Volume 142, Issue 3, March 2019

This scientific commentary refers to ‘Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis’, by Mexhitaj et al. (doi:10.1093/brain/awz017).

This scientific commentary refers to ‘Can patients with cerebellar disease switch learning mechanisms to reduce their adaptation deficits?’, by Wong et al. (doi:10.1093/brain/awy334).

This scientific commentary refers to ‘Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control’, by Hammes et al. (doi:10.1093/brain/awz007).

This scientific commentary refers to ‘Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study’ by Postuma et al. (doi:10.1093/brain/awz030).

Blood-brain barrier (BBB) pericytes regulate several vital functions of the neurovascular unit. Bertrand et al. argue that BBB pericytes are a previously unrecognized HIV target and reservoir, with HIV infection of BBB pericytes confirmed in cell cultures, a mouse model of HIV infection, and in human HIV-infected brains.

Trials of GDNF in Parkinson’s disease have yielded inconsistent results. In a randomised controlled trial, Whone et al. administer GDNF using a paradigm designed to optimize delivery to the putamen. [¹⁸F]DOPA PET reveals putamen-wide uptake, but GDNF does not differ from placebo in its effects on motor function.

The causes of toe walking in children with cerebral palsy are unclear. Lorentzen et al. report that children with cerebral palsy show impaired maturation of feedforward control of gait. The findings challenge the idea that toe walking results from spasticity and raise questions about the rationale of current treatments.

PLPBP mutations have recently been associated with B6-responsive epilepsy, however the disease mechanism is not fully understood. Johnstone et al. report evidence for a genotype-phenotype correlation using 12 previously unidentified patients, expand the clinical spectrum, and model the disease using zebrafish, yeast, and cells to help elucidate the underlying pathophysiology.

Abnormalities in aminoacyl tRNA synthetase (ARS) genes are linked to various leukodystrophies and leukoencephalopathies. Through whole-exome sequencing, Itoh et al. identify pathogenic variants in lysyl-tRNA synthetase (KARS) in seven patients from five unrelated families. All patients have progressive leukodystrophy marked by severe developmental delay or arrest, hypotonia, deafness and epilepsy.

Microcephaly is a genetically heterogeneous disorder. Through molecular genetic studies, Perez et al. demonstrate that homozygous loss-of-function mutations in C7orf43 (now termed microtubule-associated protein 11, MAP11) cause microcephaly in humans and zebrafish. Functional analyses show that MAP11 associates with α-tubulin in mitotic spindles and influences cell proliferation.

Using metabolic screening, Allen et al. identify an adenosine to inosine deamination defect in astrocytes from ALS patients. This defect is the result of reduced expression of adenosine deaminase, leading to increased susceptibility to adenosine-mediated toxicity. Astrocyte inosine supplementation reverses the motor neuron toxicity observed with patient astrocytes in co-culture.

Vestibular migraine is amongst the commonest causes of vertigo, but the regions underlying the development of symptoms including enhanced self-motion sensitivity and visually induced dizziness remain unknown. Bednarczuk et al. provide evidence for an abnormal interaction between visual and vestibular cortical regions in vestibular migraine.

See Hohlfeld (doi:10.1093/brain/awz008) for a scientific commentary on this article.

Paediatric-onset multiple sclerosis offers a window into early disease mechanisms. In a large prospective study, Mexhitaj et al. reveal abnormalities in proinflammatory T cells and deficient regulatory T cell function in affected children. Early pathogenesis likely reflects an imbalance between regulatory and effector limbs of the T cell response.

Spinal lesions hold important diagnostic and prognostic value for multiple sclerosis, but the contribution of lesion location to clinical status is not well understood. By mapping the spatial distribution of lesions in various patient groups, Eden et al. identify locations associated with progressive disease subtypes and higher levels of disability.

Fumarates are effective immunomodulators in multiple sclerosis but their mechanism of action remains elusive. Ntranos et al. show that the immunomodulatory effect of fumarates is due to epigenetic regulation of brain-homing T cells. Treatment with fumarates leads to hypermethylation of microRNA-21, preventing its upregulation in encephalitogenic T-helper and T-cytotoxic cells.

See Donchin and Timmann (10.1093/brain/awz020) for a scientific commentary on this article.

Why don’t patients with cerebellar disease, who cannot adapt their movements in response to errors, spontaneously adopt compensatory strategies? Wong et al. demonstrate that such patients retain an intact but suppressed ability to generate compensatory strategies that – when invoked – enables them to learn as well as age-matched controls.

The restorative function of sleep depends partly on its ability to synchronize cerebral networks. Surprisingly, Sanchez et al. show that white matter damage secondary to traumatic brain injury is associated with higher levels of brain synchrony during sleep, implying that such damage may not impede the restorative function of sleep.

Could a system-level approach offer insights into focal cortical dysplasia (FCD)? By applying hierarchical clustering to resting state fMRI connectome profiles, Hong et al. identify distinct functional connectivity classes. Structural equation analysis provides a mechanistic model whereby lesion structural makeup shapes functional connectivity, which in turn modulates whole-brain network topology.

Increased adenosine signalling is deleterious in Parkinson’s disease, whereas adenosine A_2A receptor blockade is beneficial. Meng et al. report that CD73-derived adenosine enhances A_2A receptor activity by inhibiting dopamine signalling. Targeting CD73 to reduce adenosine production alleviates inflammation and improves neuronal survival in disease models, representing a promising therapeutic strategy.

The role of dopamine in motivating cognitive effort remains untested. McGuigan et al. show that patients with Parkinson’s disease are more cognitively apathetic than controls, but that dopamine replacement restores cognitive motivation to healthy levels. These data provide a critical link between dopamine and multidimensional theories of apathy.

See Strafella (doi:10.1093/brain/awz010) for a scientific commentary on this article.

Impulsive-compulsive behaviours are a common side effect of dopamine replacement therapy in Parkinson’s disease. Hammes and Theis et al. report that loss of impulse control is associated with decreased dopamine synthesis capacity in the nucleus accumbens and decreased functional connectivity of this area to the anterior cingulate cortex.

See Morris and Weil (doi:10.1093/brain/awz014) for a scientific commentary on this article.

In a prospective multicentre study involving 1280 patients with idiopathic RBD, Postuma et al. show that approximately 6% of patients each year (>73.5% over 12 years) convert to full neurodegenerative disease. They test the predictive power of 21 prodromal markers of neurodegeneration, providing a template for planning neuroprotective trials.

A common presentation of the P102L prion protein mutation is Gerstmann-Straussler-Scheinker syndrome. Rudge et al. show that serial measurement of lower limb thermal thresholds predicts, within a relatively narrow time window, conversion to the symptomatic phase of the disease, and that synaptic deposition of PrP^Sc in the spinal cord underpins the pathology.

Plasma tau is a putative biomarker for Alzheimer’s disease, but evidence for a direct link to brain tau is limited. Park et al. report that total tau/Aβ1-42 in plasma is highly predictive of brain tau deposition, and strongly associated with longitudinal neuropathological changes.

Zheng et al. show that levels of histone methyltransferases EHMT1/2, and of the histone methylation H3K9me2, are elevated in prefrontal cortex of a familial Alzheimer’s disease (FAD) mouse model and human postmortem tissue. Inhibition of EHMT1/2 rescues cognitive deficits by relieving H3K9me2-mediated repression of glutamate receptor transcription in FAD mice.

Autism is diagnosed via face-to-face spoken interactions. Using a novel face-to-face fMRI paradigm, Jasmin et al. report that cortical functional connectivity is heightened in social brain areas of men with autism during face-to-face conversations but not in the resting state, while subcortical-cortical connectivity is heightened in interaction and resting states.