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  •   Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease
    Brain (IF 14.5) Pub Date : 2024-03-14
    Christopher J Record, Menelaos Pipis, Mariola Skorupinska, Julian Blake, Roy Poh, James M Polke, Kelly Eggleton, Tina Nanji, Stephan Zuchner, Andrea Cortese, Henry Houlden, Alexander M Rossor, Matilde Laura, Mary M Reilly

    Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including

  •   Dominant CST3 variants cause adult onset leukodystrophy without amyloid angiopathy
    Brain (IF 14.5) Pub Date : 2024-03-13
    Caroline G Bergner, Marjolein Breur, M Clara Soto-Bernardini, Lisa Schäfer, Julia Lier, Diana Le Duc, Linnaeus Bundalian, Susanna Schubert, David Brenner, Friedmar R Kreuz, Björn Schulte, Quinten Waisfisz, Marianna Bugiani, Wolfgang Köhler, Heinrich Sticht, Rami Abou Jamra, Marjo S van der Knaap

    Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. Recent years altered this perception, as a growing number of leukodystrophies was described to have an onset at adult ages. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16

  •   Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant
    Brain (IF 14.5) Pub Date : 2024-03-13
    Beryll Blickhäuser, Sarah L Stenton, Christiane M Neuhofer, Elisa Floride, Victoria Nesbitt, Carl Fratter, Johannes Koch, Birgit Kauffmann, Claudia Catarino, Lea Dewi Schlieben, Robert Kopajtich, Valerio Carelli, Alfredo A Sadun, Robert McFarland, Fang Fang, Chiara La Morgia, Stéphanie Paquay, Marie Cécile Nassogne, Daniele Ghezzi, Costanza Lamperti, Saskia Wortmann, Jo Poulton, Thomas Klopstock, Holger

    Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterised by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA (mtDNA) genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been

  •   Paroxysmal dystonia results from the loss of RIM4 in Purkinje cells
    Brain (IF 14.5) Pub Date : 2024-03-13
    Hyuntae Kim, Nesrine Melliti, Eva Breithausen, Katrin Michel, Sara Ferrando Colomer, Ekaterina Poguzhelskaya, Paulina Nemcova, Laura Ewell, Sandra Blaess, Albert Becker, Julika Pitsch, Dirk Dietrich, Susanne Schoch

    Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell-type specific role

  •   Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration
    Brain (IF 14.5) Pub Date : 2024-03-08
    Fengfei Ding, Qian Sun, Carter Long, Rune Nguyen Rasmussen, Sisi Peng, Qiwu Xu, Ning Kang, Wei Song, Pia Weikop, Steven A Goldman, Maiken Nedergaard

    Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal aging. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury since K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this

  •   The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders
    Brain (IF 14.5) Pub Date : 2024-03-08
    Jai Sidpra, Sniya Sudhakar, Asthik Biswas, Flavia Massey, Valentina Turchetti, Tracy Lau, Edward Cook, Javeria Raza Alvi, Hasnaa M Elbendary, Jerry L Jewell, Antonella Riva, Alessandro Orsini, Aglaia Vignoli, Zara Federico, Jessica Rosenblum, An-Sofie Schoonjans, Matthias de Wachter, Ignacio Delgado Alvarez, Ana Felipe-Rucián, Nourelhoda A Haridy, Shahzad Haider, Mashaya Zaman, Selina Banu, Najwa Anwaar

    Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural

  •   A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer’s disease vulnerable neurons
    Brain (IF 14.5) Pub Date : 2024-03-07
    Patricia Rodriguez-Rodriguez, Luis Enrique Arroyo-Garcia, Christina Tsagkogianni, Lechuan Li, Wei Wang, Ákos Végvári, Isabella Salas-Allende, Zakary Plautz, Angel Cedazo-Minguez, Subhash C Sinha, Olga Troyanskaya, Marc Flajolet, Vicky Yao, Jean-Pierre Roussarie

    Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer’s disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons

  •   Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation
    Brain (IF 14.5) Pub Date : 2024-03-06
    Jun He, Brenda Cabrera-Mendoza, Flavio De Angelis, Gita A Pathak, Dora Koller, Sharon G Curhan, Gary C Curhan, Adam P Mecca, Christopher H van Dyck, Renato Polimanti

    Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain

  •   Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis
    Brain (IF 14.5) Pub Date : 2024-03-06
    Emma L Clayton, Laura Huggon, Michael A Cousin, Sarah Mizielinska

    Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease which share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes which initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic

  •   Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection
    Brain (IF 14.5) Pub Date : 2024-03-05
    Marianna Spatola, Nadège Nziza, Edward B Irvine, Deniz Cizmeci, Wonyeong Jung, Le Hong Van, Le Thanh Hoang Nhat, Vu Thi Ngoc Ha, Nguyen Hoan Phu, Ho Dang Trung Nghia, Guy Thwaites, Douglas A Lauffenburger, Sarah Fortune, Nguyen Thuy Thuong Thuong, Galit Alter

    Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a global health burden. While Mtb is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that leads to differential disease across organs. Attention has focused on differences in T

  •   Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia
    Brain (IF 14.5) Pub Date : 2024-03-04
    Ana Paula Nascimento de Lima, Huiran Zhang, Lubin Chen, Philip R Effraim, Carolina Gomis-Perez, Xiaoyang Cheng, Jianying Huang, Stephen G Waxman, Sulayman D Dib-Hajj

    Vincristine-induced peripheral neuropathy (VIPN) is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine induced pain. Our previous studies have shown that the tetrodotoxin-sensitive

  •   The human subthalamic nucleus transiently inhibits active attentional processes
    Brain (IF 14.5) Pub Date : 2024-03-04
    Cheol Soh, Mario Hervault, Nathan H Chalkley, Cathleen M Moore, Andrea Rohl, Qiang Zhang, Ergun Y Uc, Jeremy D W Greenlee, Jan R Wessel

    The subthalamic nucleus (STN) of the basal ganglia is key to the inhibitory control of movement. Consequently, it is a primary target for the neurosurgical treatment of movement disorders like Parkinson’s Disease, where modulating the STN via deep-brain stimulation (DBS) can release excess inhibition of thalamo-cortical motor circuits. However, the STN is also anatomically connected to other thalamo-cortical

  •   Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson’s disease
    Brain (IF 14.5) Pub Date : 2024-03-01
    Verena Pesch, José Miguel Flores-Fernandez, Sara Reithofer, Liang Ma, Pelin Özdüzenciler, Yannick Busch, Aishwarya Sriraman, YongLiang Wang, Sara Amidian, Chiara V M Kroepel, Laura Müller, Yi Lien, Olivia Rudtke, Benedikt Frieg, Gunnar F Schröder, Holger Wille, Gültekin Tamgüney

    The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson’s disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates

  •   HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease
    Brain (IF 14.5) Pub Date : 2024-03-01
    Selina M Yogeshwar, Sergio Muñiz-Castrillo, Lidia Sabater, Vicente Peris-Sempere, Vamsee Mallajosyula, Guo Luo, Han Yan, Eric Yu, Jing Zhang, Ling Lin, Flavia Fagundes Bueno, Xuhuai Ji, Géraldine Picard, Véronique Rogemond, Anne Laurie Pinto, Anna Heidbreder, Romana Höftberger, Francesc Graus, Josep Dalmau, Joan Santamaria, Alex Iranzo, Bettina Schreiner, Maria Pia Giannoccaro, Rocco Liguori, Takayoshi

    Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5

  •   Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia
    Brain (IF 14.5) Pub Date : 2024-02-29
    Min Chu, Deming Jiang, Dan Li, Shaozhen Yan, Li Liu, Haitian Nan, Yingtao Wang, Yihao Wang, Ailing Yue, Liankun Ren, Kewei Chen, Pedro Rosa-Neto, Jie Lu, Liyong Wu

    Frontotemporal Dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different

  •   A machine learning approach for gene prioritization in Parkinson’s disease
    Brain (IF 14.5) Pub Date : 2024-02-28
    Aymeric Lanore, Aymeric Basset, Suzanne Lesage

    This scientific commentary refers to ‘Machine learning nominates the inositol pathway and novel genes in Parkinson’s disease’ by Yu et al. (https://doi.org/10.1093/brain/awad345).

  •   Would you believe your own consciousness?
    Brain (IF 14.5) Pub Date : 2024-02-27
    Riccardo Fesce, Joanne Ursell, Patricia Taylor

    Can we ever fully believe what someone tells us about themselves? Riccardo Fesce et al, awarded joint runners up of the Brain Essay Competition 2023, consider whether asking consciousness about itself will ever yield credible and reliable answers.

  •   Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma
    Brain (IF 14.5) Pub Date : 2024-02-27
    Benjamine Sarton, Clovis Tauber, Estéban Fridman, Patrice Péran, Beatrice Riu, Hélène Vinour, Adrian David, Thomas Geeraerts, Fanny Bounes, Vincent Minville, Clément Delmas, Anne-Sophie Salabert, Jean François Albucher, Benoit Bataille, Jean Marc Olivot, Alain Cariou, Lionel Naccache, Pierre Payoux, Nicholas Schiff, Stein Silva

    The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood, but inflammation is potentially an important but still undervalued factor. Here we present a first-in-human prospective study using translocator protein 18 kDa (TSPO) radioligand (F18-DPA714) for PET imaging, to allow in vivo neuroimmune activation quantification on patients with

  •   Novel insight into atogepant mechanisms of action in migraine prevention
    Brain (IF 14.5) Pub Date : 2024-02-27
    Agustin Melo-Carrillo, Andrew M Strassman, Ron Broide, Aubrey Adams, Brett Dabruzzo, Mitchell Brin, Rami Burstein

    Recently, we showed that while atogepant - a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist - does not fully prevent activation of nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C-fibers and late response probability in A™-fibers. The current study investigates atogepant effect on CSD-induced activation and

  •   How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?
    Brain (IF 14.5) Pub Date : 2024-02-26
    G Lorenzo Odierna, Steve Vucic, Marcus Dyer, Tracey Dickson, Adele Woodhouse, Catherine Blizzard

    Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the ‘dying forward’ excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor

  •   Limitation of life sustaining therapy in disorders of consciousness: ethics and practice
    Brain (IF 14.5) Pub Date : 2024-02-22
    India A Lissak, Michael J Young

    Clinical conversations surrounding the continuation or limitation of life-sustaining treatments (LLST) are both challenging and tragically necessary for patients with Disorders of Consciousness (DoC) following severe brain injury. Divergent cultural, philosophical, and religious perspectives contribute to vast heterogeneity in clinical approaches to LLST – as reflected in regional differences and inter-clinician

  •   ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations
    Brain (IF 14.5) Pub Date : 2024-02-22
    Lucia Laugwitz, Fubo Cheng, Stephan C Collins, Alexander Hustinx, Nicolas Navarro, Simon Welsch, Helen Cox, Tzung-Chien Hsieh, Aswinkumar Vijayananth, Rebecca Buchert, Benjamin Bender, Stephanie Efthymiou, David Murphy, Faisal Zafar, Nuzhat Rana, Ute Grasshoff, Ruth J Falb, Mona Grimmel, Annette Seibt, Wenxu Zheng, Hamid Ghaedi, Marie Thirion, Sébastien Couette, Reza Azizimalamiri, Saeid Sadeghian

    Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1,500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations, however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential

  •   A CAG repeat threshold for therapeutics targeting somatic instability in Huntington’s disease
    Brain (IF 14.5) Pub Date : 2024-02-22
    Sarah G Aldous, Edward J Smith, Christian Landles, Georgina F Osborne, Maria Cañibano-Pico, Iulia M Nita, Jemima Phillips, Yongwei Zhang, Bo Jin, Marissa B Hirst, Caroline L Benn, Brian C Bond, Winfried Edelmann, Jonathan R Greene, Gillian P Bates

    The Huntington’s disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable, and expansions of hundreds of CAGs have been detected in Huntington’s disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age

  •   L-serine treatment in patients with GRIN-related encephalopathy: A phase 2A, non-randomized study
    Brain (IF 14.5) Pub Date : 2024-02-21
    Natalia Juliá-Palacios, Mireia Olivella, Mariya Sigatullina Bondarenko, Salvador Ibáñez-Micó, Beatriz Muñoz-Cabello, Olga Alonso-Luengo, Víctor Soto-Insuga, Deyanira García-Navas, Laura Cuesta-Herraiz, Patricia Andreo-Lillo, Sergio Aguilera-Albesa, Antonio Hedrera-Fernández, Elena González Alguacil, Rocío Sánchez-Carpintero, Fernando Martín del Valle, Erika Jiménez González, Lourdes Cean Cabrera, Ines

    GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2–18 years with GRIN loss-of-function

  •   Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis
    Brain (IF 14.5) Pub Date : 2024-02-20
    Nathan Pavey, Andrew Hannaford, Mehdi van den Bos, Matthew C Kiernan, Parvathi Menon, Steve Vucic

    Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial

  •   Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features
    Brain (IF 14.5) Pub Date : 2024-02-17
    Pablo Iruzubieta, Alberto Damborenea, Mihaela Ioghen, Simon Bajew, Roberto Fernandez-Torrón, Ana Töpf, Álvaro Herrero-Reiriz, Diana Epure, Katharina Vill, Aurelio Hernández-Laín, María Manterola, Mikel Azkargorta, Oihane Pikatza-Menoio, Laura Pérez-Fernandez, Mikel García-Puga, Gisela Gaina, Alexandra Bastian, Ioana Streata, Maggie C Walter, Wolfgang Müller-Felber, Simone Thiele, Saioa Moragón, Nerea

    Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1

  •   HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING
    Brain (IF 14.5) Pub Date : 2024-02-17
    Erliang Kong, Tong Hua, Jian Li, Yongchang Li, Mei Yang, Ruifeng Ding, Haowei Wang, Huawei Wei, Xudong Feng, Chaofeng Han, Hongbin Yuan

    Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of postherpetic neuralgia (PHN). The immune escape mechanism of VZV remains to be elusive. Due to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well-established PHN mice model. Transcriptional expression analysis identified that the protein arginine

  •   Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study
    Brain (IF 14.5) Pub Date : 2024-02-17
    Patricio Millar Vernetti, Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Italo Biaggioni, Cyndya A Shibao, Amanda Peltier, Roy Freeman, Christopher Gibbons, David S Goldstein, Phillip A Low, Wolfgang Singer, Elizabeth A Coon, Mitchell G Miglis, Gregor K Wenning, Alessandra Fanciulli, Steven Vernino, Rebecca A Betensky, Horacio Kaufmann

    We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at 8 Centers (7-US based and 1 European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent

  •   Anatomo-functional basis of emotional and motor resonance elicited by facial expressions
    Brain (IF 14.5) Pub Date : 2024-02-16
    Maria Del Vecchio, Pietro Avanzini, Marzio Gerbella, Sara Costa, Flavia Maria Zauli, Piergiorgio d’Orio, Elena Focacci, Ivana Sartori, Fausto Caruana

    Simulation theories predict that the observation of other’s expressions modulates neural activity in the same centers controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization

  •   Deep brain stimulation: a tale of two targets … and closing the loop
    Brain (IF 14.5) Pub Date : 2024-02-12
    Ludvic Zrinzo

    This scientific commentary refers to ‘At home adaptive dual target deep brain stimulation in Parkinson disease with proportional control’ by Schmidt et al. (https://doi.org/10.1093/brain/awad429).

  •   Graphs and the idiographic brain
    Brain (IF 14.5) Pub Date : 2024-02-12
    Michael S Elmalem, Parashkev Nachev, Ashwani Jha

    This scientific commentary refers to ‘Integrating direct electrical brain stimulation with the human connectome’ by Coletta et al. (https://doi.org/10.1093/brain/awad402).

  •   A neuroanatomical and cognitive model of impaired social behaviour in frontotemporal dementia
    Brain (IF 14.5) Pub Date : 2024-02-09
    Matthew A Rouse, Richard J Binney, Karalyn Patterson, James B Rowe, Matthew A Lambon Ralph

    Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed

  •   Cerebrospinal fluid biomarker panel for synaptic dysfunction in a broad spectrum of neurodegenerative diseases
    Brain (IF 14.5) Pub Date : 2024-02-06
    Johanna Nilsson, Alexa Pichet Binette, Sebastian Palmqvist, Wagner S Brum, Shorena Janelidze, Nicholas J Ashton, Nicola Spotorno, Erik Stomrud, Johan Gobom, Henrik Zetterberg, Ann Brinkmalm, Kaj Blennow, Oskar Hansson

    Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measurement of synaptic proteins in cerebrospinal fluid (CSF). In the current study, the aim was to investigate and compare both known and new synaptic proteins as potential biomarkers of synaptic dysfunction, especially

  •   Spike ripples localize the epileptogenic zone best: an international intracranial study
    Brain (IF 14.5) Pub Date : 2024-02-06
    Wen Shi, Dana Shaw, Katherine G Walsh, Xue Han, Uri T Eden, Robert M Richardson, Stephen V Gliske, Julia Jacobs, Benjamin H Brinkmann, Gregory A Worrell, William C Stacey, Birgit Frauscher, John Thomas, Mark A Kramer, Catherine J Chu

    We evaluated whether spike ripples, the combination of epileptiform spikes and ripples, provide a reliable and improved biomarker for the epileptogenic zone (EZ) compared to other leading interictal biomarkers in a multicenter, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centers who subsequently

  •   Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer’s disease
    Brain (IF 14.5) Pub Date : 2024-02-04
    Hyun-Sik Yang, Wai-Ying W Yau, Becky C Carlyle, Bianca A Trombetta, Can Zhang, Zahra Shirzadi, Aaron P Schultz, Jeremy J Pruzin, Colleen D Fitzpatrick, Dylan R Kirn, Jennifer S Rabin, Rachel F Buckley, Timothy J Hohman, Dorene M Rentz, Rudolph E Tanzi, Keith A Johnson, Reisa A Sperling, Steven E Arnold, Jasmeer P Chhatwal

    Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer’s disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer’s disease and their relationships with other Alzheimer’s disease and vascular pathologies during this

  •   Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model
    Brain (IF 14.5) Pub Date : 2024-02-02
    Troy N Trevino, Avital B Fogel, Guliz Otkiran, Seshadri B Niladhuri, Mark A Sanborn, Jacob Class, Ali A Almousawi, Benoit Vanhollebeke, Leon M Tai, Jalees Rehman, Justin M Richner, Sarah E Lutz

    Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we conduced unbiased transcriptional analysis to identify brain endothelial cell signaling pathways dysregulated by mouse adapted SARS-CoV-2

  •   Impaired value-based decision-making in Parkinson’s disease apathy
    Brain (IF 14.5) Pub Date : 2024-02-02
    William Gilmour, Graeme Mackenzie, Mathias Feile, Louise Tayler-Grint, Szabolcs Suveges, Jennifer A Macfarlane, Angus D Macleod, Vicky Marshall, Iris Q Grunwald, J Douglas Steele, Tom Gilbertson

    Apathy is a common and disabling complication of Parkinson’s disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects

  •   The historical context of migraine stigma
    Brain (IF 14.5) Pub Date : 2024-02-01
    William Young

    The social and psychological stigma of disease can be profound. William Young, awarded joint runner-up of the Brain Essay Competition 2023, discusses how for people with migraine, this stigma can be a huge burden which excludes and disenfranchises them from many areas of normal life.

  •   Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
    Brain (IF 14.5) Pub Date : 2024-02-01
    Hazem Ahmed, Yuqin Wang, William J Griffiths, Allan I Levey, Irina Pikuleva, Steven H Liang, Ahmed Haider

    Cholesterol homeostasis is impaired in Alzheimer’s disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of AD. Indeed, neuronal cholesterol was linked to the

  •   Dissociation of reading and naming in ventral occipitotemporal cortex
    Brain (IF 14.5) Pub Date : 2024-01-30
    Oscar Woolnough, Nitin Tandon

    Lesions in language-dominant ventral occipitotemporal cortex (vOTC) can result in selective impairment of either reading and naming, resulting in alexia or anomia. Yet, functional imaging studies that show differential activation for naming and reading do not reveal activity exclusively tuned to one of these inputs. To resolve this dissonance in the functional architecture of vOTC, we used focused

  •   Characterization of cortico-meningeal translocator protein expression in multiple sclerosis
    Brain (IF 14.5) Pub Date : 2024-01-30
    Elena Herranz, Constantina A Treaba, Valeria T Barletta, Ambica Mehndiratta, Russell Ouellette, Jacob A Sloane, Carolina Ionete, Suma Babu, Marina Mastantuono, Stefano Magon, Marco L Loggia, Meena M Makary, Jacob M Hooker, Ciprian Catana, Revere Kinkel, Richard Nicholas, Eric C Klawiter, Roberta Magliozzi, Caterina Mainero

    Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was

  •   Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke
    Brain (IF 14.5) Pub Date : 2024-01-30
    Yong-Jie Cheng, Fei Wang, Jie Feng, Bin Yu, Bin Wang, Qing Gao, Teng-Yue Wang, Bo Hu, Xing Gao, Jing-Fei Chen, Yu-Jie Chen, Sheng-Qing Lv, Hua Feng, Lan Xiao, Feng Mei

    Ischemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserve neurons and promote functional recovery remain unavailable. Oligodendrocytes (OLs), the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischemic stroke. Technically, new OLs and myelin can be generated from the differentiation

  •   Viral-based animal models in polyglutamine disorders
    Brain (IF 14.5) Pub Date : 2024-01-29
    Carina Henriques, Miguel M Lopes, Ana C Silva, Diana D Lobo, Romina Aron Badin, Philippe Hantraye, Luís Pereira de Almeida, Rui Jorge Nobre

    Polyglutamine disorders are a complex group of incurable neurodegenerative disorders caused by an abnormal expansion in the trinucleotide cytosine-adenine-guanine tract of the affected gene. To better understand these disorders, our dependence on animal models persists, primarily relying on transgenic models. In an effort to complement and deepen our knowledge, researchers have also developed animal

  •   The basal forebrain cholinergic system as target for cell replacement therapy in Parkinson’s disease
    Brain (IF 14.5) Pub Date : 2024-01-27
    Anders Björklund, Roger A Barker

    In recent years there has been a renewed interest in the basal forebrain (BF) cholinergic system as a target for the treatment of cognitive impairments in patients with Parkinson´s disease (PD), due in part to the need to explore novel approaches to treat the cognitive symptoms of the disease, and in part to the development of more refined imaging tools that have made it possible to monitor the progressive

  •   The effect of Huntington’s disease on cognitive and physical motivation
    Brain (IF 14.5) Pub Date : 2024-01-24
    Kelly J Atkins, Sophie C Andrews, Julie C Stout, Trevor T-J Chong

    Apathy is one of the most common neuropsychiatric features of Huntington’s disease (HD). A hallmark of apathy is diminished goal-directed behaviour, which is characterised by a lower motivation to engage in cognitively or physically effortful actions. However, it remains unclear whether this reduction in goal-directed behaviour is driven primarily by a motivational deficit, and/or is secondary to the

  •   Multimodal study of multilevel pulvino-temporal connections: a new piece in the puzzle of lexical retrieval networks
    Brain (IF 14.5) Pub Date : 2024-01-18
    Igor Lima Maldonado, Maxime Descoteaux, François Rheault, Ilyess Zemmoura, Austin Benn, Daniel Margulies, Arnaud Boré, Hugues Duffau, Emmanuel Mandonnet

    Advanced methods of imaging and mapping the healthy and lesioned brain allowed to identify the cortical nodes and white matter tracts supporting the dual neurofunctional organization of language networks in a dorsal phonological and a ventral semantic stream. Much less understood are the anatomical correlates of the interaction between the two streams, one hypothesis being that of a sub-cortically

  •   Alzheimer proteopathic tau seeds are biochemically a forme fruste of mature paired helical filaments
    Brain (IF 14.5) Pub Date : 2024-01-18
    Mukesh Kumar, Noé Quittot, Simon Dujardin, Christoph N Schlaffner, Arthur Viode, Anne Wiedmer, Pieter Beerepoot, Joshua E Chun, Calina Glynn, Analiese R Fernandes, Cameron Donahue, Judith A Steen, Bradley T Hyman

    Aggregation prone molecules, such as tau, form both historically well characterized fibrillar deposits (neurofibrillary tangles) and recently identified phosphate-buffered saline (PBS) extract species called proteopathic seeds. Both can cause normal endogenous tau to undergo templated misfolding. The relationship of these seeds to the fibrils that define tau-related diseases is unknown. We characterized

  •   Disease-linked mutations in Munc18-1 deplete synaptic Doc2
    Brain (IF 14.5) Pub Date : 2024-01-17
    Noah Guy Lewis Guiberson, Luca S Black, Jillian E Haller, Aniv Brukner, Debra Abramov, Saad Ahmad, Yan Xin Xie, Manu Sharma, Jacqueline Burré

    Heterozygous de novo mutations in the neuronal protein Munc18-1/STXBP1 cause syndromic neurological symptoms, including severe epilepsy, intellectual disability, developmental delay, ataxia, and tremor, summarized as STXBP1 encephalopathies. Although haploinsufficiency is the prevailing disease mechanism, it remains unclear how the reduction in Munc18-1 levels causes synaptic dysfunction in disease

  •   Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy
    Brain (IF 14.5) Pub Date : 2024-01-17
    Lucia Abela, Lorita Gianfrancesco, Erica Tagliatti, Giada Rossignoli, Katy Barwick, Clara Zourray, Kimberley M Reid, Dimitri Budinger, Joanne Ng, John Counsell, Arlo Simpson, Toni S Pearson, Simon Edvardson, Orly Elpeleg, Frances M Brodsky, Gabriele Lignani, Serena Barral, Manju A Kurian

    DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently

  •   Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation
    Brain (IF 14.5) Pub Date : 2024-01-17
    Mikel Muñoz-Oreja, Abigail Sandoval, Ove Bruland, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Marina Villar-Fernandez, Haizea Hernández-Eguiazu, Ixiar Hernández, Yohan Park, Leire Goicoechea, Nerea Pascual-Frías, Carmen Garcia-Ruiz, Jose Fernandez-Checa, Itxaso Martí-Carrera, Francisco Javier Gil-Bea, Mazahir T Hasan, Matthew E Gegg, Cecilie Bredrup, Per-Morten Knappskog, Gorka

    Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, nor were the effects on cell membranes or the wider cell known. Using patient-derived

  •   Clinicopathological correlates in frontotemporal lobar degeneration: motor neuron disease spectrum
    Brain (IF 14.5) Pub Date : 2024-01-16
    Álvaro Carbayo, Sergi Borrego-Écija, Janina Turon-Sans, Elena Cortés-Vicente, Laura Molina-Porcel, Jordi Gascón-Bayarri, Miguel Ángel Rubio, Mónica Povedano, Josep Gámez, Javier Sotoca, Raúl Juntas-Morales, Miriam Almendrote, Marta Marquié, Raquel Sánchez-Valle, Ignacio Illán-Gala, Oriol Dols-Icardo, Sara Rubio-Guerra, Sara Bernal, Marta Caballero-Ávila, Ana Vesperinas, Ellen Gelpi, Ricard Rojas-García

    Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10-15% of cases. In the absence

  •   Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase
    Brain (IF 14.5) Pub Date : 2024-01-16
    Hye Yoon Chung, Geon Seong Lee, Soo Hyun Nam, Jeong Hyeon Lee, Jeong Pil Han, Sumin Song, Gap-Don Kim, Choonkyun Jung, Do Young Hyeon, Daehee Hwang, Byung-Ok Choi, Su Cheong Yeom

    Mutations in the Microrchidia CW-Type Zinc Finger 2 (MORC2) GHKL ATPase module cause a broad range of neuropathies, such as Charcot-Marie-Tooth disease type 2Z; however, the aetiology and therapeutic strategy are not fully understood. Previously, we reported that the Morc2a p.S87L mouse model exhibited neuropathy and muscular dysfunction through DNA damage accumulation. In the present study, we analysed

  •   Imaging chronic active lesions in multiple sclerosis: a consensus statement
    Brain (IF 14.5) Pub Date : 2024-01-13
    Francesca Bagnato, Pascal Sati, Christopher C Hemond, Colm Elliott, Susan A Gauthier, Daniel M Harrison, Caterina Mainero, Jiwon Oh, David Pitt, Russell T Shinohara, Seth A Smith, Bruce Trapp, Christina J Azevedo, Peter A Calabresi, Roland G Henry, Cornelia Laule, Daniel Ontaneda, William D Rooney, Nancy L Sicotte, Daniel S Reich, Martina Absinta

    Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis (MS) and have implications for non-relapsing biological progression. In recent years, the discovery of innovative magnetic resonance imaging (MRI) and PET derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with MS, in vivo. Paramagnetic

  •   Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer’s disease
    Brain (IF 14.5) Pub Date : 2024-01-13
    Yingying Han, Kui Chen, Bei Zhang, Hongxiang Yu, Can Cui, Hongxia Li, Yongbo Hu, Gang Li

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. Synaptic dysfunction has appeared in the early stage of AD and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here we found upregulated Maf1 transcription factor in AD, and Maf1 conditional knockout in AD transgenic mice restored

  •   Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome
    Brain (IF 14.5) Pub Date : 2024-01-13
    Stephanie Efthymiou, Marcello Scala, Vini Nagaraj, Katarzyna Ochenkowska, Fenne L Komdeur, Robin A Liang, Mohamed S Abdel-Hamid, Tipu Sultan, Tuva Barøy, Marijke Van Ghelue, Barbara Vona, Reza Maroofian, Faisal Zafar, Fowzan S Alkuraya, Maha S Zaki, Mariasavina Severino, Kingsley C Duru, Robert C Tryon, Lin Vigdis Brauteset, Morad Ansari, Mark Hamilton, Mieke M van Haelst, Gijs van Haaften, Federico

    Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harboring different homozygous LoF variants in ABCC9 and presenting with a conserved range of clinical

  •   TREM2 variants that cause early dementia and increase Alzheimer’s disease risk affect gene splicing
    Brain (IF 14.5) Pub Date : 2024-01-12
    Kostantin Kiianitsa, Maria E Lukes, Brian J Hayes, Julianna Brutman, Paul N Valdmanis, Thomas D Bird, Wendy H Raskind, Olena Korvatska

    Loss-of-function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu-Hakola disease (NHD) and behavioral variants of frontotemporal dementia (FTD), whereas heterozygous variants increase the risk of late-onset Alzheimer’s

  •   Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia
    Brain (IF 14.5) Pub Date : 2024-01-12
    Katerina A Tetzloff, Peter R Martin, Joseph R Duffy, Rene L Utianski, Heather M Clark, Hugo Botha, Mary M Machulda, Nha Trang Thu Pham, Christopher G Schwarz, Matthew L Senjem, Clifford R Jack, Val J Lowe, Keith A Josephs, Jennifer L Whitwell

    Progressive apraxia of speech is a neurodegenerative motor-speech disorder that most commonly arises from a 4-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease, but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech, and the mixed

  •   Theta frequency deep brain stimulation in the subthalamic nucleus improves working memory in Parkinson’s disease
    Brain (IF 14.5) Pub Date : 2024-01-09
    Narges Salehi, Simone Nahrgang, Wiebke Petershagen, Till A Dembek, David Pedrosa, Lars Timmermann, Immo Weber, Carina R Oehrn

    Most research in Parkinson's disease (PD) focuses on improving motor symptoms. Yet, up to 80% of patients present with non-motor symptoms that often have a large impact on patients’ quality of life. Impairment in working memory (WM), a fundamental cognitive process, is common in PD. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms in Parkinson’s disease, its

  •   Are we entering the ‘Tau-lemaic’ era of Parkinson’s disease?
    Brain (IF 14.5) Pub Date : 2024-01-08
    Alberto J Espay, Andrew Lees

    This scientific commentary refers to ‘Tau pathology in parkinsonism and Parkinson’s disease’ by Chu et al. (https://doi.org/10.1093/brain/awad388).

  •   Transcriptomics reveals CSF cellular composition in multiple sclerosis but detects no viral RNA
    Brain (IF 14.5) Pub Date : 2024-01-04
    Nicholas Schwab

    This scientific commentary refers to “Expression profiling of cerebrospinal fluid identifies dysregulated antiviral mechanisms in multiple sclerosis” by Ban et al. (https://doi.org/10.1093/brain/awad404).

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