Corrigendum to: Quantitative spinal cord MRI in MOG-antibody disease, neuromyelitis optica and multiple sclerosis 

doi : 10.1093/brain/awaa446

Brain, Volume 144, Issue 4, April 2021, Page e41

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Corrigendum to: YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations 

doi : 10.1093/brain/awaa449

Brain, Volume 144, Issue 4, April 2021, Page e40

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Erratum to: Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons 

doi : 10.1093/brain/awaa452

Brain, Volume 144, Issue 4, April 2021, Page e42

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On the 400th anniversary of the birth of Thomas Willis 

Zolt?n Moln?r

doi : 10.1093/brain/awab016

Brain, Volume 144, Issue 4, April 2021, Pages 1033–1037

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On Task

Masud Husain

doi : 10.1093/brain/awab053

Brain, Volume 144, Issue 4, April 2021, Pages 1277–1278

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Is clinical assessment enough? Moving towards early differentiation of neurodegenerative parkinsonisms

Daniel G Di Luca, Anthony E Lang

doi : 10.1093/brain/awab115

Brain, Volume 144, Issue 4, April 2021, Pages 1040–1042

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Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making 

Youssuf Saleh, Campbell Le Heron, Pierre Petitet, Michele Veldsman, Daniel Drew, Olivia Plant, Ursula Schulz, Arjune Sen, Peter M Rothwell, Sanjay Manohar ... Show more

doi : 10.1093/brain/awab013

Brain, Volume 144, Issue 4, April 2021, Pages 1247–1262

Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.

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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/awab021

Brain, Volume 144, Issue 4, April 2021, Pages 1103–1117

A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype–phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype–phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.

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Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19 

Jonas A Hosp, Andrea Dressing, Ganna Blazhenets, Tobias Bormann, Alexander Rau, Marius Schwabenland, Johannes Thurow, Dirk Wagner, Cornelius Waller, Wolf D Niesen, Lars Frings, Horst Urbach, Marco Prinz, Cornelius Weiller, Nils Schroeter, Philipp T Meyer

doi : 10.1093/brain/awab009

Brain, Volume 144, Issue 4, April 2021, Pages 1263–1276

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ?2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

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Identification of multiple system atrophy mimicking Parkinson’s disease or progressive supranuclear palsy 

Yasuo Miki, Eiki Tsushima, Sandrine C Foti, Kate M Strand, Yasmine T Asi, Adam Kenji Yamamoto, Conceiç?o Bettencourt, Marcos C B Oliveira, Eduardo De Pablo-Fern?ndez, Zane Jaunmuktane, Andrew J Lees, Koichi Wakabayashi, Thomas T Warner, Niall Quinn, Janice L Holton, Helen Ling

doi : 10.1093/brain/awab017

Brain, Volume 144, Issue 4, April 2021, Pages 1138–1151

We studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson’s disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson’s disease (i.e. Parkinson’s disease mimics; n?=?16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n?=?17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson’s disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson’s disease, n?=?35; progressive supranuclear palsy-Richardson syndrome, n?=?35; and progressive supranuclear palsy-parkinsonism, n?=?35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson’s disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson’s disease mimic versus typical Parkinson’s disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson’s disease or progressive supranuclear palsy (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson’s disease or progressive supranuclear palsy.

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Functional cognitive disorder: dementia’s blind spot

Narinder Kapur, Steven Kemp, Gus Baker

doi : 10.1093/brain/awab008

Brain, Volume 144, Issue 4, April 2021, Page e37

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Reply: The etymology of ‘neurology’, redux: early use of the term by Jean Riolan the Younger (1610)

Arpan R Mehta, Puja R Mehta, Stephen P Anderson, Barbara L H MacKinnon, Alastair Compston

doi : 10.1093/brain/awab024

Brain, Volume 144, Issue 4, April 2021, Page e39

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The etymology of ‘neurology’, redux: early use of the term by Jean Riolan the Younger (1610)

Diederik F Janssen

doi : 10.1093/brain/awab023

Brain, Volume 144, Issue 4, April 2021, Page e38

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Neuronal tau species transfer to astrocytes and induce their loss according to tau aggregation state

Anastasie Maté de Gérando, Marie d’Orange, Emma Augustin, Charlène Joséphine, Gwénaelle Aurégan, Mylène Gaudin-Guérif, Martine Guillermier, Anne-Sophie Hérard, Lev Stimmer, Fanny Petit ... Show more

doi : 10.1093/brain/awab011

Brain, Volume 144, Issue 4, April 2021, Pages 1167–1182

Deposits of different abnormal forms of tau in neurons and astrocytes represent key anatomo-pathological features of tauopathies. Although tau protein is highly enriched in neurons and poorly expressed by astrocytes, the origin of astrocytic tau is still elusive. Here, we used innovative gene transfer tools to model tauopathies in adult mouse brains and to investigate the origin of astrocytic tau. We showed in our adeno-associated virus (AAV)-based models and in Thy-Tau22 transgenic mice that astrocytic tau pathology can emerge secondarily to neuronal pathology. By designing an in vivo reporter system, we further demonstrated bidirectional exchanges of tau species between neurons and astrocytes. We then determined the consequences of tau accumulation in astrocytes on their survival in models displaying various status of tau aggregation. Using stereological counting of astrocytes, we report that, as for neurons, soluble tau species are highly toxic to some subpopulations of astrocytes in the hippocampus, whereas the accumulation of tau aggregates does not affect their survival. Thus, astrocytes are not mere bystanders of neuronal pathology. Our results strongly suggest that tau pathology in astrocytes may significantly contribute to clinical symptoms.

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Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder 

Ambra Stefani, Alex Iranzo, Evi Holzknecht, Daniela Perra, Matilde Bongianni, Carles Gaig, Beatrice Heim, Monica Serradell, Luca Sacchetto, Alicia Garrido, Stefano Capaldi, Almudena S?nchez-G?mez, Maria Paola Cecchini, Sara Mariotto, Sergio Ferrari, Michele Fiorini, Joachim Schmutzhard, Pietro Cocchiara, Isabel Vilaseca, Lorenzo Brozzetti, Salvatore Monaco, M Jose Marti, Klaus Seppi, Eduardo Tolosa, Joan Santamaria, Birgit H?gl, Werner Poewe, Gianluigi Zanusso, for the SINBAR (Sleep Innsbruck Barcelona) group

doi : 10.1093/brain/awab005

Brain, Volume 144, Issue 4, April 2021, Pages 1118–1126

Isolated REM sleep behaviour disorder (RBD) is an early-stage ?-synucleinopathy in most, if not all, affected subjects. Detection of pathological ?-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of ?-synuclein seeding activity in CSF and olfactory mucosa of patients with ?-synucleinopathies. The aim of this study was to explore RT-QuIC detection of ?-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson’s disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson’s disease patients and 59 matched control subjects were analysed by ?-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was ?-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson’s disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson’s disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive ?-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative ?-synuclein RT-QuIC (P?<?0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P?<?0.001). We provide evidence that the ?-synuclein RT-QuIC assay enables the molecular detection of neuronal ?-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson’s disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of ?-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of ?-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt ?-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.

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De novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

Jack M Shireman, Fatemeh Atashi, Gina Lee, Eunus S Ali, Miranda R Saathoff, Cheol H Park, Sol Savchuk, Shivani Baisiwala, Jason Miska, Maciej S Lesniak, C David James, Roger Stupp, Priya Kumthekar, Craig M Horbinski, Issam Ben-Sahra, Atique U Ahmed

doi : 10.1093/brain/awab020

Brain, Volume 144, Issue 4, April 2021, Pages 1230–1246

Glioblastoma is a primary brain cancer with a near 100% recurrence rate. Upon recurrence, the tumour is resistant to all conventional therapies, and because of this, 5-year survival is dismal. One of the major drivers of this high recurrence rate is the ability of glioblastoma cells to adapt to complex changes within the tumour microenvironment. To elucidate this adaptation's molecular mechanisms, specifically during temozolomide chemotherapy, we used chromatin immunoprecipitation followed by sequencing and gene expression analysis. We identified a molecular circuit in which the expression of ciliary protein ADP-ribosylation factor-like protein 13B (ARL13B) is epigenetically regulated to promote adaptation to chemotherapy. Immuno-precipitation combined with liquid chromatography-mass spectrometry binding partner analysis revealed that that ARL13B interacts with the purine biosynthetic enzyme inosine-5?-monophosphate dehydrogenase 2 (IMPDH2). Further, radioisotope tracing revealed that this interaction functions as a negative regulator for purine salvaging. Inhibition of the ARL13B-IMPDH2 interaction enhances temozolomide-induced DNA damage by forcing glioblastoma cells to rely on the purine salvage pathway. Targeting the ARLI3B-IMPDH2 circuit can be achieved using the Food and Drug Administration-approved drug, mycophenolate mofetil, which can block IMPDH2 activity and enhance the therapeutic efficacy of temozolomide. Our results suggest and support clinical evaluation of MMF in combination with temozolomide treatment in glioma patients.

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A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis 

Axel Freischmidt, Anand Goswami, Katharina Limm, Vitaly L Zimyanin, Maria Demestre, Hannes Gla?, Karlheinz Holzmann, Anika M Helferich, Sarah J Brockmann, Priyanka Tripathi, Alfred Yamoah, Ina Poser, Peter J Oefner, Tobias M B?ckers, Eleonora Aronica, Albert C Ludolph, Peter M Andersen, Andreas Hermann, Joachim Weis, J?rg Reinders, Karin M Danzer, Jochen H Weishaupt

doi : 10.1093/brain/awab018

Brain, Volume 144, Issue 4, April 2021, Pages 1214–1229

Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D?=?G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS.

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Time for N-of-1 trials in clinical decision-making

Masud Husain

doi : 10.1093/brain/awab107

Brain, Volume 144, Issue 4, April 2021, Pages 1031–1032

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Antibodies to the Caspr1/contactin-1 complex in chronic inflammatory demyelinating polyradiculoneuropathy

Elba Pascual-Go?i, Janev Fehmi, Cinta Lleixà, Lorena Mart?n-Aguilar, Jérôme Devaux, Romana H?ftberger, Emilien Delmont, Kathrin Doppler, Claudia Sommer, Aleksandar Radunovic, Alejandra Carvajal, Shane Smyth, Laura Williams, Radim Mazanec, Veronika Poto?kov?, Nigel Hinds, Julien Cassereau, Karine Viala, Mathilde Lefilliatre, Guillaume Nicolas, Peter Foley, Frank Leypoldt, Stephen Keddie, Michael P Lunn, Fritz Zimprich, Vharoon Sharma Nunkoo, Wolfgang N L?scher, Laura Mart?nez-Mart?nez, Jordi D?az-Manera, Ricard Rojas-Garcia, Isabel Illa, Simon Rinaldi, Luis Querol

doi : 10.1093/brain/awab014

Brain, Volume 144, Issue 4, April 2021, Pages 1183–1196

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

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

Nadia Dehghani, Jose Bras, Rita Guerreiro

doi : 10.1093/brain/awab028

Brain, Volume 144, Issue 4, April 2021, Pages 1067–1081

The majority of genome-wide association studies have been conducted using samples with a broadly European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this review, we aimed to illustrate the benefits to genetic characterization of Alzheimer’s disease, in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we conducted a literature search to understand the contributions of studies, on different populations, to Alzheimer’s disease genetics. Using both PubMed and Alzforum Mutation Database, we systematically quantified the number of studies reporting variants in known disease-causing genes, in a worldwide manner, and discuss the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant single nucleotide polymorphisms across populations by focusing on loci that show different association profiles between populations (a key example being APOE). Reports of variants in APP, PSEN1 and PSEN2 can initially determine whether patients from a country have been studied for Alzheimer’s disease genetics. Most genome-wide significant associations in non-Hispanic white genome-wide association studies do not reach genome-wide significance in such studies of other populations, with some suggesting an opposite effect direction; this is likely due to much smaller sample sizes attained. There are, however, genome-wide significant associations first identified in understudied populations which have yet to be replicated. Familial studies in understudied populations have identified rare, high effect variants, which have been replicated in other populations. This work functions to both highlight how understudied populations have furthered our understanding of Alzheimer’s disease genetics, and to help us gauge our progress in understanding the genetic architecture of this disease in all populations.

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A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement

Adriana P Rebelo, Andrea Cortese, Amit Abraham, Yael Eshed-Eisenbach, Gal Shner, Anna Vainshtein, Elena Buglo, Vladimir Camarena, Gabriel Gaidosh, Ramin Shiekhattar, Lisa Abreu, Steve Courel, Dennis K Burns, Yunhong Bai, Chelsea Bacon, Shawna M E Feely, Diana Castro, Elior Peles, Mary M Reilly, Michael E Shy, Stephan Zuchner

doi : 10.1093/brain/awab019

Brain, Volume 144, Issue 4, April 2021, Pages 1197–1213

The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified—by whole exome sequencing—three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys. This variant is absent in 230?000 control chromosomes from gnomAD and predicted to be pathogenic. Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement. High resolution mass spectrometry analysis detected a newly created disulphide bond in the mutant CADM3 potentially modifying the native protein conformation. Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant with CADM4 at intercellular contact sites. Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed normal nerve conduction and myelin morphology, but exhibited abnormal axonal organization, including abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations.

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Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases 

Mariely DeJesus-Hernandez, Ross A Aleff, Jazmyne L Jackson, NiCole A Finch, Matthew C Baker, Tania F Gendron, Melissa E Murray, Ian J McLaughlin, John R Harting, Neill R Graff-Radford, Bj?rn Oskarsson, David S Knopman, Keith A Josephs, Bradley F Boeve, Ronald C Petersen, John D Fryer, Leonard Petrucelli, Dennis W Dickson, Rosa Rademakers, Mark T W Ebbert, Eric D Wieben, Marka van Blitterswijk

doi : 10.1093/brain/awab006

Brain, Volume 144, Issue 4, April 2021, Pages 1082–1088

To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P?=?5.0?×?10?4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P?=?0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P?=?0.003), poly(GP) proteins (P?=?1.3?×?10??5), and poly(GA) proteins (P?=?0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.

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Emerging principles of brain immunology and immune checkpoint blockade in brain metastases 

Jawad Fares, Ilya Ulasov, Peter Timashev, Maciej S Lesniak

doi : 10.1093/brain/awab012

Brain, Volume 144, Issue 4, April 2021, Pages 1046–1066

Brain metastases are the most common type of brain tumours, harbouring an immune microenvironment that can in principle be targeted via immunotherapy. Elucidating some of the immunological intricacies of brain metastases has opened a therapeutic window to explore the potential of immune checkpoint inhibitors in this globally lethal disease. Multiple lines of evidence suggest that tumour cells hijack the immune regulatory mechanisms in the brain for the benefit of their own survival and progression. Nonetheless, the role of the immune checkpoint in the complex interplays between cancers cells and T cells and in conferring resistance to therapy remains under investigation. Meanwhile, early phase trials with immune checkpoint inhibitors have reported clinical benefit in patients with brain metastases from melanoma and non-small cell lung cancer. In this review, we explore the workings of the immune system in the brain, the immunology of brain metastases, and the current status of immune checkpoint inhibitors in the treatment of brain metastases.

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Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson’s disease 

Seong Ho Jeong, Seok Jong Chung, Han Soo Yoo, Namki Hong, Jin Ho Jung, Kyoungwon Baik, Yang Hyun Lee, Young H Sohn, Phil Hyu Lee

doi : 10.1093/brain/awab015

Brain, Volume 144, Issue 4, April 2021, Pages 1127–1137

Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson’s disease. We classified 697 drug naive patients with de novo Parkinson’s disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson’s disease being treated with (n?=?54) or without DPP4 inhibitors (n?=?85), and non-diabetic patients with Parkinson’s disease (n?=?558). Diabetic patients with Parkinson’s disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56?±?0.74 versus 2.10?±?0.50; P?=?0.016), posterior (1.83?±?0.69 versus 1.40?±?0.50; P?<?0.001), and ventral putamina (1.72?±?0.58 versus 1.35?±?0.37; P?=?0.001) than that in diabetic patients with Parkinson’s disease without DPP4 inhibitors. Additionally, diabetic patients with Parkinson’s disease being treated with DPP4 inhibitors had higher dopamine transporter availability in the posterior putamen than that in non-diabetic patients with Parkinson’s disease (1.83?±?0.69 versus 1.43?±?0.59; P?<?0.001). After adjusting for age, sex, disease duration, and vascular risk factors, linear regression models showed that a prior treatment of DPP4 inhibitors remained independently and significantly associated with dopamine transporter availability in the anterior (? = ?0.186, P?=?0.012; ? = ?0.207, P?=?0.003), posterior (? = ?0.336, P?<?0.001; ? = ?0.286, P?<?0.001), and ventral putamina (? = ?0.204, P?=?0.005; ? = ?0.250, P?<?0.001). A linear mixed model revealed that the diabetic group with Parkinson’s disease being treated with DPP4 inhibitors had a slower longitudinal increase in levodopa-equivalent dose than the other groups (P?=?0.003). Survival analyses showed that the rate of levodopa-induced dyskinesia was significantly lower in the diabetic group with a prior treatment with DPP4 inhibitors than the diabetic group without DPP4 inhibitors (hazard ratio = 0.194, P?=?0.037). These findings suggest that DPP4 inhibitors may confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with Parkinson’s disease and may extend its role into non-diabetic patients with Parkinson’s disease.

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A robust brain signature region approach for episodic memory performance in older adults 

Evan Fletcher, Brandon Gavett, Paul Crane, Anja Soldan, Timothy Hohman, Sarah Farias, Keith Widaman, Colin Groot, Miguel Arce Renteria, Laura Zahodne, Charles DeCarli, Dan Mungas, for the Alzheimer's Disease Neuroimaging Initiative

doi : 10.1093/brain/awab007

Brain, Volume 144, Issue 4, April 2021, Pages 1089–1102

The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n?=?255; mean age 75.3?±?7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 (n?=?379; mean age 75.1?±?7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer’s dementia); and from ADNI2/GO (n?=?680; mean age 72.5?±?7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer’s dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts.

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Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity 

Ann-Katrin Fleck, Stephanie Hucke, Flavio Teipel, Melanie Eschborn, Claudia Janoschka, Marie Liebmann, Haleluya Wami, Lisanne Korn, Geethanjali Pickert, Marvin Hartwig, Timo Wirth, Martin Herold, Kathrin Koch, Maren Falk-Paulsen, Ulrich Dobrindt, Stjepana Kovac, Catharina C Gross, Philip Rosenstiel, Marcel Trautmann, Heinz Wiendl, Detlef Schuppan, Tanja Kuhlmann, Luisa Klotz

doi : 10.1093/brain/awab040

Brain, Volume 144, Issue 4, April 2021, Pages 1152–1166

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut–CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. Protective effects of dietary supplementation with conjugated linoleic acid were not abrogated upon microbiota eradication, indicating that the microbiome is dispensable for these conjugated linoleic acid-mediated effects. Instead, we observed a range of direct anti-inflammatory effects of conjugated linoleic acid on murine myeloid cells including an enhanced IL10 production and the capacity to suppress T-cell proliferation. Finally, in a human pilot study in patients with multiple sclerosis (n?=?15, under first-line disease-modifying treatment), dietary conjugated linoleic acid-supplementation for 6 months significantly enhanced the anti-inflammatory profiles as well as functional signatures of circulating myeloid cells. Together, our results identify conjugated linoleic acid as a potent modulator of the gut–CNS axis by targeting myeloid cells in the intestine, which in turn control encephalitogenic T-cell responses.

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Lesion network mapping predicts post-stroke behavioural deficits and improves localization 

Alexander L Cohen, Michael A Ferguson, Michael D Fox

doi : 10.1093/brain/awab002

Brain, Volume 144, Issue 4, April 2021, Page e35

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Reply: Lesion network mapping predicts post-stroke behavioural deficits and improves localization 

Alessandro Salvalaggio, Michele De Filippo De Grazia, Lorenzo Pini, Michel Thiebaut De Schotten, Marco Zorzi, Maurizio Corbetta

doi : 10.1093/brain/awab004

Brain, Volume 144, Issue 4, April 2021, Page e36

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A robust brain signature region approach for episodic memory performance in older adults 

Amy E Jolly, Adam Hampshire

doi : 10.1093/brain/awab140

Brain, Volume 144, Issue 4, April 2021, Pages 1038–1040

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Elucidating autoimmune nodopathies and the CIDP spectrum 

Pieter A van Doorn, Robert D M Hadden, Peter Y K Van den Bergh

doi : 10.1093/brain/awab116

Brain, Volume 144, Issue 4, April 2021, Pages 1043–1045

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