H Geut1, L J M Vergouw2, Y Galis3, A Ingrassia3, F J de Jong2, M Quadri4, V Bonifati4, A W Lemstra5, A J M Rozemuller6, W D J van de Berg3. 1. Amsterdam UMC, Vrije Universiteit Amsterdam, Dept. of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, the Netherlands. Electronic address: h.geut@vumc.nl. 2. Erasmus MC, University Medical Center Rotterdam, Dept. of Neurology and Alzheimer Center, Rotterdam, the Netherlands. 3. Amsterdam UMC, Vrije Universiteit Amsterdam, Dept. of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, the Netherlands. 4. Erasmus MC, University Medical Center Rotterdam, Dept. of Clinical Genetics, Rotterdam, the Netherlands. 5. Amsterdam UMC, Vrije Universiteit Amsterdam, Dept. of Neurology, Alzheimer Center, Amsterdam Neuroscience, Amsterdam, the Netherlands. 6. Center for Prion Diseases, University Medical Center Utrecht, Utrecht, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Dept. of Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands.
Abstract
INTRODUCTION: The disease course of dementia with Lewy bodies (DLB) can be rapidly progressive, clinically resembling Creutzfeldt-Jakob's disease (CJD). To better understand factors contributing to this rapidly progressive disease course, we describe load and distribution of neuropathology, and the presence of possible disease-associated genetic defects in a post-mortem series of DLB cases clinically suspected of CJD. METHODS: We included pathologically confirmed DLB cases with a disease duration of 3.5 years or less from the Dutch Surveillance Center for Prion Diseases, collected between 1998 and 2014. Lewy body disease (LBD) and Alzheimer's disease (AD)-related pathology were staged and semi-quantitatively scored in selected brain regions. Whole exome sequencing analysis of known disease-associated genes, copy number analysis, APOE ε genotyping and C9orf72 repeat expansion analysis were performed to identify defects in genes with a well-established involvement in Parkinson's disease or AD. RESULTS: Diffuse LBD was present in nine cases, transitional LBD in six cases and brainstem-predominant LBD in one case. Neocortical alpha-synuclein load was significantly higher in cases with intermediate-to-high than in cases with low-to-none AD-related pathology (p = 0.007). We found two GBA variants (p.D140H and p.E326K) in one patient and two heterozygous rare variants of unknown significance in SORL1 in two patients. CONCLUSION: A high load of neocortical alpha-synuclein pathology was present in most, but not all DLB cases. Additional burden from presence of concomitant pathologies, synergistic effects and specific genetic defects in the known disease-associated genes may have contributed to the rapid disease progression.
INTRODUCTION: The disease course of dementia with Lewy bodies (DLB) can be rapidly progressive, clinically resembling Creutzfeldt-Jakob's disease (CJD). To better understand factors contributing to this rapidly progressive disease course, we describe load and distribution of neuropathology, and the presence of possible disease-associated genetic defects in a post-mortem series of DLB cases clinically suspected of CJD. METHODS: We included pathologically confirmed DLB cases with a disease duration of 3.5 years or less from the Dutch Surveillance Center for Prion Diseases, collected between 1998 and 2014. Lewy body disease (LBD) and Alzheimer's disease (AD)-related pathology were staged and semi-quantitatively scored in selected brain regions. Whole exome sequencing analysis of known disease-associated genes, copy number analysis, APOE ε genotyping and C9orf72 repeat expansion analysis were performed to identify defects in genes with a well-established involvement in Parkinson's disease or AD. RESULTS: Diffuse LBD was present in nine cases, transitional LBD in six cases and brainstem-predominant LBD in one case. Neocortical alpha-synuclein load was significantly higher in cases with intermediate-to-high than in cases with low-to-none AD-related pathology (p = 0.007). We found two GBA variants (p.D140H and p.E326K) in one patient and two heterozygous rare variants of unknown significance in SORL1 in two patients. CONCLUSION: A high load of neocortical alpha-synuclein pathology was present in most, but not all DLB cases. Additional burden from presence of concomitant pathologies, synergistic effects and specific genetic defects in the known disease-associated genes may have contributed to the rapid disease progression.
Authors: Rita Guerreiro; Elizabeth Gibbons; Miguel Tábuas-Pereira; Celia Kun-Rodrigues; Gustavo C Santo; Jose Bras Journal: Neurobiol Dis Date: 2020-05-19 Impact factor: 5.996
Authors: Luis M A Oliveira; Thomas Gasser; Robert Edwards; Markus Zweckstetter; Ronald Melki; Leonidas Stefanis; Hilal A Lashuel; David Sulzer; Kostas Vekrellis; Glenda M Halliday; Julianna J Tomlinson; Michael Schlossmacher; Poul Henning Jensen; Julia Schulze-Hentrich; Olaf Riess; Warren D Hirst; Omar El-Agnaf; Brit Mollenhauer; Peter Lansbury; Tiago F Outeiro Journal: NPJ Parkinsons Dis Date: 2021-07-26
Authors: Georgia Xiromerisiou; Thomas Bourinaris; Henry Houlden; Patrick A Lewis; Konstantin Senkevich; Monia Hammer; Monica Federoff; Alaa Khan; Cleanthe Spanaki; Georgios M Hadjigeorgiou; Sevasti Bonstanjopoulou; Liana Fidani; Aleksey Ermolaev; Ziv Gan-Or; Andrew Singleton; Jana Vandrovcova; John Hardy Journal: Ann Clin Transl Neurol Date: 2021-09-10 Impact factor: 4.511