Volume 138, Issue 11, November 2015

This scientific commentary refers to ‘Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot–Marie–Tooth disease in mice’, by Klein et al. (doi:10.1093/brain/awv240).

This scientific commentary refers to ‘Brain endothelial dysfunction in cerebral adrenoleukodystrophy’ by Musolino et al. (doi: 10.1093/awv250)

This scientific commentary refers to ‘Neurorestoration after traumatic brain injury through angiotensin II receptor blockage’, by Villapol et al. (doi:10.1093/brain/awv172).

This scientific commentary refers to ‘Why patients with spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) do not develop parkinsonism despite severe neuronal loss in the dopaminergic substantia nigra’ by Schöls et al. (doi:10.1093/brain/awv255).

Objective measures of cochlear hair cell function and auditory nerve/brainstem activity allow differentiation of hearing impairments caused by sensory receptor loss, synaptic dysfunction and auditory nerve disorders. To help increase diagnostic specificity further, Rance and Starr review clinical and pathophysiological features of auditory neuropathy as a function of lesion site.

Most patients with NMDAR-antibody encephalitis develop seizures. To examine the epileptogenicity of NMDAR antibodies in vivo, Wright et al. inject antibodies from patients into the mouse brain. NMDAR-Ab mice show more frequent seizures after subthreshold doses of the convulsant pentylenetetrazol than controls, while post-mortem antibody binding correlates with seizure activity.

Muscle cramps are a common complaint, but the underlying mechanisms remain unclear. Czesnik et al. examine the factors affecting excitability of peripheral axons in 20 patients with benign cramp fasciculation syndrome. Results suggest that increased HCN channel-driven inward rectification leads to both increased axonal excitability and increased motor unit discharge.

Mutations in the gene encoding Myelin Protein Zero (MPZ) are the second most common cause of Charcot-Marie-Tooth disease type 1. Sanmaneechai et al. present cross-sectional data from 103 patients with MPZ mutations, recruited by an international collaborative group. The analyses reveal genotype-phenotype correlations, and establish baseline data for clinical trials.

See Scherer (doi:10.1093/awv279) for a scientific commentary on this article.

Inflammation constituted by macrophages amplifies neuropathy in mouse models of Charcot–Marie–Tooth disease type 1 (CMT1). Klein et al. show that inhibition of colony stimulating factor 1 receptor reduces macrophage numbers and produces a substantial rescue of peripheral nerves in mouse models of two distinct CMT1 types, suggesting therapeutic potential.

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.

Cerebral adrenoleukodystrophy is a neuroinflammatory demyelinating disease caused by mutations in ABCD1. Musolino et al. report that the progressive demyelination coincides with blood-brain barrier disruption and endothelial changes. Silencing endothelial ABCD1 in vitro upregulates expression of adhesion molecules and downregulates expression of tight-junction proteins and c-MYC, promoting monocyte transmigration.

Spinocerebellar ataxia type 3 (Machado-Joseph disease) is an incurable neurodegenerative disorder caused by polyglutamine expansion within ataxin-3. In a repurposing drug screen, Teixeira-Castro et al. identify the selective serotonin reuptake inhibitor citalopram as a suppressor of mutant ataxin-3 neurotoxicity in transgenic C. elegans and mouse models of the disease.

Epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Hardies et al. establish independent evidence that autosomal recessive mutations in SLC13A5, which encodes a sodium-dependent citrate transporter, lead to a neonatal epileptic encephalopathy with developmental delay. Teeth hypoplasia is revealed as an additional feature of the disorder.

Ullman and Spencer-Smith et al. use neonatal structural MRI to predict cognitive and academic functioning at 5 and 7 years in very preterm children. Univariable and multivariable models reveal associations between the neonatal volume of regions in the vicinity of the insula and putamen, white matter microstructure and childhood working memory and mathematical skills.

A variant of the CD226 gene predisposes to multiple sclerosis. Piédavent-Salomon et al. show that CD226 expression is reduced in regulatory T cells (Treg) of CD226 risk-haplotype carriers and patients with multiple sclerosis, compared to healthy protective-haplotype carriers. Treg suppressive ability is reduced in patients, risk-haplotype carriers and Cd226-deficient mice.

In a multicentre, observational, prospective cohort study, Iaffaldano et al. compare the effectiveness of fingolimod versus interferon beta/glatiramer acetate in reducing the risk of disease reactivation after natalizumab discontinuation in multiple sclerosis. Fingolimod appears to be more effective than interferon beta/glatiramer acetate in controlling disease reactivation in a real-world setting.

Short-term disability progression over 3–6 months is commonly used in multiple sclerosis clinical trials to estimate treatment effects on long-term accumulation of irreversible disability. Kalincik et al. compare 48 criteria for disability progression, and show that 12–24 month confirmed progression provides a more accurate estimate of disability accrual.

See Moon (doi:10.1093/awv239) for a scientific commentary on this article.

Angiotensin II type 1 receptor (AT1R) blockers, or ‘sartans’, are neuroprotective and neurorestorative. Villapol et al. show that the FDA-approved drugs candesartan and telmisartan promote morphological and functional recovery in a mouse model of traumatic brain injury. Sartans with dual AT1R-blocking and PPARγ-activating properties have therapeutic potential in patients.

See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.

Patients with spinocerebellar ataxia type 2 (SCA2) or type 3 (SCA3) consistently show severe substantia nigra degeneration, but rarely develop parkinsonism. Based on PET and post-mortem analysis, Schöls et al. suggest that degeneration of the motor territory of the subthalamic nucleus in SCA2/SCA3 helps to protect these individuals from parkinsonism.

Diffuse structural connectivity loss occurs early in Huntington’s disease. However, the organizational principles underlying these changes are unclear. Using whole brain diffusion tractography and graph theoretical analysis, McColgan, Seunarine et al. identify a specific role for highly connected rich club regions as a substrate for structural connectivity loss in Huntington’s disease.

Iovino et al. generate induced pluripotent stem cell-derived neurons from human subjects with P301L or N279K MAPT mutations, and show that the cells express adult brain pattern of tau isoforms after several months in culture. MAPT mutant neurons mature earlier than control neurons and display mutation-specific phenotypes.

Symptoms suggesting altered pain and temperature processing have been described in dementia diseases. Using a semi-structured caregiver questionnaire and MRI voxel-based morphometry in patients with frontotemporal degeneration or Alzheimer’s disease, Fletcher et al. show that these symptoms are underpinned by atrophy in a distributed thalamo-temporo-insular network implicated in somatosensory processing.

Synaptic dysfunction precedes neurodegeneration and cognitive impairment in Alzheimer’s disease. Portelius et al. show that CSF levels of the postsynaptic protein neurogranin are increased in early-stage Alzheimer’s disease, and that the increase predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.

Cases of iatrogenic CJD still occur in the UK 30 years after administration of human pituitary-derived growth hormone ceased. Rudge et al. report a change over time in genotype profile at polymorphic codon 129 of the human prion protein gene in UK patients, distinct from that seen in other countries.

In a double-blind placebo-controlled trial, Watanabe et al. show that six-week oxytocin administration reduces core social symptoms of autism, increases resting-state functional connectivity in medial prefrontal cortex, and mitigates abnormalities in behavioural and neural responses during a social judgement task. The findings suggest clinical benefits of continual oxytocin use.

A key goal of addiction research is to identify biomarkers that predict subsequent dependence. Harlé et al. show that in high-functioning occasional stimulant users performing an inhibitory control task, individual differences in how the brain encodes the need to stop predict the likelihood of abuse or dependence three years later.

The inferior frontal gyrus (IFG) integrates emotional and cognitive information. Using Dynamic Causal Modelling of fMRI data from an Emotional Go/No Go task, Breakspear et al. reveal reduced effective connectivity between the IFG, anterior cingulate and DLPFC in first-degree relatives of patients with bipolar disorder, compared to patients and controls.

In a longitudinal structural MRI study of bipolar disorder, Abé et al. reveal a reduction in volume of frontal cortex in patients who experience manic episodes, but not in those who remain well. The results suggest that frontal grey matter loss in bipolar disorder can be attributed to the occurrence of mania.