Volume 143, Issue 12, December 2020

This scientific commentary refers to ‘Local sleep-like cortical reactivity in the awake brain after focal injury’, by Sarasso et al. (doi:10.1093/brain/awaa338).

This scientific commentary refers to ‘O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease’, by Lee et al. (doi:10.1093/brain/awaa320).

This scientific commentary refers to ‘CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease’, by Galiano-Landeira et al. (doi:10.1093/brain/awaa269).

This scientific commentary refers to ‘Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer’s disease’, by Benedet et al. (doi:10.1093/brain/awaa342).

This scientific commentary refers to ‘When affect overlaps with concept: emotion recognition in semantic variant of primary progressive aphasia’, by Bertoux et al. (doi:10.1093/brain/awaa313).

Clarke and Patani review the involvement of microglia in ALS, focusing specifically on evidence for spatiotemporally regulated neurotoxic and neuroprotective roles. Understanding how microglia contribute to the ‘cellular phase’ of ALS promises to advance the development of therapies with a mechanistic rationale.

Beijer and Baets review the current genetic landscape of hereditary motor neuropathies, highlighting recent reports of novel genes/mutations and discoveries related to disease mechanisms. They then link hereditary motor neuropathies to related disorders by examining the involvement of common disease pathways.

Mochel et al. describe a dominant channelopathy resulting from pathogenic variants in KCNN2, encoding the SK2 channel. This disorder is characterized by developmental delay and intellectual disability, frequently associated with early-onset movement disorders manifesting as cerebellar ataxia or extrapyramidal symptoms.

In a randomised phase 2 controlled trial in patients with progressive multiple sclerosis, Petrou et al. show that mesenchymal stem cell (MSC) transplantation is well-tolerated and reduces the risk of disease progression compared to sham injection. Intrathecal MSC administration was superior to intravenous.

Pipis et al. describe the characteristics and longitudinal follow-up of 225 patients with Charcot-Marie-Tooth disease type 2A, caused by mutations in MFN2. They describe how different mutations affect disease onset and rate of progression and identify sensitive clinical assessments that can be used for disease monitoring.

Sassani et al. use phosphorous-31 MRS to examine energy metabolism in individuals living with ALS (motor neuron disease). They detect clinically relevant alterations in metabolites in brainstem and in skeletal muscle, with implications for therapeutic research targeting mitochondrial dysfunction.

Lambru et al. argue that trigeminal neurovascular contact with morphological changes is involved in the aetiology of both SUNCT and SUNA. The absence of any significant radiological differences between SUNCT and SUNA adds to evidence suggesting they should be considered a single clinical entity.

Systemic immunosuppression is a hallmark of glioblastoma and other neurological insults including stroke and TBI. Ayasoufi et al. show that brain cancers and brain injuries suppress immunity through release of non-steroidal soluble factors that disrupt immune homeostasis and dampen responses of the peripheral immune system.

Most individuals with Down syndrome develop Alzheimer’s pathology early in life. In a cross-sectional post-mortem study, Flores-Aguilar et al. study neuroinflammation across the lifespan in Down syndrome and reveal profound changes in microglial activation and brain cytokine expression along the Alzheimer’s continuum.

See Krone and Vyazovskiy (doi:10.1093/brain/awaa396) for a scientific commentary on this article.

Using TMS and EEG in awake patients with focal cortical injuries, Sarasso et al. reveal the presence of sleep-like dynamics in perilesional areas, coexisting with typical wakefulness cortical reactivity in control areas. Reversing perilesional sleep-like dynamics could represent a novel strategy for rehabilitation.

Graham et al. show that diffuse axonal injury in the chronic phase after a single moderate-severe traumatic brain injury (TBI) strongly predicts progressive white matter atrophy. This suggests that acute injury triggers neurodegeneration and may explain the elevated rates of Alzheimer's disease and CTE after TBI.

See Hart and Huang (doi:10.1093/brain/awaa398) for a scientific commentary on this article.

Lee et al. show that O-GlcNAcylation, an evolutionarily conserved post-translational modification, is critical for the physiological functioning and survival of dopaminergic neurons. Upregulating O-GlcNAcylation mitigates neurodegeneration, synaptic impairments and motor deficits in a mouse model of Parkinson’s disease.

See Halliday (doi:10.1093/brain/awaa390) for a scientific commentary on this article.

Galiano-Landeira et al. provide evidence that CD8 T cell cytotoxic attack initiates and propagates neuronal death and synucleinopathy in Parkinson’s disease. They demonstrate that nigral CD8 T cell infiltration precedes synucleinopathy in presymptomatic individuals, and that CD8 T cell density correlates with neuronal death.

By tracking spectral and dynamic signatures of inhibitory mechanisms at the EEG source level, Meyer et al. report that impulse control disorders in Parkinson’s disease are not only associated with dysfunctions in value- or reward-based responding, but also involve dysfunctions in circuits controlling motor execution.

Degiorgis et al. use structural and functional MRI, plus behavioural and histological analysis, to investigate early connectome signatures of tauopathy in the Thy-Tau22 mouse model of Alzheimer’s disease. The results reveal modified resting state connectivity in memory networks prior to the onset of memory impairment.

Existing DNA methylation clocks are highly accurate in blood but are less precise when used in older samples or on brain tissue. Shireby et al. develop a novel epigenetic clock that performs optimally in human cortical tissue and has the potential to identify phenotypes associated with biological ageing in the brain.

Using CSF proteomics, Tijms et al. identify three Alzheimer’s disease subtypes that show: 1) hyperplasticity and increased BACE1 levels; 2) innate immune activation; and 3) blood-brain barrier dysfunction with low BACE1 levels. Future therapeutics may need tailoring to individual disease subtypes.

See Brier and Day (doi:10.1093/brain/awaa370) for a scientific commentary on this article.

Neurofilament light (NfL) is a marker of neuroaxonal injury. Benedet et al. report that plasma NfL levels differentially associate with amyloid and tau pathologies across the Alzheimer’s disease continuum, and are associated with distinct patterns of longitudinal grey and white matter volume loss.

In a longitudinal PET study, Smith et al. show that tau accumulation rates are higher in females, younger Aβ-positive individuals, and those with higher baseline tau load. This is in contrast to Aβ-accumulation rates, which are higher in APOE-ε4 carriers and older individuals.

In the phase 3 EPOCH trial, use of the BACE inhibitor verubecestat was associated with a reduction in MRI hippocampal volume relative to placebo after 78 weeks. Sur et al. present the results of further analyses exploring this effect, and show that verubecestat produced non-progressive volume losses in amyloid-rich regions.

Could somatic variants arising during brain development give rise to non-hereditary neurodegenerative disease? By sequencing DNA from brain tissue and blood from the same semantic dementia patients, van Rooij et al. identify brain-specific somatic TARDBP variants with pathogenicity supported by functional assays.

LATE neuropathological change (LATE-NC) is associated with a dementia syndrome that clinically overlaps with Alzheimer’s disease. Liu et al. show that the combination of LATE-NC and Alzheimer’s disease is not associated with greater neuropsychiatric symptom burden than either pathology alone.

See Ibanez and Schulte (doi:10.1093/brain/awaa392) for a scientific commentary on this article.

Are emotions innate or do they depend on contextual – and thus cultural – knowledge? Using neuropsychological testing and neuroimaging in patients with the semantic variant of primary progressive aphasia, Bertoux et al. show that emotion recognition depends on semantic knowledge of emotion concepts.

By applying Bayesian inference to the Adolescent Brain Cognitive Development dataset, Ang et al. show that in children, neurocognitive deficits in language and reasoning represent state- and trait-related markers of depression, but not of pre-existing vulnerability.