Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson’s disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.

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Amyloid fibrils found in plaques in Alzheimer’s disease (AD) brains are composed of amyloid‐β peptides. Oligomeric amyloid‐β 1‐42 (Aβ42) is thought to play a critical role in neurodegeneration in AD. Here, we determine how size and conformation affect neurotoxicity and internalisation of Aβ42 assemblies using biophysical methods, immunoblotting, toxicity assays and live‐cell imaging. We report significant cytotoxicity of Aβ42 oligomers and their internalisation into neurons. In contrast, Aβ42 fibrils show reduced internalisation and no toxicity. Sonicating Aβ42 fibrils generates species similar in size to oligomers but remains nontoxic. The results suggest that Aβ42 oligomers have unique properties that underlie their neurotoxic potential. Furthermore, we show that incubating cells with Aβ42 oligomers for 24 h is sufficient to trigger irreversible neurotoxicity.

Background Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. Methods We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the ‘CDR® plus NACC FTLD’ scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. Results The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. Conclusions The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.

BackgroundAlthough social cognitive dysfunction is a major feature of frontotemporal dementia (FTD) it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. MethodsWe used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the Genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the ‘CDR® plus NACC FTLD’ scale and RSMS. The RSMS Total score and its two subscores, socioemotional expressiveness (EX score), and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. ResultsThe RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores), and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. ConclusionsThe RSMS indexes socioemotional impairment at an early stage of genetic FTD, and may be a suitable outcome measure in forthcoming trials.

Accumulating evidence suggests that neurodegenerative diseases are not merely neuronal in nature but comprise multicellular involvement, with astrocytes emerging as key players. The pathomechanisms of several neurodegenerative diseases involve the deposition of misfolded protein aggregates in neurons that have characteristic prion-like behaviours such as template-directed seeding, intercellular propagation, distinct conformational strains and protein-mediated toxicity. The role of astrocytes in dealing with these pathological prion-like protein aggregates and whether their responses either protect from or conspire with the disease process is currently unclear. Here we review the existing literature implicating astrocytes in multiple neurodegenerative proteinopathies with a focus on prion-like behaviour in this context.

ObjectivesEvaluate patients’ and healthcare professionals’ attitudes towards deceptive and open-label placebo treatments, its perceived effectiveness and current use.MethodsA sixteen-item anonymous survey explored attitudes towards deceptive and open-label placebo treatments in clinical practice, its perceived effectiveness and current use. The following groups completed the survey: 288 people with a neurological condition, 138 people with a functional neurological disorder, 61 people with a medical condition, 59 healthy controls and 112 healthcare professionals, of which 45 neurologists and 20 psychiatrists/psychologists.ResultsThe overall attitude to deceptive placebo treatments was favourable amongst non-professionals (69% in favour). The healthcare professionals were more conservative, with only 48% being in favour. However, a considerable number strongly opposed deceptive placebo: 15% of medical patients, 11% of neurological patients and 22% of patients with a functional neurological disorder. Forty-one percent of functional neurological disorder patients, 46% of patients with presumed organic conditions and 70% of healthy controls believed that a deceptive placebo would improve their own symptoms. Healthcare professionals estimated that deceptive placebo treatments would be effective in 31% of purely organic symptoms and in 55% of purely functional symptoms. Major concerns surrounding deceptive placebo involved undermining trust in the medical profession. There was marked scepticism with regards to open-label placebo in all groups, with the general underlying belief that open-label placebo is fairly ineffective.Two-thirds of healthcare professionals had never used deceptive nor open-label placebo. Those who had used it, had done so rarely and mostly for non-specific or functional symptoms or for diagnostic purposes.ConclusionsDespite a generally perceived high effectiveness of deceptive placebo treatments, its prohibition in the UK seems to be in line with general concerns and some strong opposition. Future studies will show if the negative attitude to open-label placebo is justified or if this ethically viable option deserves more consideration.

Patients´ and healthcare professionals´ attitudes to deceptive and open-label placebo treatments in clinical practice were evaluated by means of an anonymous survey.The overall attitude to deceptive placebo treatments was favourable amongst the 310 neurological patients and 100 medical patients/healthy participants taking part in the survey. The 90 healthcare pro- fessionals and 140 patients with a functional neurological disorder were more conservative, with equal numbers being in favour and against.An even more crucial factor is the considerable percentage being strongly opposed to deceptive placebo– 16% of neurological patients and 30% of patients with a functional neurological disorder.The majority of healthcare professionals had never used deceptive placebo, with an even smaller pro- portion ever having used open-label placebo. There was marked scepticism with regards to open-label placebo in all groups, with the general underlying belief that open-label placebo is fairly ineffectiveThe prohibition of deceptive placebo use in the UK seems to be in line with general concerns and oppo- sition to placebo. Future studies will show if the negative attitude to open-label placebo is justified or if this ethically viable option deserves more consideration.The survey is ongoing (to take part, visit https://is.gd/hcp_placebosurvey). The final numbers and conclu- sions may thus change.anne-catherine.huys.15@ucl.ac.uk