Volume 140, Issue 11, November 2017

This scientific commentary refers to ‘TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor’, by Kariminejad et al. (doi:10.1093/brain/awx230).

This scientific commentary refers to ‘Abnormal intrinsic brain functional network dynamics in Parkinson’s disease’, by Kim et al. (doi:10.1093/brain/awx233).

This scientific commentary refers to ‘Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease’, by Rorabaugh et al. (doi:10.1093/brain/awx232).

This scientific commentary refers to ‘Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients’, by Nardo et al. (doi:10.1093/brain/awx234).

Cell-based therapies, including autologous haematopoietic stem cell transplantation, have generated substantial interest as strategies for immune modulation, neuroprotection, or repair of the damaged CNS in multiple sclerosis. Scolding et al. summarise the status of cell-based therapies and make consensus recommendations for future studies and clinical trials.

Devoy et al. develop the first mouse model to fully recapitulate human FUS-ALS, as defined by midlife-onset progressive degeneration of motor neurons with dominant inheritance. A toxic gain of function occurs in the absence of FUS protein aggregation, involving disturbance of ribosomes and mitochondria at the endoplasmic reticulum.

The mitochondrial calcium uniporter (MCU) complex plays a critical role in mitochondrial calcium homeostasis. Shamseldin et al. provide the first demonstration of MICU2 (a component of MCU) deficiency in humans, which they suggest causes a distinct neurodevelopmental phenotype secondary to impaired MCU-mediated regulation of intracellular calcium homeostasis.

Prognostic markers for primary progressive multiple sclerosis would help inform treatment decisions. In 54 patients with a 15-year clinical follow-up, Rocca et al. show that integration of clinical and imaging measures allows identification of patients at risk of long-term disease progression four years earlier than clinical assessment alone.

Riboflavin metabolites are critical components of the mitochondrial electron transport chain. Manole et al. describe the genetics, phenotypes and neuropathology of a large patient series with riboflavin-responsive neuropathy. Using in-vitro and in-vivo models, they reveal mitochondrial dysfunction in the disorder, and validate riboflavin esters as a potential therapeutic strategy.

Wang et al. describe an autosomal recessive severe or lethal presynaptic congenital myasthenic syndrome caused by N-terminal missense mutations in SLC5A7, which encodes the high-affinity choline transporter, CHT. Transporter activity studies together with C. elegans axonal transport studies provide insights into the nature and severity of disease in affected individuals.

See Ginevrino and Valente (doi:10.1093/brain/awx260) for a scientific commentary on this article.

The p.Glu303del mutation in TOR1A is the commonest cause of torsion dystonia-1. Kariminejad et al. identify three Iranian families with homozygous TOR1A mutations associated with severe arthrogryposis, developmental delay, strabismus and tremor. Two of the families carry the p.Glu303del mutation, and the third, a novel homozygous missense mutation (p.Gly318Ser).

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of progressive neurodegenerative disorders. Nibbeling et al. report five novel SCA genes identified via exome sequencing, functional validation, and network analysis in genetically undiagnosed families. Alterations in synaptic transmission and transcription regulation underlie diverse SCA types.

GABRA3 encodes the alpha3 subunit of GABAA receptors. Niturad et al. identify six GABRA3 variants in familial and sporadic cases presenting with a range of epileptic seizure types, varying degrees of intellectual disability and developmental delay, and sometimes dysmorphic features or nystagmus. All detected variants cause a loss of function.

Localized cerebral blood flow reductions may underlie focal neurological deficits following seizures. Using arterial spin labelling, Gaxiola-Valdez et al. observe postictal hypoperfusion in roughly 70% of patients, which localizes to the seizure onset zone in 80% of cases. Postictal hypoperfusion may thus constitute a marker of the seizure onset zone.

Neuroaxonal pathology is a major contributor to disease progression in multiple sclerosis, but its time course remains uncertain. Using advanced MRI in patients with early multiple sclerosis, Granberg et al. reveal neuroaxonal pathology outside typical white matter lesions, including diffuse axonal disruption and frequent cortical lesions.

MRI alone provides limited information for predicting disability progression in individual patients with multiple sclerosis. Datta et al. demonstrate that PET imaging of ongoing brain inflammation contributes, independent of MRI, to explaining variance in future disease activity. Neuroinflammation appears to shift from contributing to multi-focal to global brain injury.

Glioblastomas are aggressive brain tumours that contain a subpopulation of highly plastic self-renewing cancer cells. Harford-Wright et al. show that the vasoactive peptide apelin, secreted by brain endothelial cells, regulates glioblastoma patient-derived cells with stem-like properties. Pharmacological blockade of apelin hampers glioblastoma cell expansion and improves survival in xenografted mice.

See Nieuwhof and Helmich (doi:10.1093/brain/awx267) for a scientific commentary on this article.

Dynamic functional connectivity may serve as a biomarker of disease state in Parkinson's disease. Kim et al. investigate the temporal properties of functional connectivity states as well as the variability of network topological organization. They reveal two discrete connectivity configurations, confirming the vulnerability of functional connectivity networks in Parkinson’s disease.

Tinkhauser et al. report that long duration beta bursts are associated with an increase in local and inter-hemispheric synchronisation in Parkinson’s disease. This may compromise information coding capacity and thereby motor processing. Dopaminergic activity limits synchronisation by terminating long duration bursts, with positive consequences for network state and motor symptoms.

Foetal tissue grafts in patients with Huntington’s or Parkinson’s disease have been shown to develop Huntington- or Parkinson-like pathology. Cisbani et al. reveal that such grafts may also contain tau pathology, further implicating tau in these disorders, and suggesting that tau may spread via transynaptic propagation from the host.

‘Targeted motor and sensory reinnervation’ (TMSR) entails rerouting residual limb nerves towards intact muscles and skin to try to achieve prostheses that move and feel like real limbs. Using ultra-high field 7T fMRI, Serino et al. examine upper limb representations in M1 and S1 of amputees who have undergone TMSR.

Little is known about the interaction between Alzheimer’s disease and cerebrovascular disease with respect to network degeneration. Chong et al. demonstrate differential functional and structural network changes in patients with Alzheimer’s disease with and without cerebrovascular disease, suggesting that the two groups may have different underlying pathologies.

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article.

Hyperphosphorylated tau in the noradrenergic locus coeruleus is the first detectable sign of Alzheimer's disease-like neuropathology in humans. Rorabaugh et al. report that TgF344-AD rats display endogenous tau pathology in the locus coeruleus, associated with noradrenergic fibre loss. Chemogenetic activation of the nucleus rescues cognitive impairment in the model.

See Thompson and Woollams (doi:10.1093/brain/awx264) for a scientific commentary on this article.

Naming in aphasia can be facilitated by phonemic cueing, both as an immediate retrieval strategy and as a long-term treatment. Nardo et al. report that immediate and long-term facilitation of naming rely on common neural networks, while whole words and partial cues promote naming via different networks.

Eighty years ago, Penfield and Boldrey introduced the homunculus in a paper published in Brain. In a reappraisal of the iconic aide-mémoire, Marco Catani reanalyses the original data, and argues that through its extended network the homunculus holds the key to the precise coding that results in coordinated activation of peripheral muscles.