Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic

Heart failure (HF) is associated with progressive reduction in cerebral blood flow (CBF) and neurodegenerative changes leading to cognitive decline. The glymphatic system is crucial for the brain's waste removal, and its dysfunction is linked to neurodegeneration. In this study, we used a mouse model of HF, induced by myocardial infarction (MI), to investigate the effects of HF with reduced ejection

Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly

Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer’s disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer’s disease, 70 with other neurodegenerative diseases with

Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally

Concurrent neurodegenerative and vascular pathologies pose a diagnostic challenge in the clinical setting, with histopathology remaining the definitive modality for dementia-type diagnosis. To address this clinical challenge, we introduce a neuropathology-based, data-driven, multi-label deep learning framework to identify and quantify in-vivo biomarkers for Alzheimer's disease (AD), vascular dementia

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often requires prolonged ongoing treatment to prevent worsening. The efficacy of rituximab in preventing worsening after the discontinuation of immunoglobulin therapy in CIDP patients was assessed. In this randomized, double-blind, placebo-controlled study, conducted at seven Italian hospitals, CIDP patients under immunoglobulin therapy

There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on Phase 2 data, which then fail in Phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression

Genome-wide association studies (GWAS) have increased our understanding of Parkinson’s disease (PD) genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis, the statistical interaction between two or more genetic variants. Here, we developed a genome-wide non-exhaustive

Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize

The leptomeninges play a pivotal role in the central nervous system (CNS), serving both as a barrier and as a conduit for fluid and cellular transport. Despite their critical functions, our understanding of leptomeningeal development and maturation during human embryogenesis remains limited. This study seeks to bridge this gap. We conducted single-nucleus RNA sequencing on leptomeningeal tissues from

Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, the attention was focused on the role of dystrophin in muscle in view of the devastating progression of weakness and early death that characterises Duchenne muscular dystrophy. However, in the last few years, the role of shorter dystrophin isoforms, including development and adult expression-specific

The ability to predict the pathology spreading in patients with frontotemporal dementia (FTD) is crucial for early diagnosis and targeted interventions. This study examined the relationship between network vulnerability and longitudinal atrophy progression in FTD patients, using Network Diffusion Model (NDM) of pathology spread. Thirty behavioural-variant FTD (bvFTD), 13 semantic-variant primary progressive

Essential tremor (ET) is one of the most common movement disorders in adults. Deep brain stimulation (DBS) of the ventralis intermediate nucleus (VIM) of the thalamus and/or the posterior subthalamic area (PSA) has been shown to provide significant tremor suppression in patients with ET, but with significant inter-patient variability and habituation to the stimulation. Several non-invasive neuromodulation

Through statistical analysis and comparison of different studies, Alain Goriely challenges the widely accepted figure of 86 billion neurons in the human brain, and argues that the actual number is uncertain, with estimates ranging between 61 and 99 billion.

Gamma band and single-unit neural activity in primary motor cortex (M1) are involved in the control of movement. This activity is disrupted in Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID), a debilitating consequence of dopamine replacement therapy for PD. Physiological features of LID include pathological narrowband gamma oscillations, finely tuned gamma (FTG), and altered M1 firing

Polypathology is a major driver of heterogeneity in clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer Disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy Body Disease (LBD). Patients with Mixed Etiology Dementia (MED) such as AD+LBD have faster progression

Fibrillary aggregation of α-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson’s disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson’s disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered the clarification

This scientific commentary refers to ‘Proteostasis as a fundamental principle of Tau immunotherapy’ by Cruz et al. (https://doi.org/10.1093/brain/awae254).

Thomas Pollak explores the emergence of a new worldview which attempts to explain all manner of ills as the result of inflammation or immune dysfunction. He argues that while this view is rooted in science, it neglects the true complexity of most health conditions, and risks undermining the more holistic concepts of illness favoured by psychiatry.

Treating cognitive impairment is a holy grail of modern clinical neuroscience. In the past few years, non-invasive brain stimulation is increasingly emerging as a therapeutic approach to ameliorate performance in patients with cognitive impairment and as an augmentation approach in persons whose cognitive performance is within normal limits. In patients with Alzheimer’s disease, better understanding

Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson’s disease, negatively affecting patient’s functional capacity and quality of life. The mechanisms underlying cognitive impairment in Parkinson’s disease are still elusive, limiting treatment and prevention strategies. This study investigates the molecular and cellular basis of cognitive impairment associated with heterozygous

Facioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads

α-synucleinopathies are progressive neurodegenerative disorders characterized by intracellular aggregation of α-synuclein, yet their molecular pathogenesis remains unknow. Here, we explore cell-specific changes in gene expression across different α-synucleinopathies. We perform single-nucleus RNA sequencing on nearly 300,000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinson’s

This scientific commentary refers to ‘Enhancing cognitive performance prediction by white matter hyperintensity connectivity assessment’ by Petersen et al. (https://doi.org/10.1093/brain/awae315).

Spreading depolarization (SD) describes a propagating neuronal mass depolarization within the cerebral cortex that represents a mediator of infarct development and strongly stimulates the metabolic rate of O2 consumption. Here, we investigated the influence of Spreading Depolarization (SD) on brain tissue partial pressure of O2 (ptiO2) within the peri-infarct tissue of patients suffering malignant

Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We

This scientific commentary refers to ‘JC virus spread is potentiated by glial replication and demyelination-linked glial proliferation’ by Li et al. (https://doi.org/10.1093/brain/awae252).

B cell-directed CAR T cell therapy has fundamentally changed the treatment of hematological malignancies and its scope of application is rapidly expanding to include other diseases such as solid tumors or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other stimuli share

Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the

Alzheimer’s disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and β-amyloid. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is characterised pathologically by α-synuclein aggregates. HP-tau and β-amyloid can also occur as copathologies in LB dementia, and a diagnosis mixedAD/DLB can

In drug-resistant focal epilepsy, planning surgical resection may involve presurgical intracranial EEG recordings (iEEG) to detect seizures and other iEEG patterns to improve postsurgical seizure outcome. We hypothesized that resection of tissue generating interictal high frequency oscillations (HFOs, 80-500 Hz) in the iEEG predicts surgical outcome. Eight international epilepsy centres recorded iEEG

Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied

Brain metastasis (BrM) remains an unmet clinical need in advanced cancers with an increasing incidence and poor prognosis. The limited response to various treatments is mainly derived from the presence of the substantive barrier, blood–brain barrier (BBB) and brain–tumor barrier (BTB), which hinders the access of potentially effective therapeutics to the metastatic tumor of brain. Recently, the understanding

Mitochondrial (MT) dysfunction is a hallmark of Alzheimer’s Disease (AD), but the scope and severity of these specific deficits across forms of AD are not well characterized. We designed a high-throughput, longitudinal, phenotypic assay to track MT dynamics and bioenergetics in glutamatergic iPSC-derived human neurons possessing mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and the amyloid

This scientific commentary refers to ‘Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline’ by Peretti et al. (https://doi.org/10.1093/brain/awae211).

Enlarged perivascular spaces are a feature of cerebral small vessel disease, and it has been hypothesized that they may reflect impaired glymphatic drainage. The mechanisms underlying perivascular spaces enlargement are not fully understood, but both increased inflammation and blood brain barrier permeability have been hypothesized to play a role. We investigated the relationship between perivascular

The COVID-19 pandemic and lockdowns prompted a major concern for mental health effects. Comprehensive nationwide studies are lacking on the indirect effect of the COVID-19 pandemic on the population’s mental health. We aimed to determine whether the COVID-19 pandemic and lockdowns affected mental health service usage, suicide attempts, and suicides. This comprehensive nationwide register-linked study

While preclinical studies assessing drugs for Alzheimer’s disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well-established that amyloid (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict

Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive

Individuals with mild cognitive impairment that have high dual-task gait cost (≥20% slowing in gait speed while performing a cognitive brain demanding task), are three-fold more likely to progress to dementia. However, the cortical regions that may explain this association are unknown, which may identify potentially treatable areas. The aim of the current study is to investigate whether brain grey

Background Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease due to mutations in the DMD gene, leading to a deficient and less functional dystrophin mainly in skeletal and cardiac muscle. Understanding the natural history of BMD is crucial for optimizing patient care and developing targeted treatments. Materials and methods Retrospective data were collected from 943 patients diagnosed

Parkinson's disease is a progressive neurodegenerative disease with well-documented motor symptoms as well as less recognised, but significant, non-motor symptoms. These non-motor symptoms include prodromal pain and peripheral neuropathy, the causes of which are unknown. We investigated the role of DJ-1/PARK7, a Parkinson's disease-associated gene, in prodromal pain and peripheral neuropathy. Using

The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant

Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fiber size variation, nuclear centralization, and abnormal mitochondrial distribution. The mechanisms underlying this disease are

The neuromuscular circuit mechanisms of freezing of gait in Parkinson’s disease have received little study. Technological progress enables researchers chronically to sense local field potential activity of the basal ganglia in patients while walking. To study subthalamic activity and the circuit processes of supraspinal contributions to spinal motor integration, we recorded local field potentials,

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer’s disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against

Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for