Issues | Brain | Oxford Academic (2024)

This scientific commentary relates to ‘Neurocomputational model of compulsivity: deviating from an uncertain goal-directed system’ by Kim et al. (https://doi.org/10.1093/brain/awae102).

This scientific commentary refers to ‘Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer’s disease and 5XFAD mice’ by Barbour et al. (https://doi.org/10.1093/brain/awae126).

This scientific commentary refers to ‘Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer’s disease’ by Cody et al. (https://doi.org/10.1093/brain/awae116).

Degeneration of the basal forebrain cholinergic system is a major cause of cognitive impairments and dementia in patients with Parkinson’s disease. Björklund and Barker summarize the extensive experimental data in support of the idea that transplants of cholinergic neurons could be used to restore cognitive function.

Rouse et al. propose an integrative neurocognitive model of controlled social behaviour that can explain the observed impairment of social behaviours in frontotemporal dementia. The model can also account for findings from other patient groups, including individuals with semantic dementia, and from studies of the healthy brain.

Blickhäuser et al. examine why certain individuals carrying specific mitochondrial DNA variants primarily associated with optic neuropathy experience exceptionally severe Leigh syndrome spectrum disease. They conclude that the co-occurrence of these variants with a second variant in an interacting gene causes the more severe phenotype.

Al-Fatly et al. use lesion-network mapping to identify a network of brain regions involved in the pathophysiology of lesion-induced oculogyric crises, and show that the topography of the network overlaps spatially with the expression of dopamine receptor type 2 in the brain.

Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. Ousingsawat et al. identify an association between ANO3 variants and paroxysmal dystonia and investigate the underlying mechanisms.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson’s disease. In a prospective longitudinal study, Kmiecik et al. find that genotyped LRRK2 G2019S carriers report a similar burden of motor symptoms to non-carriers with Parkinson’s disease, but fewer non-motor symptoms including cognitive difficulties and hyposmia.

Neueder et al. reveal an accumulation of mitochondrial DNA mutations and impairments in mitochondrial quality control in fresh skeletal muscle samples from patients with Huntington’s disease. Accelerated mitochondrial ageing may thus be one of the biological signatures of Huntington’s disease, including in peripheral tissues.

Abela et al. identify neurodevelopmental and synaptic vesicle recycling defects in a patient-derived neuronal cell model of early-onset DNAJC6 parkinsonism. Rescue of key cellular disease features using lentiviral DNAJC6 delivery demonstrates the utility and feasibility of a potential gene therapy approach.

Olaru et al. used neurostimulators with sensing capabilities to record over 900 h of motor cortex and basal ganglia activity from patients with Parkinson’s disease in their own homes, with wearable monitors providing scores of motor impairment. The results revealed a relationship between excessive gamma rhythms and dyskinesia.

Droppelmann et al. show that an N-terminal fragment of a protein called RGNEF (NF242) competes with RNA to interact directly with TDP-43. In fruit fly and mouse models of ALS, NF242 extended lifespan and reduced motor impairments, suggesting that this approach could be a promising therapeutic strategy for TDP-43 proteinopathies.

Launay et al. identify abnormalities in mitochondrial dynamics, favouring increased mitochondrial fission, in models of the inherited neurodegenerative disorder, X-linked adrenoleukodystrophy. Targeting mitochondrial dynamics could be a new avenue for therapeutic intervention.

Biallelic pathogenic variants in PNPLA6, which encodes neuropathy target esterase (NTE), cause a broad spectrum of neurological disorders. Liu et al. show that NTE activity predicts neurological phenotypes among affected individuals, suggesting that PNPLA6 disorders are a continuous spectrum of pleiotropic phenotypes defined by the activity of NTE.

Brady et al. show that axonal toxicity of mutant huntingtin requires a proline rich domain (PRD) adjacent to the polyQ tract which contains SH3-binding motifs and which is normally sequestered in wildtype huntingtin. PolyQ expansion leads to PRD exposure, resulting in aberrant activation of a MAP kinase and axonal degeneration.

Mutations in the Microrchidia CW-type zinc finger 2 (MORC2) gene give rise to Charcot-Marie-Tooth disease type 2Z, but the underlying mechanism is unclear. Chung, Lee et al. demonstrate in mice that Morc2a variants cause hydroxyl radical-mediated neuropathy and show that this can be rescued through AAV-based gene therapy.

Han, Chen et al. show that the transcription factor Maf1 is upregulated in the hippocampus of patients with Alzheimer’s disease and in APP/PS1 mice. Maf1 regulates the expression of NMDAR1 by binding to the promoter of the Grin1 gene and could represent a potential therapeutic target for Alzheimer’s disease.

Cody et al. implement a novel time framework to characterize the accumulation of tau pathology and cognitive decline relative to amyloid onset in Alzheimer’s disease. Characterizing the temporal disease cascade with respect to amyloid explains a considerable amount of heterogeneity in early disease progression.

See Coomans et al. (https://doi.org/10.1093/brain/awae147) for a scientific commentary on this article.

Yang and Yau et al. studied blood markers of vascular health in older adults and found that the plasma levels of two proteins involved in blood vessel formation predicted future Alzheimer’s disease pathology and cognitive decline. The results suggest potential diagnostic and therapeutic targets in early-stage Alzheimer’s disease.

Barbour et al. report that seizures worsen cognitive decline and excitatory:inhibitory imbalance in patients with Alzheimer's disease. Chronic treatment with the mTORC1 inhibitor rapamycin rescued aspects of this imbalance in an Alzheimer’s disease mouse model, suggesting therapeutic promise for patients with a seizure history.

See Blum et al. (https://doi.org/10.1093/brain/awae146) for a scientific commentary on this article.

Mutations in Munc18-1/STXBP1 cause encephalopathies, but the underlying disease mechanism is unclear. Guiberson et al. show that mutations in Munc18-1 not only affect Munc18-1 itself, but also deplete its interactor Doc2. The severity of this effect is dependent on the Munc18-1 mutation, which may explain symptom heterogeneity.

By studying the locations of lesions causing stroke-induced stuttering, Theys, Jaakkola et al. identify a common acquired stuttering network, centred around the left posterior putamen. This network is also associated with the severity of developmental stuttering, providing support for a shared neural basis across aetiologies.

Blast traumatic brain injury is associated with an increased risk of long-term neurological and psychiatric sequelae, but the underlying mechanisms are unclear. Using clinical and preclinical data, Braun et al. show that blast injury may impair the function of the glymphatic system, responsible for the removal of waste from the brain.

Kim et al. propose that compulsivity in obsessive-compulsive disorder results from reduced top-down control of a habit controller (the putamen) by a prefrontal arbitrator. Enhancing fronto-striatal connectivity could be a promising strategy for reducing compulsivity and improving adaptive decision-making.

See Robbins et al. (https://doi.org/10.1093/brain/awae133) for a scientific commentary on this article.

Maldonado et al. use in vivo tractography and post-mortem dissections to study the connections joining the pulvinar to the temporal lobe. They describe four branches, including one parallel to the auditory radiations, and show by electrical stimulation in awake surgery that this branch has a causal role in lexical retrieval.