Brain

Parkinson’s disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson’s disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson’s disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of ?-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson’s disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of ?-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson’s disease.

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Tumour immune landscape of paediatric high-grade gliomas

James L Ross, Jose Velazquez Vega, Ashley Plant, Tobey J MacDonald, Oren J Becher, Dolores Hambardzumyan

doi : 10.1093/brain/awab155

Brain, Volume 144, Issue 9, September 2021, Pages 2594–2609

Over the past decade, remarkable progress has been made towards elucidating the origin and genomic landscape of childhood high-grade brain tumours. It has become evident that paediatric high-grade gliomas differ from those in adults with respect to multiple defining aspects including: DNA copy number, gene expression profiles, tumour locations within the CNS and genetic alterations such as somatic histone mutations.

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HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia

Edoardo Monfrini, Michael Zech, Dora Steel, Manju A Kurian, Juliane Winkelmann, Alessio Di Fonzo

doi : 10.1093/brain/awab161

Brain, Volume 144, Issue 9, September 2021, Pages 2610–2615

The homotypic fusion and protein sorting (HOPS) complex is the structural bridge necessary for the fusion of late endosomes and autophagosomes with lysosomes.

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Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic

Thibault Coste, Dominique Hervé, Jean Philippe Neau, Eric Jouvent, Fatoumata Ba, Françoise Bergametti, Matthias Lamy, Julien Cogez, Nathalie Derache, Romain Schneckenburger, Maude Grelet, Cédric Gollion, Livia Lanotte, Valérie Lauer, Valérie Layet, Cédric Urbanczyk, Mira Didic, Igor Raynouard, Laure Delaval, Jérémie Dassa, Alexandru Florea, Carmen Badiu, Karine Nguyen, Elisabeth Tournier-Lasserve

doi : 10.1093/brain/awab271

Brain, Volume 144, Issue 9, September 2021, Pages 2616–2624

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P?=?3.12 × 10?17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P?=?7.6 × 10?18, OR = 27.1) and 1000 Genomes (P?=?1.5 × 10?5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.

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Classification of neurological diseases using multi-dimensional CSF analysis

Catharina C Gross, Andreas Schulte-Mecklenbeck, Lohith Madireddy, Marc Pawlitzki, Christine Strippel, Saskia Räuber, Julia Krämer, Leoni Rolfes, Tobias Ruck, Carolin Beuker, Antje Schmidt-Pogoda, Lisa Lohmann, Tilman Schneider-Hohendorf, Tim Hahn, Nicholas Schwab, Jens Minnerup, Nico Melzer, Luisa Klotz, Sven G Meuth, Gerd Meyer zu Hörste, Sergio E Baranzini, Heinz Wiendl

doi : 10.1093/brain/awab147

Brain, Volume 144, Issue 9, September 2021, Pages 2625–2634

Although CSF analysis routinely enables the diagnosis of neurological diseases, it is mainly used for the gross distinction between infectious, autoimmune inflammatory, and degenerative disorders of the CNS. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analysed 546 patients with autoimmune neuroinflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters that were altered across all autoimmune neuroinflammatory CNS diseases and differentiated them from other neurological conditions and inter-autoimmunity classifiers that subdifferentiate variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist the classification of neurological patients. Overall, we showed that the integrated analysis of blood and CSF parameters improves the differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.

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The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial

Eleonora Dalla Bella, Enrica Bersano, Giovanni Antonini, Giuseppe Borghero, Margherita Capasso, Claudia Caponnetto, Adriano Chiò, Massimo Corbo, Massimiliano Filosto, Fabio Giannini, Rossella Spataro, Christian Lunetta, Jessica Mandrioli, Sonia Messina, Maria Rosaria Monsurrò, Gabriele Mora, Nilo Riva, Romana Rizzi, Gabriele Siciliano, Vincenzo Silani, Isabella Simone, Gianni Sorarù, Valeria Tugnoli, Lorenzo Verriello, Paolo Volanti, Roberto Furlan, John M Nolan, Emmanuelle Abgueguen, Irene Tramacere, Giuseppe Lauria

doi : 10.1093/brain/awab167

Brain, Volume 144, Issue 9, September 2021, Pages 2635–2647

Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2?-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown.

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Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations

Tao Hong, Xiao Xiao, Jian Ren, Bing Cui, Yuru Zong, Jian Zou, Zqi Kou, Nan Jiang, Guolu Meng, Gao Zeng, Yongzhi Shan, Hao Wu, Zan Chen, Jiantao Liang, Xinru Xiao, Jie Tang, Yukui Wei, Ming Ye, Liyong Sun, Guilin Li, Peng Hu, Rutai Hui, Hongqi Zhang, Yibo Wang

doi : 10.1093/brain/awab117

Brain, Volume 144, Issue 9, September 2021, Pages 2648–2658

Cavernous malformations affecting the CNS occur in ?0.16–0.4% of the general population. The majority (85%) of cavernous malformations are in a sporadic form, but the genetic background of sporadic cavernous malformations remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in two genes: MAP3K3 and PIK3CA by whole-exome sequencing. The mutation spectrum correlated with lesion size (P?=?0.001), anatomical distribution (P?<?0.001), MRI appearance (P?=?0.004) and haemorrhage events (P?=?0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P?=?0.003, odds ratio = 11.252, 95% confidence interval = 2.275–55.648). Enrichment of endothelial cell population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of endothelial cell models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic cavernous malformations were identified by single cell RNA sequencing and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic cavernous malformations and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic cavernous malformations.

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Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Edgard Verdura, Agustí Rodríguez-Palmero, Valentina Vélez-Santamaria, Laura Planas-Serra, Irene de la Calle, Miquel Raspall-Chaure, Agathe Roubertie, Mehdi Benkirane, Francesco Saettini, Lisa Pavinato, Giorgia Mandrile, Melanie O’Leary, Emily O’Heir, Estibaliz Barredo, Almudena Chacón, Vincent Michaud, Cyril Goizet, Montserrat Ruiz, Agatha Schlüter, Isabelle Rouvet, Julia Sala-Coromina, Chiara Fossati, Maria Iascone, Francesco Canonico, Anna Marcé-Grau, Precilla de Souza, David R Adams, Carlos Casasnovas, Heidi L Rehm, Heather C Mefford, Luis González Gutierrez-Solana, Alfredo Brusco, Michel Koenig, Alfons Macaya, Aurora Pujol

doi : 10.1093/brain/awab124

Brain, Volume 144, Issue 9, September 2021, Pages 2659–2669

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

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Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities

Rainer Malik, Nathalie Beaufort, Simon Frerich, Benno Gesierich, Marios K Georgakis, Kristiina Rannikmäe, Amy C Ferguson, Christof Haffner, Matthew Traylor, Michael Ehrmann, Cathie L M Sudlow, Martin Dichgans

doi : 10.1093/brain/awab253

Brain, Volume 144, Issue 9, September 2021, Pages 2670–2682

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, ??=??0.74, standard error (SE)?=?0.13, P?=?9.7 × 10?9].

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TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy

Christoph Mahler, Adrian-Minh Schumacher, Marcus Unterrainer, Lena Kaiser, Thomas Höllbacher, Simon Lindner, Joachim Havla, Birgit Ertl-Wagner, Maximilian Patzig, Klaus Seelos, Julia Neitzel, Matthias Mäurer, Markus Krumbholz, Imke Metz, Wolfgang Brück, Christine Stadelmann, Doron Merkler, Achim Gass, Vladimir Milenkovic, Peter Bartenstein, Nathalie L Albert, Tania Kümpfel, Martin Kerschensteiner

doi : 10.1093/brain/awab127

Brain, Volume 144, Issue 9, September 2021, Pages 2683–2695

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited.

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COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital

Kiran T Thakur, Emily Happy Miller, Michael D Glendinning, Osama Al-Dalahmah, Matei A Banu, Amelia K Boehme, Alexandra L Boubour, Samuel S Bruce, Alexander M Chong, Jan Claassen, Phyllis L Faust, Gunnar Hargus, Richard A Hickman, Sachin Jambawalikar, Alexander G Khandji, Carla Y Kim, Robyn S Klein, Angela Lignelli-Dipple, Chun-Chieh Lin, Yang Liu, Michael L Miller, Gul Moonis, Anna S Nordvig, Jonathan B Overdevest, Morgan L Prust, Serge Przedborski, William H Roth, Allison Soung, Kurenai Tanji, Andrew F Teich, Dritan Agalliu, Anne-Catrin Uhlemann, James E Goldman, Peter Canoll

doi : 10.1093/brain/awab148

Brain, Volume 144, Issue 9, September 2021, Pages 2696–2708

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74?years (38–97?years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24?h of hospital admission, while 11 (27%) died more than 4?weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

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Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis

Sergio Muñiz-Castrillo, Julien Jacques Hedou, Aditya Ambati, David Jones, Alberto Vogrig, Anne-Laurie Pinto, Marie Benaiteau, Thomas de Broucker, Laura Fechtenbaum, Pierre Labauge, Matthew Murnane, Claire Nocon, Irina Taifas, Clément Vialatte de Pémille, Dimitri Psimaras, Bastien Joubert, Valérie Dubois, Valentin Wucher, Virginie Desestret, Emmanuel Mignot, Jérôme Honnorat

doi : 10.1093/brain/awab153

Brain, Volume 144, Issue 9, September 2021, Pages 2709–2721

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66?years (range 48–94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR)?=?13.4, 95% confidence interval (CI): 3.8–47.4], C*07:01 (8/11, 72.7%; OR?=?11.0, 95% CI: 2.9–42.5), DRB1*03:01 (8/11, 72.7%; OR?=?14.4, 95% CI: 3.7–55.7), DQB1*02:01 (8/11, 72.7%; OR?=?13.5, 95% CI: 3.5–52.0) and DQA1*05:01 (8/11, 72.7%; OR?=?14.4, 95% CI: 3.7–55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR?=?16.5, 95% CI: 4.8–57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

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MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase

Osorio Lopes Abath Neto, Livija Medne, Sandra Donkervoort, Maria Elena Rodríguez-García, Véronique Bolduc, Ying Hu, Eleonora Guadagnin, A Reghan Foley, John F Brandsema, Allan M Glanzman, Gihan I Tennekoon, Mariarita Santi, Justin H Berger, Lynn A Megeney, Hirofumi Komaki, Michio Inoue, Francisco Javier Cotrina-Vinagre, Aurelio Hernández-Lain, Elena Martin-Hernández, Linford Williams, Sabine Borell, David Schorling, Kimberly Lin, Konstantinos Kolokotronis, Uta Lichter-Konecki, Janbernd Kirschner, Ichizo Nishino, Brenda Banwell, Francisco Martínez-Azorín, Patrick G Burgon, Carsten G Bönnemann

doi : 10.1093/brain/awab275

Brain, Volume 144, Issue 9, September 2021, Pages 2722–2731

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients’ skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP’s role in normal and diseased skeletal muscle homeostasis.

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Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson’s disease

Christopher E J Doppler, Martin B Kinnerup, Corinna Brune, Ezequiel Farrher, Matthew Betts, Tatyana D Fedorova, Jeppe L Schaldemose, Karoline Knudsen, Rola Ismail, Aline D Seger, Allan K Hansen, Kristian Stær, Gereon R Fink, David J Brooks, Adjmal Nahimi, Per Borghammer, Michael Sommerauer

doi : 10.1093/brain/awab236

Brain, Volume 144, Issue 9, September 2021, Pages 2732–2744

Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters.

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An in vivo Caenorhabditis elegans model for therapeutic research in human prion diseases

Nicolas Bizat, Valeria Parrales, Sofian Laoues, Sébastien Normant, Etienne Levavasseur, Julian Roussel, Nicolas Privat, Alexianne Gougerot, Philippe Ravassard, Patrice Beaudry, Jean-Philippe Brandel, Jean-Louis Laplanche, Stéphane Haïk

doi : 10.1093/brain/awab152

Brain, Volume 144, Issue 9, September 2021, Pages 2745–2758

Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival.

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Amyloid-? toxicity modulates tau phosphorylation through the PAX6 signalling pathway

Yalun Zhang, Yi Zhang, Yahyah Aman, Cheung Toa Ng, Wing-Hin Chau, Zhigang Zhang, Ming Yue, Christopher Bohm, Yizhen Jia, Siwen Li, Qiuju Yuan, Jennifer Griffin, Kin Chiu, Dana S M Wong, Binbin Wang, Dongyan Jin, Ekaterina Rogaeva, Paul E Fraser, Evandro F Fang, Peter St George-Hyslop, You-Qiang Song

doi : 10.1093/brain/awab134

Brain, Volume 144, Issue 9, September 2021, Pages 2759–2770

The molecular link between amyloid-? plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-? peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-?-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-? and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-? peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-? toxicity pathway. Mechanistically, amyloid-? upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3?, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3? activation and tau pathology, providing novel potential targets for pharmaceutical intervention.

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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory

David Berron, Jacob W Vogel, Philip S Insel, Joana B Pereira, Long Xie, Laura E M Wisse, Paul A Yushkevich, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Erik Stomrud, Ruben Smith, Olof Strandberg, Oskar Hansson

doi : 10.1093/brain/awab114

Brain, Volume 144, Issue 9, September 2021, Pages 2771–2783

In Alzheimer’s disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-?? cognitively unimpaired, 81 amyloid-?+ cognitively unimpaired and 87 amyloid-?+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.

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Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe

Paul A Yushkevich, Mónica Muñoz López, María Mercedes Iñiguez de Onzoño Martin, Ranjit Ittyerah, Sydney Lim, Sadhana Ravikumar, Madigan L Bedard, Stephen Pickup, Weixia Liu, Jiancong Wang, Ling Yu Hung, Jade Lasserve, Nicolas Vergnet, Long Xie, Mengjin Dong, Salena Cui, Lauren McCollum, John L Robinson, Theresa Schuck, Robin de Flores, Murray Grossman, M Dylan Tisdall, Karthik Prabhakaran, Gabor Mizsei, Sandhitsu R Das, Emilio Artacho-Pérula, Mar?’a del Mar Arroyo Jiménez, Mar?’a Pilar Marcos Raba, Francisco Javier Molina Romero, Sandra Cebada Sánchez, José Carlos Delgado González, Carlos de la Rosa-Prieto, Marta Córcoles Parada, Edward B Lee, John Q Trojanowski, Daniel T Ohm, Laura E M Wisse, David A Wolk, David J Irwin, Ricardo Insausti

doi : 10.1093/brain/awab262

Brain, Volume 144, Issue 9, September 2021, Pages 2784–2797

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely.

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SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Mathieu Barbier, Agnès Camuzat, Khalid El Hachimi, Justine Guegan, Daisy Rinaldi, Serena Lattante, Marion Houot, Raquel Sánchez-Valle, Mario Sabatelli, Anna Antonell, Laura Molina-Porcel, Fabienne Clot, Philippe Couratier, Emma van der Ende, Julie van der Zee, Claudia Manzoni, William Camu, Cécile Cazeneuve, François Sellal, Mira Didic, Véronique Golfier, Florence Pasquier, Charles Duyckaerts, Giacomina Rossi, Amalia C Bruni, Victoria Alvarez, Estrella Gómez-Tortosa, Alexandre de Mendonça, Caroline Graff, Mario Masellis, Benedetta Nacmias, Badreddine Mohand Oumoussa, Ludmila Jornea, Sylvie Forlani, The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS, Viviana Van Deerlin, Jonathan D Rohrer, Ellen Gelpi, Rosa Rademakers, John Van Swieten, Eric Le Guern, Christine Van Broeckhoven, Raffaele Ferrari, Emmanuelle Génin, Alexis Brice, Isabelle Le Ber

doi : 10.1093/brain/awab171

Brain, Volume 144, Issue 9, September 2021, Pages 2798–2811

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P?=?1 × 10?5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P?=?0.009). The protective major allele delayed the onset of dementia from 5 to 13?years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P?=?0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

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A passive and objective measure of recognition memory in Alzheimer’s disease using Fastball memory assessment

George Stothart, Laura J Smith, Alexander Milton, Elizabeth Coulthard

doi : 10.1093/brain/awab154

Brain, Volume 144, Issue 9, September 2021, Pages 2812–2825

Earlier diagnosis of Alzheimer’s disease requires biomarkers sensitive to associated structural and functional changes. While considerable progress has been made in the development of structural biomarkers, functional biomarkers of early cognitive change, unconfounded by effort, practice and level of education, are still needed. We present Fastball, a new EEG method for the passive and objective measurement of recognition memory, that requires no behavioural memory response or comprehension of the task . Younger adults, older adults and Alzheimer’s disease patients (n?=?20 per group) completed the Fastball task, lasting just under 3 min. Participants passively viewed rapidly presented images and EEG assessed their automatic ability to differentiate between images based on previous exposure, i.e. old/new. Participants were not instructed to attend to previously seen images and provided no behavioural response. Following the Fastball task, participants completed a two-alternative forced choice (2AFC) task to measure their explicit behavioural recognition of previously seen stimuli. Fastball EEG detected significantly impaired recognition memory in Alzheimer’s disease compared to healthy older adults (P?<?0.001, Cohen’s d?=?1.52), whereas behavioural recognition was not significantly different between Alzheimer’s disease and healthy older adults. Alzheimer’s disease patients could be discriminated with high accuracy from healthy older adult controls using the Fastball measure of recognition memory (AUC?=?0.86, P?<?0.001), whereas discrimination performance was poor using behavioural 2AFC accuracy (AUC?=?0.63, P?=?0.148). There were no significant effects of healthy ageing, with older and younger adult controls performing equivalently in both the Fastball task and behavioural 2AFC task. Early diagnosis of Alzheimer’s disease offers potential for early treatment when quality of life and independence can be retained through disease modification and cognitive enhancement. Fastball provides an alternative way of testing recognition responses that holds promise as a functional marker of disease pathology in stages where behavioural performance deficits are not yet evident. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball provides a new powerful method for the assessment of cognition in dementia and opens a new door in the development of early diagnosis tools.

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Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects

Joana B Pereira, Shorena Janelidze, Erik Stomrud, Sebastian Palmqvist, Danielle van Westen, Jeffrey L Dage, Niklas Mattsson-Carlgren, Oskar Hansson

doi : 10.1093/brain/awab163

Brain, Volume 144, Issue 9, September 2021, Pages 2826–2836

It is currently unclear whether plasma biomarkers can be used as independent prognostic tools to predict changes associated with early Alzheimer’s disease.

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Mapping autonomic, mood and cognitive effects of hypothalamic region deep brain stimulation

Clemens Neudorfer, Gavin J B Elias, Martin Jakobs, Alexandre Boutet, Jürgen Germann, Keshav Narang, Aaron Loh, Michelle Paff, Andreas Horn, Walter Kucharczyk, Wissam Deeb, Bryan Salvato, Leonardo Almeida, Kelly D Foote, Paul B Rosenberg, David F Tang-Wai, William S Anderson, Zoltan Mari, Francisco A Ponce, David A Wolk, Anna D Burke, Stephen Salloway, Marwan N Sabbagh, M Mallar Chakravarty, Gwenn S Smith, Constantine G Lyketsos, Michael S Okun, Andres M Lozano

doi : 10.1093/brain/awab170

Brain, Volume 144, Issue 9, September 2021, Pages 2837–2851

Because of its involvement in a wide variety of cardiovascular, metabolic and behavioural functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequelae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied—at multiple international centres—58 patients (mean age: 68.5?±?7.9?years, 26 females) suffering from mild Alzheimer’s disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation—including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear—were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic grey and white matter structures. K-nearest neighbour classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves between 0.67 and 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.

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Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer’s disease

Brendan P Lucey, Julie Wisch, Anna H Boerwinkle, Eric C Landsness, Cristina D Toedebusch, Jennifer S McLeland, Omar H Butt, Jason Hassenstab, John C Morris, Beau M Ances, David M Holtzman

doi : 10.1093/brain/awab272

Brain, Volume 144, Issue 9, September 2021, Pages 2852–2862

Sleep monitoring may provide markers for future Alzheimer’s disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer’s disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer’s disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity.

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Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Isamu Aiba, Jeffrey L Noebels

doi : 10.1093/brain/awab141

Brain, Volume 144, Issue 9, September 2021, Pages 2863–2878

Spreading depolarization is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link depolarizing molecular defects in Ca2+ flux, Na+ current in interneurons, and glial Na+-K+ ATPase with spreading depolarization susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining spreading depolarization threshold. In contrast, although gene mutations in voltage-gated potassium ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility, it is not known whether epileptogenic mutations that regulate membrane repolarization also modify spreading depolarization threshold and propagation. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is a spreading depolarization modulatory gene with significant control over the seizure-spreading depolarization transition threshold, bi-hemispheric cortical expression, and diurnal temporal susceptibility. Chronic DC-band cortical EEG recording from behaving conditional Kcnq2 deletion mice (Emx1cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and spreading depolarization. In contrast to the related potassium channel deficient model, Kv1.1-KO mice, spontaneous cortical spreading depolarizations in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the non-selective Kv7.2 inhibitor XE991 to Kv1.1-KO mice partly reproduced the Kcnq2 cKO-like spreading depolarization phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents can directly and actively modulate spreading depolarization properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical spreading depolarization threshold, whereas pharmacological Kv7.2 activators elevate the threshold to multiple depolarizing and hypometabolic spreading depolarization triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive spreading depolarization regulatory gene, and point to spreading depolarization as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as a potential adjunctive therapeutic target to inhibit spreading depolarization incidence.

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Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants

Joseph D Symonds, Katherine S Elliott, Jay Shetty, Martin Armstrong, Andreas Brunklaus, Ioana Cutcutache, Louise A Diver, Liam Dorris, Sarah Gardiner, Alice Jollands, Shelagh Joss, Martin Kirkpatrick, Ailsa McLellan, Stewart MacLeod, Mary O’Regan, Matthew Page, Elizabeth Pilley, Daniela T Pilz, Elma Stephen, Kirsty Stewart, Houman Ashrafian, Julian C Knight, Sameer M Zuberi

doi : 10.1093/brain/awab162

Brain, Volume 144, Issue 9, September 2021, Pages 2879–2891

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24?months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100?000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100?000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100?000 live births, 95% CI 139–233), ?2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.

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Senior moments

A J Lees

doi : 10.1093/brain/awab270

Brain, Volume 144, Issue 9, September 2021, Pages 2892–2895

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MATR3 haploinsufficiency and early-onset neurodegeneration

Michael Zech, Annette Seibt, Barbara Zumbaum, Dirk Klee, Thomas Meitinger, Juliane Winkelmann, Ertan Mayatepek, Matias Wagner, Felix Distelmaier

doi : 10.1093/brain/awab240

Brain, Volume 144, Issue 9, September 2021, Page e72

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Reply: Functional cognitive disorder: dementia’s blind spot

Harriet A Ball, Laura McWhirter, Clive Ballard, Rohan Bhome, Daniel J Blackburn, Mark J Edwards, Nick C Fox, Robert Howard, Jonathan Huntley, Jeremy D Isaacs, A J Larner, Timothy R Nicholson, Catherine M Pennington, Norman Poole, Gary Price, J P Price, Markus Reuber, Craig Ritchie, Martin N Rossor, Jonathan M Schott, Annalena Venneri, Jon Stone, Alan J Carson

doi : 10.1093/brain/awab305

Brain, Volume 144, Issue 9, September 2021, Page e73

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Myopathic mitochondrial DNA depletion syndrome associated with biallelic variants in LIG3

Federica Invernizzi, Andrea Legati, Alessia Nasca, Eleonora Lamantea, Barbara Garavaglia, Mirjana Gusic, Robert Kopajtich, Holger Prokisch, Massimo Zeviani, Costanza Lamperti, Daniele Ghezzi

doi : 10.1093/brain/awab238

Brain, Volume 144, Issue 9, September 2021, Page e74

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Looking beyond indirect lesion network mapping of prosopagnosia: direct measures required

Maria A Bobes, Jan Van den Stock, Minye Zhan, Mitchell Valdes-Sosa, Beatrice de Gelder

doi : 10.1093/brain/awab276

Brain, Volume 144, Issue 9, September 2021, Page e75

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Reply: Looking beyond indirect lesion network mapping of prosopagnosia: direct measures required

Alexander L Cohen, Michael D Fox

doi : 10.1093/brain/awab277

Brain, Volume 144, Issue 9, September 2021, Page e76

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Erratum to: Reply: Broca’s area: why was neurosurgery neglected for so long when seeking to re-establish the scientific truth? and Where is the speech production area? Evidence from direct cortical electrical stimulation mapping

Diego L Lorca-Puls, Andrea Gajardo-Vidal, David W Green, Cathy J Price

doi : 10.1093/brain/awab229

Brain, Volume 144, Issue 9, September 2021, Page e77

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Erratum to: Reply:?UQCRC1?variants in Parkinson’s disease: a large cohort study in Chinese mainland population

Chin-Hsien Lin, Matthew J Farrer, Ruey-Meei Wu

doi : 10.1093/brain/awab228

Brain, Volume 144, Issue 9, September 2021, Page e78

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Erratum to: Medial septal GABAergic neurons reduce seizure duration upon optogenetic closed-loop stimulation

doi : 10.1093/brain/awab212

Brain, Volume 144, Issue 9, September 2021, Page e79

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Erratum to: The Developing Human Connectome Project: typical and disrupted perinatal functional connectivity

Michael Eyre, Sean P Fitzgibbon, Judit Ciarrusta, Lucilio Cordero-Grande, Anthony N Price, Tanya Poppe, Andreas Schuh, Emer Hughes, Camilla O’Keeffe, Jakki Brandon, Daniel Cromb, Katy Vecchiato, Jesper Andersson, Eugene P Duff, Serena J Counsell, Stephen M Smith, Daniel Rueckert, Joseph V Hajnal, Tomoki Arichi, Jonathan O’Muircheartaigh, Dafnis Batalle, A David Edwards

doi : 10.1093/brain/awab234

Brain, Volume 144, Issue 9, September 2021, Page e80

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Erratum to: The GGC repeat expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy type 3

doi : 10.1093/brain/awab266

Brain, Volume 144, Issue 9, September 2021, Page e81

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Corrigendum to: CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer’s disease

Kanta Horie, Nicolas R Barthélemy, Chihiro Sato, Randall J Bateman

doi : 10.1093/brain/awab227

Brain, Volume 144, Issue 9, September 2021, Page e82

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Corrigendum to: Formation and immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity

Meike Mitsdoerffer, Giovanni Di Liberto, Sarah Dötsch, Christopher Sie, Ingrid Wagner, Monika Pfaller, Mario Kreutzfeldt, Simon Fräßle, Lilian Aly, Benjamin Knier, Dirk H Busch, Doron Merkler, Thomas Korn

doi : 10.1093/brain/awab235

Brain, Volume 144, Issue 9, September 2021, Page e83

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Corrigendum to: Medial temporal lobe connectivity and its associations with cognition in early Alzheimer’s disease

David Berron, Danielle van Westen, Rik Ossenkoppele, Olof Strandberg, Oskar Hansson

doi : 10.1093/brain/awab244

Brain, Volume 144, Issue 9, September 2021, Page e84

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