Drawing on two decades of clinical experience with affective disorders, Jesús Ramírez-Bermúdez— runner up in the Brain Essay Competition 2024—explores the cultural significance of melancholy, with the aid of historical archives from the Inquisition and the introspections of a 17th century poet.

Matt Butler, runner up in the Brain Essay Competition 2024, considers what happens when memories fragment and certainties fade in this fictional tale of a professor of literature who loses her grasp on time.

The historical understanding of cerebrospinal fluid (CSF) production and flow comprises CSF production primarily in the choroid plexus of the 1st-3rd ventricles, flow through the aqueduct of Sylvius en route to the 4th ventricle, circulation around the subarachnoid space, and ultimately resorption into the blood circulation through arachnoid granulations. Since the discovery of a perivascular CSF clearance

Apathy is a common neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD) but can emerge earlier in prodromal and even preclinical stages as part of mild behavioural impairment (MBI-apathy), a syndrome defined by emergent and persistent NPS. In dementia, apathy is associated with higher morbidity, mortality, and caregiver distress. However, the significance of MBI-apathy in dementia-free persons

Monoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a preCGG repeat expansion in the FMR1 gene. Individuals with the FMR1 premutation often exhibit neuropsychiatric symptoms before FXTAS onset, leading to the identification of fragile X-associated neuropsychiatric disorders (FXAND). Rodent models of FXTAS show motor impairments, pathological intranuclear

A number of neuropeptides including pituitary adenylate cyclase-activating polypeptide (PACAP) play an important role in the pathophysiology of migraine. Infusions of PACAP in patients with migraine can provoked migraine attacks. A placebo-controlled study with a monoclonal antibody directed against the PACAP-receptor failed to show efficacy. In a small, short, proof of concept study a monoclonal antibody

Targeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer’s disease (AD). Semorinemab is a humanized IgG4 monoclonal antibody that binds to all known isoforms of full-length tau with high affinity and specificity. Semorinemab’s safety and efficacy have been studied in two Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials:

SLC35A2 encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline genetic SLC35A2 variants have been identified in congenital disorders of glycosylation and somatic SLC35A2 variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these

Parkinson’s disease is most recognized for its impact on the CNS. However, recent breakthroughs underscore the crucial role of interactions between central and peripheral systems in Parkinson’s disease pathogenesis. The spotlight is now shifting as we explore beyond the CNS, discovering that peripheral changes such as inflammatory dysfunctions may predict the rate of disease progression and severity

Although growing evidence suggests that cholinergic basal forebrain degeneration is linked to cognitive impairment and axial motor symptoms in Lewy body disorders (LBDs), the cholinergic contribution to their prodromal phase remains largely unknown. Herein, we aimed to address three important yet unresolved questions focusing on prodromal LBDs: (1) to examine whether and where basal forebrain degeneration

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein (PrPC) into its infectious β-sheet-rich isoform (PrPSc). Conventionally, prions were thought to be incapable of eliciting robust immune responses because PrPC and PrPSc share an identical primary structure. However, recent evidence highlights the critical involvement of type I interferon (I-IFN) signaling

The current research challenge in pure autonomic failure (PAF) lies in identifying specific biomarkers that can differentiate it from the other Lewy body disorders (Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies) and multiple system atrophy in the early stages and predict phenoconversion trajectories to more widespread impairment. In this study, we described the natural

Neuroscience has evolved by framing numerous neuropsychiatric conditions as network diseases. Alterations within neurotransmitter (NT) systems are central to the development of these diseases. Recently, normative data on whole-brain NT fingerprints derived from PET tracer data has become accessible; limited data related such information to sequelae after stroke. This work aims to explore (1) the integration

The natural history of pediatric brain arteriovenous malformations (AVMs) remains uncertain, particularly regarding their origin (congenital versus postnatal) and risk of rupture. This study analyzes age-related patterns in AVM presentation from a single quaternary referral center. A retrospective review of 275 pediatric AVM cases from 2009–2022, was conducted using radiological, surgical, and hospital

Deep intronic FGF14 repeat expansions have been identified as a frequent genetic cause of late-onset cerebellar ataxias, explaining up to 30% of patients. Interruptions between repeats have previously been identified to impact the penetrance in other repeat expansion disorders. Repeat interruptions within FGF14 have yet to be characterized in detail. We utilized long-range PCR, Sanger sequencing, repeat-primed

Astrocytic dysfunction is a crucial factor for the pathogenesis of Alzheimer’s disease. Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in the brain and is a key molecule that regulates synaptic transmission and plasticity. It has been shown that mGluR5 is elevated in astrocytes in Alzheimer’s disease. However, it remains elusive how astrocytic mGluR5 contributes to the pathogenesis

Structural MRI can robustly assess brain tissue alterations related to neurological diseases and ageing. Traditional morphological MRI metrics, such as cortical volume and thickness, only partially relate to functional impairment and disease trajectories at the individual level. Emerging research has increasingly focused on reconstructing interregional meso- and macro-structural relationships in the

With the declaration of monkeypox virus (MPXV) infection as a global health emergency in 2022 by the WHO and its ongoing presence, Orthopoxviruses have garnered increasing attention, including their capacity to cause neurological disease. Indeed, the mpox syndrome caused by MPXV infection is recapitulated in humans for several other Orthopoxviruses including variola (VARV, the cause of smallpox), Vaccinia

This scientific commentary refers to ‘Medial temporal lobe atrophy in Down syndrome along the Alzheimer’s disease continuum’ by Buehner et al. (https://doi.org/10.1093/brain/awaf133).

Neurodevelopment is an intricate process encompassing the proliferation, differentiation, migration, and maturation of neural cells. Disruptions in these tightly regulated events can lead to a variety of neurodevelopmental disorders. Filamin A (FLNA), a key actin-binding protein, plays a pivotal role in regulating neuronal migration, morphological development, and synaptic connectivity by modulating

Swallowing is a complex sensorimotor task critical for maintaining nutrition, hydration, and quality of life. Given the widespread neural involvement and combined volitional and reflexive control, many neurologic conditions can result in swallowing disorders (dysphagia). There is no classification framework for neurogenic dysphagia according to where dysfunction lies within the sensorimotor hierarchy

What do you, a bilingual person, do when a surgeon asks which language you wish to keep as he is about to perform an awake craniotomy to remove your right frontal lobe brain tumour? Winner of the Brain Essay Competition 2024, Camille Bégin shares her personal experience of brain surgery.

This scientific commentary refers to ‘Serotonergic dysfunction in patients with impulse control disorders in Parkinson’s disease’ by Prange et al. (https://doi.org/10.1093/brain/awaf087).

Primary familial brain calcification (PFBC) provides valuable insights into the mechanisms underlying brain calcification as it singles out the proteins that potentially are involved in the relevant cellular pathways. To date, seven genes have been linked to PFBC, and studying their encoded proteins marks an exciting new era in understanding the disease mechanisms, which may ultimately lead to therapeutic

Spasticity, a prevalent motor issue characterized by network hyperexcitability, causes pain and discomfort, with existing treatments offering limited relief. While past research has focused on neuronal factors, the role of astrocytes in spasticity has been overlooked. This study explores the potential of restoring astrocytic potassium (K+) uptake to reduce spasticity following spinal cord injury (SCI)

Epstein-Barr virus (EBV) is strongly associated with multiple sclerosis (MS). It is likely to play a causal role in the pathogenesis of MS, possibly via triggering autoimmunity through molecular mimicry, autoantigenic presentation or immune dysregulation. Alternatively, evidence supports a direct role for EBV in driving MS disease activity via latent-lytic infection cycling either within the central

Migraine has an assumed polygenic basis, but the genetic risk variants identified in genome-wide association studies only explain a proportion of the heritability. We aimed to develop machine learning models, capturing non-additive and interactive effects, to address the missing heritability. This was a cross-sectional population-based study of participants in the second and third Trøndelag Health

The neuropathological process in Parkinson’s disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders. Here, we investigate the role of the macrostructural integrity of the nucleus basalis of Meynert

This scientific commentary refers to ‘Combinatorial approaches increasing neuronal activity accelerate recovery after spinal cord injury’ by Chen et al. (https://doi.org/10.1093/brain/awaf099).

Chronic hypoperfusion has been considered a major mechanism of cerebral small vessel disease. Nonetheless, brain tissue may increase oxygen extraction fraction to mitigate hypoxia and delay parenchymal damage. This study aims to investigate oxygen extraction fraction in cerebral small vessel disease and understand its relationship to disease burden and progression. We retrospectively included 195 patients

Hippocampal sclerosis of aging (HS-A) –severe cell loss and gliosis in the hippocampal formation– is a neuropathologic change (NC) that affects up to 20% of elderly persons with dementia. The etiology of HS-A is heterogeneous, but HS-A is strongly associated with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC). Other NCs have also been implicated in relation to HS-A, but these associations

Vanishing white matter (VWM) is a leukodystrophy caused by mutations in any of the genes encoding the subunits of the eukaryotic translation initiation factor 2B (eIF2B), a central factor in mRNA translation initiation and regulator of the translation rate during the integrated stress response (ISR). Clinically, VWM is characterized by chronic motor and cognitive decline and premature death. Neuropathology

This scientific commentary refers to ‘Impaired reward sensitivity in Parkinson’s depression is unresponsive to dopamine treatment’ by Costello et al. (https://doi.org/10.1093/brain/awaf098).

The adaptive immune system and neurodegenerative Alzheimer’s disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease

Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analyzed blood and fibroblast DNA methylation, transcriptomes, proteomes, and phenotypes of 53 MORC2 patients

A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function

Targeted radiotherapy (RT) is integral to the increasing survival of cancer patients; however, it has significant side-effects, the underlying cellular and molecular mechanisms of which are ill-defined. It is well documented that RT induces epigenetic changes in neoplastic tissue, which impacts tumour evolution, however whether epigenetic deregulation also occurs in the surrounding non-neoplastic tissue

Krabbe disease (KD) is an autosomal recessive sphingolipidosis due to mutations of the GALC gene encoding for the lysosomal β-galactosylceramidase (GALC) that removes β-galactose from β-galactosylceramide, β-lactosylceramide (LacCer), and the neurotoxic metabolite β-galactosylsphingosine (psychosine). At present, the accumulation of psychosine is thought to be the main cause of demyelination, neurodegeneration

tRNA-derived small RNAs (tsRNAs), previously considered inactive tRNA degradation products, have now been shown to be functional small noncoding RNAs. They may play important roles within the central nervous system (CNS) and in brain-body interactions both during normal developmental stages as well as in diverse brain pathologies. Among the cell types found in the CNS, tsRNAs are most abundant in neurons

About 25% of cognitively unimpaired older adults have an elevated brain amyloid burden comparable to that of individuals with symptomatic Alzheimer’s disease. Pomara and Imbimbo examine the ongoing debate over whether these individuals should be classified as having preclinical Alzheimer’s disease or simply be considered ‘at risk’.

This study evaluates the efficacy of arsa-cel gene therapy (GT) in mitigating the severity and progression of peripheral neuropathy as assessed by nerve conduction velocity (NCV) in individuals affected by late-infantile metachromatic leukodystrophy (LI-MLD). This is a post-hoc analysis conducted on pre-symptomatic patients affected by LI-MLD treated with ex vivo autologous hematopoietic stem cell

Idiopathic immune myopathies (IIM) represent a heterogeneous group of diseases, in which muscle lesions result from deregulated immune reactions. Typical histological features include myofibre necrosis, leukocyte infiltration, and aberrant myofibre Major Histocompatibility Complex (MHC) expression. To investigate the link between MHC expression, inflammation, and muscle lesions, muscle biopsies from

Pathogenic variants in GRIN2D, encoding one of the subunits of the NMDA receptor (NMDAR), are associated with developmental and epileptic encephalopathies (DEEs). Unusual for de novo mutations, the recurrent, de-novo, gain of function, missense mutation c.1999G>A (p.Val667Ile) was discovered in multiple patients. We characterized a mouse model carrying the orthologous Grin2d mutation, using behavioral

Neuroaxonal injury is a major driver of irreversible disability in demyelinating conditions. Accurate assessment of the association between demyelination and axonal pathology is critical for evaluating and developing effective therapeutic approaches. Measuring neurofilament light chain (NfL) in blood could putatively allow longitudinal monitoring of neuroaxonal injury at “single protein resolution”

Inherited erythromelalgia, small fiber neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage gated sodium channel Nav1.7. How different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations remains unknown. Most of the work analysing the impact of these mutations on electrophysiological

Whether or not neuropsychiatric symptoms (NPS) in advance of dementia are associated with Alzheimer disease (AD) and/or other neurodegenerative dementias remains to be determined. The mild behavioural impairment (MBI) construct selects persons with NPS that are later-life emergent and persistent to identify a high-risk group for cognitive decline and incident dementia. Here, in older adults without