Brain

Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer’s disease, Parkinson’s disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.

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Consciousness among delta waves: a paradox?

Joel Frohlich, Daniel Toker, Martin M Monti

doi : 10.1093/brain/awab095

Brain, Volume 144, Issue 8, August 2021, Pages 2257–2277

A common observation in EEG research is that consciousness vanishes with the appearance of delta (1–4?Hz) waves, particularly when those waves are high amplitude. High amplitude delta oscillations are frequently observed in states of diminished consciousness, including slow wave sleep, anaesthesia, generalized epileptic seizures, and disorders of consciousness, such as coma and the vegetative state. This strong correlation between loss of consciousness and high amplitude delta oscillations is thought to stem from the widespread cortical deactivation that occurs during the ‘down states’ or troughs of these slow oscillations. Recently, however, many studies have reported the presence of prominent delta activity during conscious states, which casts doubt on the hypothesis that high amplitude delta oscillations are an indicator of unconsciousness. These studies include work in Angelman syndrome, epilepsy, behavioural responsiveness during propofol anaesthesia, postoperative delirium, and states of dissociation from the environment such as dreaming and powerful psychedelic states. The foregoing studies complement an older, yet largely unacknowledged, body of literature that has documented awake, conscious patients with high amplitude delta oscillations in clinical reports from Rett syndrome, Lennox-Gastaut syndrome, schizophrenia, mitochondrial diseases, hepatic encephalopathy, and non-convulsive status epilepticus. At the same time, a largely parallel body of recent work has reported convincing evidence that the complexity or entropy of EEG and magnetoencephalographic signals strongly relates to an individual’s level of consciousness. Having reviewed this literature, we discuss plausible mechanisms that would resolve the seeming contradiction between high amplitude delta oscillations and consciousness. We also consider implications concerning theories of consciousness, such as integrated information theory and the entropic brain hypothesis. Finally, we conclude that false inferences of unconscious states can be best avoided by examining measures of electrophysiological complexity in addition to spectral power.

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The neuroimaging evidence of brain abnormalities in functional movement disorders

Sanskriti Sasikumar, Antonio P Strafella

doi : 10.1093/brain/awab131

Brain, Volume 144, Issue 8, August 2021, Pages 2278–2283

Neuroimaging has been pivotal in identifying and reframing our understanding of functional movement disorders. If accessible, it compensates for the limitations of the clinical exam and is especially useful where there is overlap of functional symptoms with classical presentations of disease. Imaging in functional movement disorders has increasingly identified structural and functional abnormalities that implicate hypoactivation of the cortical and subcortical motor pathways and increased modulation by the limbic system. Neurobiological theories suggest an impaired sense of agency, faulty top-down regulation of motor movement and abnormal emotional processing in these individuals. This framework challenges our traditional understanding of functional movement disorders as distinct from the deceptive term of ‘organic’ diseases and proposes that these conditions are not considered as mutually exclusive. This update summarizes the literature to date and explores the role of imaging in the diagnosis of functional movement disorders and in detecting its underlying molecular network.

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Discriminatory ability of next-generation tau PET tracers for Alzheimer’s disease

Steven Y Yap, Barbara Frias, Melissa C Wren, Michael Sch?ll, Nick C Fox, Erik ?rstad, Tammaryn Lashley, Kerstin Sander

doi : 10.1093/brain/awab120

Brain, Volume 144, Issue 8, August 2021, Pages 2284–2290

A next generation of tau PET tracers for the imaging of Alzheimer’s disease and other dementias has recently been developed. Whilst the new compounds have now entered clinical studies, there is limited information available to assess their suitability for clinical applications. Head-to-head comparisons are urgently needed to understand differences in the radiotracer binding profiles. We characterized the binding of the tau tracers PI2620, RO948, MK6240 and JNJ067 in human post-mortem brain tissue from a cohort of 25 dementia cases and age-matched controls using quantitative phosphorimaging with tritium-labelled radiotracers in conjunction with phospho-tau specific immunohistochemistry. The four radiotracers depicted tau inclusions composed of paired helical filaments with high specificity, both in cases with Alzheimer’s disease and in primary tauopathy cases with concomitant Alzheimer’s disease pathology. In contrast, cortical binding to primary tauopathy in cases without paired helical filament tau was found to be within the range of age-matched controls. Off-target binding to monoamine oxidase B has been overcome, as demonstrated by heterologous blocking studies in basal ganglia tissue. The high variability of cortical tracer binding within the Alzheimer’s disease group followed the same pattern with each tracer, suggesting that all compounds are suited to differentiate Alzheimer’s disease from other dementias.

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BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis

Mark A Petersen, Reshmi Tognatta, Anke Meyer-Franke, Eric A Bushong, Andrew S Mendiola, Zhaoqi Yan, Abinaya Muthusamy, Mario Merlini, Rosa Meza-Acevedo, Belinda Cabriga, Yungui Zhou, Reuben Thomas, Jae Kyu Ryu, Hans Lassmann, Mark H Ellisman, Katerina Akassoglou

doi : 10.1093/brain/awab106

Brain, Volume 144, Issue 8, August 2021, Pages 2291–2301

Extrinsic inhibitors at sites of blood–brain barrier disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome the extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodelling at sites of neurovascular dysfunction are largely unknown. By integrating in vivo two-photon imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found that oligodendrocyte precursor cells clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing a screen (OPC-X-screen) to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue the extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein type I receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate, with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive oligodendrocyte precursor cell differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the bone morphogenetic protein signalling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.

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Tau mis-splicing correlates with motor impairments and striatal dysfunction in a model of tauopathy

Ana Damianich, Carolina Lucia Facal, Javier Andrés Mu?iz, Camilo Mininni, Mariano Soiza-Reilly, Magdalena Ponce De Le?n, Leandro Urrutia, German Falasco, Juan Esteban Ferrario, Mar?a Elena Avale

doi : 10.1093/brain/awab130

Brain, Volume 144, Issue 8, August 2021, Pages 2302–2309

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein tau (MAPT), which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in MAPT pre-mRNA produces equal amounts of protein isoforms with either three (3R) or four (4R) microtubule binding domains. Imbalance in the 3R:4R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which harbour abnormal 3R:4R tau isoforms content, and in contrast to TauKO mice, are unresponsive to L-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses indicated the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results suggest that abnormal striatal tau isoform content might lead to parkinsonian-like phenotypes and demonstrate a proof of concept that modulation of tau mis-splicing is a plausible disease-modifying therapy for some primary tauopathies.

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Motor and cognitive outcomes of cerebello-spinal stimulation in neurodegenerative ataxia

Alberto Benussi, Valentina Cantoni, Marta Manes, Ilenia Libri, Valentina Dell’Era, Abhishek Datta, Chris Thomas, Camilla Ferrari, Alessio Di Fonzo, Roberto Fancellu, Mario Grassi, Alfredo Brusco, Antonella Alberici, Barbara Borroni

doi : 10.1093/brain/awab157

Brain, Volume 144, Issue 8, August 2021, Pages 2310–2321

Cerebellar ataxias represent a heterogeneous group of disabling disorders characterized by motor and cognitive disturbances, for which no effective treatment is currently available. In this randomized, double-blind, sham-controlled trial, followed by an open-label phase, we investigated whether treatment with cerebello-spinal transcranial direct current stimulation (tDCS) could improve both motor and cognitive symptoms in patients with neurodegenerative ataxia at short and long-term. Sixty-one patients were randomized in two groups for the first controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS) while Group 2 received anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5?days/week for 2 weeks (T1), with a 12-week (T2) follow-up (randomized, double-blind, sham controlled phase). At the 12-week follow-up (T2), all patients (Group 1 and Group 2) received a second treatment of anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5?days/week for 2 weeks, with a 14-week (T3), 24-week (T4), 36-week (T5) and 52-week follow-up (T6) (open-label phase). At each time point, a clinical, neuropsychological and neurophysiological evaluation was performed. Cerebellar-motor cortex connectivity was evaluated using transcranial magnetic stimulation. We observed a significant improvement in all motor scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale), in cognition (evaluated with the cerebellar cognitive affective syndrome scale), in quality-of-life scores, in motor cortex excitability and in cerebellar inhibition after real tDCS compared to sham stimulation and compared to baseline (T0), both at short and long-term. We observed an addon-effect after two repeated treatments with real tDCS compared to a single treatment with real tDCS. The improvement at motor and cognitive scores correlated with the restoration of cerebellar inhibition evaluated with transcranial magnetic stimulation. Cerebello-spinal tDCS represents a promising therapeutic approach for both motor and cognitive symptoms in patients with neurodegenerative ataxia, a still orphan disorder of any pharmacological intervention.

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Opening of ATP sensitive potassium channels causes migraine attacks with aura

Mohammad Al-Mahdi Al-Karagholi, Hashmat Ghanizada, Cherie Amalie Waldorff Nielsen, Anders Hougaard, Messoud Ashina

doi : 10.1093/brain/awab136

Brain, Volume 144, Issue 8, August 2021, Pages 2322–2332

Migraine afflicts more than one billion individuals worldwide and is a leading cause of years lived with disability. In about a third of individuals with migraine aura occur in relation to migraine headache. The common pathophysiological mechanisms underlying migraine headache and migraine aura are yet to be identified. Based on recent data, we hypothesized that levcromakalim, an ATP-sensitive potassium channel opener, would trigger migraine attacks with aura in patients. In a randomized, double-blind, placebo-controlled, crossover study, 17 patients aged 21–59?years and diagnosed with migraine with aura exclusively were randomly allocated to receive an infusion of 0.05?mg/min levcromakalim or placebo (isotonic saline) on two different days (ClinicalTrials.gov, ID: NCT04012047). The primary end points were the difference in incidence of migraine attacks with or without aura, headache and the difference in the area under the curve for headache intensity scores (0–12?h). Seventeen patients completed the study. Fourteen of 17 (82%) patients developed migraine attacks with and without aura after levcromakalim compared with 1 of 17 (6%) after placebo (P?<?0.001). Ten patients (59%) developed migraine with aura after levcromakalim compared with none after placebo (P?=?0.002). One additional patient reported ‘possible’ aura, only partially fulfilling the criteria. Levcromakalim is likely a novel migraine aura-inducing substance in humans. These findings highlight the ATP-sensitive potassium channel as a shared target in migraine aura and migraine headache. Likely, ATP-sensitive potassium channel opening leads to triggering of aura and headache, respectively, via distinct mechanisms.

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Human tauopathy-derived tau strains determine the substrates recruited for templated amplification

Airi Tarutani, Haruka Miyata, Takashi Nonaka, Kazuko Hasegawa, Mari Yoshida, Yuko Saito, Shigeo Murayama, Andrew C Robinson, David M A Mann, Taisuke Tomita, Masato Hasegawa

doi : 10.1093/brain/awab091

Brain, Volume 144, Issue 8, August 2021, Pages 2333–2348

Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer’s disease, three-repeat tau in Pick’s disease (PiD) and four-repeat tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryogenic electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and Alzheimer’s disease (AD)-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrate. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.

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Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Jordi Duran, Arnau Hervera, Kia H Markussen, Olga Varea, Iliana L?pez-Soldado, Ramon C Sun, Jose Antonio del R?o, Matthew S Gentry, Joan J Guinovart

doi : 10.1093/brain/awab110

Brain, Volume 144, Issue 8, August 2021, Pages 2349–2360

The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes—thus impeding Lafora bodies accumulation in this cell type—prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

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MOG autoantibodies trigger a tightly-controlled FcR and BTK-driven microglia proliferative response

Kathryn Pellerin, Stephen J Rubino, Jeremy C Burns, Benjamin A Smith, Christie-Ann McCarl, Jing Zhu, Luke Jandreski, Patrick Cullen, Thomas M Carlile, Angela Li, Jorge Vera Rebollar, Jennifer Sybulski, Taylor L Reynolds, Baohong Zhang, Rebecca Basile, Hao Tang, Chelsea Parker Harp, Alex Pellerin, John Silbereis, Nathalie Franchimont, Ellen Cahir-McFarland, Richard M Ransohoff, Thomas O Cameron, Michael Mingueneau

doi : 10.1093/brain/awab231

Brain, Volume 144, Issue 8, August 2021, Pages 2361–2374

Autoantibodies are a hallmark of numerous neurological disorders, including multiple sclerosis, autoimmune encephalitides and neuromyelitis optica. Whilst well understood in peripheral myeloid cells, the pathophysiological significance of autoantibody-induced Fc receptor signalling in microglia remains unknown, in part due to the lack of a robust in vivo model. Moreover, the application of therapeutic antibodies for neurodegenerative disease also highlights the importance of understanding Fc receptor signalling in microglia.

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Features of MOG required for recognition by patients with MOG antibody-associated disorders

Caterina Macrini, Ramona Gerhards, Stephan Winklmeier, Lena Bergmann, Simone Mader, Melania Spadaro, Atay Vural, Michaela Smolle, Reinhard Hohlfeld, Tania Kümpfel, Stefan F Lichtenthaler, Henri G Franquelim, Dieter Jenne, Edgar Meinl

doi : 10.1093/brain/awab105

Brain, Volume 144, Issue 8, August 2021, Pages 2375–2389

Antibodies to myelin oligodendrocyte glycoprotein (MOG-Abs) define a distinct disease entity. Here we aimed to understand essential structural features of MOG required for recognition by autoantibodies from patients. We produced the N-terminal part of MOG in a conformationally correct form; this domain was insufficient to identify patients with MOG-Abs by ELISA even after site-directed binding. This was neither due to a lack of lipid embedding nor to a missing putative epitope at the C-terminus, which we confirmed to be an intracellular domain. When MOG was displayed on transfected cells, patients with MOG-Abs recognized full-length MOG much better than its N-terminal part with the first hydrophobic domain (P?<?0.0001). Even antibodies affinity-purified with the extracellular part of MOG recognized full-length MOG better than the extracellular part of MOG after transfection. The second hydrophobic domain of MOG enhanced the recognition of the extracellular part of MOG by antibodies from patients as seen with truncated variants of MOG. We confirmed the pivotal role of the second hydrophobic domain by fusing the intracellular part of MOG from the evolutionary distant opossum to the human extracellular part; the chimeric construct restored the antibody binding completely. Further, we found that in contrast to 8-18C5, MOG-Abs from patients bound preferentially as F(ab?)2 rather than Fab. It was previously found that bivalent binding of human IgG1, the prominent isotype of MOG-Abs, requires that its target antigen is displayed at a distance of 13–16?nm. We found that, upon transfection, molecules of MOG did not interact so closely to induce a F?rster resonance energy transfer signal, indicating that they are more than 6?nm apart. We propose that the intracellular part of MOG holds the monomers apart at a suitable distance for bivalent binding; this could explain why a cell-based assay is needed to identify MOG-Abs. Our finding that MOG-Abs from most patients require bivalent binding has implications for understanding the pathogenesis of MOG-Ab associated disorders. Since bivalently bound antibodies have been reported to only poorly bind C1q, we speculate that the pathogenicity of MOG-Abs is mostly mediated by other mechanisms than complement activation. Therefore, therapeutic inhibition of complement activation should be less efficient in MOG-Ab associated disorders than in patients with antibodies to aquaporin-4 .

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Hospital-diagnosed infections before age 20 and risk of a subsequent multiple sclerosis diagnosis

Yin Xu, Kelsi A Smith, Ayako Hiyoshi, Fredrik Piehl, Tomas Olsson, Scott Montgomery

doi : 10.1093/brain/awab100

Brain, Volume 144, Issue 8, August 2021, Pages 2390–2400

The involvement of specific viral and bacterial infections as risk factors for multiple sclerosis has been studied extensively. However, whether this extends to infections in a broader sense is less clear and little is known about whether risk of a multiple sclerosis diagnosis is associated with other types and sites of infections such as the CNS. This study aims to assess if hospital-diagnosed infections by type and site before age 20?years are associated with risk of a subsequent multiple sclerosis diagnosis and whether this association is explained entirely by infectious mononucleosis, pneumonia, and CNS infections. Individuals born in Sweden between 1970 and 1994 were identified using the Swedish Total Population Register (n?=?2?422?969). Multiple sclerosis diagnoses from age 20?years and hospital-diagnosed infections before age 20?years were identified using the Swedish National Patient Register. Risk of a multiple sclerosis diagnosis associated with various infections in adolescence (11–19?years) and earlier childhood (birth–10?years) was estimated using Cox regression, with adjustment for sex, parental socio-economic position, and infection type. None of the infections by age 10?years were associated with risk of a multiple sclerosis diagnosis. Any infection in adolescence increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.33, 95% confidence interval 1.21–1.46) and remained statistically significant after exclusion of infectious mononucleosis, pneumonia, and CNS infection (hazard ratio 1.17, 95% confidence interval 1.06–1.30). CNS infection in adolescence (excluding encephalomyelitis to avoid including acute disseminated encephalitis) increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.85, 95% confidence interval 1.11–3.07). The increased risk of a multiple sclerosis diagnosis associated with viral infection in adolescence was largely explained by infectious mononucleosis. Bacterial infections in adolescence increased risk of a multiple sclerosis diagnosis, but the magnitude of risk reduced after excluding infectious mononucleosis, pneumonia and CNS infection (hazard ratio 1.31, 95% confidence interval 1.13–1.51). Respiratory infection in adolescence also increased risk of a multiple sclerosis diagnosis (hazard ratio 1.51, 95% confidence interval 1.30–1.75), but was not statistically significant after excluding infectious mononucleosis and pneumonia. These findings suggest that a variety of serious infections in adolescence, including novel evidence for CNS infections, are risk factors for a subsequent multiple sclerosis diagnosis, further demonstrating adolescence is a critical period of susceptibility to environmental exposures that raise the risk of a multiple sclerosis diagnosis. Importantly, this increased risk cannot be entirely explained by infectious mononucleosis, pneumonia, or CNS infections.

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Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders

Yoshiki Takai, Tatsuro Misu, Hiroyoshi Suzuki, Toshiyuki Takahashi, Hiromi Okada, Shinya Tanaka, Kenji Okita, Shunichi Sasou, Mika Watanabe, Chihiro Namatame, Yuki Matsumoto, Hirohiko Ono, Kimihiko Kaneko, Shuhei Nishiyama, Hiroshi Kuroda, Ichiro Nakashima, Hans Lassmann, Kazuo Fujihara, Yasuto Itoyama, Masashi Aoki

doi : 10.1093/brain/awab102

Brain, Volume 144, Issue 8, August 2021, Pages 2401–2415

Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. Cases comprised six females and two males, with a median age of 56.5?years (range, 46–71?years) and a median disease duration of 62.5?months (range, 0.6–252?months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for GFAP: (i) astrocyte lysis: extensive loss of astrocytes with fragmented and/or dust-like particles; (ii) progenitor recruitment: loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (iii) protoplasmic gliosis: presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (iv) fibrous gliosis: lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2?months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD.

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Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Caty Carrera, Jara C?rcel-M?rquez, Natalia Cullell, Nuria Torres-?guila, Elena Mui?o, José Castillo, Tom?s Sobrino, Francisco Campos, Emilio Rodr?guez-Castro, Laia Llucià-Carol, M?nica Mill?n, Luc?a Mu?oz-Narbona, Elena L?pez-Cancio, Alejandro Bustamante, Marc Rib?, José ?lvarez-Sab?n, Jordi Jiménez-Conde, Jaume Roquer, Eva Giralt-Steinhauer, Carolina Soriano-T?rraga, Marina Mola-Caminal, Crist?fol Vives-Bauza, Rosa D?az Navarro, Silvia Tur, Victor Obach, Juan Francisco Arenillas, Tom?s Segura, Gemma Serrano-Heras, Joan Mart?-Fàbregas, Raquel Delgado-Mederos, M Mar Freijo-Guerrero, Francisco Moniche, Juan Antonio Cabezas, Mar Castellanos, Cristina Gallego-Fabrega, Jonathan Gonz?lez-Sanchez, Jurek Krupinsky, Daniel Strbian, Turgut Tatlisumak, Vincent Thijs, Robin Lemmens, Agnieszka Slowik, Johanna Pera, Steven Kittner, John Cole, Laura Heitsch, Laura Iba?ez, Carlos Cruchaga, Jin-Moo Lee, Joan Montaner, Israel Fern?ndez-Cadenas on behalf of the International Stroke Genetic Consortium and the Spanish Stroke Genetic Consortium

doi : 10.1093/brain/awab090

Brain, Volume 144, Issue 8, August 2021, Pages 2416–2426

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n?=?1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10?5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P?<?5 × 10?8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7?989?272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P?=?2.49 × 10?8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82–26.55]. In the replication cohort (n?=?580), the rs76484331 polymorphism was associated with parenchymal haematoma (P?=?0.01), and the overall association after meta-analysis increased (P?=?1.61 × 10?8; OR: 5.84; 95% CI: 3.16–10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.

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INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH

Denisa Hathazi, Dan Cox, Adele D'Amico, Giorgio Tasca, Richard Charlton, Robert-Yves Carlier, Jennifer Baumann, Laxmikanth Kollipara, René P Zahedi, Ingo Feldmann, Jean-Francois Deleuze, Annalaura Torella, Ronald Cohn, Emily Robinson, Francesco Ricci, Heinz Jungbluth, Fabiana Fattori, Anne Boland, Emily O’Connor, Rita Horvath, Rita Barresi, Hanns Lochmüller, Andoni Urtizberea, Marie-Line Jacquemont, Isabelle Nelson, Laura Swan, Gisèle Bonne, Andreas Roos

doi : 10.1093/brain/awab133

Brain, Volume 144, Issue 8, August 2021, Pages 2427–2442

Marinesco-Sj?gren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sj?gren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sj?gren syndrome and INPP5K patients and identified alterations in D-3-PHGDH as a common molecular feature. D-3-PHGDH modulates the production of L-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sj?gren syndrome and INPP5K disease. As L-serine administration represents a promising therapeutic strategy for D-3-PHGDH patients, we tested the effect of L-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

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Aromatic L-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies

Giada Rossignoli, Karolin Kr?mer, Eleonora Lugarà, Haya Alrashidi, Simon Pope, Carmen De La Fuente Barrigon, Katy Barwick, Giovanni Bisello, Joanne Ng, John Counsell, Gabriele Lignani, Simon J R Heales, Mariarita Bertoldi, Serena Barral, Manju A Kurian

doi : 10.1093/brain/awab123

Brain, Volume 144, Issue 8, August 2021, Pages 2443–2456

Aromatic L-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by L-3,4-dihydroxyphenylalanine (L-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where L-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches.

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Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy

Hai-Lin Dong, Yin Ma, Hao Yu, Qiao Wei, Jia-Qi Li, Gong-Lu Liu, Hong-Fu Li, Lei Chen, Dian-Fu Chen, Ge Bai, Zhi-Ying Wu

doi : 10.1093/brain/awab135

Brain, Volume 144, Issue 8, August 2021, Pages 2457–2470

Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified. Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene. We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A>G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient’s fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients’ fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV. Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.

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Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Jonas Van Lent, Peter Verstraelen, Bob Asselbergh, Elias Adriaenssens, Ligia Mateiu, Christophe Verbist, Vicky De Winter, Kristel Eggermont, Ludo Van Den Bosch, Winnok H De Vos, Vincent Timmerman

doi : 10.1093/brain/awab226

Brain, Volume 144, Issue 8, August 2021, Pages 2471–2485

Axonal Charcot-Marie-Tooth neuropathies (CMT type 2) are caused by inherited mutations in various genes functioning in different pathways. The types of genes and multiplicity of mutations reflect the clinical and genetic heterogeneity in CMT2 disease, which complicates its diagnosis and has inhibited the development of therapies. Here, we used CMT2 patient-derived pluripotent stem cells (iPSCs) to identify common hallmarks of axonal degeneration shared by different CMT2 subtypes. We compared the cellular phenotypes of neurons differentiated from CMT2 patient iPSCs with those from healthy controls and a CRISPR/Cas9-corrected isogenic line. Our results demonstrated neurite network alterations along with extracellular electrophysiological abnormalities in the differentiated motor neurons. Progressive deficits in mitochondrial and lysosomal trafficking, as well as in mitochondrial morphology, were observed in all CMT2 patient lines. Differentiation of the same CMT2 iPSC lines into peripheral sensory neurons only gave rise to cellular phenotypes in subtypes with sensory involvement, supporting the notion that some gene mutations predominantly affect motor neurons. We revealed a common mitochondrial dysfunction in CMT2-derived motor neurons, supported by alterations in the expression pattern and oxidative phosphorylation, which could be recapitulated in the sciatic nerve tissue of a symptomatic mouse model. Inhibition of a dual leucine zipper kinase could partially ameliorate the mitochondrial disease phenotypes in CMT2 subtypes. Altogether, our data reveal shared cellular phenotypes across different CMT2 subtypes and suggests that targeting such common pathomechanisms could allow the development of a uniform treatment for CMT2.

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Atypical neural topographies underpin dysfunctional pattern separation in temporal lobe epilepsy

Qiongling Li, Shahin Tavakol, Jessica Royer, Sara Larivière, Reinder Vos De Wael, Bo-yong Park, Casey Paquola, Debin Zeng, Benoitu Caldairou, Danielle S Bassett, Andrea Bernasconi, Neda Bernasconi, Birgit Frauscher, Jonathan Smallwood, Lorenzo Caciagli, Shuyu Li, Boris C Bernhardt

doi : 10.1093/brain/awab121

Brain, Volume 144, Issue 8, August 2021, Pages 2486–2498

Episodic memory is the ability to remember events from our past accurately. The process of pattern separation is hypothesized to underpin this ability and is defined as the capacity to orthogonalize memory traces, to maximize the features that make them unique. Contemporary cognitive neuroscience suggests that pattern separation entails complex interactions between the hippocampus and neocortex, where specific hippocampal subregions shape neural reinstatement in the neocortex. To test this hypothesis, the current work studied both healthy controls and patients with temporal lobe epilepsy who presented with hippocampal structural anomalies. We measured neural activity in all participants using functional MRI while they retrieved memorized items or lure items, which shared features with the target. Behaviourally, patients with temporal lobe epilepsy were less able to exclude lures than controls and showed a reduction in pattern separation. To assess the hypothesized relationship between neural patterns in the hippocampus and neocortex, we identified the topographic gradients of intrinsic connectivity along neocortical and hippocampal subfield surfaces and determined the topographic profile of the neural activity accompanying pattern separation. In healthy controls, pattern separation followed a graded topography of neural activity, both along the hippocampal long axis (and peaked in anterior segments that are more heavily engaged in transmodal processing) and along the neocortical hierarchy running from unimodal to transmodal regions (peaking in transmodal default mode regions). In patients with temporal lobe epilepsy, however, this concordance between task-based functional activations and topographic gradients was markedly reduced. Furthermore, person-specific measures of concordance between task-related activity and connectivity gradients in patients and controls were related to inter-individual differences in behavioural measures of pattern separation and episodic memory, highlighting the functional relevance of the observed topographic motifs. Our work is consistent with an emerging understanding that successful discrimination between memories with similar features entails a shift in the locus of neural activity away from sensory systems, a pattern that is mirrored along the hippocampal long axis and with respect to neocortical hierarchies. More broadly, our study establishes topographic profiling using intrinsic connectivity gradients, capturing the functional underpinnings of episodic memory processes in a manner that is sensitive to their reorganization in pathology.

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Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons

Felicia Mermer, Sarah Poliquin, Kathryn Rigsby, Anuj Rastogi, Wangzhen Shen, Alejandra Romero-Morales, Gerald Nwosu, Patrick McGrath, Scott Demerast, Jason Aoto, Ganna Bilousova, Dennis Lal, Vivian Gama, Jing-Qiong Kang

doi : 10.1093/brain/awab207

Brain, Volume 144, Issue 8, August 2021, Pages 2499–2512

Solute carrier family 6 member 1 (SLC6A1) is abundantly expressed in the developing brain even before the CNS is formed. Its encoded GABA transporter 1 (GAT-1) is responsible for the reuptake of GABA into presynaptic neurons and glia, thereby modulating neurotransmission. GAT-1 is expressed globally in the brain, in both astrocytes and neurons. The GABA uptake function of GAT-1 in neurons cannot be compensated for by other GABA transporters, while the function in glia can be partially replaced by GABA transporter 3. Recently, many variants in SLC6A1 have been associated with a spectrum of epilepsy syndromes and neurodevelopmental disorders, including myoclonic atonic epilepsy, childhood absence epilepsy, autism, and intellectual disability, but the pathomechanisms associated with these phenotypes remain unclear. The presence of GAT-1 in both neurons and astrocytes further obscures the role of abnormal GAT-1 in the heterogeneous disease phenotype manifestations. Here we examine the impact on transporter trafficking and function of 22 SLC6A1 variants identified in patients with a broad spectrum of phenotypes. We also evaluate changes in protein expression and subcellular localization of the variant GAT-1 in various cell types, including neurons and astrocytes derived from human patient induced pluripotent stem cells. We found that a partial or complete loss-of-function represents a common disease mechanism, although the extent of GABA uptake reduction is variable. The reduced GABA uptake appears to be due to reduced cell surface expression of the variant transporter caused by variant protein misfolding, endoplasmic reticulum retention, and subsequent degradation. Although the extent of reduction of the total protein, surface protein, and the GABA uptake level of the variant transporters is variable, the loss of GABA uptake function and endoplasmic reticulum retention is consistent across induced pluripotent stem cell-derived cell types, including astrocytes and neurons, for the surveyed variants. Interestingly, we did not find a clear correlation of GABA uptake function and the disease phenotypes, such as myoclonic atonic epilepsy versus developmental delay, in this study. Together, our study suggests that impaired transporter protein trafficking and surface expression are the major disease-associated mechanisms associated with pathogenic SLC6A1 variants. Our results resemble findings from pathogenic variants in other genes affecting the GABA pathway, such as GABAA receptors. This study provides critical insight into therapeutic developments for SLC6A1 variant-mediated disorders and implicates that boosting transporter function by either genetic or pharmacological approaches would be beneficial.

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Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson’s disease

Claire O’Callaghan, Frank H Hezemans, Rong Ye, Catarina Rua, P Simon Jones, Alexander G Murley, Negin Holland, Ralf Regenthal, Kamen A Tsvetanov, Noham Wolpe, Roger A Barker, Caroline H Williams-Gray, Trevor W Robbins, Luca Passamonti, James B Rowe

doi : 10.1093/brain/awab142

Brain, Volume 144, Issue 8, August 2021, Pages 2513–2526

Cognitive decline is a common feature of Parkinson’s disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson’s disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomized crossover design, 19 patients with Parkinson’s disease completed an acute psychopharmacological challenge with 40?mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7?T imaging of the locus coeruleus using a neuromelanin-sensitive magnetization transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in patients with Parkinson’s disease. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalized treatment approaches.

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Neuronal SETD2 activity links microtubule methylation to an anxiety-like phenotype in mice

Matthias Koenning, Xianlong Wang, Menuka Karki, Rahul Kumar Jangid, Sarah Kearns, Durga Nand Tripathi, Michael Cianfrocco, Kristen J Verhey, Sung Yun Jung, Cristian Coarfa, Christopher Scott Ward, Brian Thomas Kalish, Sandra L Grimm, W Kimryn Rathmell, Ricardo Mostany, Ruhee Dere, Matthew Neil Rasband, Cheryl Lyn Walker, In Young Park

doi : 10.1093/brain/awab200

Brain, Volume 144, Issue 8, August 2021, Pages 2527–2540

Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the ‘readers, writers and erasers’ of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 ?-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of ?-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype.

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Functional maps of direct electrical stimulation-induced speech arrest and anomia: a multicentre retrospective study

Junfeng Lu, Zehao Zhao, Jie Zhang, Bin Wu, Yanming Zhu, Edward F Chang, Jinsong Wu, Hugues Duffau, Mitchel S Berger

doi : 10.1093/brain/awab125

Brain, Volume 144, Issue 8, August 2021, Pages 2541–2553

Direct electrical stimulation, the transient ‘lesional’ method probing brain function, has been utilized in identifying the language cortex and preserving language function during epilepsy and neuro-oncological surgeries for about a century. However, comparison of functional maps of the language cortex across languages/continents based on cortical stimulation remains unclear. We conducted a retrospective multicentre study including four cohorts of direct electrical stimulation mapping from four centres across three continents, where three indigenous languages (English, French and Mandarin) are spoken. All subjects performed the two most common language tasks: number counting and picture naming during stimulation. All language sites were recorded and normalized to the same brain template. Next, Spearman’s correlation analysis was performed to explore the consistency of the distributions of the language cortex across centres, a kernel density estimation to localize the peak coordinates, and a hierarchical cluster analysis was performed to detect the crucial epicenters. A total of 598 subjects with 917 speech arrest sites (complete interruption of ongoing counting) and 423 anomia sites (inability to name or misnaming) were included. Different centres presented highly consistent distribution patterns for speech arrest (Spearman’s coefficient r ranged from 0.60 to 0.85, all pair-wise correlations P?<?0.05), and similar patterns for anomia (Spearman’s coefficient r ranged from 0.37 to 0.80). The combinational speech arrest map was divided into four clusters: cluster 1 mainly located in the ventral precentral gyrus and pars opercularis, which contained the peak of speech arrest in the ventral precentral gyrus; cluster 2 in the ventral and dorsal precentral gyrus; cluster 3 in the supplementary motor area; cluster 4 in the posterior superior temporal gyrus and supramarginal gyrus. The anomia map revealed two clusters: one was in the posterior part of the superior and middle temporal gyri, which peaked at the posterior superior temporal gyrus; and the other within the inferior frontal gyrus, peaked at the pars triangularis. This study constitutes the largest series to date of language maps generated from direct electrical stimulation mapping. The consistency of data provides evidence for common language networks across languages, in the context of both speech and naming circuit. Our results not only clinically offer an atlas for language mapping and protection, but also scientifically provide better insight into the functional organization of language networks.

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From early limbic inflammation to long COVID sequelae

Eric Guedj, Silvia Morbelli, Elsa Kaphan, Jacques-Yves Campion, Pierre Dudouet, Mathieu Ceccaldi, Serge Cammilleri, Flavio Nobili, Carole Eldin

doi : 10.1093/brain/awab215

Brain, Volume 144, Issue 8, August 2021, Page e65

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Reply: From early limbic inflammation to long COVID sequelae

Philipp T Meyer, Ganna Blazhenets, Marco Prinz, Jonas A Hosp

doi : 10.1093/brain/awab216

Brain, Volume 144, Issue 8, August 2021, Page e66

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Erratum to: Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment

Takeshi Mizuguchi, Tomoko Toyota, Satoko Miyatake, Satomi Mitsuhashi, Hiroshi Doi, Yosuke Kudo, Hitaru Kishida, Noriko Hayashi, Rie S Tsuburaya, Masako Kinoshita, Tetsuhiro Fukuyama, Hiromi Fukuda, Eriko Koshimizu, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Atsushi Takata, Noriko Miyake, Mitsuhiro Kato, Fumiaki Tanaka, Hiroaki Adachi, Naomichi Matsumoto

doi : 10.1093/brain/awab183

Brain, Volume 144, Issue 8, August 2021, Page e67

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Erratum to: Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia

Joachim Mazere, Bixente Dilharreguy, Gwenaëlle Catheline, Marie Vidailhet, Marc Deffains, Delphine Vimont, Bastien Ribot, Elodie Barse, Laura Cif, Bernard Mazoyer, Nicolas Langbour, Antonio Pisani, Michèle Allard, Frédéric Lamare, Dominique Guehl, Philippe Fernandez, Pierre Burbaud

doi : 10.1093/brain/awab172

Brain, Volume 144, Issue 8, August 2021, Page e68

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Erratum to: How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

Nadia Dehghani, Jose Bras, Rita Guerreiro

doi : 10.1093/brain/awab180

Brain, Volume 144, Issue 8, August 2021, Page e69

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Erratum to: Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S Müller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M Santorelli, Ahmed A Alfares, Changlian Zhu, Anna Uhrova Meszarosova, Elham Alehabib, Somayeh Bakhtiari, Andreas R Janecke, Maria Gabriela Otero, Jin Yun Helen Chen, James T Peterson, Tim M Strom, Peter De Jonghe, Tine Deconinck, Willem De Ridder, Jonathan De Winter, Rossella Pasquariello, Ivana Ricca, Majid Alfadhel, Bart P van de Warrenburg, Ruben Portier, Carsten Bergmann, Saghar Ghasemi Firouzabadi, Sheng Chih Jin, Kaya Bilguvar, Sherifa Hamed, Mohammed Abdelhameed, Nourelhoda A Haridy, Shazia Maqbool, Fatima Rahman, Najwa Anwar, Jenny Carmichael, Alistair T Pagnamenta, Nick W Wood, Frederic Tran Mau-Them, Tobias Haack, Genomics England Research Consortium, PREPARE network, Maja Di Rocco, Isabella Ceccherini, Michele Iacomino, Federico Zara, Vincenzo Salpietro, Marcello Scala, Marta Rusmini, Yiran Xu, Yinghong Wang, Yasuhiro Suzuki, Kishin Koh, Haitian Nan, Hiroyuki Ishiura, Shoji Tsuji, Laëtitia Lambert, Emmanuelle Schmitt, Elodie Lacaze, Hanna Küpper, David Dredge, Cara Skraban, Amy Goldstein, Mary J H Willis, Katheryn Grand, John M Graham, Jr, Richard A Lewis, Francisca Millan, ?zgür Duman, Nihal Olgac Dundar, G?khan Uyanik, Ludger Sch?ls, Peter Nürnberg, Gudrun Nürnberg, Andrea Català-Bordes, Pavel Seeman, Martin Kuchar, Hossein Darvish, Adriana Rebelo, Filipa Bouçanova, Jean-Jacques Medard, Roman Chrast, Michaela Auer-Grumbach, Fowzan S Alkuraya, Hanan Shamseldin, Saeed Al Tala, Jamileh Rezazadeh Varaghchi, Maryam Najafi, Selina Deschner, Dieter Gl?ser, Wolfgang Hüttel, Michael C Kruer, Erik-Jan Kamsteeg, Yoshihisa Takiyama, Stephan Züchner, Jonathan Baets, Matthis Synofzik, Rebecca Schüle, Rita Horvath, Henry Houlden, Luca Bartesaghi, Hwei-Jen Lee, Konstantinos Ampatzis, Tyler Mark Pierson, Jan Senderek

doi : 10.1093/brain/awab193

Brain, Volume 144, Issue 8, August 2021, Page e70

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Corrigendum to: Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation

Takashi Tsuboi, Joshua K Wong, Robert S Eisinger, Lela Okromelidze, Mathew R Burns, Adolfo Ramirez-Zamora, Leonardo Almeida, Aparna Wagle Shukla, Kelly D Foote, Michael S Okun, Sanjeet S Grewal, Erik H Middlebrooks

doi : 10.1093/brain/awab192

Brain, Volume 144, Issue 8, August 2021, Page e71

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