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Gene therapy targeting the blood–brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency Brain (IF 15.255) Pub Date : 2022-08-05 Sivaraj M Sundaram, Adriana Arrulo Pereira, Helge Müller-Fielitz, Hannes Köpke, Meri De Angelis, Timo D Müller, Heike Heuer, Jakob Körbelin, Markus Krohn, Jens Mittag, Ruben Nogueiras, Vincent Prevot, Markus Schwaninger
A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan–Herndon–Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested
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Neurofilament light levels predict clinical progression and death in multiple system atrophy Brain (IF 15.255) Pub Date : 2022-07-29 Viorica Chelban, Elham Nikram, Alexandra Perez-Soriano, Carlo Wilke, Alexandra Foubert-Samier, Nirosen Vijiaratnam, Tong Guo, Edwin Jabbari, Simisola Olufodun, Mariel Gonzalez, Konstantin Senkevich, Brice Laurens, Patrice Péran, Olivier Rascol, Anne Pavy Le Traon, Emily G Todd, Alyssa A. Costantini, Sondos Alikhwan, Ambreen Tariq, Bai Lin Ng, Esteban Muñoz, Celia Painous, Yaroslau Compta, Carme Junque
Disease-modifying treatments are currently being trialed in multiple system atrophy (MSA). Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data in multiple system atrophy have been limited. Therefore, neurofilament
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Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity Brain (IF 15.255) Pub Date : 2022-07-28 Rita Perelroizen, Bar Philosof, Noga Budick-Harmelin, Tom Chernobylsky, Ariel Ron, Rotem Katzir, Dor Shimon, Adi Tessler, Orit Adir, Anat Gaoni-Yogev, Tom Meyer, Avivit Krivitsky, Nuphar Shidlovsky, Asaf Madi, Eytan Ruppin, Lior Mayo
Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma
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Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing? Brain (IF 15.255) Pub Date : 2022-07-27 Andrew T Hale, Aswin Chari, Rod C Scott, J Helen Cross, Curtis J Rozzelle, Jeffrey P Blount, Martin M Tisdall
Epilepsy surgery is an established safe and effective treatment for selected candidates with drug-resistant epilepsy. In this opinion piece, we outline the clinical and experimental evidence for selectively considering epilepsy surgery prior to drug resistance. Our rationale for expedited surgery is based on the observations that, 1) a high proportion of patients with lesional epilepsies (e.g. focal
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RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology. Brain (IF 15.255) Pub Date : 2022-07-27 Mehdi Benkirane, Dylan Da Cunha, Cecilia Marelli, Lise Larrieu, Mathilde Renaud, Jessica Varilh, Morgane Pointaux, David Baux, Olivier Ardouin, Charles Vangoethem, Magali Taulan, Benjamin Daumas Duport, Anne Bergougnoux, Anne Gaelle Corbillé, Mireille Cossée, Raul Juntas Morales, Sylvie Tuffery-Giraud, Michel Koenig, Bertrand Isidor, Marie Claire Vincent
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late onset ataxia
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CSF-derived extracellular vesicles from patients with Parkinson's disease induce symptoms and pathology Brain (IF 15.255) Pub Date : 2022-07-26 Shay Herman, Ruth Djaldetti, Brit Mollenhauer, Daniel Offen
Parkinson’s disease is characterized by the gradual appearance of intraneuronal inclusions that are primarily composed of misfolded α-synuclein protein, leading to cytotoxicity and neural death. Recent in vitro and in vivo studies suggest that misfolded α-synuclein may spread transcellularly in a prion-like manner, inducing pathological aggregates in healthy neurons, and is disseminated via secretion
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Negative symptoms, striatal dopamine, and model-free reward decision-making in schizophrenia Brain (IF 15.255) Pub Date : 2022-07-25 Felix Brandl, Franziska Knolle, Mihai Avram, Claudia Leucht, Igor Yakushev, Josef Priller, Stefan Leucht, Sibylle Ziegler, Klaus Wunderlich, Christian Sorg
Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free
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Distinct movement disorders in contactin-associated-protein-like-2 antibody associated autoimmune encephalitis Brain (IF 15.255) Pub Date : 2022-07-25 Felix Gövert, Ligia Abrante, Jos Becktepe, Bettina Balint, Christos Ganos, Ulrich Hofstadt-van Oy, Christos Krogias, James Varley, Sarosh R Irani, Sofija Paneva, Maarten J Titulaer, Juna M de Vries, Agnita J W Boon, Marco W J Schreurs, Bastien Joubert, Jerome Honnorat, Alberto Vogrig, Helena Ariño, Lidia Sabater, Josep Dalmau, Sangeeta Scotton, Saiju Jacob, Nico Melzer, Christian G Bien, Christian
Autoimmune encephalitis (AE) can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory etiologies. In the elderly, anti-leucin-rich-glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2) antibody-associated diseases compose a relevant fraction of AE. Patients with LGI1 autoantibodies
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TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy Brain (IF 15.255) Pub Date : 2022-07-24 Aida Marcotti, Jorge Fernández-Trillo, Alejandro González, Marta Vizcaíno-Escoto, Pablo Ros-Arlanzón, Luz Romero, José Miguel Vela, Ana Gomis, Félix Viana, Elvira de la Peña
Chemotherapy induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of CIPN characterized by mechanical and cold hypersensitivity. Current therapies for CIPN are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin
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Epilepsy syndromes in cerebral palsy: varied, evolving and mostly self-limited Brain (IF 15.255) Pub Date : 2022-07-24 Monica S Cooper, Mark T Mackay, Charuta Dagia, Michael C Fahey, Katherine B Howell, Dinah Reddihough, Susan Reid, A Simon Harvey
Seizures occur in approximately one third of children with cerebral palsy. This study aimed to determine epilepsy syndromes in children with seizures and cerebral palsy due to vascular injury, anticipating that this would inform treatment and prognosis. We studied a population-based cohort of children with cerebral palsy due to prenatal or perinatal vascular injuries, born 1999-2006. Each child’s MRI
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Sex-specific effects of microglial activation on Alzheimer’s disease proteinopathy in older adults Brain (IF 15.255) Pub Date : 2022-07-23 Kaitlin B Casaletto, Emma Nichols, Vahan Aslanyan, Stephanie M Simone, Jennifer S Rabin, Renaud LaJoie, Adam M Brickman, Kristen Dams-O’Connor, Priya Palta, Raj G Kumar, Kristen M George, Claudia L Satizabal, Julie Schneider, Judy Pa
Women show disproportionate burden of Alzheimer’s disease (AD) pathology and higher AD dementia prevalences compared to men, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunologic functioning, and neuroimmune processes are implicated in AD genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial
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Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract Brain (IF 15.255) Pub Date : 2022-07-23 James M Shine, Claire O’Callaghan, Ishan C Walpola, Gabriel Wainstein, Natasha Taylor, Jaan Aru, Bryce Huebner, Yohan J John
The neuromodulatory arousal system imbues the nervous system with the flexibility and robustness required to facilitate adaptive behaviour. While there are well-understood mechanisms linking dopamine, noradrenaline and acetylcholine to distinct behavioural states, similar conclusions have not been as readily available for serotonin. Fascinatingly, despite clear links between serotonergic function and
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SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction Brain (IF 15.255) Pub Date : 2022-07-22 Chanawee Hirunpattarasilp, Greg James, Jaturon Kwanthongdee, Felipe Freitas, Jiandong Huo, Huma Sethi, Josef T Kittler, Raymond J Owens, Laura E McCoy, David Attwell
The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but
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Ligand-free mitochondria-localized mutant AR-induced cytotoxicity in spinal bulbar muscular atrophy Brain (IF 15.255) Pub Date : 2022-07-22 Xia Feng, Xiu Tang Cheng, Pengli Zheng, Yan Li, Jill Hakim, Shirley Q Zhang, Stacie M Anderson, Kaari Linask, Jizhong Zou, Zu Hang Sheng, Craig Blackstone
Spinal bulbar muscular atrophy (SBMA), the first identified CAG-repeat expansion disorder, is an X-linked neuromuscular disorder involving CAG-repeat-expansion mutations in the androgen receptor (AR) gene. We utilized CRISPR-Cas9 gene editing to engineer novel isogenic human induced pluripotent stem cell (hiPSC) models, consisting of isogenic AR knockout, control, and disease lines expressing mutant
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RNA profiling of human dorsal root ganglia reveals sex-differences in mechanisms promoting neuropathic pain Brain (IF 15.255) Pub Date : 2022-07-22 Pradipta R Ray, Stephanie Shiers, James P Caruso, Diana Tavares-Ferreira, Ishwarya Sankaranarayanan, Megan L Uhelski, Yan Li, Robert Y North, Claudio Tatsui, Gregory Dussor, Michael D Burton, Patrick M Dougherty, Theodore J Price
Neuropathic pain is a leading cause of high impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of
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Preclinical Alzheimer’s disease biomarkers accurately predict cognitive and neuropathological outcomes Brain (IF 15.255) Pub Date : 2022-07-22 Justin M Long, Dean W Coble, Chengjie Xiong, Suzanne E Schindler, Richard J Perrin, Brian A Gordon, Tammie L S Benzinger, Elizabeth Grant, Anne M Fagan, Oscar Harari, Carlos Cruchaga, David M Holtzman, John C Morris
Alzheimer’s disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer’s disease biomarkers predict Alzheimer’s neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer’s disease neuropathological findings
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SHH activation restores interneurons and cognitive function in newborns with intraventricular haemorrhage Brain (IF 15.255) Pub Date : 2022-07-22 Bokun Cheng, Deep R Sharma, Ajeet Kumar, Hardik Sheth, Alex Agyemang, Michael Aschner, Xusheng Zhang, Praveen Ballabh
Premature infants with germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) suffer from neurobehavioral deficits as they enter childhood and adolescence. Yet the underlying mechanisms remain unclear. Impaired development and function of interneurons contribute to neuropsychiatric disorders. Therefore, we hypothesized that the occurrence of IVH would reduce interneuron neurogenesis in the
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Emotional bias modification weakens game-related compulsivity and reshapes fronto-striatal pathways Brain (IF 15.255) Pub Date : 2022-07-21 Lulu Wu, Jiahua Xu, Kunru Song, Lei Zhu, Nan Zhou, Linxuan Xu, Guanqun Liu, Ziliang Wang, Rui Wang, Shaozheng Qin, Xiaoyi Fang, Jintao Zhang, Marc N Potenza
Addiction is characterized by compulsive engagement despite adverse consequences. Psychobehavioral interventions targeting compulsivity in addictions are relatively rare, particularly for behavioral addictions like internet gaming disorder (IGD). Free from confounding drug-on-brain effects, IGD provides a promising model for understanding neuropsychological processes of addictions. IGD is a global
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Vestibular migraine treatment: a comprehensive practical review Brain (IF 15.255) Pub Date : 2022-07-21 Duncan Smyth, Zelie Britton, Louisa Murdin, Qadeer Arshad, Diego Kaski
Vestibular migraine is an underdiagnosed but increasingly recognised neurological condition that causes episodic vertigo associated with other features of migraine. It is now thought to be the most common cause of spontaneous (non-positional) episodic vertigo, affecting up to 1% of the population. A meta-analysis of preventative treatments for vestibular migraine was published in 2021 but the authors
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Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue Brain (IF 15.255) Pub Date : 2022-07-21 Brendan Monogue, Yixi Chen, Hadrian Sparks, Ranya Behbehani, Andrew Chai, Alexander J Rajic, Aaron Massey, B K Kleinschmidt-Demasters, Matthieu Vermeren, Tilo Kunath, J David Beckham
The protein alpha-synuclein is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinson’s disease and dementia with Lewy bodies. However, the normal function of alpha-synuclein in neurons is not clearly defined. We have previously shown that mice lacking alpha-synuclein expression exhibit markedly increased viral growth in the brain, increased mortality and
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Understanding the multidimensional cognitive deficits of logopenic variant primary progressive aphasia Brain (IF 15.255) Pub Date : 2022-07-20 Siddharth Ramanan, Muireann Irish, Karalyn Patterson, James B Rowe, Maria Luisa Gorno-Tempini, Matthew A Lambon Ralph
The logopenic variant of primary progressive aphasia is characterized by early deficits in language production and phonological short-term memory, attributed to left-lateralized temporoparietal, inferior parietal and posterior temporal neurodegeneration. Despite patients primarily complaining of language difficulties, emerging evidence points to performance deficits in non-linguistic domains. Temporoparietal
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Lyme neuroborreliosis: known knowns, known unknowns Brain (IF 15.255) Pub Date : 2022-07-18 John J Halperin, Randi Eikeland, John A Branda, Rick Dersch
Lyme borreliosis affects the nervous system in three principal ways—mononuclear cell meningitis, cranial neuropathies and radiculoneuropathies—the last a broad term encompassing painful radiculopathy, unifocal and multifocal peripheral nerve involvement. Diagnostic tools have been significantly refined—including improved peripheral blood and CSF serodiagnostics—and much has been learned about the interactions
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Extracellular vesicle biomarkers for cognitive impairment in Parkinson’s disease Brain (IF 15.255) Pub Date : 2022-07-14 Joseph Blommer, Toni Pitcher, Maja Mustapic, Erden Eren, Pamela J Yao, Michael P Vreones, Krishna A Pucha, John Dalrymple-Alford, Reza Shoorangiz, Wassilios G Meissner, Tim Anderson, Dimitrios Kapogiannis
Besides motor symptoms, many individuals with Parkinson’s disease develop cognitive impairment perhaps due to co-existing α-synuclein and Alzheimer’s disease pathologies and impaired brain insulin signaling. Discovering biomarkers for cognitive impairment in Parkinson’s disease could help clarify the underlying pathogenic processes and improve Parkinson’s disease diagnosis and prognosis. This study
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Neurodegenerative phagocytes mediate synaptic stripping in Neuro-HIV. Brain (IF 15.255) Pub Date : 2022-07-09 Giovanni Di Liberto,Kristof Egervari,Mario Kreutzfeldt,Christian M Schürch,Ekkehard Hewer,Ingrid Wagner,Renaud Du Pasquier,Doron Merkler
Glial cell activation is a hallmark of several neurodegenerative and neuroinflammatory diseases. During HIV infection, neuroinflammation is associated with cognitive impairment, even during sustained long-term suppressive antiretroviral therapy. However, the cellular subsets contributing to neuronal damage in the CNS during HIV infection remain unclear. Using post-mortem brain samples from eight HIV
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Cerebral organoids containing an AUTS2 missense variant model microcephaly Brain (IF 15.255) Pub Date : 2022-07-08 Summer R Fair, Wesley Schwind, Dominic Julian, Alecia Biel, Gongbo Guo, Ryan Rutherford, Swetha Ramadesikan, Jesse Westfall, Katherine E Miller, Meisam Naeimi Kararoudi, Scott E Hickey, Theresa Mihalic Mosher, Kim L McBride, Reid Neinast, James Fitch, Dean Lee, Peter White, Richard K Wilson, Tracy A Bedrosian, Daniel C Koboldt, Mark E Hester
Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid (CO) model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly
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Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome Brain (IF 15.255) Pub Date : 2022-07-08 Lucy Norcliffe-Kaufmann, Jose Alberto Palma, Jose Martinez, Celeste Camargo, Horacio Kaufmann
Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion upon standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 women) and 21 matched controls
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Reply: Methodological drawbacks in the alleged association between foetal sonographic anomalies and autism. Brain (IF 15.255) Pub Date : 2022-07-08 Idan Menashe,Ohad Regev,Amnon Hadar,Gal Meiri,Analya Michaelovski,Ilan Dinstein,Reli Hershkovitz
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Methodological drawbacks in the alleged association between foetal sonographic anomalies and autism. Brain (IF 15.255) Pub Date : 2022-07-08 Lena Sagi-Dain,Boaz Weisz,Karina Haratz Krajden,Amihood Singer,Yuval Yaron,Ron Maymon
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Vitamins B6 and B12, levodopa, and their complex interactions in patients with Parkinson's disease. Brain (IF 15.255) Pub Date : 2022-07-08 Karlo J Lizárraga,Anthony E Lang
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Brain volume abnormalities and clinical outcomes following paediatric traumatic brain injury. Brain (IF 15.255) Pub Date : 2022-07-08 Niall J Bourke,Célia Demarchi,Sara De Simoni,Ravjeet Samra,Maneesh C Patel,Adam Kuczynski,Quen Mok,Neil Wimalasundera,Fareneh Vargha-Khadem,David J Sharp
Long-term outcomes are difficult to predict after paediatric traumatic brain injury. The presence or absence of focal brain injuries often do not explain cognitive, emotional and behavioural disabilities that are common and disabling. In adults, traumatic brain injury produces progressive brain atrophy that can be accurately measured and is associated with cognitive decline. However, the effect of
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Alternative processing of human HTT mRNA with implications for Huntington's disease therapeutics. Brain (IF 15.255) Pub Date : 2022-07-06 Sandra Fienko,Christian Landles,Kirupa Sathasivam,Sean J McAteer,Rebecca E Milton,Georgina F Osborne,Edward J Smith,Samuel T Jones,Marie K Bondulich,Emily C E Danby,Jemima Phillips,Bridget A Taxy,Holly B Kordasiewicz,Gillian P Bates
Huntington disease is caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that is translated into a polyglutamine stretch in the huntingtin protein (HTT). We previously showed that HTT mRNA carrying an expanded CAG repeat was incompletely spliced to generate HTT1a, an exon 1 only transcript, which was translated to produce the highly aggregation-prone and pathogenic exon 1 HTT protein
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Expanding PRDX3 disease: broad range of onset age and infratentorial MRI signal changes. Brain (IF 15.255) Pub Date : 2022-07-06 Adriana P Rebelo,Benjamin Bender,Tobias B Haack,Stephan Zuchner,,Nazli Basak,Matthis Synofzik
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Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease Brain (IF 15.255) Pub Date : 2022-07-05 Qi Wang, Xiaomin Huang, Yixun Su, Guowei Yin, Shouyu Wang, Bin Yu, Hui Li, Junhua Qi, Hui Chen, Wen Zeng, Kai Zhang, Alexei Verkhratsky, Jianqin Niu, Chenju Yi
Alzheimer’s disease (AD) is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for AD pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the
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Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy. Brain (IF 15.255) Pub Date : 2022-07-04 Luca Gozzelino,Gaga Kochlamazashvili,Sara Baldassari,Albert Ian Mackintosh,Laura Licchetta,Emanuela Iovino,Yu Chi Liu,Caitlin A Bennett,Mark F Bennett,John A Damiano,Gábor Zsurka,Caterina Marconi,Tania Giangregorio,Pamela Magini,Marijn Kuijpers,Tanja Maritzen,Giuseppe Danilo Norata,Stéphanie Baulac,Laura Canafoglia,Marco Seri,Paolo Tinuper,Ingrid E Scheffer,Melanie Bahlo,Samuel F Berkovic,Michael S
Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy
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Progressive multifocal leukoencephalopathy: epidemiology and spectrum of predisposing conditions Brain (IF 15.255) Pub Date : 2022-07-02 Marine Joly, Cécile Conte, Charles Cazanave, Vincent Le Moing, Pierre Tattevin, Pierre Delobel, Agnès Sommet, Guillaume Martin-Blondel
Population-based data on the epidemiology of progressive multifocal leukoencephalopathy, its predisposing conditions and mortality rate are lacking, although such data are crucial to raise awareness among clinicians and to lay foundations for future therapeutic trials in immunomodulating therapies. In our study, patients were identified by interrogating the French national healthcare reimbursement
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Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration Brain (IF 15.255) Pub Date : 2022-07-01 Rachel E James Bates, Eleanor Browne, Renee Schalks, Heather Jacobs, Li Tan, Puja Parekh, Roberta Magliozzi, Massimiliano Calabrese, Nicholas D Mazarakis, Richard Reynolds
Organised meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the cerebrospinal fluid of naïve and progressive multiple
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Reply: Is it time to rename hereditary cases of cerebral palsy? Brain (IF 15.255) Pub Date : 2022-07-01 Hao Hu,Kaishou Xu
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Is it time to rename hereditary cases of cerebral palsy? Brain (IF 15.255) Pub Date : 2022-07-01 Anamarija Kavcic
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Contribution of B cells to cortical damage in multiple sclerosis Brain (IF 15.255) Pub Date : 2022-07-01 Pavan Bhargava, Hans Peter Hartung, Peter A Calabresi
Multiple sclerosis is associated with lesions not just in the white matter, but also involving the cortex. Cortical involvement has been linked to greater disease severity and hence understanding the factor underlying cortical pathology could help identify new therapeutic strategies for multiple sclerosis. The critical role of B cells in multiple sclerosis has been clarified by multiple pivotal trials
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A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders. Brain (IF 15.255) Pub Date : 2022-07-01 Megan Conrow-Graham,Jamal B Williams,Jennifer Martin,Ping Zhong,Qing Cao,Benjamin Rein,Zhen Yan
ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished
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mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion. Brain (IF 15.255) Pub Date : 2022-06-30 Jeffrey D Calhoun,Miriam C Aziz,Hannah C Happ,Jonathan Gunti,Colleen Gleason,Najma Mohamed,Kristy Zeng,Meredith Hiller,Emily Bryant,Divakar S Mithal,Irena Bellinski,Lisa Kinsley,Mona Grimmel,Eva M C Schwaibold,Constance Smith-Hicks,Anna Chassevent,Marcello Scala,Andrea Accogli,Annalaura Torella,Pasquale Striano,Valeria Capra,Lynne M Bird,Issam Ben-Sahra,Nina Ekhilevich,Tova Hershkovitz,Karin Weiss
Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional
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Neuropathic pain correlates with worsening cognition in people with human immunodeficiency virus. Brain (IF 15.255) Pub Date : 2022-06-30 Ronald J Ellis,Ned Sacktor,David B Clifford,Christina M Marra,Ann C Collier,Benjamin Gelman,Jessica Robinson-Papp,Scott L Letendre,Robert K Heaton,
Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants
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Towards network-guided neuromodulation for epilepsy Brain (IF 15.255) Pub Date : 2022-06-30 Rory J Piper, R Mark Richardson, Gregory Worrell, David W Carmichael, Torsten Baldeweg, Brian Litt, Timothy Denison, Martin M Tisdall
Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce
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A deeper dive into top-down control of pain and itch. Brain (IF 15.255) Pub Date : 2022-06-30 Howard L Fields
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Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders. Brain (IF 15.255) Pub Date : 2022-06-30 Nataliya Di Donato,Renzo Guerrini,Charles J Billington,A James Barkovich,Philine Dinkel,Elena Freri,Michael Heide,Elliot S Gershon,Tracy S Gertler,Robert J Hopkin,Suma Jacob,Sarah K Keedy,Daniz Kooshavar,Paul J Lockhart,Dietmar R Lohmann,Iman G Mahmoud,Elena Parrini,Evelin Schrock,Giulia Severi,Andrew E Timms,Richard I Webster,Mary J H Willis,Maha S Zaki,Joseph G Gleeson,Richard J Leventer,William
Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches
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Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimer’s disease Brain (IF 15.255) Pub Date : 2022-06-28 Jeremy A Tanner, Leonardo Iaccarino, Lauren Edwards, Breton M Asken, Maria L Gorno-Tempini, Joel H Kramer, Julie Pham, David C Perry, Katherine Possin, Maura Malpetti, Taylor Mellinger, Bruce L Miller, Zachary Miller, Nidhi S Mundada, Howard J Rosen, David N Soleimani-Meigooni, Amelia Strom, Renaud La Joie, Gil D Rabinovici
Early-onset (age < 65) Alzheimer’s disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration, and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ±
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Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline. Brain (IF 15.255) Pub Date : 2022-06-27 Jennifer S Rabin,Emma Nichols,Renaud La Joie,Kaitlin B Casaletto,Priya Palta,Kristen Dams-O'Connor,Raj G Kumar,Kristen M George,Claudia L Satizabal,Julie A Schneider,Judy Pa,Adam M Brickman
Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's
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Mutations in TAF8 cause a neurodegenerative disorder. Brain (IF 15.255) Pub Date : 2022-06-27 Keit Men Wong,Wayne M Jepsen,Stephanie Efthymiou,Vincenzo Salpietro,Meredith Sanchez-Castillo,Janice Yip,Yamna Kriouile,Susann Diegmann,Steffi Dreha-Kulaczewski,Janine Altmüller,Holger Thiele,Peter Nürnberg,Mehran Beiraghi Toosi,Javad Akhondian,Ehsan Ghayoor Karimiani,Hannah Hummel-Abmeier,Brenda Huppke,Henry Houlden,Jutta Gärtner,Reza Maroofian,Peter Huppke
TAF8 is part of the transcription factor II D complex, composed of the TATA-binding protein and 13 TATA-binding protein-associated factors (TAFs). Transcription factor II D is the first general transcription factor recruited at promoters to assemble the RNA polymerase II preinitiation complex. So far disorders related to variants in 5 of the 13 subunits of human transcription factor II D have been
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Neurofilament light associated connectivity in young-adult Huntington’s disease is related to neuronal genes Brain (IF 15.255) Pub Date : 2022-06-27 Peter McColgan, Sarah Gregory, Paul Zeun, Angeliki Zarkali, Eileanoir B Johnson, Christopher Parker, Kate Fayer, Jessica Lowe, Akshay Nair, Carlos Estevez-Fraga, Marina Papoutsi, Hui Zhang, Rachael I Scahill, Sarah J Tabrizi, Geraint Rees
Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington’s disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene-carriers much further from onset has yet to be explored. We characterised functional network connectivity throughout the brain and related
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Elucidating the relationship between migraine risk and brain structure using genetic data. Brain (IF 15.255) Pub Date : 2022-06-23 Brittany L Mitchell,Santiago Diaz-Torres,Svetlana Bivol,Gabriel Cuellar-Partida,,Zachary F Gerring,Nicholas G Martin,Sarah E Medland,Katrina L Grasby,Dale R Nyholt,Miguel E Rentería
Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between
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Right temporal lobe and socioemotional semantics: semantic behavioural variant frontotemporal dementia Brain (IF 15.255) Pub Date : 2022-06-22 Kyan Younes, Valentina Borghesani, Maxime Montembeault, Salvatore Spina, Maria Luisa Mandelli, Ariane E Welch, Elizabeth Weis, Patrick Callahan, Fanny M Elahi, Alice Y Hua, David C Perry, Anna Karydas, Daniel Geschwind, Eric Huang, Lea T Grinberg, Joel H Kramer, Adam L Boxer, Gil D Rabinovici, Howard J Rosen, William W Seeley, Zachary A Miller, Bruce L Miller, Virginia E Sturm, Katherine P Rankin,
Focal anterior temporal lobe (ATL) degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, patients with early right ATL (rATL) atrophy are more difficult to diagnose as their symptoms
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Do genetic factors contribute to sex-specific differences in resilience to amyloid pathology? Brain (IF 15.255) Pub Date : 2022-06-21 Colin Groot,Henne Holstege,Rik Ossenkoppele
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The kappa free light chain index and oligoclonal bands have a similar role in the McDonald criteria Brain (IF 15.255) Pub Date : 2022-06-21 Georgina Arrambide, Carmen Espejo, Pere Carbonell-Mirabent, Romina Dieli-Crimi, Marta Rodríguez-Barranco, Mireia Castillo, Cristina Auger, Simón Cárdenas-Robledo, Joaquín Castilló, Álvaro Cobo-Calvo, Ingrid Galán, Luciana Midaglia, Carlos Nos, Susana Otero-Romero, Jordi Río, Breogán Rodríguez-Acevedo, Mariano Ruiz-Ortiz, Annalaura Salerno, Paula Tagliani, Carmen Tur, Angela Vidal-Jordana, Ana Zabalza
Intrathecal production of kappa free light chains (KFLC) occurs in multiple sclerosis and can be measured using the KFLC index. KFLC index values can be determined more easily than oligoclonal bands (OB) detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of OB, KFLC index cut-offs 5.9, 6.6, and 10.61, and IgG index to diagnose
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The Wernicke conundrum revisited: evidence from connectome-based lesion-symptom mapping Brain (IF 15.255) Pub Date : 2022-06-21 William Matchin, Dirk Bart den Ouden, Gregory Hickok, Argye E Hillis, Leonardo Bonilha, Julius Fridriksson
Wernicke’s area has been assumed since the 1800s to be the primary region supporting word and sentence comprehension. However, in 2015 and 2019, Mesulam and colleagues raised what they termed the ‘Wernicke conundrum’, noting widespread variability in the anatomical definition of this area and presenting data from primary progressive aphasia that challenged this classical assumption. To resolve the
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Multicompartmental models and diffusion abnormalities in paediatric mild traumatic brain injury Brain (IF 15.255) Pub Date : 2022-06-21 Andrew R Mayer, Josef M Ling, Andrew B Dodd, David D Stephenson, Sharvani Pabbathi Reddy, Cidney R Robertson-Benta, Erik B Erhardt, Robbert L Harms, Timothy B Meier, Andrei A Vakhtin, Richard A Campbell, Robert E Sapien, John P Phillips
The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicate that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples
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Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1 Brain (IF 15.255) Pub Date : 2022-06-21 Jorge Ramirez-Franco, Kévin Debreux, Johanna Extremet, Yves Maulet, Maya Belghazi, Claude Villard, Marion Sangiardi, Fahamoe Youssouf, Lara El Far, Christian Lévêque, Claire Debarnot, Pascale Marchot, Sofija Paneva, Dominique Debanne, Michael Russier, Michael Seagar, Sarosh R Irani, Oussama El Far
Autoantibodies against leucine-rich glioma-inactivated 1 occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localisation of these features, and hence gain broader insights into LGI1’s neurobiology, we analysed the detailed
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Detection of neuron-derived pathological α-synuclein in blood. Brain (IF 15.255) Pub Date : 2022-06-20 Annika Kluge,Josina Bunk,Eva Schaeffer,Alice Drobny,Wei Xiang,Henrike Knacke,Simon Bub,Wiebke Lückstädt,Philipp Arnold,Ralph Lucius,Daniela Berg,Friederike Zunke
To date, no reliable clinically applicable biomarker has been established for Parkinson's disease. Our results indicate that a long anticipated blood test for Parkinson's disease may be realized. Following the isolation of neuron-derived extracellular vesicles of Parkinson's disease patients and non-Parkinson's disease individuals, immunoblot analyses were performed to detect extracellular vesicle-derived
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TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia. Brain (IF 15.255) Pub Date : 2022-06-20 Luis Carlos Tábara,Fatema Al-Salmi,Reza Maroofian,Amna Mohammed Al-Futaisi,Fathiya Al-Murshedi,Joanna Kennedy,Jacob O Day,Thomas Courtin,Aisha Al-Khayat,Hamid Galedari,Neda Mazaheri,Margherita Protasoni,Mark Johnson,Joseph S Leslie,Claire G Salter,Lettie E Rawlins,James Fasham,Almundher Al-Maawali,Nikol Voutsina,Perrine Charles,Laura Harrold,Boris Keren,Edmund R S Kunji,Barbara Vona,Gholamreza Jelodar
The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical
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Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia Brain (IF 15.255) Pub Date : 2022-06-17 Yosuke Hashimoto, Karine Poirier, Nathalie Boddaert, Laurence Hubert, Melodie Aubart, Anna Kaminska, Marianne Alison, Isabelle Desguerre, Arnold Munnich, Matthew Campbell
Claudin-5 is the most enriched tight junction protein at the blood brain barrier (BBB). Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never previously been reported. Here, we report the identification of a novel de novo mutation (c.178G > A) in the CLDN5
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Stimulating native seizures with neural resonance: a new approach to localize the seizure onset zone Brain (IF 15.255) Pub Date : 2022-06-15 Rachel J Smith, Mark A Hays, Golnoosh Kamali, Christopher Coogan, Nathan E Crone, Joon Y Kang, Sridevi V Sarma
Successful outcomes in epilepsy surgery rely on the accurate localization of the seizure onset zone (SOZ). Localizing the SOZ is often a costly and time-consuming process wherein a patient undergoes intracranial EEG (iEEG) monitoring, and a team of clinicians wait for seizures to occur. Clinicians then analyze the iEEG before each seizure onset to identify the SOZ, and localization accuracy increases