Volume 142, Issue 11, November 2019

This scientific commentary refers to ‘Polygenic burden in focal and generalized epilepsies’, by Leu et al. (doi:10.1093/brain/awz292).

This scientific commentary refers to ‘Magnetoencephalography imaging of high frequency oscillations strengthens presurgical localization and outcome prediction’, by Velmurugan et al. (doi:10.1093/brain/awz284).

This scientific commentary refers to ‘Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes’, by Chu et al. (doi:10.1093/brain/awz296).

This scientific commentary refers to ‘Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptors’, by Carvalho et al. (doi:10.1093/brain/awz288).

Morbidity and mortality in bacterial meningitis are driven by an uncontrolled host inflammatory response. Koelman et al. evaluate the detrimental role of the complement system in spurring this inflammation, and conclude that anaphylatoxin C5a is a promising treatment target in bacterial meningitis.

Fluctuating cognition is a core diagnostic feature of the Lewy body dementias, but it can be clinically challenging to identify and characterise and remains poorly understood. O’Dowd et al. review the clinical features and explore the possible aetiological mechanisms underpinning this phenomenon. They also identify potential future research avenues.

Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes a p21-activated kinase, which has been implicated in brain development and control of brain size.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal disorder characterized by adult-onset cortical tremor and generalized seizures. Using whole genome sequencing, Yeetong et al. identify the causative mutation for type 4 of the disorder (BAFME4), providing insights into the underlying pathogenesis.

Polymicrogyria is a malformation of cortical development. Chatron et al. describe four patients with a lethal syndromic polymicrogyria with necrotic and calcified areas in the basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Exome sequencing reveals the role of ATP1A2 homozygous variants in this new phenotype.

Zhang, Dilliott et al. examine a unique family with early- and late-onset Alzheimer’s disease phenotypes, as well as disease-discordant monozygotic triplets. The triplets and the patient with early-onset disease are carriers of the APOE ε4-allele plus rare substitutions in other genes. Epigenetic analyses suggest accelerated ageing in the early-onset patient.

Vaz, McDermott et al. identify variants in PCYT2, which encodes a key gene in phospholipid biosynthesis, in five individuals with a new complex hereditary spastic paraplegia. Functional studies in fibroblasts and a zebrafish model confirm the pathogenic nature of the variants, while lipidomic analysis reveals potential treatment strategies and plasma biomarkers.

Immunoglobulin G autoantibodies to glycine receptors are found in many patients with progressive encephalomyelitis with rigidity and myoclonus (PERM). Crisp et al. show that purified patient IgGs disrupt inhibitory neurotransmission in cultured motoneurons, and provide evidence for direct antagonistic actions on glycine receptors.

Specific immune-cell populations patrol the CNS in search of pathogens and tumours. Herich et al. identify CD4+ CCR5^high GzmK+ effector-memory cells as a brain-surveilling subpopulation capable of crossing the uninflamed blood-brain barrier, and reveal alterations in this population in HIV+ patients with neurological symptoms and in patients with multiple sclerosis.

Changes in both structural and functional connectivities are observed in multiple sclerosis, but little is known about how the evolution of one affects the other. Koubiyr et al. investigate the longitudinal multimodal reorganization of brain networks in the year following clinically isolated syndrome, and reveal structural-functional decoupling in several networks.

Radioligands targeting the 18 kDa translocator protein (TSPO) are increasingly used to visualise inflammation in the brain. Nutma et al. report that TSPO expression in multiple sclerosis lesions originates mainly from astrocytes and microglia, but is not restricted to cells with a specific pro-inflammatory phenotype.

White matter repair through transplantation of allogeneic glial progenitors is now feasible in immune-deficient animals, but the immunological barrier precludes its clinical translation. Li et al. develop a strategy based on co-stimulation blockade that induces immunological hyporesponsiveness and supports long-term functionality of allotransplanted myelinating oligodendrocytes.

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article.

Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment.

Benzodiazepine-resistant status epilepticus is an ongoing clinical challenge. Burman et al. show that longer seizure duration is a useful clinical indicator of benzodiazepine resistance, and that resistance is caused by changes in GABA_A receptor-mediated synaptic transmission. The findings could help optimise current management protocols.

Focal epilepsy is associated with large-scale brain dysfunction. Dahal et al. reveal that interictal epileptiform discharges modulate normal brain rhythms in regions beyond the epileptic network, potentially impairing processes that rely heavily upon intercortical communication, such as cognition and memory.

See van Klink and Zijlmans (doi:10.1093/brain/awz321) for a scientific commentary on this article.

Velmuruganet al. report that detecting and localizing high‐frequency oscillations (HFOs: 80–200 Hz) with MEG can improve presurgical assessment and postsurgical outcome prediction in epilepsy. Source localization of HFOs identifies an epileptogenic region with accuracy of 75%. When such localized sources are surgically resected, patients have an approximately 80% probability of achieving seizure freedom.

The role of the pre-supplementary motor area (pre-SMA) in linking goals to actions remains unclear. Using single-neuron recordings in human pre-SMA, Wang et al. identify cells that signal when a fixation lands on a target across several different visual search tasks. One function of pre-SMA may thus be goal detection.

Traumatic microbleeds are a common neuroimaging finding in traumatic brain injury, yet their clinical significance remains unclear. Griffin et al. report that traumatic microbleeds predict disability, and use MRI-guided histopathology to elucidate the underlying pathophysiology. They conclude that traumatic microbleeds may be a form of traumatic vascular injury.

See Dehay and Bezard (doi:10.1093/brain/awz329) for a scientific commentary on this article.

Intrastriatal injections of fibrillar α-synuclein in rodents have been shown to induce a Parkinson’s disease-like spreading of Lewy body pathology. Chu et al. inject exogenous α-synuclein pre-formed fibrils into the putamen of non-human primates, and observe spreading of pathology, nigrostriatal degeneration, and dopamine transporter upregulation indicative of early Parkinson’s disease.

Impulsive compulsive behaviours (ICBs) are common in Parkinson’s disease. In a post-mortem study, Barbosa et al. show that Parkinson’s disease patients with ICBs have lower alpha-synuclein load and dopamine D3 receptor levels in the nucleus accumbens. Excessive dopaminergic stimulation and relative preservation of the ventral striatum may contribute to ICBs.

Deep brain stimulation of the subthalamic nucleus improves non-motor symptoms in Parkinson’s disease, but with considerable inter-individual variability. Petry-Schmelzer et al. show that neurostimulation in specific subregions of the subthalamic nucleus has differential effects on mood/apathy, attention/memory and sleep-related outcomes. Neurostimulation could thus be tailored to patients’ individual non-motor profiles.

McCoy et al. show that dopaminergic medication in Parkinson’s disease leads to changes in striatal signalling and in behaviour during learning, but that changes are specific to the processing of negative reinforcements. These within-patient changes are predictive of changes in future value-based choice behaviour and striatal responses.

The specific effect of TDP-43 pathology on grey matter volume in individuals without frontotemporal lobar degeneration is unclear. Bejanin et al. reveal a major and independent contribution of TDP-43 to neurodegeneration and shed light on the regional distribution of TDP-43-related atrophy in older adults.

See Cunha (doi:10.1093/brain/awz335) for a scientific commentary on this article.

Carvalho et al. provide clues to the onset of immune dysregulation underlying early synaptic loss in Alzheimer’s disease and tauopathies, by linking overactivation of adenosine A_2A receptors in tau pathology to a particular microglial signature (upregulation of C1q and TREM2) allied to the loss of glutamatergic synapses and cognitive deficits.