Blood tests to screen for Alzheimer’s disease

Masud Husain

doi : 10.1093/brain/awaa462

Brain, Volume 144, Issue 2, February 2021, Pages 355–356

Every now and then, you think you get a glimpse of the future. Sometimes it is a fleeting vision, a shimmering phantom. Too ephemeral to distinguish its form clearly, it promises much but ultimately fades into obscurity, failing to deliver. Very occasionally though it is a longer lasting apparition, one that reveals itself for sufficient time to consider its significance, to ponder what it might mean. The last few months have witnessed such a revelation. For the first time, we can seriously consider the possibility of a blood test to screen for Alzheimer’s disease. The ramifications are profound.

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COVID-19 vaccine and Guillain-Barré syndrome: let’s not leap to associations

Michael P Lunn, David R Cornblath, Bart C Jacobs, Luis Querol, Peter A van Doorn ...

doi : 10.1093/brain/awaa444

Brain, Volume 144, Issue 2, February 2021, Pages 357–360

A worldwide mass vaccination campaign to control the COVID-19 pandemic is imminent. Understanding the epidemiology of rare diseases whose onset will inevitably occur by coincidence following SARS-CoV-2 vaccination, but which have little to no evidence of being caused by them in any significant number of cases, is critical. Failure to appreciate these issues will result in misattribution of adverse events to the vaccination programme. This could lead to poor uptake of vaccines, delay or even withdrawal of vaccines, or vaccine programmes...

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A space-time continuum in DBS: structural and functional advances in Parkinson’s disease

Philip Starr, Simon Little

doi : 10.1093/brain/awaa463

Brain, Volume 144, Issue 2, February 2021, Pages 357–359

Parkinson’s disease is a severe neurological disorder causing disabling motor and non-motor symptoms. The relationship between Parkinson’s disease and dopamine denervation has long been established; however, how a focal degeneration of neurons in the substantia nigra leads to such widespread network dysfunction has been somewhat of a puzzle. Broadly, two separate lines of research have been investigating this issue with complementary approaches—one structural and the other functional. Early pivotal work by Mahlon DeLong’s group showed that subthalamic nucleus (STN) inactivation in...

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Go, cancer stem cell, go! CSCs overcome myelin inhibition to move within white matter pathways

Daniel J Silver, Justin D Lathia

doi : 10.1093/brain/awaa467

Brain, Volume 144, Issue 2, February 2021, Pages 357–360

Glioblastoma (GBM) tumours are notoriously refractory to treatment. Cellular heterogeneity, including multiple co-existing cancer stem cell (CSC) populations, combines with diffuse tumour cell infiltration to counter the successful management of this incurable and lethal brain cancer. The problem of extensive tissue invasion was initially revealed in 1928 in Walter Dandy’s seminal experiments with hemispherectomy in human GBM patients (Dandy, 1928). These patients underwent the removal of their entire tumour-bearing hemisphere only to later succumb to the secondary growth of their...

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Untangling the tau microtubule-binding region

Jamie Toombs, Henrik Zetterberg

doi : 10.1093/brain/awaa468

Brain, Volume 144, Issue 2, February 2021, Pages 359–362

Human tau exists as six isoforms, all produced mainly by neurons. A range of post-translational modifications, as well as fragmentation by a variety of proteases, together determine the aggregation and propagation potential of tau (Quinn et al., 2018). In general, tau functions are regulated by the phosphorylation and dephosphorylation of combinations of its 45 serine, 35 threonine and five tyrosine residues.

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Genetic alterations of VWA1: a new link between extracellular matrix and neuromuscular diseases

Yoan Arribat

doi : 10.1093/brain/awaa464

Brain, Volume 144, Issue 2, February 2021, Pages 362–365

The genetic and phenotypic variability observed in neuromuscular diseases represents a challenge when it comes to establishing a molecular diagnosis. Nevertheless, over the last few decades, improvements in sequencing strategies and the emergence of international collaborations have contributed to the unveiling, one by one, of the causes of many hereditary neuropathies and myopathies. While neuropathies often involve changes in cytoskeletal or organelle dynamics, in neuromuscular diseases...

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The association between systemic autoimmune disorders and epilepsy and its clinical implications

Claude Steriade, Maarten J Titulaer, Annamaria Vezzani, Josemir W Sander, Roland D Thijs

doi : 10.1093/brain/awaa362

Brain, Volume 144, Issue 2, February 2021, Pages 372–390

Systemic autoimmune disorders occur more frequently in patients with epilepsy than in the general population, suggesting shared disease mechanisms. The risk of epilepsy is elevated across the spectrum of systemic autoimmune disorders but is highest in systemic lupus erythematosus and type 1 diabetes mellitus. Vascular and metabolic factors are the most important mediators between systemic autoimmune disorders and epilepsy. Systemic immune dysfunction can also affect neuronal excitability, not only through innate immune activation and blood–brain barrier dysfunction in most epilepsies but also adaptive immunity in autoimmune encephalitis. The presence of systemic autoimmune disorders in subjects with acute seizures warrants evaluation for infectious, vascular, toxic and metabolic causes of acute symptomatic seizures, but clinical signs of autoimmune encephalitis should not be missed. Immunosuppressive medications may have antiseizure properties and trigger certain drug interactions with antiseizure treatments. A better understanding of mechanisms underlying the co-existence of epilepsy and systemic autoimmune disorders is needed to guide new antiseizure and anti-epileptogenic treatments. This review aims to summarize the epidemiological evidence for systemic autoimmune disorders as comorbidities of epilepsy, explore potential immune and non-immune mechanisms, and provide practical implications on diagnostic and therapeutic approach to epilepsy in those with comorbid systemic autoimmune disorders.

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Hearing and dementia: from ears to brain

Jeremy C S Johnson, Charles R Marshall, Rimona S Weil, Doris-Eva Bamiou, Chris J D Hardy ...

doi : 10.1093/brain/awaa429

Brain, Volume 144, Issue 2, February 2021, Pages 391–401

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain, and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between ‘peripheral’ and ‘central’ hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer’s disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory ‘cognitive stress tests’ and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity.

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Hypoxia in multiple sclerosis; is it the chicken or the egg?

Sebok K Halder, Richard Milner

doi : 10.1093/brain/awaa427

Brain, Volume 144, Issue 2, February 2021, Pages 402–410

Over the past 50 years, intense research effort has taught us a great deal about multiple sclerosis. We know that it is the most common neurological disease affecting the young-middle aged, that it affects two to three times more females than males, and that it is characterized as an autoimmune disease, in which autoreactive T lymphocytes cross the blood–brain barrier, resulting in demyelinating lesions. But despite all the knowledge gained, a key question still remains; what is the initial event that triggers the inflammatory demyelinating process? While most research effort to date has focused on the immune system, more recently, another potential candidate has emerged: hypoxia. Specifically, a growing number of studies have described the presence of hypoxia (both ‘virtual’ and real) at an early stage of demyelinating lesions, and several groups, including our own, have begun to investigate how manipulation of inspired oxygen levels impacts disease progression. In this review we summarize the findings of these hypoxia studies, and in particular, address three main questions: (i) is the hypoxia found in demyelinating lesions ‘virtual’ or real; (ii) what causes this hypoxia; and (iii) how does manipulation of inspired oxygen impact disease progression?

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De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy

Korbinian M Riedhammer, Sylvia Stockler, Rafal Ploski, Maren Wenzel, Burkhard Adis-Dutschmann ...

doi : 10.1093/brain/awaa410

Brain, Volume 144, Issue 2, February 2021, Pages 411–419

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

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Predictors of volitional motor recovery with epidural stimulation in individuals with chronic spinal cord injury

Samineh Mesbah, Tyler Ball, Claudia Angeli, Enrico Rejc, Nicholas Dietz ...

doi : 10.1093/brain/awaa423

Brain, Volume 144, Issue 2, February 2021, Pages 420–433

Spinal cord epidural stimulation (scES) has enabled volitional lower extremity movements in individuals with chronic and clinically motor complete spinal cord injury and no clinically detectable brain influence. The aim of this study was to understand whether the individuals’ neuroanatomical characteristics or positioning of the scES electrode were important factors influencing the extent of initial recovery of lower limb voluntary movements in those with clinically motor complete paralysis. We hypothesized that there would be significant correlations between the number of joints moved during attempts with scES prior to any training interventions and the amount of cervical cord atrophy above the injury, length of post-traumatic myelomalacia and the amount of volume coverage of lumbosacral enlargement by the stimulation electrode array. The clinical and imaging records of 20 individuals with chronic and clinically motor complete spinal cord injury who underwent scES implantation were reviewed and analysed using MRI and X-ray integration, image segmentation and spinal cord volumetric reconstruction techniques. All individuals that participated in the scES study (n?=?20) achieved, to some extent, lower extremity voluntary movements post scES implant and prior to any locomotor, voluntary movement or cardiovascular training. The correlation results showed that neither the cross-section area of spinal cord at C3 (n?=?19, r?=?0.33, P?=?0.16) nor the length of severe myelomalacia (n?=?18, r = ?0.02, P?=?0.93) correlated significantly with volitional lower limb movement ability. However, there was a significant, moderate correlation (n?=?20, r?=?0.59, P?=?0.006) between the estimated percentage of the lumbosacral enlargement coverage by the paddle electrode as well as the position of the paddle relative to the maximal lumbosacral enlargement and the conus tip (n?=?20, r?=?0.50, P?=?0.026) with the number of joints moved volitionally. These results suggest that greater coverage of the lumbosacral enlargement by scES may improve motor recovery prior to any training, possibly because of direct modulatory effects on the spinal networks that control lower extremity movements indicating the significant role of motor control at the level of the spinal cord.

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Population-based blood screening for preclinical Alzheimer’s disease in a British birth cohort at age 70

Ashvini Keshavan, Josef Pannee, Thomas K Karikari, Juan Lantero Rodriguez, Nicholas J Ashton ...

doi : 10.1093/brain/awaa403

Brain, Volume 144, Issue 2, February 2021, Pages 434–449

Alzheimer’s disease has a preclinical stage when cerebral amyloid-? deposition occurs before symptoms emerge, and when amyloid-?-targeted therapies may have maximum benefits. Existing amyloid-? status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques—liquid chromatography-mass spectrometry measures of plasma amyloid-?, and single molecule array (Simoa) measures of plasma amyloid-? and phospho-tau181—to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ?4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden’s index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ?4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The two best-performing Simoa plasma biomarkers were amyloid-?42/40 (0.620; 0.548–0.691) and phospho-tau181 (0.707; 0.646–0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-?1-42/1-40: 0.817; 0.770–0.864 and amyloid-? composite: 0.820; 0.775–0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-?1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ?4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-?1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10–50%, mass spectrometry measures of amyloid-?1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

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Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis

Kicheol Kim, Anne-Katrin Pr?bstel, Ryan Baumann, Julia Dyckow, James Landefeld ...

doi : 10.1093/brain/awaa421

Brain, Volume 144, Issue 2, February 2021, Pages 450–461

Multiple sclerosis is an autoimmune disease of the CNS in which both genetic and environmental factors are involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbour genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in patients with multiple sclerosis are still open questions in the field. To assess cell type-specific gene expression in a large cohort of patients with multiple sclerosis, we sequenced the whole transcriptome of fluorescence-activated cell sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive patients with multiple sclerosis (n?=?106) and healthy subjects (n?=?22). We identified 479 differentially expressed genes in CD4+ T cells, 435 in monocytes, and 54 in CD8+ T cells. Importantly, in CD4+ T cells, we discovered upregulated transcripts from the NAE1 gene, a critical subunit of the NEDD8 activating enzyme, which activates the neddylation pathway, a post-translational modification analogous to ubiquitination. Finally, we demonstrated that inhibition of NEDD8 activating enzyme using the specific inhibitor pevonedistat (MLN4924) significantly ameliorated disease severity in murine experimental autoimmune encephalomyelitis. Our findings provide novel insights into multiple sclerosis-associated gene regulation unravelling neddylation as a crucial pathway in multiple sclerosis pathogenesis with implications for the development of tailored disease-modifying agents.

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Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations

Uladzislau Rudakou, Eric Yu, Lynne Krohn, Jennifer A Ruskey, Farnaz Asayesh ...

doi : 10.1093/brain/awaa401

Brain, Volume 144, Issue 2, February 2021, Pages 462–472

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3? UTR variant (rs945006601) and was independent of GBA variants (P?=?5.23?×?10?5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5? UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson’s disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (odds ratio 0.73, 95% confidence interval 0.60–0.89, P?=?1.161?×?10?3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson’s disease-related genes.

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Modulation of beta bursts in subthalamic sensorimotor circuits predicts improvement in bradykinesia

Yasmine M Kehnemouyi, Kevin B Wilkins, Chioma M Anidi, Ross W Anderson, Muhammad Furqan Afzal ...

doi : 10.1093/brain/awaa394

Brain, Volume 144, Issue 2, February 2021, Pages 473–486

No biomarker of Parkinson’s disease exists that allows clinicians to adjust chronic therapy, either medication or deep brain stimulation, with real-time feedback. Consequently, clinicians rely on time-intensive, empirical, and subjective clinical assessments of motor behaviour and adverse events to adjust therapies. Accumulating evidence suggests that hypokinetic aspects of Parkinson’s disease and their improvement with therapy are related to pathological neural activity in the beta band (beta oscillopathy) in the subthalamic nucleus. Additionally, effectiveness of deep brain stimulation may depend on modulation of the dorsolateral sensorimotor region of the subthalamic nucleus, which is the primary site of this beta oscillopathy. Despite the feasibility of utilizing this information to provide integrated, biomarker-driven precise deep brain stimulation, these measures have not been brought together in awake freely moving individuals. We sought to directly test whether stimulation-related improvements in bradykinesia were contingent on reduction of beta power and burst durations, and/or the volume of the sensorimotor subthalamic nucleus that was modulated. We recorded synchronized local field potentials and kinematic data in 16 subthalamic nuclei of individuals with Parkinson’s disease chronically implanted with neurostimulators during a repetitive wrist-flexion extension task, while administering randomized different intensities of high frequency stimulation. Increased intensities of deep brain stimulation improved movement velocity and were associated with an intensity-dependent reduction in beta power and mean burst duration, measured during movement. The degree of reduction in this beta oscillopathy was associated with the improvement in movement velocity. Moreover, the reduction in beta power and beta burst durations was dependent on the theoretical degree of tissue modulated in the sensorimotor region of the subthalamic nucleus. Finally, the degree of attenuation of both beta power and beta burst durations, together with the degree of overlap of stimulation with the sensorimotor subthalamic nucleus significantly explained the stimulation-related improvement in movement velocity. The above results provide direct evidence that subthalamic nucleus deep brain stimulation-related improvements in bradykinesia are related to the reduction in beta oscillopathy within the sensorimotor region. With the advent of sensing neurostimulators, this beta oscillopathy combined with lead location could be used as a marker for real-time feedback to adjust clinical settings or to drive closed-loop deep brain stimulation in freely moving individuals with Parkinson’s disease.

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Spatiotemporal features of ?-? phase-amplitude coupling in Parkinson’s disease derived from scalp EEG

Ruxue Gong, Mirko Wegscheider, Christoph Mühlberg, Richard Gast, Christopher Fricke ...

doi : 10.1093/brain/awaa400

Brain, Volume 144, Issue 2, February 2021, Pages 487–503

Abnormal phase-amplitude coupling between ? and broadband-? activities has been identified in recordings from the cortex or scalp of patients with Parkinson’s disease. While enhanced phase-amplitude coupling has been proposed as a biomarker of Parkinson’s disease, the neuronal mechanisms underlying the abnormal coupling and its relationship to motor impairments in Parkinson’s disease remain unclear. To address these issues, we performed an in-depth analysis of high-density EEG recordings at rest in 19 patients with Parkinson’s disease and 20 age- and sex-matched healthy control subjects. EEG signals were projected onto the individual cortical surfaces using source reconstruction techniques and separated into spatiotemporal components using independent component analysis. Compared to healthy controls, phase-amplitude coupling of Parkinson’s disease patients was enhanced in dorsolateral prefrontal cortex, premotor cortex, primary motor cortex and somatosensory cortex, the difference being statistically significant in the hemisphere contralateral to the clinically more affected side. ? and ? signals involved in generating abnormal phase-amplitude coupling were not strictly phase-phase coupled, ruling out that phase-amplitude coupling merely reflects the abnormal activity of a single oscillator in a recurrent network. We found important differences for couplings between the ? and ? signals from identical components as opposed to those from different components (originating from distinct spatial locations). While both couplings were abnormally enhanced in patients, only the latter were correlated with clinical motor severity as indexed by part III of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale. Correlations with parkinsonian motor symptoms of such inter-component couplings were found in premotor, primary motor and somatosensory cortex, but not in dorsolateral prefrontal cortex, suggesting motor domain specificity. The topography of phase-amplitude coupling demonstrated profound differences in patients compared to controls. These findings suggest, first, that enhanced phase-amplitude coupling in Parkinson’s disease patients originates from the coupling between distinct neural networks in several brain regions involved in motor control. Because these regions included the somatosensory cortex, abnormal phase-amplitude coupling is not exclusively tied to the hyperdirect tract connecting cortical regions monosynaptically with the subthalamic nucleus. Second, only the coupling between ? and ? signals from different components appears to have pathophysiological significance, suggesting that therapeutic approaches breaking the abnormal lateral coupling between neuronal circuits may be more promising than targeting phase-amplitude coupling per se.

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Antisaccade, a predictive marker for freezing of gait in Parkinson’s disease and gait/gaze network connectivity

Cécile Gallea, Benoit Wicki, Claire Ewenczyk, Sophie Rivaud-Péchoux, Lydia Yahia-Cherif ...

doi : 10.1093/brain/awaa407

Brain, Volume 144, Issue 2, February 2021, Pages 504–514

Freezing of gait is a challenging sign of Parkinson’s disease associated with disease severity and progression and involving the mesencephalic locomotor region. No predictive factor of freezing has been reported so far. The primary objective of this study was to identify predictors of freezing occurrence at 5 years. In addition, we tested whether functional connectivity of the mesencephalic locomotor region could explain the oculomotor factors at baseline that were predictive of freezing onset. We performed a prospective study investigating markers (parkinsonian signs, cognitive status and oculomotor recordings, with a particular focus on the antisaccade latencies) of disease progression at baseline and at 5 years. We identified two groups of patients defined by the onset of freezing at 5 years of follow-up; the ‘Freezer’ group was defined by the onset of freezing in the ON medication condition during follow-up (n?=?17), while the ‘non-Freezer’ group did not (n?=?8). Whole brain resting-state functional MRI was recorded at baseline to determine how antisaccade latencies were associated with connectivity of the mesencephalic locomotor region networks in patients compared to 25 age-matched healthy volunteers. Results showed that, at baseline and compared to the non-Freezer group, the Freezer group had equivalent motor or cognitive signs, but increased antisaccade latencies (P?=?0.008). The 5-year course of freezing of gait was correlated with worsening antisaccade latencies (P?=?0.0007). Baseline antisaccade latencies was also predictive of the freezing onset (?2 = 0.008). Resting state connectivity of mesencephalic locomotor region networks correlated with (i) antisaccade latency differently in patients and healthy volunteers at baseline; and (ii) the further increase of antisaccade latency at 5 years. We concluded that antisaccade latency is a predictive marker of the 5-year onset of freezing of gait. Our study suggests that functional networks associated with gait and gaze control are concurrently altered during the course of the disease.

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

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

doi : 10.1093/brain/awaa373

Brain, Volume 144, Issue 2, February 2021, Pages 515–527

Tau is a microtubule associated protein in the brain that aggregates in Alzheimer’s disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer’s disease. In contrast, levels of soluble forms of tau, such as CSF total tau and phosphorylated tau-181 and tau-217, increase prior to tau aggregation in Alzheimer’s disease, but these biomarkers do not measure the MTBR of tau. Thus, how CSF MTBR-tau is altered in Alzheimer’s disease remains unclear. In this study, we used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyse MTBR-tau species in Alzheimer’s disease and control CSF. We quantified MTBR-tau-specific regions in the CSF and identified that species containing the region beginning at residue 243 were the most highly correlated with tau PET and cognitive measures. This finding suggests that CSF level of tau species containing the upstream region of MTBR may reflect changes in tau pathology that occur in Alzheimer’s disease and could serve as biomarkers to stage Alzheimer’s disease and track the development of tau-directed therapeutics.

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Gamma subunit of complement component 8 is a neuroinflammation inhibitor

Jong-Heon Kim, Ruqayya Afridi, Jin Han, Hyun-Gug Jung, Seung-Chan Kim ...

doi : 10.1093/brain/awaa425

Brain, Volume 144, Issue 2, February 2021, Pages 528–552

The complement system is part of the innate immune system that comprises several small proteins activated by sequential cleavages. The majority of these complement components, such as components 3a (C3a) and C5a, are chemotactic and pro-inflammatory. However, in this study, we revealed an inhibitory role of complement component 8 gamma (C8G) in neuroinflammation. In patients with Alzheimer's disease, who exhibit strong neuroinflammation, we found higher C8G levels in brain tissue, CSF, and plasma. Our novel findings also showed that the expression level of C8G increases in the inflamed mouse brain, and that C8G is mainly localized to brain astrocytes. Experiments using recombinant C8G protein and shRNA-mediated knockdown showed that C8G inhibits glial hyperactivation, neuroinflammation, and cognitive decline in acute and chronic animal models of Alzheimer’s disease. Additionally, we identified sphingosine-1-phosphate receptor 2 (S1PR2) as a novel interaction protein of C8G and demonstrated that astrocyte-derived C8G interacts with S1PR2 to antagonize the pro-inflammatory action of S1P in microglia. Taken together, our results reveal the previously unrecognized role of C8G as a neuroinflammation inhibitor. Our findings pave the way towards therapeutic containment of neuroinflammation in Alzheimer’s disease and related neurological diseases.

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Three-dimensional analysis of synaptic organization in the hippocampal CA1 field in Alzheimer’s disease

Marta Montero-Crespo, Marta Dom?nguez-?lvaro, Lidia Alonso-Nanclares, Javier DeFelipe, Lidia Blazquez-Llorca

doi : 10.1093/brain/awaa406

Brain, Volume 144, Issue 2, February 2021, Pages 553–573

Alzheimer’s disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer’s disease is typically associated with extracellular deposits of amyloid-? peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-? and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer’s disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer’s disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer’s disease cases with different stages of the disease, using focused ion beam/scanning electron microscopy (FIB/SEM). In cases with early stages of Alzheimer’s disease, the synapse morphology looks normal and we observed no significant differences between control and Alzheimer’s disease cases regarding the synaptic density, the ratio of excitatory and inhibitory synapses, or the spatial distribution of synapses. However, differences in the distribution of postsynaptic targets and synaptic shapes were found. Furthermore, a lower proportion of larger excitatory synapses in both strata were found in Alzheimer’s disease cases. Individuals in late stages of the disease suffered the most severe synaptic alterations, including a decrease in synaptic density and morphological alterations of the remaining synapses. Since Alzheimer’s disease cases show cortical atrophy, our data indicate a reduction in the total number (but not the density) of synapses at early stages of the disease, with this reduction being much more accentuated in subjects with late stages of Alzheimer’s disease. The observed synaptic alterations may represent a structural basis for the progressive learning and memory dysfunctions seen in Alzheimer’s disease cases.

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Bi-allelic truncating mutations in VWA1 cause neuromyopathy

Marcus Deschauer, Holger Hengel, Katrin Rupprich, Martina Krei?, Beate Schlotter-Weigel ...

doi : 10.1093/brain/awaa418

Brain, Volume 144, Issue 2, February 2021, Pages 574–583

The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

Alistair T Pagnamenta, Rauan Kaiyrzhanov, Yaqun Zou, Sahar I Da'as, Reza Maroofian ...

doi : 10.1093/brain/awaa420

Brain, Volume 144, Issue 2, February 2021, Pages 584–600

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74?180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6–83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0?±?1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

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5? UTR CGG repeat expansion in GIPC1 is associated with oculopharyngodistal myopathy

Jianying Xi, Xilu Wang, Dongyue Yue, Tonghai Dou, Qunfeng Wu ...

doi : 10.1093/brain/awaa426

Brain, Volume 144, Issue 2, February 2021, Pages 601–614

Oculopharyngodistal myopathy is a late-onset degenerative muscle disorder characterized by ptosis and weakness of the facial, pharyngeal, and distal limb muscles. A recent report suggested a non-coding trinucleotide repeat expansion in LRP12 to be associated with the disease. Here we report a genetic study in a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). In a large family with 12 affected individuals, combined haplotype and linkage analysis revealed a maximum two-point logarithm of the odds (LOD) score of 3.3 in chromosomal region chr19p13.11-p13.2 and narrowed the candidate region to an interval of 4.5 Mb. Using a comprehensive strategy combining whole-exome sequencing, long-read sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal CGG repeat expansion in the 5? UTR of the GIPC1 gene that co-segregated with disease. Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases), while the repeat expansion in LRP12 was only identified in one sporadic case (3.7%) in our cohort. The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident. These results further support that non-coding CGG repeat expansion plays an essential role in the pathogenesis of oculopharyngodistal myopathy.

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Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish

Juanjuan Luo, Pei Liu, Chunjiao Lu, Wanping Bian, Dongsheng Su ...

doi : 10.1093/brain/awaa404

Brain, Volume 144, Issue 2, February 2021, Pages 615–635

The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human gliomagenesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment.

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Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma

Jun-Hee Hong, Sangjo Kang, Jason K Sa, Gunwoo Park, Young Taek Oh ...

doi : 10.1093/brain/awaa408

Brain, Volume 144, Issue 2, February 2021, Pages 636–654

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

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Machine phenotyping of cluster headache and its response to verapamil

Amy R Tso, Mikael Brudfors, Daisuke Danno, Lou Grangeon, Sanjay Cheema ...

doi : 10.1093/brain/awaa388

Brain, Volume 144, Issue 2, February 2021, Pages 655–664

Cluster headache is characterized by recurrent, unilateral attacks of excruciating pain associated with ipsilateral cranial autonomic symptoms. Although a wide array of clinical, anatomical, physiological, and genetic data have informed multiple theories about the underlying pathophysiology, the lack of a comprehensive mechanistic understanding has inhibited, on the one hand, the development of new treatments and, on the other, the identification of features predictive of response to established ones. The first-line drug, verapamil, is found to be effective in only half of all patients, and after several weeks of dose escalation, rendering therapeutic selection both uncertain and slow. Here we use high-dimensional modelling of routinely acquired phenotypic and MRI data to quantify the predictability of verapamil responsiveness and to illuminate its neural dependants, across a cohort of 708 patients evaluated for cluster headache at the National Hospital for Neurology and Neurosurgery between 2007 and 2017. We derive a succinct latent representation of cluster headache from non-linear dimensionality reduction of structured clinical features, revealing novel phenotypic clusters. In a subset of patients, we show that individually predictive models based on gradient boosting machines can predict verapamil responsiveness from clinical (410 patients) and imaging (194 patients) features. Models combining clinical and imaging data establish the first benchmark for predicting verapamil responsiveness, with an area under the receiver operating characteristic curve of 0.689 on cross-validation (95% confidence interval: 0.651 to 0.710) and 0.621 on held-out data. In the imaged patients, voxel-based morphometry revealed a grey matter cluster in lobule VI of the cerebellum (?4,??66,??20) exhibiting enhanced grey matter concentrations in verapamil non-responders compared with responders (familywise error-corrected P?=?0.008, 29 voxels). We propose a mechanism for the therapeutic effect of verapamil that draws on the neuroanatomy and neurochemistry of the identified region. Our results reveal previously unrecognized high-dimensional structure within the phenotypic landscape of cluster headache that enables prediction of treatment response with modest fidelity. An analogous approach applied to larger, globally representative datasets could facilitate data-driven redefinition of diagnostic criteria and stronger, more generalizable predictive models of treatment responsiveness.

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Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition

Zilong Wang, Changyu Jiang, Hongyu Yao, Ouyang Chen, Sreya Rahman ...

doi : 10.1093/brain/awaa430

Brain, Volume 144, Issue 2, February 2021, Pages 665–681

Opioids such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that intrathecal injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching as well as licking and biting, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons [Oprm1-Vgat (Slc32a1)]. Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons. Furthermore, morphine suppressed evoked inhibitory postsynaptic currents in postsynaptic Vgat? excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by intrathecal administration of NPY and abolished by spinal ablation of GRPR+ neurons with intrathecal injection of bombesin-saporin, whereas intrathecal GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Intrathecal bombesin-saporin treatment reduced the number of GRPR+ neurons by 97% in the lumber spinal cord and 91% in the cervical spinal cord, without changing the number of Oprm1+ neurons. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the CTCL model, indicating a contribution of central MOR signalling to chronic itch. Our findings demonstrate that intrathecal morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also provide mechanistic insights into the current treatment of chronic itch with opioid receptor antagonist such as naloxone.

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Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome

Stephen Keddie, Julia Pakpoor, Christina Mousele, Menelaos Pipis, Pedro M Machado ...

doi : 10.1093/brain/awaa433

Brain, Volume 144, Issue 2, February 2021, Pages 682–693

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65–1.88 per 100?000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016–19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r?=?0.06, 95% confidence interval: ?0.56 to 0.63, P?=?0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

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Growth differentiation factor 5 exerts neuroprotection in an ?-synuclein rat model of Parkinson’s disease

Susan R Goulding, Ruth M Concannon, Noelia Morales-Prieto, Francisca Villalobos-Manriquez, Gerard Clarke ...

doi : 10.1093/brain/awaa367

Brain, Volume 144, Issue 2, February 2021, Page e14

The concept of neurotrophic factor therapy holds significant promise as a disease-modifying therapy for Parkinson’s disease (Paul and Sullivan, 2019). Whone et al. (2019) recently reported the results of a randomized, double-blind, placebo-controlled trial of intermittent intraputamenal convection-enhanced delivery of glial cell line-derived neurotrophic factor (GDNF) in Parkinson’s disease patients. Despite an extensive body of excellent work and significant improvements to dosing and delivery, this trial failed to reach its primary end point. This outcome is largely consistent with an earlier randomized, placebo-controlled trial of GDNF in Parkinson’s disease (Lang et al., 2006). Preclinical studies have shown that delivery of...

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BMP5/7 protect dopaminergic neurons in an ?-synuclein mouse model of Parkinson’s disease

Zagorka Vitic, Hazem Safory, Vukasin M Jovanovic, Yael Sarusi, Alexandra Stavsky ...

doi : 10.1093/brain/awaa368

Brain, Volume 144, Issue 2, February 2021, Page e15

Whone et al. (2019) recently reported a randomized clinical trial of intermittent intraputamenal glial cell line-derived neurotrophic factor (GDNF) in Parkinson’s disease. Whone et al. achieved an important milestone by demonstrating that convection-enhanced delivery is an efficient and safe way for long-term intraparenchymal drug application. GDNF was well tolerated and caused a significant increase in 18F-DOPA uptake. However, the study failed to reach its clinical end points.

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Reply: Growth differentiation factor 5 exerts neuroprotection in an ?-synuclein rat model of Parkinson’s disease and BMP5/7 protect dopaminergic neurons in an ?-synuclein mouse model of Parkinson’s disease

Alan Whone

doi : 10.1093/brain/awaa369

Brain, Volume 144, Issue 2, February 2021, Page e16

Rita Levi-Montalchini and Stanley Cohen shared the Nobel prize in 1986 for elucidating neurotrophic factor, a naturally occurring growth factor, and showing it to be essential to the survival of nerve cells. Since this seminal work, numerous studies have revealed that a large collection of growth factors exists, capable of reducing neurodegeneration and enhancing function of intact and degenerating neurons. In Parkinson’s disease, the TGF-? protein superfamily, particularly glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), have been most investigated. Multiple preclinical studies, in numerous species, have reported neurorestorative and neuroprotective effects of GDNF and NTN on dopamine neurons in various toxin models of...

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PCYT2 mutations disrupting etherlipid biosynthesis: phenotypes converging on the CDP-ethanolamine pathway

Jonathan De Winter, Danique Beijer, Willem De Ridder, Matthis Synofzik, Stephan L Zuchner ...

doi : 10.1093/brain/awaa389

Brain, Volume 144, Issue 2, February 2021, Page e17

The study by Vaz et al. published in Brain in 2019 established a novel firm link between disrupted etherlipid biosynthesis and complex forms of hereditary spastic paraplegia (HSP) through the identification of recessive mutations in the PCYT2 gene (Synofzik and Schule, 2017; Darios et al., 2020; Rickman et al., 2020). Before, genetic causes of HSP had been found in genes with diverse functional roles (Shribman et al., 2019) including chaperone activity, axonal transport, mitochondrial function and many others. However, mutations in genes involved in complex lipid metabolism have increasingly been implicated in the pathology of HSP...

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MN1 gene loss-of-function mutation causes cleft palate in a pedigree

Li Shu, Dinghua He, Dan Wu, Ying Peng, Hui Xi ...

doi : 10.1093/brain/awaa431

Brain, Volume 144, Issue 2, February 2021, Page e18

We read with great interest the article entitled ‘MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis’ published in Brain by Mak et al. (2020). They reported 22 patients with CEBALID syndrome who showed severe symptoms including global developmental delay, craniofacial and brain abnormalities. All of these patients carried MN1 heterozygous C-terminal mutations which may have a dominant-negative or gain-of-function effect.

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Reply: MN1 gene loss-of-function mutation causes cleft palate in a pedigree

Nancy Vegas, Karen Low, Christopher C Y Mak, Jasmine L F Fung, Anne V Hing ...

doi : 10.1093/brain/awaa432

Brain, Volume 144, Issue 2, February 2021, Page e19

We read with interest the Letter to the Editor by Shu et al. (2021), describing members of a family presenting cleft palate and conductive hearing loss in association with a truncating variant in the MN1 gene (MIM 156100). MN1 encodes a developmentally expressed transcriptional co-regulator with poorly defined molecular functions, and has an unusual gene structure, with one large first exon and a small second exon encoding the C-terminus of the protein (Fig. 1A). Previously, we and others reported 25 patients with germline truncating mutations towards the C-terminus of MN1, associated with distinctive craniofacial features (midface hypoplasia, hypertelorism, skull shape...

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Reference values for the Cerebellar Cognitive Affective Syndrome Scale: age and education matter

Andreas Thieme, Sandra R?ske, Jennifer Faber, Patricia Sulzer, Martina Minnerop ...

doi : 10.1093/brain/awaa417

Brain, Volume 144, Issue 2, February 2021, Page e20

During recent decades, many studies have yielded evidence for cerebellar involvement in cognitive, emotional and affective processes besides the well-known cerebellar contribution to motor performance and learning (Koziol et al., 2014; Marien et al., 2014; Van Overwalle et al., 2014; Strata, 2015; Adamaszek et al., 2017; Kansal et al., 2017; Guell et al., 2018; King et al., 2019). Cerebellar diseases can result in executive, linguistic and visuospatial dysfunctions as well as problems with the regulation of emotion and affect. This combination of non-motor symptoms has been named cerebellar cognitive...

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Reply: Reference values for the Cerebellar Cognitive Affective Syndrome Scale: age and education matter

Jeremy D Schmahmann, Mark G Vangel, Franziska Hoche, Xavier Guell, Janet C Sherman

doi : 10.1093/brain/awaa419

Brain, Volume 144, Issue 2, February 2021, Page e21

We thank Thieme et al. (2020a) for their letter, and we appreciated the opportunity to participate in the translation of the Cerebellar Cognitive Affective Syndrome (CCAS)/Schmahmann scale into German (Thieme et al., 2020b). The scale has been or is in the process of being translated into 12 languages: Arabic, Bengali, Chinese, Dutch, French, Japanese, Korean, Polish, Portuguese, Spanish and Ukrainian, highlighting the need for this cognitive screening measure in cerebellar patients worldwide.

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Early-onset phenotype of bi-allelic GRN mutations

Caroline Neuray, Tipu Sultan, Javeira Raza Alvi, Marcondes C Franca, Jr, Birgit Assmann ...

doi : 10.1093/brain/awaa414

Brain, Volume 144, Issue 2, February 2021, Page e22

We read with great interest the original article ‘Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms’ by Huin et al. (2020).

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Reply: Early-onset phenotype of bi-allelic GRN mutations

Vincent Huin, Mathieu Barbier, Alexandra Durr, Isabelle Le Ber

doi : 10.1093/brain/awaa415

Brain, Volume 144, Issue 2, February 2021, Page e23

Neuray et al. report in this work a series of five new patients from four unrelated families with bi-allelic mutations of GRN (Neuray, et al., 2021). This work nicely completes the few existing reports of similar cases, and refers to our recent publication describing six homozygous GRN pathogenic variant carriers with divergent phenotypes and ages at onset (Huin et al., 2020). This study provides solid data regarding clinical features of early-onset bi-allelic GRN mutations. All heterozygous pathogenic GRN variants reported here were previously associated with frontotemporal dementia (FTD) (Rademakers et al., 2007; Gijselinck et al.,...

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Corrigendum to: Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease

doi : 10.1093/brain/awaa355

Brain, Volume 144, Issue 2, February 2021, Page e24

Emma Biondetti, Rahul Gaurav, Lydia Yahia-Cherif, Graziella Mangone, Nadya Pyatigorskaya, Romain Valabrègue, Claire Ewenczyk, Matthew Hutchison, Chantal François, Isabelle Arnulf, Jean-Christophe Corvol, Marie Vidailhet and Stéphane Lehéricy. Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease. Brain 2020; 143: 2757–70. doi:10.1093/brain/awaa216.

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