Volume 142, Issue 4, April 2019

This scientific commentary refers to ‘Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics’, by Vandervore et al. (doi:10.1093/brain/awz045).

This scientific commentary refers to ‘Gut microbiota-dependent CCR9⁺ CD4⁺ T cells are altered in secondary progressive multiple sclerosis’, by Kadowaki et al. (doi:10.1093/brain/awz012).

This scientific commentary refers to ‘Theta burst stimulation in neglect after stroke: functional outcome and response variability origins’, by Nyffeler et al. (doi:10.1093/brain/awz029).

This scientific commentary refers to ‘In vivo imaging reveals reduced activity of neuronal circuits in a mouse tauopathy model’, by Marinković et al. (doi:10.1093/brain/awz035).

Although gliomas are thought to arise from a neural-glial lineage of ectodermal origin, many gliomas express a mesenchymal signature. Behnan et al. review the origins of this signature in glioma: it may arise via the tumour stroma, via NF1-mutation in tumour cells and be influenced by the cell of origin, or arise in response to radiotherapy/chemotherapy/anti-angiogenic treatment.

See Uzquiano and Francis (doi:10.1093/brain/awz048) for a scientific commentary on this article.

Mutations in RTTN, which encodes Rotatin, give rise to various brain malformations. Vandervore et al. reveal mitotic failure, aneuploidy, apoptosis and defective ciliogenesis in patient cells. Rotatin binds to myosin subunits in the leading edge of human neurons, which may explain the proliferation and migration defects observed.

Brain calcifications are common in aged individuals, but the mechanisms underlying their formation are unclear. Zarb et al. show that in primary familial brain calcification, a neuropsychiatric disorder featuring bilateral vessel-associated calcifications in the basal ganglia, vessel calcification is accompanied by an osteogenic environment which elicits a neurotoxic astrocyte response.

London et al. show that the asymptomatic optic nerve involvement detected on MRI in patients with clinically isolated syndrome drives the asymptomatic retinal axonal loss measured by optical coherence tomography. Moreover, the length of the optic nerve lesion correlates with retinal axonal loss and visual disability.

See Wekerle (doi:10.1093/brain/awz068) for a scientific commentary on this article.

The peripheral immunological changes associated with conversion of multiple sclerosis to the secondary progressive phase are largely unknown. Kadowaki et al. demonstrate that CCR9+CD4+ T cells – whose frequencies vary with age and with gut microbiota status – are reduced in number and show altered regulatory function in secondary progressive disease.

Accurate identification of seizure-generating brain tissue is challenging, particularly when MRI shows no clear abnormality or extensive abnormality. Plummer et al. achieve this non-invasively by analysing the earliest detectable part of the electromagnetic seizure signal recordable across the head surface. Their findings challenge current practice with its reliance on invasive intracranial monitoring.

Rech et al. report the first probabilistic map of negative motor areas that generate arrest of movement during direct brain electrostimulation. Analysis of data from 117 patients who experienced 386 negative motor responses during awake surgery, reveals a clustered organization of negative motor areas within a large-scale movement control network.

The neurobiological basis of developmental speech disorders remains elusive. Liégeois et al. present neuroimaging findings from a large family with childhood apraxia of speech. Structural and functional MRI analysis reveal disruption of the dorsal language stream as a novel neural phenotype of this severe and persistent developmental speech disorder.

Whether the systemic immune response to stroke contributes to long-term disability is unclear. Using deep immune profiling of peripheral blood over a one-year period following ischaemic stroke, Tsai et al. identify three immunological phases characterized by sequential engagement of innate and adaptive immune compartments, which correlate with post-stroke cognitive trajectories.

See Bartolomeo (doi:10.1093/brain/awz043) for a scientific commentary on this article.

The effects of transcranial magnetic stimulation (TMS) vary between patients, posing an obstacle to its broader therapeutic use. Using post-stroke spatial neglect as a model, Nyffeler et al. show that the integrity of inter-hemispheric connections is a critical predictor of whether or not patients will respond to TMS.

Mishra et al. present a composite extreme-phenotype strategy for gene mapping of cerebral small vessel disease in population cohorts of older persons. They identify associations with variants in HTRA1 and NOTCH3, and describe two participants heterozygous for known pathogenic variants for familial small vessel disease in NOTCH3 and HTRA1.

Using a dynamic graph theoretical approach, Shine et al. show that individuals with Parkinson’s disease demonstrate heightened network-level integration during the ‘Off’ state that is inversely correlated with motor symptom severity. Network-level integration relates to two measures of neurocognitive reserve, suggesting a protective function for ‘Off’ state integration.

Using cell culture and animal models of prion diseases, Ishibashi et al. show that type I interferon signalling interferes with prion infection in mammals. A selective type I interferon receptor agonist inhibits prion invasion and prolongs survival of prion-infected mice, suggesting potential clinical applications.

See Busche (doi:10.1093/brain/awz060) for a scientific commentary on this article.

The exact nature of the tau protein species implicated in neurodegeneration is unclear. Using in vivo calcium imaging in a mouse tauopathy model, Marinkovic et al. show that reductions in neuronal activity are independent of neurofibrillary tangles, suggesting a pathological role for the soluble tau species present before tangle formation.

Gordon et al. examine how tauopathy measured with PET varies over the course of autosomal dominant Alzheimer’s disease. Tau PET binding is elevated in cognitively impaired individuals relative to asymptomatic mutation carriers, and levels of tau strongly correlate with beta-amyloid levels, glucose metabolism, and cortical thickness.

Impairment of blood-brain barrier integrity has been implicated in Alzheimer’s disease. Yamazaki et al. show that the loss of cortical tight junction proteins is a common event in Alzheimer’s disease, and is associated with synaptic degeneration. The effects of compromised tight junctions may be both additive and synergistic to amyloid-β and tau pathologies.

Tau pathology spreads in distinct spatial patterns across neurodegenerative diseases. Franzmeier et al. show that tau pathology relates to functional brain architecture, with functional connectivity predicting tau distribution across normal ageing, Alzheimer’s disease and vascular cognitive impairment. The findings are consistent with prion-like tau spreading facilitated by neural activity.

Imaging biomarkers are needed to detect early brain changes in presymptomatic carriers harbouring FTD mutations. Using arterial spin labelling-MRI, Mutsaerts, Mirza et al. identify an inverse association between cerebral perfusion in frontotemporoparietal regions and expected age of onset. Cerebral perfusion may be a promising imaging biomarker for presymptomatic genetic FTD.

Cortical mean diffusivity has been proposed as a useful biomarker for the study of cortical microstructure in neurodegenerative diseases. Illán-Gala et al. show that cortical mean diffusivity may be a more sensitive biomarker than cortical thickness for detection of the first cortical changes in behavioural variant FTD.

Approximately 50% of adults over 80 with significant Alzheimer’s disease pathology show normal cognition. Arenaza-Urquijo et al. identify a brain metabolic ´resilience signature´ in cognitively stable 80-plus adults that adds predictive value in explaining cognitive change beyond established imaging biomarkers. This signature may provide important information for determining clinical prognosis.

Studies involving multiple Alzheimer’s disease biomarkers typically rely on dichotomous categorization. Knopman et al. examine how continuous distributions of amyloid PET, tau PET and cortical thickness in medial temporal lobe structures relate to cognition in non-demented persons. Independent associations with memory are seen for all three biomarkers in entorhinal cortex.