Browsing by Subject "Lewy Body Disease"

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    Early-onset Dementia with Lewy Bodies
    (Wiley, 2004-04) Takao, Masaki; Ghetti, Bernardino; Yoshida, Hirotaka; Piccardo, Pedro; Narain, Yolanda; Murrell, Jill R.; Vidal, Ruben; Glazier, Bradley S.; Jakes, Ross; Tsutsui, Miho; Grazia Spillantini, Maria; Crowther, R. Anthony; Goedert, Michel; Koto, Atsuo; Pathology and Laboratory Medicine, School of Medicine
    The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.
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    Enhanced quantitation of pathological α-synuclein in patient biospecimens by RT-QuIC seed amplification assays
    (Public Library of Science, 2024-09-20) Srivastava, Ankit; Wang, Qinlu; Orrù, Christina D.; Fernandez, Manel; Compta, Yaroslau; Ghetti, Bernardino; Zanusso, Gianluigi; Zou, Wen-Quan; Caughey, Byron; Beauchemin, Catherine A. A.; Pathology and Laboratory Medicine, School of Medicine
    Disease associated pathological aggregates of alpha-synuclein (αSynD) exhibit prion-like spreading in synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Seed amplification assays (SAAs) such as real-time quaking-induced conversion (RT-QuIC) have shown high diagnostic sensitivity and specificity for detecting proteopathic αSynD seeds in a variety of biospecimens from PD and DLB patients. However, the extent to which relative proteopathic seed concentrations are useful as indices of a patient's disease stage or prognosis remains unresolved. One feature of current SAAs that complicates attempts to correlate SAA results with patients' clinical and other laboratory findings is their quantitative imprecision, which has typically been limited to discriminating large differences (e.g. 5-10 fold) in seed concentration. We used end-point dilution (ED) RT-QuIC assays to determine αSynD seed concentrations in patient biospecimens and tested the influence of various assay variables such as serial dilution factor, replicate number and data processing methods. The use of 2-fold versus 10-fold dilution factors and 12 versus 4 replicate reactions per dilution reduced ED-RT-QuIC assay error by as much as 70%. This enhanced assay format discriminated as little as 2-fold differences in αSynD seed concentration besides detecting ~2-16-fold seed reductions caused by inactivation treatments. In some scenarios, analysis of the data using Poisson and midSIN algorithms provided more consistent and statistically significant discrimination of different seed concentrations. We applied our improved assay strategies to multiple diagnostically relevant PD and DLB antemortem patient biospecimens, including cerebrospinal fluid, skin, and brushings of the olfactory mucosa. Using ED αSyn RT-QuIC as a model SAA, we show how to markedly improve the inter-assay reproducibility and quantitative accuracy. Enhanced quantitative SAA accuracy should facilitate assessments of pathological seeding activities as biomarkers in proteinopathy diagnostics and prognostics, as well as in patient cohort selection and assessments of pharmacodynamics and target engagement in drug trials.
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    Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
    (Springer Nature, 2021-03) Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara; Saez-Atienzar, Sara; Reynolds, Regina H.; Gustavsson, Emil; Walton, Ronald L.; Ahmed, Sarah; Viollet, Coralie; Ding, Jinhui; Makarious, Mary B.; Diez-Fairen, Monica; Portley, Makayla K.; Shah, Zalak; Abramzon, Yevgeniya; Hernandez, Dena G.; Blauwendraat, Cornelis; Stone, David J.; Eicher, John; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; St. George-Hyslop, Peter; Londos, Elisabet; Morgan, Kevin; Lashley, Tammaryn; Warner, Thomas T.; Jaunmuktane, Zane; Galasko, Douglas; Santana, Isabel; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Cairns, Nigel J.; Morris, John C.; Halliday, Glenda M.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grassano, Maurizio; Calvo, Andrea; Mora, Gabriele; Canosa, Antonio; Floris, Gianluca; Bohannan, Ryan C.; Brett, Francesca; Gan-Or, Ziv; Geiger, Joshua T.; Moore, Anni; May, Patrick; Krüger, Rejko; Goldstein, David S.; Lopez, Grisel; Tayebi, Nahid; Sidransky, Ellen; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio; Shakkottai, Vikram G.; Perkins, Matthew; Newell, Kathy L.; Gasser, Thomas; Schulte, Claudia; Landi, Francesco; Salvi, Erika; Cusi, Daniele; Masliah, Eliezer; Kim, Ronald C.; Caraway, Chad A.; Monuki, Edwin S.; Brunetti, Maura; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Flanagan, Margaret E.; Mao, Qinwen; Bigio, Eileen H.; Rodríguez-Rodríguez, Eloy; Infante, Jon; Lage, Carmen; González-Aramburu, Isabel; Sanchez-Juan, Pascual; Ghetti, Bernardino; Keith, Julia; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Duyckaerts, Charles; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Barrett, Matthew J.; Tilley, Bension S.; Gentleman, Steve; Logroscino, Giancarlo; Serrano, Geidy E.; Beach, Thomas G.; McKeith, Ian G.; Thomas, Alan J.; Attems, Johannes; Morris, Christopher M.; Palmer, Laura; Love, Seth; Troakes, Claire; Al-Sarraj, Safa; Hodges, Angela K.; Aarsland, Dag; Klein, Gregory; Kaiser, Scott M.; Woltjer, Randy; Pastor, Pau; Bekris, Lynn M.; Leverenz, James B.; Besser, Lilah M.; Kuzma, Amanda; Renton, Alan E.; Goate, Alison; Bennett, David A.; Scherzer, Clemens R.; Morris, Huw R.; Ferrari, Raffaele; Albani, Diego; Pickering-Brown, Stuart; Faber, Kelley; Kukull, Walter A.; Morenas-Rodriguez, Estrella; Lleó, Alberto; Fortea, Juan; Alcolea, Daniel; Clarimon, Jordi; Nalls, Mike A.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Foroud, Tatiana M.; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Ferman, Tanis; Boeve, Bradley F.; Hardy, John A.; Topol, Eric J.; Torkamani, Ali; Singleton, Andrew B.; Ryten, Mina; Dickson, Dennis W.; Chiò, Adriano; Ross, Owen A.; Gibbs, J. Raphael; Dalgard, Clifton L.; Traynor, Bryan J.; Scholz, Sonja W.; Pathology and Laboratory Medicine, School of Medicine
    The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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    Structures of α-synuclein filaments from human brains with Lewy pathology
    (Springer Nature, 2022) Yang, Yang; Shi, Yang; Schweighauser, Manuel; Zhang, Xianjun; Kotecha, Abhay; Murzin, Alexey G.; Garringer, Holly J.; Cullinane, Patrick W.; Saito, Yuko; Foroud, Tatiana; Warner, Thomas T.; Hasegawa, Kazuko; Vidal, Ruben; Murayama, Shigeo; Revesz, Tamas; Ghetti, Bernardino; Hasegawa, Masato; Lashley, Tammaryn; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
    Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.