Volume 144, Issue 10, October 2021

Lutters and Koehler mark the 50th anniversary of the introduction of CT scanners into clinical practice. By enabling clinicians to perform ‘a living autopsy’ of the brain, the scanners revolutionized neurological care. But concerns over high costs and indiscriminate usage meant that their value did not go entirely undisputed.

This scientific commentary refers to ‘Elevated iron concentration in putamen and cortical speech motor network in developmental stuttering’, by Cler et al. (doi:10.1093/brain/awab283).

This scientific commentary refers to ‘Interictal spikes with and without high-frequency oscillation have different single-neuron correlates’ by Guth et al. (doi:10.1093/brain/awab288).

This scientific commentary refers to ‘Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity’ by Liebmann et al. (doi:10.1093/brain/awab307).

This scientific commentary refers to ‘Progression and regression of nerve fibre pathology and dysfunction early in diabetes over 5 years’ by Ziegler et al. (doi:10.1093/brain/awab330).

Pasha et al. review the evidence that karyopherins – which mediate nucleocytoplasmic transport – can shield aggregation-prone proteins against misfolding and irreversible phase transition into insoluble aggregates. Abnormalities in karyopherins could be a novel pathogenic mechanism underlying neurodegeneration.

Van Broeckhoven et al. review the complex phagocytic response of macrophages after spinal cord injury. They explore how macrophage phagocytosis can promote either remyelination and regeneration or demyelination, degeneration and axonal dieback. In addition, they suggest targets for modulating the phagocytic response.

Verdi et al. highlight heterogeneity in dementia and how it can cause problems for statistical design. An emerging alternative approach is introduced, namely spatial normative modelling, that uses neuroimaging to map individual differences to uncover heterogeneous patterns of brain changes in dementia patients.

Bittner et al. discuss the association of emerging biomarker serum neurofilament light chain (sNfL) with clinical activity, disease progression, MRI measures and therapeutic interventions in multiple sclerosis. They propose specific scenarios implementing sNfL for individualized clinical decision-making.

O’Connor et al. reveal significant differences in plasma Aβ ratios between PSEN1 and APP carriers, broadening understanding of the molecular drivers of Alzheimer’s disease. They also show associations between higher Aβ42:40 and Aβ42:38 ratios and earlier disease onset, supporting the pathogenicity of these peptide ratios.

Koboldt et al. reveal brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly, and demonstrate the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.

See Sommer et al. (doi:10.1093/brain/awab348) for a scientific commentary on this article.

Using quantitative MRI brain mapping, Cler et al. reveal higher levels of iron in brain regions relevant to speech motor control in adults who stutter. Higher levels of iron may indicate elevated dopamine levels or lysosomal dysfunction, providing evidence to support theoretical accounts of stuttering.

Ahonen et al. show that an antisense oligonucleotide targeting the brain-expressed glycogen synthase 1 gene corrects the neuropathological bases of Lafora disease in mouse models. The work provides proof of principle that an antisense oligonucleotide could halt progression of this catastrophic neurodegenerative epilepsy.

In a randomized, double-blind, sham-controlled trial, Hamani et al. examine the efficacy of motor cortex stimulation via surgically implanted electrodes for medically refractory chronic neuropathic pain, and characterize predictors of response.

Sinnett et al. show that miniMECP2 gene therapy for Rett syndrome has similar dose-dependent toxicity to full-length MECP2 gene therapy. By developing a novel regulatory element to limit exogenous miniMECP2 expression, they demonstrate that the safety of miniMECP2 gene therapy can be improved without compromising efficacy.

Sferra et al. identify homozygous missense variants in RNF220 as the cause of a novel form of leukodystrophy with ataxia and sensorineural deafness (AR-LAD). RNF220 encodes the ubiquitin E3 ligase, which has a critical role in regulating the function of proteins of the nuclear lamina.

Schneeberger et al. report that biallelic variants in VPS50 give rise to a neurodevelopmental disorder with neonatal cholestasis. VPS50 is a subunit of the EARP complex, and the observed mutations cause a delay in transferrin receptor recycling. The findings extend the known spectrum of GARP/EARP deficiency disorders in humans.

Wang et al. present clinical and experimental evidence suggesting that UNC13B is a novel epilepsy gene. They describe UNC13B mutations in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families, and show seizure-like behaviour and increased neural firing in Unc13b knockdown flies.

Repudi et al. show that WWOX-deficient human oligocortical spheroids, and mice with neuronal deletion of Wwox, display hyperexcitability, impaired maturation of oligodendrocytes, and hypomyelination. These findings underscore the significance of WWOX in brain disorders.

See Huberfeld and Le Van Quyen (doi:10.1093/brain/awab349) for a scientific commentary on this article.

Recent studies have suggested that high-frequency oscillations distinguish epileptogenic spikes from spikes that are less pathological or possibly even protective. Guth et al. report that these two types of spikes have clearly different single-neuron correlates.

Segar et al. present an in-depth analysis of outcomes and lesion size following focused ultrasound thalamotomy, demonstrating that the timing of energy delivery and maximum power delivery are unexpected but important predictors of lesion size. These findings will help clinicians optimize treatment strategies for this new therapy.

Liu et al. show that arteriolar cerebral blood volume is altered prior to motor symptoms and brain atrophy in a mouse model of Huntington’s disease, and that a non-invasive neurovascular MRI measure can detect therapeutic efficacy of HTT silencing in the premanifest stage of the disease.

Using multi-modal imaging (MRI and SPECT) in patients with prodromal and early clinical Parkinson’s disease, Biondetti et al. reveal dopaminergic changes, abnormal iron metabolism and neuromelanin changes first in the sensorimotor, then the associative and finally the limbic regions of the nigrostriatal system.

See Mousa and Jones (doi:10.1093/brain/awab361) for a scientific commentary on this article.

Liebmann et al. demonstrate that dimethyl fumarate is a bona fide immune-metabolic drug that targets the antioxidative capacities of T cells, leading to impaired mitochondrial function and increased T-cell apoptosis. These actions are key to the anti-inflammatory effects of dimethyl fumarate in CNS autoimmunity.

Nebie et al. show the therapeutic potential of sequential topical and intranasal administration of human platelet lysate (HPL) in two mouse models of traumatic brain injury. This HPL biotherapy reduced cortical inflammation, oxidative stress and synaptic impairments at the injury site and improved motor and cognitive functions.

Monocytes are crucial for the regenerative processes after spinal cord injury. Heller et al. reveal an association between an early increase in concentrations of intermediate CD14-/CD16+/IL10+/CXCR4int monocytes and greater odds of CNS regeneration and enhanced neurological remission.

Cholesterol synthesis is reduced in Huntington’s disease brains due to impaired activity of the master regulator SREBP2. Birolini et al. show that a gene therapy approach targeting astrocytes to stimulate cholesterol biosynthesis rescues neuropathological, synaptic and behavioural deficits in mice.

Statins are widely used for the primary and secondary prevention of cardiovascular disease. In a retrospective study, Jeong et al. show that statins may have detrimental effects on baseline striatal dopamine depletion and long-term motor and cognitive outcomes in patients with Parkinson’s disease.

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dose-dependent effect on brain tau deposition. Using ¹⁸F-flortaucipir PET, Yan et al. investigate whether there are sex differences in this dose effect in cognitively impaired individuals.

Schumacher et al. report that concurrent Alzheimer’s disease pathology in dementia with Lewy bodies patients is associated with a more Alzheimer’s-like functional connectivity profile, and that similar mechanisms of connectivity-related occurrence of tau pathology might be at work in both diseases.

Bosanac et al. identify new small molecule inhibitors of SARM1, an NAD-consuming enzyme responsible for axonal degeneration, and show that they protect axons in vitro and in a paclitaxel model of chemotherapy-induced peripheral neuropathy. SARM inhibition may have therapeutic potential in peripheral neuropathies and CNS degeneration.

Bharucha-Goebel et al. present the largest clinical dataset on giant axonal neuropathy (GAN) to date. The study integrates genotype and disease stage with measures of disease severity, thus defining disease phenotypes as well as key motor outcome measures, along with measures of autonomic impairment in GAN.

See Jensen and Finnerup (doi:10.1093/brain/awab355) for a scientific commentary on this article.

Ziegler et al. show that early damage to both small and large nerve fibres occurs in parallel in individuals with diabetes, particularly type 2, and that nerve pathology and dysfunction can both progress and regress to a clinically meaningful degree. These findings may help reveal strategies to prevent and treat polyneuropathy.

By applying lesion network-symptom-mapping to lesions identified in case reports of pathological laughter and crying, Klingbeil et al. devise a two-hit model of the phenomenon: it arises when a combination of direct lesion and indirect diaschisis effects causes the loss of inhibitory cortical control of a dysfunctional emotional system.