Volume 144, Issue 9, September 2021

This year marks the 130th anniversary of the untimely death of Heinrich Lissauer (1861–91). Paolo Bartolomeo explores how the anatomical account of dissociations between perception and imagery deficits proposed by Lissauer in his 1890 article on visual agnosia, resonates with the present debate on the neural bases of visual mental imagery.

This scientific commentary refers to ‘MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline high serum creatine kinase’, by Lopes Abath Neto et al. (doi:10.1093/brain/awab275).

This scientific commentary refers to ‘Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson’s disease’, by Doppler et al. (doi:10.1093/brain/awab236).

This scientific commentary refers to ‘Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe’, by Yushkevich et al. (doi:10.1093/brain/awab262).

This scientific commentary refers to ‘Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer disease’ by Lucey et al. (doi:10.1093/brain/awab272).

Wang et al. review alterations in the gut microbiota in Parkinson’s disease and highlight recent mechanistic insights into the role of gut dysbiosis in Parkinson’s disease pathophysiology. In addition, they discuss the interactions between production and transmission of α-synuclein and gut inflammation and neuroinflammation.

Ross et al. provide a comprehensive review of the immune landscape of paediatric high-grade gliomas. They explore how different genetic alterations lead to the creation of specific tumour subgroups with distinct immune profiles, and discuss current and emerging immunotherapies.

Monfrini et al. describe a novel group of neurological disorders caused by genetic defects of the HOPS complex, and predominantly characterized by dystonia, which they propose should be named HOPS-associated neurological disorders (HOPSANDs).

Missense HTRA1 mutations have been associated with cerebral small vessel disease whereas the pathogenicity of loss of function mutations has been unclear. In a large cohort of CSVD patients, Coste et al. establish that heterozygous HTRA1 stop codon mutations are also pathogenic, providing valuable information for diagnosis.

By investigating patients with neuroinflammatory, -degenerative, and -vascular disorders, Gross et al. identify cellular parameters in blood and CSF that can improve the differential diagnosis of neurological diseases, and that provide insights into shared and distinct pathophysiological processes.

ER stress plays a key role in ALS pathogenesis through altered regulation of proteostasis. In a phase 2 futility trial, Dalla Bella et al. show that the alpha-2 adrenergic receptor agonist guanabenz reduces the proportion of patients progressing to higher stages of disease at 6 months compared to historical controls.

Hong et al. identify activating MAP3K3 and PIK3CA somatic variants in 90.1% of sporadic CNS cavernous malformations, and show that PIK3CA mutations confer a higher risk for overt haemorrhage. The findings underscore the possibility of molecular classification of sporadic cavernous malformations.

Verdura et al. report a novel rare brain metabolic disorder caused by recessive mutations in PI4KA, which encodes an enzyme with a pivotal role in phosphoinositide metabolism at the cell membrane. The description of this syndrome will simplify the identification of undiagnosed cases with similar clinical features.

White matter hyperintensities (WMH) are an established risk factor for stroke and dementia. Using whole-exome burden tests and biochemical experiments, Malik et al. show that rare HTRA1 protease domain variants, occurring with a frequency of 1 in 450 in the UK Biobank, associate with WMH volume and result in reduced HTRA1 protease activity.

Progressive multifocal leukoencephalopathy is a severe opportunistic infection of the CNS that can occur in multiple sclerosis patients treated with natalizumab. Mahler et al. present data suggesting that TSPO PET can make a clinically meaningful contribution to the early identification, longitudinal monitoring and differential diagnosis of affected individuals.

Thakur et al. present clinical, neuropathological, and molecular findings from 41 patients with SARS-CoV-2 infections. Widespread hypoxic injury and microglial activation were seen in brain tissue, but little to no viral RNA or protein, suggesting that the neurological consequences of COVID do not result from viral infection of the brain.

Muñiz-Castrillo et al. identify 10 new patients with anti-AK5 encephalitis and review those previously described, characterizing the clinical presentation of the disease. HLA genotyping and CSF proteomic analyses provide new insights into the pathogenesis of anti-AK5 encephalitis.

Lopes Abath Neto et al. identify recessive pathogenic genetic variants in MLIP in six families from different ethnic backgrounds with a myopathy characterized by exercise-induced muscle pain, susceptibility to spontaneous episodes of rhabdomyolysis, and elevated baseline serum creatine kinase levels.

See Helmich and Lehéricy (doi:10.1093/brain/awab286) for a scientific commentary on this article.

Combining neuromelanin-sensitive MRI and ¹¹C-MeNER PET, Doppler et al. show pronounced degeneration of terminal compared to somatic structures of the noradrenergic system in Parkinson’s disease. Fine-mapping of the locus coeruleus’ microstructure reveals a distinct pattern of degeneration with sparing of its rostral part.

Bizat et al. present a C. elegans model of genetic prion diseases that breaks down a technological barrier limiting therapeutic research in the field. By using the model to screen FDA-approved CNS-penetrant drugs, they identify novel compounds able to reduce prion protein misfolding and prion-induced neurodegeneration.

Zhang et al. report that the transcription factor PAX6 is upregulated in both Alzheimer’s disease mouse and human brains. They show that PAX6 mediates the effects of amyloid-β on tau hyperphosphorylation, and that downregulation of PAX6 reduces amyloid-β-induced cell death and tau hyperphosphorylation through GSK-3β.

Berron et al. reveal the sequence of tau pathology progression through MTL regions and memory networks in vivo during the earliest stages of Alzheimer’s disease. Memory performance was associated with functional connectivity in cognitively unimpaired individuals, and with posterior hippocampal atrophy in MCI patients.

See Khan et al. (doi:10.1093/brain/awab314) for a scientific commentary on this article.

Yushkevich et al. use MRI and dense serial histology to construct the first three-dimensional maps of tau neurofibrillary tangle pathology at individual and group levels. The maps show a more extensive involvement of medial temporal lobe regions in tau deposition than previously thought.

Barbier et al. reveal an X-linked polymorphism upstream of SLITRK2 that influences age at onset in C9orf72 frontotemporal dementia. Functional investigations suggest that SLITRK2 up-regulation worsens synaptic dysfunction in C9orf72 patients, whereas these effects are modulated by the protective allele.

Stothart et al. present ‘Fastball’, a new EEG method for the passive and objective measurement of memory in Alzheimer’s disease. Fastball EEG is sensitive to changes in patients’ memory function that are not observable behaviourally and, crucially, patients do not need to understand the task or even provide a response.

Pereira et al. show that plasma Aβ42/40 is an independent predictor of future amyloid accumulation, whereas plasma P-tau217 is an independent predictor of tau accumulation, brain atrophy and cognitive decline. Both measures could thus serve as prognostic markers to predict future Alzheimer’s disease pathology.

Neudorfer et al. investigate the acute effects of hypothalamic deep brain stimulation. Based on an analysis of 627 recorded autonomic and behavioural responses, they identify symptom-specific, spatially separable clusters providing voxel-wise insights into the clinico-anatomical relationships within this complex region.

Lucey et al. investigate associations between sleep and longitudinal cognitive function in impaired and unimpaired older adults. The results show that sleep duration, sleep efficiency, and slow wave activity are all predictive of cognitive decline in a non-linear inverse ‘U-shaped’ relationship.

Aiba and Noebels show that the Kcnq2/Kv7.2 gene has a key regulatory role in cortical spreading depolarization, and identify spreading depolarization as a potential pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes.

In a prospective study involving all children presenting with epilepsy aged under 3 years in Scotland, Symonds et al. show that epilepsies of undetermined aetiology present more frequently in socially disadvantaged groups. Aetiology is the strongest predictor of outcome, and genetic testing should be prioritized.