Brain : a journal of neurology最新文献

{"title":"Black and white art: emotion, intellect and functional specialisation in the visual brain.","authors":"G. Schott","doi":"10.1093/brain/awac118","DOIUrl":"https://doi.org/10.1093/brain/awac118","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129555785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.","authors":"S. Miyatake, Kunihiro Yoshida, E. Koshimizu, H. Doi, M. Yamada, Y. Miyaji, N. Ueda, J. Tsuyuzaki, M. Kodaira, H. Onoue, M. Taguri, Shintaro Imamura, Hiromi Fukuda, K. Hamanaka, A. Fujita, Mai Satoh, Takabumi Miyama, Nobuko Watanabe, Yusuke Kurita, Masaki Okubo, Kenichi Tanaka, H. Kishida, S. Koyano, Tatsuya Takahashi, Yoya Ono, K. Higashida, N. Yoshikura, K. Ogata, Rumiko Kato, N. Tsuchida, Yuri Uchiyama, N. Miyake, T. Shimohata, F. Tanaka, T. Mizuguchi, N. Matsumoto","doi":"10.1093/brain/awab363","DOIUrl":"https://doi.org/10.1093/brain/awab363","url":null,"abstract":"Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123441148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wheelchair use in genetically-confirmed FSHD1 from a large cohort study in Chinese population.","authors":"L. Qiu, Longquan Chen, Fuze Zheng, M-T Lin, Yi Lin, Ying Fu, Ning Wang, Zhiqiang Wang","doi":"10.1093/brain/awac097","DOIUrl":"https://doi.org/10.1093/brain/awac097","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"315 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132797806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration.","authors":"Y. Riku, Y. Iwasaki, S. Ishigaki, A. Akagi, M. Hasegawa, K. Nishioka, Yuanzhe Li, Miho Riku, T. Ikeuchi, Y. Fujioka, Hiroaki Miyahara, J. Sone, N. Hattori, Mari Yoshida, M. Katsuno, G. Sobue","doi":"10.1093/brain/awac091","DOIUrl":"https://doi.org/10.1093/brain/awac091","url":null,"abstract":"Transactive response DNA-binding protein 43 kDa (TDP-43) is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in amyotrophic lateral sclerosis (ALS) cases. TDP-43 pathology has also been found in brain tissues under non-ALS conditions, suggesting mechanistic links between TDP-43-related ALS (ALS-TDP) and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (PSP, n = 26), corticobasal degeneration (CBD, n = 12), globular glial tauopathy (GGT, n = 5), Alzheimer's disease (AD, n = 21), or Pick disease (PiD, n = 6) and neurologically healthy controls (n = 36). Ten of the PSP cases (38%) and seven of the CBD cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43-aggregates were found to be skein-like, round-shaped, granular, or dot-like and contained insoluble C-terminal fragments showing blotting pattern of ALS or frontotemporal lobar degeneration (FTLD). The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in hematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and 4-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the AD, PiD, GGT, and control groups. Next, we assessed splicing factor proline/glutamine rich (SFPQ) expression in spinal cord motor neurons; SFPQ is a recently-identified regulator of ALS/FTLD pathogenesis, and it is also reported that interaction between SFPQ and fused-in-sarcoma (FUS) regulates splicing of microtubule-associated protein tau exon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of PSP, CBD, and ALS-TDP cases but not in AD, PiD, and GGT cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of PSP and CBD cases. Our results indicate that PSP and CBD may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with ALS-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"48 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121311653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Genotype-phenotype correlations in SCN8A-related epilepsy: a cohort study of Chinese children in southern China.","authors":"K. Johannesen, Yuanyuan Liu, E. Gardella, H. Lerche, Rikke S. Møller","doi":"10.1093/brain/awac039","DOIUrl":"https://doi.org/10.1093/brain/awac039","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123902192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression","authors":"S. Rahayel, C. Tremblay, A. Vo, Ying-Qiu Zheng, S. Lehéricy, I. Arnulf, M. Vidailhet, J. Corvol, J. Gagnon, R. Postuma, J. Montplaisir, S. Lewis, E. Matar, K. E. Ehgoetz Martens, P. Borghammer, K. Knudsen, A. Hansen, O. Monchi, B. Mišić, A. Dagher","doi":"10.1101/2021.12.27.21268442","DOIUrl":"https://doi.org/10.1101/2021.12.27.21268442","url":null,"abstract":"Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the atrophy simulated based on brain connectivity and gene expression recreated cortical thinning (r=0.51, p=0.0007) and tissue deformation (r=0.52, p=0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive functioning, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122142042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Broca: neural architecture and evolution of a dual motor speech coordination system.","authors":"G. Hickok, Jonathan H. Venezia, A. Teghipco","doi":"10.31234/osf.io/tewna","DOIUrl":"https://doi.org/10.31234/osf.io/tewna","url":null,"abstract":"Classical neural architecture models of speech production propose a single system centered on Broca's area coordinating all the vocal articulators from lips to larynx. Modern evidence has challenged both the idea that Broca's area is involved in motor speech coordination and that there is only one coordination network. Drawing on a wide range of evidence, here we propose a dual speech coordination model in which laryngeal control of pitch-related aspects of prosody and song are coordinated by a hierarchically organized dorsolateral system while supralaryngeal articulation at the phonetic/syllabic level is coordinated by a more ventral system posterior to Broca's area. We argue further that these two speech production subsystems have distinguishable evolutionary histories and discuss the implications for models of language evolution.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"39 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126976781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide contribution of common short-tandem repeats to Parkinson's disease genetic risk","authors":"B. Bustos, Kimberley J. Billingsley, C. Blauwendraat, J. Gibbs, Z. Gan-Or, D. Krainc, A. Singleton, S. Lubbe, Ruth Davee","doi":"10.1101/2021.07.01.21259645","DOIUrl":"https://doi.org/10.1101/2021.07.01.21259645","url":null,"abstract":"Parkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component, where most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (Indels). DNA repetitive elements account for >50% of the human genome, however little is known of their contribution to PD etiology. While select short tandem repeats (STRs) within candidate genes have been studied in PD, their genome-wide contribution remains unknown. Here we present the first genome-wide association study (GWAS) of STRs in PD. Through a meta-analysis of 16 imputed GWAS cohorts from the International Parkinson's Disease Genomic Consortium (IPDGC), totalling 39,087 individuals (16,642 PD cases and 22,445 controls of European ancestry) we identified 34 genome-wide significant STR loci (p < 5.34x10-6), with the strongest signal located in KANSL1 (chr17:44205351:[T]11, p=3x10-39, OR=1.31 [CI 95%=1.26-1.36]). Conditional-joint analyses suggested that 4 significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1 were independent from known PD risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTR) in RNASeq data from 13 brain regions, identified significant associations of STRs influencing the expression of multiple genes, including PD known genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here we show that STRs at known and novel candidate PD loci contribute to PD risk, and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting PD risk loci.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124929729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy","authors":"S. Manivannan, Jolien Roovers, N. Smal, C. Myers, D. Turkdoğan, F. Roelens, Oguz Kanca, Hyung-Lok Chung, Tasja Scholz, K. Hermann, T. Bierhals, S. Çağlayan, Hannah Stamberger, H. Mefford, P. de Jonghe, Shinya Yamamoto, S. Weckhuysen, H. Bellen","doi":"10.1101/2021.06.12.21256778","DOIUrl":"https://doi.org/10.1101/2021.06.12.21256778","url":null,"abstract":"FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment, both through the control of the cell cycle and through its multiple functions in post-mitotic neurons. In this study, the evaluation of 250 unrelated patients with developmental epileptic encephalopathies (DEE) and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Two variants led to the same amino acid change. All individuals had a DEE with childhood-onset generalized epilepsy, intellectual disability, mild ataxia, and normal head circumference. Two individuals were diagnosed with the DEE subtype Myoclonic Atonic Epilepsy (MAE). We provide gene burden testing using two independent statistical tests to support FZR1 association with DEE. Further, we provide functional evidence that the missense variants are loss-of-function (LOF) alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants do not support proper neurodevelopment. Along with a recent report of a patient with neonatal-onset DEE with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and DEE, and expands the associated phenotype. We conclude that heterozygous LOF of FZR1 leads to DEE associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay, and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed MAE/DEE cases.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129675120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On Task.","authors":"M. Husain","doi":"10.1093/brain/awab053","DOIUrl":"https://doi.org/10.1093/brain/awab053","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128396046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}