Pub Date : 2024-09-02DOI: 10.1101/2024.08.27.24312648
Xiwei She, Wendy Qi, Kerry C. Nix, Miguel Menchaca, Christopher C. Cline, Wei Wu, Zihuai He, Fiona M. Baumer
Objective Interictal epileptiform discharges (IEDs) alter brain connectivity in children with epilepsy; this connectivity change may be a mechanism by which epilepsy induces cognitive deficits. Here, we test whether repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, modulates connectivity and reduces IEDs in children with epilepsy.
{"title":"Repetitive Transcranial Magnetic Stimulation Modulates Brain Connectivity in Children with Self-limited Epilepsy with Centrotemporal Spikes","authors":"Xiwei She, Wendy Qi, Kerry C. Nix, Miguel Menchaca, Christopher C. Cline, Wei Wu, Zihuai He, Fiona M. Baumer","doi":"10.1101/2024.08.27.24312648","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312648","url":null,"abstract":"<strong>Objective</strong> Interictal epileptiform discharges (IEDs) alter brain connectivity in children with epilepsy; this connectivity change may be a mechanism by which epilepsy induces cognitive deficits. Here, we test whether repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, modulates connectivity and reduces IEDs in children with epilepsy.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1101/2024.09.01.24312907
Ahmed Y. Azzam, Mahmoud Nassar, Ahmed Saad Al Zomia, Adam Elswedy, Mahmoud M. Morsy, Adham A. Mohamed, Osman Elamin, Omar S. Elsayed, Mohammed A. Azab, Muhammed Amir Essibayi, Jin Wu, Adam A. Dmytirw, David J. Altschul
Introduction Idiopathic intracranial hypertension (IIH) remains a challenging condition to manage, with limited therapeutic options. This study investigated the potential of metformin as a novel treatment for IIH, exploring its effects on disease outcomes and safety profile.
{"title":"Safety and Efficacy of Metformin for Idiopathic Intracranial Hypertension. A U.S-Based Real-World Data Retrospective Multicenter Cohort Study","authors":"Ahmed Y. Azzam, Mahmoud Nassar, Ahmed Saad Al Zomia, Adam Elswedy, Mahmoud M. Morsy, Adham A. Mohamed, Osman Elamin, Omar S. Elsayed, Mohammed A. Azab, Muhammed Amir Essibayi, Jin Wu, Adam A. Dmytirw, David J. Altschul","doi":"10.1101/2024.09.01.24312907","DOIUrl":"https://doi.org/10.1101/2024.09.01.24312907","url":null,"abstract":"<strong>Introduction</strong> Idiopathic intracranial hypertension (IIH) remains a challenging condition to manage, with limited therapeutic options. This study investigated the potential of metformin as a novel treatment for IIH, exploring its effects on disease outcomes and safety profile.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"171 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1101/2024.09.01.24312543
Kevin Peikert, Adrian Spranger, Gabriel Miltenberger-Miltenyi, Hannes Glaß, Björn Falkenburger, Christian Klose, Donatienne Tyteca, Andreas Hermann
Background VPS13A disease (chorea-acanthocytosis) is an ultra-rare disorder caused by loss of function mutations in VPS13A characterized by striatal degeneration and by red blood cell (RBC) acanthocytosis. VPS13A is a bridge-like protein mediating bulk lipid transfer at membrane contact sites.
{"title":"Phosphatidylethanolamines are the main lipid class altered in red blood cells from patients with VPS13A disease/chorea-acanthocytosis","authors":"Kevin Peikert, Adrian Spranger, Gabriel Miltenberger-Miltenyi, Hannes Glaß, Björn Falkenburger, Christian Klose, Donatienne Tyteca, Andreas Hermann","doi":"10.1101/2024.09.01.24312543","DOIUrl":"https://doi.org/10.1101/2024.09.01.24312543","url":null,"abstract":"<strong>Background</strong> VPS13A disease (chorea-acanthocytosis) is an ultra-rare disorder caused by loss of function mutations in VPS13A characterized by striatal degeneration and by red blood cell (RBC) acanthocytosis. VPS13A is a bridge-like protein mediating bulk lipid transfer at membrane contact sites.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"69 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1101/2024.08.31.24312796
Justin Simo, Heather M. Lugar, Elka Miller, Adi Wilf-Yarkoni, Yael Goldberg, Ayça Kocaağa, Shoichi Ito, Sirio Cocozza, Giulio Frontino, Cristina Baldoli, Aziz Benbachir, Catherine Ashton, Guy Rouleau, Tamara Hershey, Yann Nadjar, Roberta La Piana
Background and Objectives Wolfram syndrome (WFS) is a genetic disorder mainly caused by pathogenic variants in the WFS1 gene. It is characterized clinically by optic atrophy (OA), diabetes mellitus (DM), sensorineural hearing loss (SNHL), diabetes insipidus (DI), and variable neurological/psychiatric symptoms. WFS typically manifests before age 20 and progresses into adulthood. Classical neuroradiological features include cerebellar and/or brainstem atrophy as well as white matter abnormalities ranging from small, ovoid lesions to diffuse, symmetrical changes along the visual pathway. Following the identification of multifocal, progressive white matter abnormalities that prompted the consideration of multiple sclerosis (MS) in two molecularly confirmed WFS subjects, we sought to verify whether MS-like lesions constitute a novel WFS-associated MRI pattern.
{"title":"Expanding the spectrum of white matter abnormalities in Wolfram syndrome: A retrospective review","authors":"Justin Simo, Heather M. Lugar, Elka Miller, Adi Wilf-Yarkoni, Yael Goldberg, Ayça Kocaağa, Shoichi Ito, Sirio Cocozza, Giulio Frontino, Cristina Baldoli, Aziz Benbachir, Catherine Ashton, Guy Rouleau, Tamara Hershey, Yann Nadjar, Roberta La Piana","doi":"10.1101/2024.08.31.24312796","DOIUrl":"https://doi.org/10.1101/2024.08.31.24312796","url":null,"abstract":"<strong>Background and Objectives</strong> Wolfram syndrome (WFS) is a genetic disorder mainly caused by pathogenic variants in the <em>WFS1</em> gene. It is characterized clinically by optic atrophy (OA), diabetes mellitus (DM), sensorineural hearing loss (SNHL), diabetes insipidus (DI), and variable neurological/psychiatric symptoms. WFS typically manifests before age 20 and progresses into adulthood. Classical neuroradiological features include cerebellar and/or brainstem atrophy as well as white matter abnormalities ranging from small, ovoid lesions to diffuse, symmetrical changes along the visual pathway. Following the identification of multifocal, progressive white matter abnormalities that prompted the consideration of multiple sclerosis (MS) in two molecularly confirmed WFS subjects, we sought to verify whether MS-like lesions constitute a novel WFS-associated MRI pattern.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142225098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Ischemic stroke is a major global public health concern. This study evaluates the burden of ischemic stroke in 2021, analyzes trends since 1990, and predicts future burdens.
{"title":"Global and regional burden of ischemic stroke disease from 1990 to 2021: an age-period cohort analysis","authors":"Weimin Zhu, Xiaxia He, Daochao Huang, Yiqing Jiang, Weijun Hong, Shaofa Ke, En Wang, Feng Wang, Xianwei Wang, Renfei Shan, Suzhi Liu, Yinghe Xu, Yongpo Jiang","doi":"10.1101/2024.08.29.24312683","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312683","url":null,"abstract":"<strong>Background</strong> Ischemic stroke is a major global public health concern. This study evaluates the burden of ischemic stroke in 2021, analyzes trends since 1990, and predicts future burdens.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"202 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.28.24312758
Ashley Reynolds, Rachel E. Stirling, Samuel Håkansson, Philippa Karoly, Alan Lai, David B. Grayden, Mark J. Cook, Ewan Nurse, Andre Peterson
Objective The periodicity of seizures, ranging from circadian to circannual cycles, is increasingly recognized as a significant opportunity to advance epilepsy management. Current methods for detecting seizure cycles rely on intrusive techniques or specialised biomarkers, limiting their accessibility.
{"title":"Monitoring seizure cycles with seizure diaries","authors":"Ashley Reynolds, Rachel E. Stirling, Samuel Håkansson, Philippa Karoly, Alan Lai, David B. Grayden, Mark J. Cook, Ewan Nurse, Andre Peterson","doi":"10.1101/2024.08.28.24312758","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312758","url":null,"abstract":"<strong>Objective</strong> The periodicity of seizures, ranging from circadian to circannual cycles, is increasingly recognized as a significant opportunity to advance epilepsy management. Current methods for detecting seizure cycles rely on intrusive techniques or specialised biomarkers, limiting their accessibility.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"626 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, resulting in dystrophin loss. Exon-skipping using antisense oligonucleotides (ASO) is a promising approach that partially restores dystrophin by correcting the frameshift during pre-mRNA splicing. However, a weakness of the current approach is that it is mutation-specific and has poor efficacy. To address these, we aim to develop brogidirsen, a new dual-targeting ASO that targets two sequences in exon 44 of the DMD using phosphorodiamidate morpholino oligomer. Here, we conducted an open-label, dose-escalation, Phase I/II trial to evaluate the safety, pharmacokinetics, and activity of brogidirsen, administered intravenously to six ambulant patients with DMD amenable to exon 44 skipping. The study consisted of a dose-escalation part to determine the optimal doses, followed by extended treatment with 40 mg/kg or 80 mg/kg weekly dose for 24 weeks. There were no serious adverse events related to brogidirsen. The results indicated a dose-dependent increase in dystrophin levels, reaching 10.27% and 15.79% of the normal level in the two cohorts. Motor functional tests suggested a trend toward maintaining or slightly improving motor function. There was a dose-dependent increase in Cmax and AUC0–t. High-throughput proteomic assays revealed that serum proteins such as PADI2, TTN, MYOM2, and MYLPF were observed to reduce, suggesting them as biomarkers for therapeutic effects. Notably, in vitro assays using urine-derived cells from patients with DMD support brogidirsen’s high efficacy in the first-in-human studies. These promising results warrant a subsequent multinational trial for DMD.
{"title":"Phase I/II Trial of Brogidirsen: Dual-Targeting Antisense Oligonucleotides for Exon 44 Skipping in Duchenne Muscular Dystrophy","authors":"Hirofumi Komaki, Eri Takeshita, Katsuhiko Kunitake, Takami Ishizuka, Yuko Shimizu-Motohashi, Akihiko Ishiyama, Masayuki Sasaki, Chihiro Yonee, Shinsuke Maruyama, Eisuke Hida, Yoshitsugu Aoki","doi":"10.1101/2024.08.28.24312624","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312624","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, resulting in dystrophin loss. Exon-skipping using antisense oligonucleotides (ASO) is a promising approach that partially restores dystrophin by correcting the frameshift during pre-mRNA splicing. However, a weakness of the current approach is that it is mutation-specific and has poor efficacy. To address these, we aim to develop brogidirsen, a new dual-targeting ASO that targets two sequences in exon 44 of the <em>DMD</em> using phosphorodiamidate morpholino oligomer. Here, we conducted an open-label, dose-escalation, Phase I/II trial to evaluate the safety, pharmacokinetics, and activity of brogidirsen, administered intravenously to six ambulant patients with DMD amenable to exon 44 skipping. The study consisted of a dose-escalation part to determine the optimal doses, followed by extended treatment with 40 mg/kg or 80 mg/kg weekly dose for 24 weeks. There were no serious adverse events related to brogidirsen. The results indicated a dose-dependent increase in dystrophin levels, reaching 10.27% and 15.79% of the normal level in the two cohorts. Motor functional tests suggested a trend toward maintaining or slightly improving motor function. There was a dose-dependent increase in Cmax and AUC0–t. High-throughput proteomic assays revealed that serum proteins such as PADI2, TTN, MYOM2, and MYLPF were observed to reduce, suggesting them as biomarkers for therapeutic effects. Notably, in vitro assays using urine-derived cells from patients with DMD support brogidirsen’s high efficacy in the first-in-human studies. These promising results warrant a subsequent multinational trial for DMD.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142225100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.29.24312799
Melina Wirtz, Saif Salman, Yujia Wei, Vishal Patel, Rohan Sharma, Vikash Gupta, Qiangqiang Gu, Benoit Dherin, Sanjana Reddy, Rabih Tawk, Bradley J Erickson, William David Freeman
Objectives To automate subarachnoid hemorrhage volume (SAHV) calculation (SAHVAI-SAHV ArtificialIntelligence) and create 3D volumetric images (SAHVAI-3D) using non-contrast head CT (NCCT) imaging data in aneurysmal subarachnoid hemorrhage (SAH) patients. We also defined SAHVAI-4D, representing SAHV over time. The aim was to compare automated SAHVAI volumes to manual SAHV methods and computation times, explore these imaging biomarkers’ potential in identifying at-risk brain regions for delayed cerebral ischemia (DCI), and explore potential insights in future neurotherapeutic interventions for SAH patient recovery.
{"title":"SAHVAI-3D and 4D: A New, Automated Subarachnoid Hemorrhage Volumetric Artificial Intelligence (SAHVAI) Measurement Approach Using Non-Contrast Head CT Scans","authors":"Melina Wirtz, Saif Salman, Yujia Wei, Vishal Patel, Rohan Sharma, Vikash Gupta, Qiangqiang Gu, Benoit Dherin, Sanjana Reddy, Rabih Tawk, Bradley J Erickson, William David Freeman","doi":"10.1101/2024.08.29.24312799","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312799","url":null,"abstract":"<strong>Objectives</strong> To automate subarachnoid hemorrhage volume (SAHV) calculation (<strong><em>SAHVAI-SAHV A</em></strong><em>rtificial</em> <strong><em>I</em></strong><em>ntelligence)</em> and create 3D volumetric images (SAHVAI-3D) using non-contrast head CT (NCCT) imaging data in aneurysmal subarachnoid hemorrhage (SAH) patients. We also defined SAHVAI-4D, representing SAHV over time. The aim was to compare automated SAHVAI volumes to manual SAHV methods and computation times, explore these imaging biomarkers’ potential in identifying at-risk brain regions for delayed cerebral ischemia (DCI), and explore potential insights in future neurotherapeutic interventions for SAH patient recovery.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"132 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.29.24312734
Daniel Hupalo, Jacob L. McCauley, Lissette Gomez, Anthony J. Griswold, Gabriela Hoher, Ioanna Konidari, Jose Lorenzo, Griffin S. Parker, Julianna Pascual, Amanda R. Sandford, Patrice L. Whitehead, David A. Davis, Susanna Garamszegi, S. Humayun Gultekin, Xiaoyan Sun, Regina T. Vontell, Michael Chatigny, Darren Chernicky, Myrtha M. Constant, Isabelle G. Darling, David J. Ennulat, John M. Esposito, Kiely Morris, Elisabeth S. Lawton, Neda R. Morakabati, Phyllis Oduor, Allison P. Rodgers, Lorelle A. Sang, Kathleen M. Sullivan, Catalina J. Tabit, Tori Turpin, Aya Zeabi, Tina Zheng, Sabina Berretta, Torsten Klengel, Derek H. Oakley, W. Brad Ruzicka, Thomas Blanchard, Eric Ho, Robert Johnson, Alexandra LeFevre, Maxwell Bustamante, Vahram Haroutunian, Pavel Katsel, Christine Marino, Stephen Panopoulos, Dushyant P. Purohit, Michael Wysocki, Jill R. Glausier, David .A. Lewis, Rashed M. Nagra, Camille Alba, Julianna Martin, Elizabeth Rice, John Rosenberger, Grace Smith, Gauthaman Sukumar, Miranda Tompkins, Matthew Wilkerson, Clifton L. Dalgard, William K. Scott
Central nervous system diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors including genetic risk. Here we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered in 15 broad categories by ICD-10 coding. These donors were collected by six repositories comprising the NIH NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants detected by Whole-Genome Sequencing (WGS) were called genome-wide and annotated to describe their functional impact, resulting in 171,121,209 unique mutations and 1,078,774 non-silent mutations. This whole-genome resource has been made available in the NIMH Data Archive (nda.nih.gov) and accompanying deep demographic and phenotypic descriptions are available at the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate an application of this resource, we replicated the strong association observed in previous studies between pathogenic CAG repeat expansions in the HTT gene with the clinical diagnosis of Huntington’s disease.
{"title":"The NeuroBioBank Whole-Genome Catalog: Sequencing from human brain donors with central nervous system disorders","authors":"Daniel Hupalo, Jacob L. McCauley, Lissette Gomez, Anthony J. Griswold, Gabriela Hoher, Ioanna Konidari, Jose Lorenzo, Griffin S. Parker, Julianna Pascual, Amanda R. Sandford, Patrice L. Whitehead, David A. Davis, Susanna Garamszegi, S. Humayun Gultekin, Xiaoyan Sun, Regina T. Vontell, Michael Chatigny, Darren Chernicky, Myrtha M. Constant, Isabelle G. Darling, David J. Ennulat, John M. Esposito, Kiely Morris, Elisabeth S. Lawton, Neda R. Morakabati, Phyllis Oduor, Allison P. Rodgers, Lorelle A. Sang, Kathleen M. Sullivan, Catalina J. Tabit, Tori Turpin, Aya Zeabi, Tina Zheng, Sabina Berretta, Torsten Klengel, Derek H. Oakley, W. Brad Ruzicka, Thomas Blanchard, Eric Ho, Robert Johnson, Alexandra LeFevre, Maxwell Bustamante, Vahram Haroutunian, Pavel Katsel, Christine Marino, Stephen Panopoulos, Dushyant P. Purohit, Michael Wysocki, Jill R. Glausier, David .A. Lewis, Rashed M. Nagra, Camille Alba, Julianna Martin, Elizabeth Rice, John Rosenberger, Grace Smith, Gauthaman Sukumar, Miranda Tompkins, Matthew Wilkerson, Clifton L. Dalgard, William K. Scott","doi":"10.1101/2024.08.29.24312734","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312734","url":null,"abstract":"Central nervous system diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors including genetic risk. Here we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered in 15 broad categories by ICD-10 coding. These donors were collected by six repositories comprising the NIH NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants detected by Whole-Genome Sequencing (WGS) were called genome-wide and annotated to describe their functional impact, resulting in 171,121,209 unique mutations and 1,078,774 non-silent mutations. This whole-genome resource has been made available in the NIMH Data Archive (nda.nih.gov) and accompanying deep demographic and phenotypic descriptions are available at the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate an application of this resource, we replicated the strong association observed in previous studies between pathogenic CAG repeat expansions in the <em>HTT</em> gene with the clinical diagnosis of Huntington’s disease.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.29.24312807
Jet M.J. Vonk, Brittany T. Morin, Janhavi Pillai, David Rosado Rolon, Rian Bogley, David Paul Baquirin, Zoe Ezzes, Boon Lead Tee, Jessica DeLeon, Lisa Wauters, Sladjana Lukic, Maxime Montembeault, Kyan Younes, Zachary Miller, Adolfo M. García, Maria Luisa Mandelli, Virginia E. Sturm, Bruce L. Miller, Maria Luisa Gorno-Tempini
Background and Objectives Within frontotemporal dementia (FTD), the behavioral variant (bvFTD) characterized by frontal atrophy, and semantic behavioral variant (sbvFTD) characterized by right anterior temporal lobe (rATL) atrophy, present diagnostic challenges due to overlapping symptoms and neuroanatomy. Accurate differentiation is crucial for clinical trial inclusion targeting TDP-43 proteinopathies. This study investigated whether automated speech analysis can distinguish between FTD-related rATL and frontal atrophy, potentially offering a non-invasive diagnostic tool.
{"title":"Digital language markers distinguish frontal from right anterior temporal lobe atrophy in frontotemporal dementia","authors":"Jet M.J. Vonk, Brittany T. Morin, Janhavi Pillai, David Rosado Rolon, Rian Bogley, David Paul Baquirin, Zoe Ezzes, Boon Lead Tee, Jessica DeLeon, Lisa Wauters, Sladjana Lukic, Maxime Montembeault, Kyan Younes, Zachary Miller, Adolfo M. García, Maria Luisa Mandelli, Virginia E. Sturm, Bruce L. Miller, Maria Luisa Gorno-Tempini","doi":"10.1101/2024.08.29.24312807","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312807","url":null,"abstract":"<strong>Background and Objectives</strong> Within frontotemporal dementia (FTD), the behavioral variant (bvFTD) characterized by frontal atrophy, and semantic behavioral variant (sbvFTD) characterized by right anterior temporal lobe (rATL) atrophy, present diagnostic challenges due to overlapping symptoms and neuroanatomy. Accurate differentiation is crucial for clinical trial inclusion targeting TDP-43 proteinopathies. This study investigated whether automated speech analysis can distinguish between FTD-related rATL and frontal atrophy, potentially offering a non-invasive diagnostic tool.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142225099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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