Volume 142, Issue 6, June 2019

This scientific commentary refers to ‘Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation’ by Howett et al. (doi:10.1093/brain/awz116).

This scientific commentary refers to ‘Dysfunctional brain dynamics and their origin in Lewy body dementia’, by Schumacher et al. (doi:10.1093/brain/awz069).

This scientific commentary refers to ‘A distinct inferential mechanism for delusions in schizophrenia’, by Baker et al. (doi:10.1093/brain/awz051).

This scientific commentary refers to ‘Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms’, by Avram et al. (doi:10.1093/brain/awz093).

Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes.

Mayer et al. reveal AHR to be a novel disease gene for a recessively inherited disorder characterized by foveal hypoplasia and infantile nystagmus. Using whole exome sequencing, they identify a homozygous premature stop mutation in AHR in a consanguineous family from Northern Israel with three affected children.

Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. Dedek et al. report that downregulation of tyrosine phosphatase STEP₆₁ links disinhibition to NMDAR potentiation in human and rodent spinal pain processing, and develop an ex vivo human preclinical model to help bridge the translational divide.

Mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Rodriguez Cruz et al. describe the clinical and genetic spectrum associated with COL13A1 mutations, and the key clinical features to look out for.

Mutations in the fatty acid 2-hydroxylase gene FA2H disturb sphingolipid metabolism. In a large cohort of FA2H patients, Rattay et al. define the phenotypic spectrum, identify a unique hair phenotype (‘bristle hair’) and reveal an imaging ‘fingerprint’ of FA2H-disease captured by the acronym ‘WHAT’.

MYORG mutations cause autosomal recessive Primary Familial Brain Calcification (PFBC). Grangeon et al. compare 16 MYORG patients with 102 patients with autosomal dominant PFBC. MYORG patients exhibit a new syndrome at the crossroads between PFBC and spinocerebellar ataxias with extensive calcifications, cerebellar atrophy and a prominent motor phenotype.

Munk Nielsen et al. show that first-generation immigrants arriving in Denmark aged <15 years have a risk of multiple sclerosis higher than in their country of birth but lower than in ethnic Danes. Risk among individuals aged ≥15 years on arrival remains closer to that in their country of birth.

Autoantibodies targeting aquaporin-4 mediate the pathology of neuromyelitis optica, but the source of these autoantibodies is unclear. Cotzomi et al. report that they develop from naïve B cells that escape counter-selection due to dysfunctional B cell tolerance checkpoints. These findings define new mechanistic details of neuromyelitis optica immunopathology.

Through genetic and transcriptomic analyses, Guelfi et al. identify neuronal and glial mechanisms for intractable partial epilepsy. They provide a data resource that will help accelerate the discovery of new epilepsy genetic loci and improve understanding of how these loci contribute to disease.

Many patients with anti-GABA_BR encephalitis respond to immunotherapy, emphasizing the importance of early diagnosis. Van Coevorden-Hameete et al. show that while the majority of patients have epilepsy, others present with progressive dementia without seizures. Adding KCTD16, an auxiliary protein, to a GABA_BR cell-based assay improves sensitivity without loss of specificity.

Clinical features of dystonic tremor can resemble those of essential tremor, complicating diagnosis. Using task fMRI, DeSimone et al. reveal widespread network connectivity differences between patients with dystonic tremor versus patients with essential tremor and healthy controls, across cortical, subcortical and cerebellar regions.

The brain network responsible for cervical dystonia is unknown. Using lesion network mapping, Corp et al. show that lesions causing cervical dystonia are functionally connected to the cerebellum and sensorimotor cortex. The authors then validate the abnormality of this network in a cohort of cervical dystonia patients without brain lesions.

Why are dopaminergic neurons particularly vulnerable in Parkinson’s disease? Kuzumaki et al. show an increase in the expression of catechol-O-methyltransferase, and a reduction in DNA methylation, in iPSC-derived dopaminergic neurons from patients with PARK2 mutations. These changes may contribute to the initial dysfunction of dopaminergic transmission in Parkinson’s disease.

Dopamine neurons implanted into the striatum of patients with Parkinson’s disease eventually develop Lewy body pathology. By examining post-mortem tissue from patients who died between 18 months and 16 years post-grafting, Olanow et al. show that microglial infiltration occurs well before the formation of α-synuclein-positive Lewy bodies in the graft.

Non-amnestic Alzheimer’s disease is associated with hippocampal sparing; however, the progression of this condition is understudied. Phillips and Da Re et al. show that the focus and rate of atrophy differ across non-amnestic phenotypes, and that longitudinal atrophy is associated with both domain-specific cognitive decline and degree of structural connectivity.

Using flortaucipir, Pontecorvo et al. reveal an increase in cortical tau over 18 months in Aβ+ but not Aβ- subjects, and an association between baseline tau and the magnitude of changes in tau and cognitive performance. The abundance and distribution of tau may influence both tau spreading and cognitive decline.

Immunotargeting of extracellular tau could slow the prion-like spreading of neurodegeneration. Albert et al. report that antibodies that recognize a central epitope on tau are the most effective at blocking both seeding and propagation of tau pathological species in transgenic mouse models seeded by materials derived from Alzheimer’s disease brains.

See Maass and Shine (doi:10.1093/brain/awz121) for a scientific commentary on this article.

Entorhinal cortex is affected early in Alzheimer’s disease and is critical for navigation. Using immersive virtual reality, Howett et al. reveal navigational deficits in biomarker-positive patients with mild cognitive impairment. Navigational deficits are more sensitive and specific to Alzheimer’s disease risk than a battery of reference cognitive tests.

See Jeganathan and Breakspear (doi:10.1093/brain/awz132) for a scientific commentary on this article.

Schumacher et al. report a marked and generalised slowing of whole-brain EEG dynamics in Lewy body dementia that distinguishes it from Alzheimer’s disease and healthy ageing. The slowing is related to a loss of dynamic interaction between basal ganglia-thalamic networks and large-scale cortical networks, and may contribute to fluctuating cognition.

Sleep supports changes in the neuronal representation of emotional experiences to make those experiences less distressing when subsequently recalled. Wassing et al. show that individuals with insomnia disorder activate the anterior cingulate cortex during both new and relived emotional experiences. The findings suggest insufficient adaptation to emotional distress in people who are vulnerable to developing insomnia disorder.

See Schmack and Sterzer (doi:10.1093/brain/awz092) for a scientific commentary on this article.

Delusions are thought to reflect abnormal inference, but direct evidence in support of this is currently lacking. Using a novel paradigm, Baker et al. present behavioural and computational evidence for a specific correlation between abnormal inference on hidden states and delusion severity in patients with psychosis.

See Gründer and Cumming (doi:10.1093/brain/awz133) for a scientific commentary on this article.

Presynaptic striatal dopamine synthesis capacity (DSC) is elevated in patients with schizophrenia during psychosis; however, it is unknown whether this also holds for psychotic remission. Using ¹⁸F-DOPA-PET, Avram, Brandl et al. demonstrate that for patients in remission of positive symptoms, striatal DSC is reduced and links with patients’ cognitive difficulties.

High relapse rates are a core problem in tackling nicotine addiction. Using an EEG neurofeedback protocol, Bu et al. trained smokers to deactivate brain activity patterns corresponding to smoking cue reactivity. Participants completing two sessions show reduced cigarette craving and daily smoking at 4-month follow-up compared to yoked controls.