B. Laurent, Dan Spiegelman, Stanley Fahn, Cheryl Waters, S. Pablo Sardi, Sara Bandres-Ciga, Roy N. Alcalay, Ziv Gan-Or, Konstantin Senkevich
Summary: The study found that the LRRK2 p.M1646T variant is associated with an increased risk of PD and elevated GCase activity in peripheral blood. However, the effect of this variant on PD risk is relatively small.
NEUROBIOLOGY OF AGING
(2021)
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
Neurosciences
Kalpana M. Merchant, Tanya Simuni, Janel Fedler, Chelsea Caspell-Garcia, Michael Brumm, Kelly N. H. Nudelman, Elizabeth Tengstrandt, Frank Hsieh, Roy N. Alcalay, Christopher Coffey, Lana Chahine, Tatiana Foroud, Andrew Singleton, Daniel Weintraub, Samantha Hutten, Todd Sherer, Brit Mollenhauer, Andrew Siderowf, Caroline Tanner, Ken Marek
Summary: We quantified concentrations of three isoforms of BMP in different cohorts of Parkinson's disease patients and found that LRRK2 and GBA1 gene mutations were associated with elevated BMP levels. However, BMP is not a prognostic or disease progression biomarker.
NPJ PARKINSONS DISEASE
(2023)
Article
Medicine, General & Internal
David Devos, Julien Labreuche, Olivier Rascol, Jean-Christophe Corvol, Alain Duhamel, P. Guyon Delannoy, Werner Poewe, Yaroslau Compta, Nicola Pavese, Evzen Ruzicka, Petr Dusek, Bart Post, Bastiaan R. Bloem, Daniela Berg, Walter Maetzler, Markus Otto, Marie-Odile Habert, Stephane Lehericy, Joaquim Ferreira, Richard Dodel, Christine Tranchant, Alexandre Eusebio, Stephane Thobois, Ana-Raquel Marques, Wassilios G. Meissner, Fabienne Ory-Magne, Uwe Walter, Rob M. A. de Bie, Miguel Gago, Dolores Vilas, Jaime Kulisevsky, Cristina Januario, Miguel V. S. Coelho, Stefanie Behnke, Paul Worth, Klaus Seppi, Thavarak Ouk, Camille Potey, Celine Leclercq, Romain Viard, Gregory Kuchcinski, Renaud Lopes, Jean-Pierre Pruvo, Pascal Pigny, Guillaume Garcon, Ophelie Simonin, Jessica Carpentier, Anne-Sophie Rolland, Dag Nyholm, Christoph Scherfler, Jean-Francois Mangin, Marie Chupin, Regis Bordet, David T. Dexter, Caroline Fradette, Michael Spino, Fernando Tricta, Scott Ayton, Ashley I. Bush, Jean-Christophe Devedjian, James A. Duce, Ioav Cabantchik, Luc Defebvre, Dominique Deplanque, Caroline Moreau
Summary: In a 36-week trial involving participants with early Parkinson's disease who had not received levodopa, treatment with the iron chelator deferiprone led to worse scores in measures of parkinsonism compared to placebo.
NEW ENGLAND JOURNAL OF MEDICINE
(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
Clinical Neurology
Avner Thaler, Nurit Omer, Nir Giladi, Tanya Gurevich, Anat Bar-Shira, Mali Gana-Weisz, Orly Goldstein, Meir Kestenbaum, Jesse M. Cedarbaum, Avi Orr-Urtreger, Shani Shenhar-Tsarfaty, Anat Mirelman
Summary: The study aimed to evaluate the association between biochemical markers, PD severity, and prodromal PD probability score among carriers of GBA and LRRK2 mutations. The results showed that sub-clinical renal impairment is linked to an increased likelihood of prodromal PD, regardless of genetic status, suggesting a potential role of kidney function in PD pathogenesis.
JOURNAL OF NEUROLOGY
(2021)
Review
Neurosciences
Emily M. Rocha, Matthew T. Keeney, Roberto Di Maio, Briana R. De Miranda, J. Timothy Greenamyre
Summary: The etiology of idiopathic Parkinson's disease involves multiple factors, including genetics and environmental exposures. LRRK2 plays an important role in iPD, regardless of mutations, by influencing kinase activation and substrate phosphorylation, which contribute to the pathogenesis.
TRENDS IN NEUROSCIENCES
(2022)
Article
Clinical Neurology
Eun Hye Jeong, Jae Yong Lee, Sun-Ku Han, Yoo Sung Song
Summary: Genetic research in Parkinson's disease has significantly impacted clinical treatment, and a subtyping strategy based on clinical symptoms holds promise in enhancing the diagnosis and treatment of PD.
FRONTIERS IN NEUROLOGY
(2023)
Article
Clinical Neurology
Tatiana Usnich, Eva-Juliane Vollstedt, Nathalie Schell, Volha Skrahina, Xenia Bogdanovic, Hanaa Gaber, Toni M. Foerster, Andreas Heuer, Natalia Koleva-Alazeh, Ilona Csoti, Ayse Nazli Basak, Sibel Ertan, Gencer Genc, Peter Bauer, Katja Lohmann, Anne Gruenewald, Emma L. Schymanski, Joanne Trinh, Susen Schaake, Daniela Berg, Doreen Gruber, Stuart H. Isaacson, Andrea A. Kuehn, Brit Mollenhauer, David J. Pedrosa, Kathrin Reetz, Esther M. Sammler, Enza Maria Valente, Franco Valzania, Jens Volkmann, Simone Zittel, Norbert Brueggemann, Meike Kasten, Arndt Rolfs, Christine Klein
Summary: The LIPAD project aims to systematically assess clinical signs and symptoms in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls, and investigate modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.
FRONTIERS IN NEUROLOGY
(2021)
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
Medicine, General & Internal
Jia-Hung Chen, Lung Chan, Chen-Chih Chung, Oluwaseun Adebayo Bamodu, Chien-Tai Hong
Summary: Elevated blood neurofilament light chain is being increasingly recognized as a diagnostic and outcome-predicting biomarker for neurological diseases, but its implications in Parkinson's disease remain unclear. Studies have shown conflicting data on blood NfL levels in PD cohorts, possibly due to demographic heterogeneity. By adjusting for age and gender, the comparability of NfL levels between different PD studies can be enhanced, helping to eliminate conflicting factors and enhance the understanding of this biomarker's significance.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Neurosciences
Shirley Yin-Yu Pang, Rachel Cheuk Nam Lo, Philip Wing-Lok Ho, Hui-Fang Liu, Eunice Eun Seo Chang, Chi-Ting Leung, Yasine Malki, Zoe Yuen-Kiu Choi, Wing Yan Wong, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
Summary: Mutations in LRRK2 and GBA are the most common genetic causes of Parkinson's disease, affecting the autophagic-lysosomal pathway. These genes influence each other, leading to autophagic defects, alpha-synuclein accumulation, and worsened clinical symptoms. Inhibitors of LRRK2 kinase and activators of GCase show promise in pre-clinical models, but their efficacy in idiopathic Parkinson's disease remains uncertain.
TRANSLATIONAL NEURODEGENERATION
(2022)
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
Neurosciences
Anastasia Bougea, Christos Koros, Nikolaos Papagiannakis, Athina-Maria Simitsi, Andreas Prentakis, Dimitra Papadimitriou, Ioanna Pachi, Roubina Antonelou, Efthalia Angelopoulou, Ion Beratis, Maria Bozi, Sokratis G. Papageorgiou, Xenia Geronicola Trapali, Maria Stamelou, Leonidas Stefanis
Summary: Longitudinal comparison of serum uric acid levels in iPD, LRRK2 + PD, and HC patients revealed significantly lower uric acid concentrations in LRRK2 + PD patients compared to HC during a 5-year follow-up. However, there were no significant associations between uric acid levels and disease severity indices after adjusting for age, sex, and baseline BMI.
JOURNAL OF PARKINSONS DISEASE
(2021)
Article
Clinical Neurology
Raquel Real, Alejandro Martinez-Carrasco, Regina H. Reynolds, Michael A. Lawton, Manuela M. X. Tan, Maryam Shoai, Jean-Christophe Corvol, Mina Ryten, Catherine Bresner, Leon Hubbard, Alexis Brice, Suzanne Lesage, Johann Faouzi, Alexis Elbaz, Fanny Artaud, Nigel Williams, Michele T. M. Hu, Yoav Ben-Shlomo, Donald G. Grosset, John Hardy, Huw R. Morris
Summary: Researchers performed a genome-wide survival study on almost 4000 Parkinson's disease patients and identified new genetic loci associated with faster progression to Parkinson's disease dementia, including the LRP1B receptor. Parkinson's disease is a common neurodegenerative disorder, and cognitive impairment and dementia are important features in the later stages of the disease. The genetic basis for the heterogeneity in cognitive decline among Parkinson's disease patients is not fully understood.
Article
Neurosciences
Christina B. Young, Emily Johns, Gabriel Kennedy, Michael E. Belloy, Philip S. Insel, Michael D. Greicius, Reisa A. Sperling, Keith A. Johnson, Kathleen L. Poston, Elizabeth C. Mormino
Summary: APOE variants are associated with abnormal amyloid aggregation and also have direct effects on tau aggregation. This study examined the effects of APOE on amyloid and tau burden in clinically unimpaired individuals. The results showed that APOE2 was associated with lower amyloid burden and reduced regional tau, while APOE4 was associated with higher amyloid burden and greater regional tau. These findings suggest that APOE influences early tau burden independent of amyloid burden and targeting APOE-related mechanisms may modify tau accumulation.
MOLECULAR NEURODEGENERATION
(2023)
Article
Clinical Neurology
Duygu Tosun, Pamela Thropp, Sudeepti Southekal, Bruce Spottiswoode, Rachid Fahmi
Summary: This study used an unsupervised data-driven whole-brain pattern analysis to identify distinct tau accumulation profiles and build baseline models predictive of tau-accumulation type. Screening for fast tau accumulation and A beta positivity in early Alzheimer's disease requires a lower sample size to achieve 80% power for a specific treatment.
ALZHEIMERS & DEMENTIA
(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.
Letter
Clinical Neurology
Guenther Deuschl, Angelo Antonini, Joao Costa, Katarzyna Smilowska, Daniela Berg, Jean-Christophe Corvol, Giovanni Fabbrini, Joaquim Ferreira, Tom Foltynie, Pablo Mir, Anette Schrag, Klaus Seppi, Pille Taba, Evzen Ruzicka, Marianna Selikhova, Nicholas Henschke, Gemma Villanueva, Elena Moro
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Duygu Tosun, Ozlem Yardibi, Tammie L. S. Benzinger, Walter A. Kukull, Colin L. Masters, Richard J. Perrin, Michael W. Weiner, Arthur Simen, Adam J. Schwarz, lzheimers Dis Neuroimaging Initiative
Summary: In this study, a multilabel non-ADNC classifier using MRI signatures was developed for the identification of non-Alzheimer's disease neuropathological changes. The model showed high accuracy in distinguishing TDP-43, LBD, and CAA, outperforming reference models without MRI and ADNC biomarkers. Considering non-ADNC decreased the required sample size to detect cognitive decline.
ALZHEIMERS & DEMENTIA
(2023)
Review
Medicine, Research & Experimental
Matteo Ciocca, Barry M. Seemungal, Yen F. Tai
Summary: This study reviewed preclinical and clinical studies of spinal cord stimulation (SCS) for treating gait dysfunction in Parkinson's disease (PD) and other parkinsonian disorders. While animal studies showed positive results, the outcomes of human studies were inconsistent. Limitations in the field include the lack of blind and statistically powered studies, heterogeneity in patient selection and study outcomes, and poor understanding of the mechanisms of action of SCS.
Article
Clinical Neurology
Thanaphong Phongpreecha, Dana Godrich, Eloise Berson, Camilo Espinosa, Yeasul Kim, Brenna Cholerton, Alan L. Chang, Samson Mataraso, Syed A. Bukhari, Amalia Perna, Koya Yakabi, Kathleen S. Montine, Kathleen L. Poston, Elizabeth Mormino, Lon White, Gary Beecham, Nima Aghaeepour, Thomas J. Montine
Summary: The study proposes a framework for defining cognitive resilience (CR) as a continuous variable for each neuropsychological test, aiming to address discrepancies and shortcomings of the current CR definition. The framework clarifies the relationship between CR and closely related terms and provides insights into the underlying mechanisms of CR.
ALZHEIMERS RESEARCH & THERAPY
(2023)
Article
Neurosciences
Michael C. Brumm, Andrew Siderowf, Tanya Simuni, Elliot Burghardt, Seung Ho Choi, Chelsea Caspell-Garcia, Lana M. Chahine, Brit Mollenhauer, Tatiana Foroud, Douglas Galasko, Kalpana Merchant, Vanessa Arnedo, Samantha J. Hutten, Alyssa N. O'Grady, Kathleen L. Poston, Caroline M. Tanner, Daniel Weintraub, Karl Kieburtz, Kenneth Marek, Christopher S. Coffey
Summary: Clinically relevant milestones in Parkinson's disease occur frequently, even in early stages, and are associated with baseline features but not with symptomatic treatment. Further studies are needed to validate these results and explore their translation into outcome measures for observational and therapeutic studies.
JOURNAL OF PARKINSONS DISEASE
(2023)
Article
Clinical Neurology
Alberto J. Espay, Robert A. Hauser, Rohit Dhall, Sandeep Thakkar, Leslie Cloud, Leonid Zeitlin, Ghazal Banisadr, Stanley Fisher, Hester Visser
Summary: In this open-label extension of a phase 3 study, IPX203 demonstrated a favorable safety profile and sustained efficacy similar to the double-blind study. Improvements in efficacy were maintained throughout the trial, and adverse events were mostly mild or moderate and occurred within the first 90 days of treatment.
MOVEMENT DISORDERS
(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
Cecile Di Folco, Raphael Couronne, Isabelle Arnulf, Graziella Mangone, Smaranda Leu-Semenescu, Pauline Dodet, Marie Vidailhet, Jean-Christophe Corvol, Stephane Lehericy, Stanley Durrleman
Summary: This study proposes a disease course map for Parkinson's disease (PD) and investigates the progression profiles of patients with or without rapid eye movement sleep behavioral disorders (RBD). The findings reveal distinct patterns of progression between PD patients with and without RBD, emphasizing the importance of understanding heterogeneity in PD progression for precision medicine.
MOVEMENT DISORDERS
(2023)
Letter
Clinical Neurology
Matthew C. Kiernan, Glenda M. Halliday, Dominic B. Rowe, Rachel H. Tan
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2023)
Article
Clinical Neurology
Daniel Weintraub
MOVEMENT DISORDERS
(2023)