In drug-resistant temporal lobe epilepsy (TLE), precise predictions of drug response, surgical outcome, and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant "one-size-fits-all" group-level analytical approaches that does not allow parsing inter-individual variations along the disease spectrum. Conversely, analyzing inter-patient heterogeneity

Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger

During a verbal conversation, our brain moves through a series of complex linguistic processing stages: sound decoding, semantic comprehension, retrieval of semantically coherent words, and overt production of speech outputs. Each process is thought to be supported by a network consisting of local and long-range connections bridging between major cortical areas. Both temporal and extratemporal lobe

Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases (MDs). With respect to the latter, mutations in subunit-encoding genes and assembly factors of the

Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through cerebrospinal fluid. However, animal studies have also indicated that substances and cells may enter the intracranial compartment directly from bone marrow. We utilized magnetic resonance imaging and a cerebrospinal fluid tracer to investigate in vivo whether intracranial molecules

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. ALS is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We

Persistent fatigue is a major debilitating symptom in many psychiatric and neurological conditions, including stroke. Post-stroke fatigue has been linked to low corticomotor excitability. Yet, it remains elusive what the neuronal mechanisms are that underlie motor cortex excitability and chronic persistence of fatigue. In this cross-sectional observational study, in two experiments we examined a total

Amyotrophic lateral sclerosis (ALS) is a relatively common and rapidly progressive neurodegenerative disease which, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies (GWAS), combined with the advent of Mendelian randomization (MR) is opening significant new opportunities to identify

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain magnetic resonance imaging (MRI), in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA

FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions (COPC). Whether COPC represents a distinct pathophysiology from the occurrence of pain at only one site is unknown. Using genome-wide approaches, we compared genetic determinants of chronic single-site vs. multisite pain in the UK Biobank. We found that different genetic signals underlie

With more than forty causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3: c.1165G>A: p.G389R,

MRI-guided focused ultrasound thalamotomy has been shown to be an effective treatment for medication refractory essential tremor. Here, we report a clinical-radiological analysis of 123 cases of MRI-guided focused ultrasound thalamotomy, and explore the relationships between treatment parameters, lesion characteristics and outcomes. All patients undergoing focused ultrasound thalamotomy by a single

Theoretical accounts of developmental stuttering implicate dysfunctional cortico-striatal-thalamo-cortical motor loops through the putamen. However, the analysis of conventional MRI brain scans in individuals who stutter has failed to yield strong support for this theory in terms of reliable differences in the structure or function of the basal ganglia. Here, we performed quantitative mapping of brain

AbstractNeuromyelitis optica is an autoimmune inflammatory disorder targeting aquaporin-4 water channels in CNS astrocytes. Histopathologic descriptions of astrocytic lesions reported in neuromyelitis optica to date have emphasized a characteristic loss of aquaporin-4, with deposition of IgG and complement and lysis of astrocytes, but sublytic reactions have been underappreciated. We performed a multi-modality

White matter vasculature plays a major role in the pathophysiology of permanent neurological deficits following a stroke or progressive cognitive alteration related to small vessel disease. Thus, knowledge of the complex vascularization and functional aspects of the deep white matter territories is paramount to comprehend clinical manifestations of brain ischemia.

Disease course in multiple sclerosis is notably heterogenous, and few prognostic indicators have been consistently associated with multiple sclerosis severity. In the general population, socioeconomic disparity is associated with multimorbidity and may contribute to worse disease outcomes in multiple sclerosis. Herein, we assessed whether indicators of socioeconomic status (SES) are associated with

The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies (DLB). In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2,466 DLB cases versus 2,928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5’ and 3’ splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction

People with epilepsy have variable and dynamic trajectories in response to antiseizure medications. Accurately modelling long-term treatment response will aid prognostication at the individual level and health resource planning at the societal level. Unfortunately, a robust model is lacking. We aimed to develop a Markov model to predict the probability of future seizure-freedom based on current seizure

Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration

Although white matter hyperintensities on fluid-attenuated inversion recovery (FLAIR) brain MRI are frequent incidental findings without any apparent clinical abnormality, they are widely viewed as an imaging marker of cerebral small vessel disease1 and indicate future risk of stroke and other adverse outcomes.2 Furthermore, understanding the origin and risk factors for this common entity is crucial

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials

This scientific commentary refers to ‘Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer disease’ by Lucey et al. (doi:10.1093/brain/awab272).

Sleep monitoring may provide markers for future Alzheimer’s disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer’s disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer’s disease change with age, a greater understanding of how

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted

This scientific commentary refers to ‘MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline high serum creatine kinase’, by Lopes Abath Neto et al. (doi:10.1093/brain/awab275).

AbstractStriated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds

Earlier diagnosis of Alzheimer’s disease requires biomarkers sensitive to associated structural and functional changes. While considerable progress has been made in the development of structural biomarkers, functional biomarkers of early cognitive change, unconfounded by effort, practice and level of education, are still needed. We present Fastball, a new EEG method for the passive and objective measurement

Jiaxi Yu, Jianwen Deng, Xueyu Guo, Jingli Shan, Xinghua Luan, Li Cao, Juan Zhao, Meng Yu, Wei Zhang, He Lv, Zhiying Xie, LingChao Meng, Yiming Zheng, Yawen Zhao, Qiang Gang, Qingqing Wang, Jing Liu, Min Zhu, Binbin Zhou, Pidong Li, Yinzhe Liu, Yang Wang, Chuanzhu Yan, Daojun Hong, Yun Yuan, Zhaoxia Wang. The GGC repeat expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy type 3. Brain

The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced

This scientific commentary refers to ‘Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe’, by Yushkevich et al. (doi:10.1093/brain/awab262).

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here

National Institute for Health Research10.13039/501100000272NIHR Academic Clinical FellowshipAlzheimer's Research UK & RosetreesNational Institute for Health Research Sheffield Biomedical Research CentreNIHR10.13039/100006662Medical Research Council10.13039/501100000265Wellcome Trust & the Royal SocietyWellcome Clinical Research Career Development FellowshipNational Institute for Health Research University

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), spinal muscular atrophy,

Language and its associated disorders have puzzled humanity since the dawn of civilization. The first descriptions of aphasia go back to classical antiquity. The Egyptians and Babylonians believed speech was a divine gift to mortals, and their descriptions of aphasia attributed these events to their Gods' anger and disfavor. The Edwin Smith Surgical Papyrus and the Hippocratic Corpus report several

AbstractDisability in leprosy is a direct consequence of damage to the peripheral nervous system which is usually worse in patients with no skin manifestations, an underdiagnosed subtype of leprosy known as primary neural leprosy. We evaluated clinical, neurophysiological and laboratory findings of 164 patients with definite and probable primary neural leprosy diagnoses. To better understand the disease

Tau is one of several proteins associated with frontotemporal dementia (FTD). While knowing which protein is causing a patient’s disease is crucial, no biomarker currently exists for identifying tau in vivo in FTD. The objective of this study was to investigate the potential for the promising [18F]MK-6240 positron emission tomography (PET) tracer to bind to tau in vivo in genetic FTD.

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed

AbstractAlthough clinical neuroscience and the neuroscience of consciousness have long sought mechanistic explanations of tactile-awareness disorders, mechanistic insights are rare, mainly because of the difficulty of depicting the fine-grained neural dynamics underlying somatosensory processes. Here, we combined the stereo-EEG responses to somatosensory stimulation with the lesion mapping of patients

Visual snow syndrome is a neurological condition characterised by a persistent visual disturbance, visual snow, in conjunction with additional visual symptoms. Cortical hyperexcitability is a potential pathophysiological mechanism, which could be explained by increased gain in neural responses to visual input. Alternatively, neural noise in the visual pathway could be abnormally elevated. We assessed

Several CSF and blood biomarkers for genetic frontotemporal dementia (FTD) have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)), synapse dysfunction (neuronal pentraxin 2 (NPTX2)), astrogliosis (glial fibrillary acidic protein (GFAP)), and complement activation (C1q, C3b). Determining the sequence in which

The gating of movement depends on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways—the direct and indirect basal ganglia pathway. Both are complex and polysynaptic but the overall effect of activity within these pathways is thought to encourage and inhibit movement respectively. In Huntington’s disease (HD), the

The negative impact of smoking in MS is well established, however, there is much less evidence as to whether smoking cessation is beneficial to progression in MS.

The activity of frontal motor areas during hand-object interaction is coordinated by dense communication along specific white matter pathways. This architecture allows the continuous shaping of voluntary motor output and, despite extensively investigated in non-human primate studies, remains poorly understood in humans. Disclosure of this system is crucial for predicting and treatment of motor deficits

Brain machine interfaces allow neuroscientists to causally link specific neural activity patterns to a particular behaviour. Thus, in addition to their current clinical applications, brain machine interfaces can also be used as a tool to investigate neural mechanisms of learning and plasticity in the brain. Decades of research using such brain machine interfaces has shown that animals (nonhuman primates

Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known.

James L. Ross, Jose Velazquez Vega, Ashley Plant, Tobey J. MacDonald, Oren J. Becher and Dolores Hambardzumyan. Tumour immune landscape of paediatric high-grade gliomas. Brain; awab155. doi:10.1093/brain/awab155