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1. Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Author

Tatiana Orme, Dena Hernandez, Owen A. Ross, Celia Kun-Rodrigues, Lee Darwent, Claire E. Shepherd, Laura Parkkinen, Olaf Ansorge, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, John Q. Trojanowski, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Valentina Escott-Price, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda Halliday, David J. Stone, Dennis W. Dickson, John Hardy, Andrew Singleton, Rita Guerreiro, and Jose Bras

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.

Published
2020
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2. Heritability and genetic variance of dementia with Lewy bodies

Author

Rita Guerreiro, Valentina Escott-Price, Dena G. Hernandez, Celia Kun-Rodrigues, Owen A. Ross, Tatiana Orme, Joao Luis Neto, Susana Carmona, Nadia Dehghani, John D. Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G. Heckman, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda M. Halliday, John Hardy, John Q. Trojanowski, Dennis W. Dickson, Andrew Singleton, David J. Stone, and Jose Bras

Subjects
Genetic variance, Dementia, Lewy bodies, Genetic correlation, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Published
2019
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3. Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF

Author

Walter Boiten, Inger van Steenoven, Mei-Fang Xiao, Paul Worley, Barbara Noli, Cristina Cocco, Gian-Luca Ferri, Afina Lemstra, Charlotte Teunissen, Laboratory Medicine, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Lewy Body Disease, Male, neuronal pentraxin 2, medicine.medical_specialty, Nerve Tissue Proteins, Inhibitory postsynaptic potential, Article, Cohort Studies, chemistry.chemical_compound, α-synuclein, Internal medicine, mental disorders, Humans, Medicine, Cognitive Dysfunction, Nerve Growth Factors, Cognitive decline, cerebral spinal fluid, Spatial domain, lcsh:QH301-705.5, cognitive function, Aged, Alpha-synuclein, Cerebral Spinal Fluid, business.industry, Dementia with Lewy bodies, biomarkers, Cognition, visual spatial domain, General Medicine, dementia with Lewy bodies, Alzheimer’s disease, VGF (non-acronym), Middle Aged, medicine.disease, nervous system diseases, C-Reactive Protein, Endocrinology, lcsh:Biology (General), chemistry, nervous system, Case-Control Studies, alpha-Synuclein, GABAergic, Female, business
Abstract

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain.

Published
2020
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4. Additional file 3 of Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Author

Orme, Tatiana, Hernandez, Dena, Ross, Owen, Kun-Rodrigues, Celia, Darwent, Lee, Shepherd, Claire, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence, Marder, Karen, Afina Lemstra, Rogaeva, Ekaterina, George-Hyslop, Peter St., Londos, Elisabet, Zetterberg, Henrik, Morgan, Kevin, Troakes, Claire, Al-Sarraj, Safa, Tammaryn Lashley, Holton, Janice, Yaroslau Compta, Vivianna Deerlin, Trojanowski, John, Geidy Serrano, Beach, Thomas, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pau Pastor, Tienari, Pentti, Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad, Petersen, Ronald, Tanis Ferman, Escott-Price, Valentina, Graff-Radford, Neill, Cairns, Nigel, Morris, John, Pickering-Brown, Stuart, Mann, David, Halliday, Glenda, Stone, David, Dickson, Dennis, Hardy, John, Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Abstract

Additional file 3: Table S3. Variants identified in the studied DLB cohort that have been previously reported in disease and have a gnomAD european allele count > 5. GnomAD NFE AC = gnomAD non-Finnish European allele count. GnomAD NFE AN = gnomAD non-Finnish European allele number. GnomAD Total MAF = gnomAD all populations minor allele frequency.

Published
2020
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5. Additional file 1 of Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Author

Orme, Tatiana, Hernandez, Dena, Ross, Owen, Kun-Rodrigues, Celia, Darwent, Lee, Shepherd, Claire, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence, Marder, Karen, Afina Lemstra, Rogaeva, Ekaterina, George-Hyslop, Peter St., Londos, Elisabet, Zetterberg, Henrik, Morgan, Kevin, Troakes, Claire, Al-Sarraj, Safa, Tammaryn Lashley, Holton, Janice, Yaroslau Compta, Vivianna Deerlin, Trojanowski, John, Geidy Serrano, Beach, Thomas, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pau Pastor, Tienari, Pentti, Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad, Petersen, Ronald, Tanis Ferman, Escott-Price, Valentina, Graff-Radford, Neill, Cairns, Nigel, Morris, John, Pickering-Brown, Stuart, Mann, David, Halliday, Glenda, Stone, David, Dickson, Dennis, Hardy, John, Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Subjects
mental disorders
Abstract

Additional file 1: Table S1. Sources of samples. Research groups, clinical teams and brain banks where the DLB samples included in this study were collected from.

Published
2020
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7. Additional file 1: of Impact of a clinical decision support tool on prediction of progression in early-stage dementia: a prospective validation study

Author

Bruun, Marie, Frederiksen, Kristian, Rhodius-Meester, Hanneke, Baroni, Marta, Gjerum, Le, Koikkalainen, Juha, Urhemaa, Timo, Tolonen, Antti, Gils, Mark, Rueckert, Daniel, Dyremose, Nadia, Andersen, Birgitte, Afina Lemstra, Hallikainen, Merja, Kurl, Sudhir, Sanna-Kaisa Herukka, Remes, Anne, Waldemar, Gunhild, Soininen, Hilkka, Mecocci, Patrizia, Flier, Wiesje, LĂśtjĂśnen, Jyrki, and Hasselbalch, Steen

Abstract

Presents additional results, such as demographics, accuracy, and performance for subgroups. (PDF 2187 kb)

Published
2019
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8. Additional file 1: Table S1. of Disease-related determinants are associated with mortality in dementia due to Alzheimerâ s disease

Author

Rhodius-Meester, Hanneke, Liedes, Hilkka, Koene, Ted, Afina Lemstra, Teunissen, Charlotte, Barkhof, Frederik, Scheltens, Philip, Gils, Mark Van, LĂśtjĂśnen, Jyrki, and Flier, Wiesje Van Der

Abstract

Cox proportional hazard models using nonimputed data; influence of baseline characteristics and medical history on survival status. Table S2. Cox proportional hazard models based on nonimputed data; influence of CSF and MRI on survival status. (DOCX 26 kb)

Published
2018
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9. LRP10 in α-synucleinopathies

Author

Rita Guerreiro, Tatiana Orme, João Luís Neto, Jose Bras, John Hardy, Celia Kun-Rodrigues, Lee Darwent, Joao Neto, Susana Carmona, Olaf Ansorge, Laura Parkkinen, Kevin Morgan, Kristelle Brown, Anne Braae, Imelda Barber, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Tamas Revesz, Andrew Lees, Henrik Zetterberg, Valentina Escott-Price, Stuart Pickering-Brown, David Mann, Andrew Singleton, Dena Hernandez, Owen Ross, Dennis Dickson, Neill Graff-Radford, Tanis Ferman, Ronald Petersen, Brad Boeve, Michael Heckman, John Q. Trojanowski, Vivianna Van Deerlin, Nigel Cairns, John Morris, David A. Stone, John Eicher, Lorraine Clark, Lawrence Honig, Karen Marder, Geidy Serrano, Thomas Beach, Douglas Galasko, Eliezer Masliah, Ekaterina Rogaeva, Peter St. George-Hyslop, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Pau Pastor, Monica Diez-Fairen, Miquel Aquilar, Claire Shepherd, Glenda Halliday, Pentti Tienari, Liisa Myllykangas, Minna Oinas, Isabel Santana, Suzanne Lesage, Elisabet Londos, Afina Lemstra, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Synucleinopathies, business.industry, MEDLINE, Computational biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, Genetic linkage, Medicine, Dementia, Neurology (clinical), business, Lewy body disease, 030217 neurology & neurosurgery
Published
2018
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10. Additional file 2: Table S2. of Atypical Creutzfeldt-Jakob disease with PrP-amyloid plaques in white matter: molecular characterization and transmission to bank voles show the M1 strain signature

Author

Rossi, Marcello, Saverioni, Daniela, Bari, Michele Di, Baiardi, Simone, Afina Lemstra, Pirisinu, Laura, Capellari, Sabina, Rozemuller, Annemieke, Nonno, Romolo, and Parchi, Piero

Subjects
nervous system
Abstract

Semi-quantitative evaluation of gray matter spongiform change and astrocytosis. Each lesion was scored semi-quantitatively using a 0â 3 scale (0, absence of significant spongiosis or astrocytosis, + mild, ++ moderate, and +++ severe spongiosis or astrocytosis; SS, status spongiosus, F, focal). F-CTX, frontal cortex; T-CTX; temporal cortex; O-CTX, occipital cortex, HIPP-CA1, hippocampus-cornu ammonis 1; STR, striatum; THAL, thalamus; CRBL, cerebellum. *Atrophic molecular layer. In the cerebellum, lesions were evaluated in the molecular layer. (DOCX 15 kb)

Published
2017
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11. Additional file 5: Table S3. of Atypical Creutzfeldt-Jakob disease with PrP-amyloid plaques in white matter: molecular characterization and transmission to bank voles show the M1 strain signature

Author

Rossi, Marcello, Saverioni, Daniela, Bari, Michele Di, Baiardi, Simone, Afina Lemstra, Pirisinu, Laura, Capellari, Sabina, Rozemuller, Annemieke, Nonno, Romolo, and Parchi, Piero

Abstract

PrPSc glycoform ratio in p-CJDMM1 and np-CJDMM1. Values represent the percentage (meanâ Âąâ standard deviation) of glycoforms referred to the total PrPSc amount. D: diglycosylated, M: monoglycosylated, U: unglycosylated PrPSc. (DOCX 13 kb)

Published
2017
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12. Additional file 4: Table S2. of Atypical Creutzfeldt-Jakob disease with PrP-amyloid plaques in white matter: molecular characterization and transmission to bank voles show the M1 strain signature

Author

Rossi, Marcello, Saverioni, Daniela, Bari, Michele Di, Baiardi, Simone, Afina Lemstra, Pirisinu, Laura, Capellari, Sabina, Rozemuller, Annemieke, Nonno, Romolo, and Parchi, Piero

Abstract

Relative amounts of PrPSc fragments in samples from p-CJDMM1 and np-CJDMM1. Values represent the percentage (mean ± standard deviation) of fragments referred to the total PrPSc amount. Differences were not statistically significant (Student’s t test). (DOCX 13 kb)

Published
2017
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13. Additional file 2 of Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Author

Orme, Tatiana, Hernandez, Dena, Ross, Owen, Kun-Rodrigues, Celia, Darwent, Lee, Shepherd, Claire, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence, Marder, Karen, Afina Lemstra, Rogaeva, Ekaterina, George-Hyslop, Peter St., Londos, Elisabet, Zetterberg, Henrik, Morgan, Kevin, Troakes, Claire, Al-Sarraj, Safa, Tammaryn Lashley, Holton, Janice, Yaroslau Compta, Vivianna Deerlin, Trojanowski, John, Geidy Serrano, Beach, Thomas, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pau Pastor, Tienari, Pentti, Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad, Petersen, Ronald, Tanis Ferman, Escott-Price, Valentina, Graff-Radford, Neill, Cairns, Nigel, Morris, John, Pickering-Brown, Stuart, Mann, David, Halliday, Glenda, Stone, David, Dickson, Dennis, Hardy, John, Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Subjects
3. Good health
Abstract

Additional file 2: Table S2. Neurodegenerative disease-causing genes and DLB risk genes analysed in this study. Genes known to cause neurodegenerative diseases are presented according to the mode of inheritance of the respective mendelian disease. Genes such as PARK2, FBXO7, SYNJ1, and DNAJC6, among others, are commonly referred to as parkinson’s disease genes, although the clinical and pathological characteristics may be atypical in some cases. FTD/ALS - frontotemporal dementia/Amyotrophic lateral sclerosis, CADASIL - Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, CARASIL - Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy *Both TMEM230 and DNAJC13 have been hypothesised to be the cause of Parkinson’s disease in the same family.

14. Additional file 2 of Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Author

Orme, Tatiana, Hernandez, Dena, Ross, Owen, Kun-Rodrigues, Celia, Darwent, Lee, Shepherd, Claire, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence, Marder, Karen, Afina Lemstra, Rogaeva, Ekaterina, George-Hyslop, Peter St., Londos, Elisabet, Zetterberg, Henrik, Morgan, Kevin, Troakes, Claire, Al-Sarraj, Safa, Tammaryn Lashley, Holton, Janice, Yaroslau Compta, Vivianna Deerlin, Trojanowski, John, Geidy Serrano, Beach, Thomas, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pau Pastor, Tienari, Pentti, Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad, Petersen, Ronald, Tanis Ferman, Escott-Price, Valentina, Graff-Radford, Neill, Cairns, Nigel, Morris, John, Pickering-Brown, Stuart, Mann, David, Halliday, Glenda, Stone, David, Dickson, Dennis, Hardy, John, Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Subjects
3. Good health
Abstract

Additional file 2: Table S2. Neurodegenerative disease-causing genes and DLB risk genes analysed in this study. Genes known to cause neurodegenerative diseases are presented according to the mode of inheritance of the respective mendelian disease. Genes such as PARK2, FBXO7, SYNJ1, and DNAJC6, among others, are commonly referred to as parkinson’s disease genes, although the clinical and pathological characteristics may be atypical in some cases. FTD/ALS - frontotemporal dementia/Amyotrophic lateral sclerosis, CADASIL - Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, CARASIL - Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy *Both TMEM230 and DNAJC13 have been hypothesised to be the cause of Parkinson’s disease in the same family.

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