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Volume 147, Issue 6
June 2024
Cover image
Cover image
Cover image: Ostriches in the Namib desert run compulsively ahead of cars even when there is no clear beneficial goal, but occasionally they stop to evaluate the situation. How people arbitrate between habitual and goal-directed actions is considered in. Brain. 2024; 147(6):2230–2244. (Image courtesy of Ammar Al-Chalabi).
ISSN 0006-8950
EISSN 1460-2156
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Editorial
Beyond ventral and dorsal streams: thalamo-cortical connections for subcortical language integration
Dorothee Saur
Brain, Volume 147, Issue 6, June 2024, Pages 1927–1928, https://doi.org/10.1093/brain/awae152
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Scientific Commentaries
The brain’s arbitration system and obsessive-compulsive disorder
Trevor W Robbins
Brain, Volume 147, Issue 6, June 2024, Pages 1929–1930, https://doi.org/10.1093/brain/awae133
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).
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Targeting excitatory:inhibitory network imbalance in Alzheimer’s disease
David Blum and Sabine Levi
Brain, Volume 147, Issue 6, June 2024, Pages 1931–1933, https://doi.org/10.1093/brain/awae146
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).
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The implications of amyloid-β pathology: only time will tell
Emma M Coomans and Rik Ossenkoppele
Brain, Volume 147, Issue 6, June 2024, Pages 1934–1936, https://doi.org/10.1093/brain/awae147
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).
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Review Articles
The basal forebrain cholinergic system as target for cell replacement therapy in Parkinson’s disease
Anders Björklund and Roger A Barker
Brain, Volume 147, Issue 6, June 2024, Pages 1937–1952, https://doi.org/10.1093/brain/awae026
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.
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A neuroanatomical and cognitive model of impaired social behaviour in frontotemporal dementia
Matthew A Rouse and others
Brain, Volume 147, Issue 6, June 2024, Pages 1953–1966, https://doi.org/10.1093/brain/awae040
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.
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Reports
Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant
Beryll Blickhäuser and others
Brain, Volume 147, Issue 6, June 2024, Pages 1967–1974, https://doi.org/10.1093/brain/awae057
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.
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Lesion network of oculogyric crises maps to brain dopaminergic transcriptomic signature
Bassam Al-Fatly and others
Brain, Volume 147, Issue 6, June 2024, Pages 1975–1981, https://doi.org/10.1093/brain/awae094
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.
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Original Articles
Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia
Jirap*rn Ousingsawat and others
Brain, Volume 147, Issue 6, June 2024, Pages 1982–1995, https://doi.org/10.1093/brain/awad412
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.
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Genetic analysis and natural history of Parkinson’s disease due to the LRRK2 G2019S variant
Matthew J Kmiecik and others
Brain, Volume 147, Issue 6, June 2024, Pages 1996–2008, https://doi.org/10.1093/brain/awae073
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.
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Huntington’s disease affects mitochondrial network dynamics predisposing to pathogenic mitochondrial DNA mutations
Andreas Neueder and others
Brain, Volume 147, Issue 6, June 2024, Pages 2009–2022, https://doi.org/10.1093/brain/awae007
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.
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Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy
Lucia Abela and others
Brain, Volume 147, Issue 6, June 2024, Pages 2023–2037, https://doi.org/10.1093/brain/awae020
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.
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Editor's Choice
Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson’s disease
Maria Olaru and others
Brain, Volume 147, Issue 6, June 2024, Pages 2038–2052, https://doi.org/10.1093/brain/awae004
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.
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Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models
Cristian A Droppelmann and others
Brain, Volume 147, Issue 6, June 2024, Pages 2053–2068, https://doi.org/10.1093/brain/awae078
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.
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Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy
Nathalie Launay and others
Brain, Volume 147, Issue 6, June 2024, Pages 2069–2084, https://doi.org/10.1093/brain/awae038
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.
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Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders
James Liu and others
Brain, Volume 147, Issue 6, June 2024, Pages 2085–2097, https://doi.org/10.1093/brain/awae055
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.
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Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain
Scott T Brady and others
Brain, Volume 147, Issue 6, June 2024, Pages 2098–2113, https://doi.org/10.1093/brain/awad280
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.
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Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase
Hye Yoon Chung and others
Brain, Volume 147, Issue 6, June 2024, Pages 2114–2127, https://doi.org/10.1093/brain/awae017
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.
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Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer’s disease
Yingying Han and others
Brain, Volume 147, Issue 6, June 2024, Pages 2128–2143, https://doi.org/10.1093/brain/awae015
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.
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Editor's Choice
Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer’s disease
Karly A Cody and others
Brain, Volume 147, Issue 6, June 2024, Pages 2144–2157, https://doi.org/10.1093/brain/awae116
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.
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Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer’s disease
Hyun-Sik Yang and others
Brain, Volume 147, Issue 6, June 2024, Pages 2158–2168, https://doi.org/10.1093/brain/awae034
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.
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Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer’s disease and 5XFAD mice
Aaron J Barbour and others
Brain, Volume 147, Issue 6, June 2024, Pages 2169–2184, https://doi.org/10.1093/brain/awae126
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.
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Disease-linked mutations in Munc18-1 deplete synaptic Doc2
Noah Guy Lewis Guiberson and others
Brain, Volume 147, Issue 6, June 2024, Pages 2185–2202, https://doi.org/10.1093/brain/awae019
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.
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Localization of stuttering based on causal brain lesions
Catherine Theys and others
Brain, Volume 147, Issue 6, June 2024, Pages 2203–2213, https://doi.org/10.1093/brain/awae059
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.
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Macroscopic changes in aquaporin-4 underlie blast traumatic brain injury-related impairment in glymphatic function
Molly Braun and others
Brain, Volume 147, Issue 6, June 2024, Pages 2214–2229, https://doi.org/10.1093/brain/awae065
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.
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Neurocomputational model of compulsivity: deviating from an uncertain goal-directed system
Taekwan Kim and others
Brain, Volume 147, Issue 6, June 2024, Pages 2230–2244, https://doi.org/10.1093/brain/awae102
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.
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Multimodal study of multilevel pulvino-temporal connections: a new piece in the puzzle of lexical retrieval networks
Igor Lima Maldonado and others
Brain, Volume 147, Issue 6, June 2024, Pages 2245–2257, https://doi.org/10.1093/brain/awae021
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.
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