Volume 146, Issue 9, September 2023

How do socioeconomic disparities shape brain health and disease? Ibáñez et al. discuss the need for further research into how wealth and socioeconomic status affect biological models of dementia, highlighting the biological ripple effects of socioeconomic inequalities and the importance of globally inclusive brain health research.

This scientific commentary refers to ‘Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells’ by Bodin et al. (https://doi.org/10.1093/brain/awad228).

This scientific commentary refers to ‘Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies’ by Okkels et al. (https://doi.org/10.1093/brain/awad192).

This scientific commentary refers to ‘Corticostriatal beta oscillation changes associated with cognitive function in Parkinson’s disease’ by Paulo et al. (https://doi.org/10.1093/brain/awad206).

This scientific commentary refers to ‘Impulse control disorder in Parkinson’s disease is associated with abnormal frontal value signalling’ by Tichelaar et al. (https://doi.org/10.1093/brain/awad162).

Herz and Brown review observations of movement slowness in Parkinson’s disease and discuss these findings in a behavioural framework borrowing principles from optimal control. They conclude that bradykinesia may result from abnormal utility computations based on the rewards and efforts associated with an action.

Calabresi et al. review the physiological and pathological roles of alpha-synuclein, focusing on its pre- and post-synaptic effects. Discussing findings from preclinical models of Parkinson’s disease, they explore how alterations at the cellular level contribute to the spread of pathology at the network level.

Dadario and Sughrue provide an update on the structural and functional organization of the precuneus from a connectivity-based perspective. The role of the precuneus in higher cognitive functions and disease states can be understood based on its involvement in three functionally relevant brain networks.

Jeon et al. report that the TGFβ4/Nodal axis plays a key role in the pathogenesis of Charcot-Marie-Tooth disease type 1A and could represent a potential therapeutic target.

Pinard et al. identify rare variants in ANO1, which encodes the calcium-activated chloride channel anoctamin-1, in families with moyamoya disease, a cerebrovascular arteriopathy that leads to strokes in children and young adults. Functional assays show that the majority of the variants increase the activity of the chloride channel.

Using sub-diffraction imaging, Bodin et al. reveal localization of TDP-43 at the centrosome throughout all phases of the cell cycle. This first description of TDP-43 centrosomal enrichment in human cells paves the way to a more comprehensive understanding of TDP-43 physiology and pathology.

See Megan Dykstra and Sami J. Barmada (https://doi.org/10.1093/brain/awad268) for a scientific commentary on this article.

Ren et al. identify a specific MAP3K3 mutation in approximately 40% of a cohort of patients with cerebral cavernous malformations (CCMs), and develop a mouse model by expressing the mutation in the CNS endothelium. The mice show phenotypes similar to those of patients, illustrating that a single genetic hit can be sufficient to cause CCMs.

Rosenzopf et al. investigate the network changes underlying ‘pusher syndrome’, in which perception of upright body posture is impaired following unilateral stroke. Structural and functional connectivity analyses suggest that pusher syndrome is a consequence of direct damage to or disconnection of the posterior thalamus.

By recording local field potentials from patients with Parkinson’s disease performing a verbal working memory task during deep brain stimulation surgery, Paulo et al. reveal changes in corticostriatal beta power associated with cognitive impairment. Individuals with cognitive impairment show smaller decreases in beta power during encoding.

See Mansoureh Fahimi Hnazaee and Vladimir Litvak (https://doi.org/10.1093/brain/awad273) for a scientific commentary on this article.

Tichelaar et al. examine the effect of dopaminergic medication on reward learning in Parkinson’s disease. Patients with impulse control disorders are particularly sensitive to rewards when on dopaminergic medication, and this reward sensitivity is associated with increased value signalling in the medial prefrontal cortex.

Okkels et al. provide evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, and suggest that degeneration of the cholinergic system leads to altered brain metabolism and may be linked with degeneration in other transmitter systems.

See Simon J. G. Lewis (https://doi.org/10.1093/brain/awad241) for a scientific commentary on this article.

Asci et al. investigate the pathophysiology of rigidity in Parkinson’s disease by combining biomechanical and neurophysiological measures. Using a robotic device, they measure objective rigidity and its velocity-dependent features and clarify the pathophysiological role of long-latency reflexes.

Bocancea et al. investigate the factors that allow some individuals to maintain intact brain structure and cognitive performance despite abundant tau pathology. The results confirm the robust association between education and resilience, but also suggest that resilience may be depleted with advancing pathology.

Coomans & Tomassen et al. test associations between amyloid-β, tau, neurodegeneration and cognitive decline within pairs of identical twins using within-pair difference models, thereby ruling out potential confounding by genetic and shared environmental factors. The results are compatible with the amyloid cascade hypothesis.

Normal pressure hydrocephalus is a neurodegenerative disorder treatable by shunt surgery, but identifying patients who could benefit from surgery is a major challenge. Using genome-wide RNA sequencing of CSF, Levin et al. identify genes that predict shunt surgery responses with high accuracy.

The development of gene therapies for amyotrophic lateral sclerosis (ALS) has led to increased interest in genetic testing, including for patients with the sporadic form of the disease. Van Daele et al. characterize variability in ALS-associated genes, and search for likely pathogenic variants, in more than 6000 patients with sporadic ALS.

Catanese et al. use a multiomics approach to study ALS at transcriptomic, epigenetic and genetic levels. They identify a mutation-independent disease signature, providing insights into how different mutations and divergent pathomechanisms can converge into a singular presentation of disease.

De Lorenzo et al. report that intracerebroventricular administration of cerebral dopamine neurotrophic factor protects motor neurons, improves motor behaviour and delays disease progression in three rodent models of ALS.

De Bruyn et al. examine the clinical phenotype and genetic spectrum of a large European multicentre cohort of individuals with ANO5-related myopathies, and search for potential genotype–phenotype correlations.

In a nationwide study of 1066 Danish adults with viral meningitis, Petersen et al. report that incomplete recovery persists in one in five patients 30 days after discharge. Female patients in particular have an increased risk of an unfavourable outcome, whereas the type of virus is not associated with the prognosis.

Rehbein et al. present findings from a longitudinal study of the clinical phenotypes of adults and children with Charcot-Marie-Tooth disease type 4C caused by mutations in SH3TC2, including 14 previously unpublished variants. The results suggest that different mutation types may give rise to variations in phenotype.

Manolaras et al. demonstrate that COQ8A-ataxia is primarily caused by mitochondrial dysfunction leading to calcium dysregulation in Purkinje neurons of the cerebellum. These abnormalities can be rescued in vitro by treatment with coenzyme Q10.

Mikaeili et al. identify the molecular basis of FAAH-OUT-associated pain insensitivity, in which painlessness is accompanied by reduced anxiety and accelerated wound healing. The FAAH-OUT long non-coding RNA gene regulates FAAH expression via two transcription-dependent mechanisms, providing a platform for future gene therapy.

Wang et al. identify a sensory neuron-specific long non-coding RNA expressed predominantly in small neurons of the dorsal root ganglion, and show that this RNA contributes to the development and maintenance of neuropathic pain by regulating KCNN1 expression.

Dravet syndrome is typically considered monogenic, but shows marked phenotypic heterogeneity that is incompletely explained by differences in the causal SCN1A variant. Martins Custodio et al. now show that additional genomic variation beyond SCN1A contributes to and influences Dravet syndrome phenotypes.

Matarrese et al. provide insights into the pathophysiology of epilepsy by linking spike propagation and effective connectivity. They highlight the clinical value of spike onset as a biomarker that may improve presurgical evaluation and outcome prediction in patients with drug-resistant epilepsy.

Epilepsy surgery aims to alleviate seizures through the removal of the epileptic focus. Sainburg et al. provide evidence that this focal resection leads to functional changes in distant brain regions that are related to these regions’ structural disconnection from the resected epileptic focus.

Royer et al. examine mechanisms of memory impairment in temporal lobe epilepsy, and find that regions showing atypical functional connectivity during a memory task also show microstructural imbalances; that is, attenuated differences in intracortical lamination and myelination from neighbouring cortices.

Matsumoto et al. find that 70% of a cohort of patients with MOGAD are MOG-IgG-positive in both serum and CSF, whereas the remaining individuals are MOG-IgG-positive in serum (13%) or CSF (17%) alone. MOG-IgG positivity in serum versus CSF appears to be associated with differences in clinical phenotype.