Volume 141, Issue 7, July 2018

This scientific commentary refers to ‘Eliciting inflammation enables successful rehabilitative training in chronic spinal cord injury’, by Torres-Espín et al. (doi:10.1093/brain/awy128).

This scientific commentary refers to ‘Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury’, by Agostinone et al. (doi:10.1093/brain/awy142).

This scientific commentary refers to ‘Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated’, by Robinson et al. (doi:10.1093/brain/awy146).

This scientific commentary refers to ‘Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis’, by Schifani et al. (doi:10.1093/brain/awy133).

Increasing evidence suggests that there is intestinal barrier dysfunction in multiple sclerosis. Camara-Lemarroy et al. address the mechanisms by which an altered intestinal barrier could lead to an altered neuroinflammatory response, and discuss the potential of barrier-stabilizing strategies as novel therapeutic avenues in multiple sclerosis.

Hampel et al. review the role of the cholinergic system in cognition and how cholinergic deficits in Alzheimer’s disease interact with other aspects of disease pathophysiology. They document the benefits of cholinergic therapies at various stages of disease, and argue that the weight of the evidence confirms their continued value.

Ufmylation is the post-translational modification of proteins through the addition of UFM1. Nahorksi et al. identify mutations in UFM1 and in UFC1, which encodes an enzyme required for ufmylation, in individuals with severe early-onset encephalopathy with progressive microcephaly. The findings suggest an essential role for ufmylation in human brain development.

See Spejo and Moon (doi:10.1093/brain/awy148) for a scientific commentary on this article.

The effectiveness of rehabilitative training decreases with time after spinal cord injury. Torres-Espin et al. show that inducing mild systemic inflammation improves the efficacy of rehabilitative training on forelimb function in rats with chronic spinal cord injury. Eliciting inflammation may reopen a window of opportunity for reparative plasticity.

See Peterson and Benowitz (doi:10.1093/brain/awy165) for a scientific commentary on this article.

Dendrites retract and disconnect from their cellular partners in a number of psychiatric and neurodegenerative diseases. Agostinone et al. show that injured mammalian retinal ganglion cells have the capacity to regenerate dendrites and reestablish functional connections, and identify insulin signalling as paramount for a successful pro-regenerative response.

Spinocerebellar ataxia type 37 is an adult-onset dominant ataxia characterised by altered vertical eye movements. Corral-Juan et al. demonstrate that an ATTTC expansion mutation within the DAB1 gene is the genetic cause of SCA37, present the first neuropathological findings, and provide evidence of cerebellar dysregulation of Reelin-DAB1 and PI3K/AKT signalling.

Using gene panel and whole exome sequencing, Chemin et al. show that de novo events are a major genetic cause of childhood-onset cerebellar atrophy. De novo gain of function mutations in the calcium channel CACNA1G/Ca_v3.1 give rise to a cerebellar syndrome via a potentially druggable disease mechanism.

Tordo et al. present a novel AAV gene therapy vector, AAV-TT, which exceeds the current benchmark neurotropic serotypes AAV9 and AAVrh10 and enables unprecedented correction of a lysosomal transmembrane enzyme deficiency. AAV-TT based gene therapies may thus be suitable for the treatment of human neurological diseases characterised by global neuropathology.

Pericytes are specialized vascular cells that can modulate the microcirculation by constricting brain capillaries. Khennouf et al. reveal that pericytes play a role in functional hyperaemia and in the long-lasting oligaemia that follows spreading depolarization. Changes in pericyte function may be an additional vascular mechanism in migraine with aura.

Hypothetically, transgender individuals receiving hormonal therapy may have an increased risk of (hormone-sensitive) brain tumours. Nota et al. report that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, and somatotrophinomas in transmen. Nevertheless, low tumour incidence suggests that regular screening may be unnecessary.

Bertero et al. report impaired functional connectivity in carriers of the 16p11.2 microdeletion, which is associated with autism spectrum disorders. A genetic mouse model shows similar connectivity impairments, plus thalamo-frontal miswiring and neural de-synchronization. These results reveal a mechanistic link between genetic risk for developmental disorders and long-range functional coupling.

The nature of the inflammatory response in the MS brain is poorly defined. Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8⁺ T-cells and CD20⁺ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.

Observed rapid seizure spread through large brain areas seems at odds with the classical view that seizures arise from small foci. Using an acute animal model, Liou et al. demonstrate that seizure propagation can proceed via two topologically distinct patterns that both depend on the same breakdown of inhibition.

Although thrombectomy improves recanalization rates, fewer than 50% of thrombectomized patients achieve functional independence, emphasizing the need for novel therapeutic targets. Morris et al. reveal selective neuronal loss, but only weak microglial activation, in the salvaged penumbra in man. Preventing neuronal loss in the hyperacute stage may improve post-stroke outcomes.

Anomia, a disruption of semantic memory access, is common in dementia and following damage to temporal cortex. Using electrocorticography in patients undergoing localization of epileptic foci, Forseth et al. reveal the neurobiological foundation of semantic memory, identifying a hub in middle fusiform gyrus that provides access to object semantic information.

Woodhead et al. present results from a randomized trial of a novel reading therapy app (‘iReadMore’) coupled with anodal transcranial direct current stimulation (tDCS) in patients with post-stroke central alexia. Use of iReadMore improves reading accuracy for trained words, while concurrent tDCS facilitates training and improves generalization to untrained stimuli.

Ventral intermediate thalamic stimulation is effective in treating essential tremor and tremor-dominant Parkinson’s disease, but its precise mechanism of action is unclear. Milosevic et al. show that thalamic inhibition of neuronal firing is necessary for tremor reduction, suggesting that the thalamus acts as a filter for uncoupling central and peripheral tremor networks.

Owing to compensatory processes, the initial stages of neurodegeneration are marked by normal performance despite the presence of pathology. Using their explicit mathematical model, Gregory et al. report the first empirical examination of compensation over time in neurodegeneration, showing evidence of motor and cognitive compensation in a Huntington’s disease cohort.

Genome-Wide Association Studies of imaging-derived biomarkers in Alzheimer’s disease have focused on phenotypes derived from single imaging modalities. Scelsi et al. report the first use of a multimodal phenotype, derived through disease progression modelling, and identify a novel variant that is protective against conversion from healthy ageing to Alzheimer’s disease.

See Coulthard and Love (doi:10.1093/brain/awy153) for a scientific commentary on this article.

The burden of co-pathologies across neurodegenerative diseases is unknown. Robinson et al. assess tau, Aβ, alpha-synuclein and TDP-43 proteinopathies in post-mortem individuals representing a spectrum of neurodegenerative disease. Co-pathologies are common, with age and APOE ɛ4 status affecting co-pathology prevalence. The findings have implications for clinical trials focusing on monotherapies.

In vivo tau reduction strategies thus far have been studied in the absence of Aβ deposition. DeVos et al. suppress human tau in mice that develop both Aβ and tau pathologies. Lowering human tau expression reduces neurofibrillary tangles and prevents neuronal loss equally effectively in the presence of Aβ plaques.

See Gomes and Grace (doi:10.1093/brain/awy156) for a scientific commentary on this article.

Schifani et al. investigate the relationship between prefrontocortical dopamine release and stress response in schizophrenia. Associations between dopamine release and cortisol response to stress observed in controls and those at clinical high risk for psychosis are absent in schizophrenia, providing direct evidence of disrupted prefrontocortical dopamine-stress regulation in schizophrenia.