👤 Andreea Nicoleta Anton

Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classic Richardson's syndrome (RS) and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We included 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309 and SLC2A13 rs2242367 single nucleotide polymorphism data were collated. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: (i) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; (ii) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, including region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; (iii) associations potentially linking biological sex, MAPT haplotype and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; (iv) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and (v) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to cortical regions and two characterised by early, simultaneous involvement of subcortical grey matter and cortical regions. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks and via intrinsic regional susceptibility mechanisms, possibly influenced by sex, genetic factors and co-pathology. Show less

This study determines the phenotypic and functional characteristics that define distinct fibroblast-like synoviocyte (FLS) populations in rheumatoid arthritis (RA) vs psoriatic arthritis (PsA). Single-cell RNA sequencing and multiparametric flow cytometry analysis (21 markers) were performed on RA and PsA synovial cell suspensions to determine FLS phenotype/function. Podoplanin (PDPN) Flow analysis of PDPN RA and PsA possess distinct FLS populations with unique functional and metabolic properties, which may facilitate improved understanding of disease pathogenesis and therapeutic response. Show less

In this functional magnetic resonance imaging study, we investigated whether language production and understanding recruit similar phoneme-specific networks. We did so by comparing the brain's response to different phoneme categories in minimal pairs: Bilabial-initial words (eg "monkey") were contrasted to alveolar-initial words (eg "donkey") in 37 participants performing both language production and comprehension tasks. Individual-specific region-of-interest analyses showed that the same sensorimotor networks were activated across the language modalities. In motor regions, word production and comprehension elicited the same phoneme-specific topographical activity patterns, with stronger haemodynamic activations for alveolar-initial words in the tongue cortex and stronger activations for bilabial-initial words in the lip cortex. In the posterior and middle superior temporal cortex, production and comprehension likewise resulted in similar activity patterns, with enhanced activations to alveolar- compared to bilabial-initial words. These results disagree with the classical asymmetry between language production and understanding in neurobiological models of language, and instead advocate for a cortical organization where phonology is carried by similar topographical activations in motor cortex and distributed activations in temporal cortex across the language modalities. Show less

Reading relies on the ability to map written symbols with speech sounds. A specific part of the left ventral occipitotemporal cortex, known as the Visual Word Form Area (VWFA), plays a crucial role in this process. Through the automatization of the mapping ability, this area progressively becomes specialized in written word recognition. Yet, despite its key role in reading, the area also responds to speech. This observation raises questions about the actual nature of neural representations encoded in the VWFA and, therefore, the underlying mechanism of the cross-modal responses. Here, we addressed this issue by applying fine-grained analyses of within- and cross-modal repetition suppression effects (RSEs) and Multi-Voxel Pattern Analyses in fMRI and sEEG experiments. Convergent evidence across analysis methods and protocols showed significant RSEs and successful decoding in both within-modal visual and auditory conditions, suggesting that populations of neurons within the VWFA distinctively encode written and spoken language. This functional organization of neural populations enables the area to respond to both written and spoken inputs. The finding opens further discussions on how the human brain may be prepared and adapted for an acquisition of a complex ability such as reading. Show less

Prediction has become a key concept for understanding language comprehension, language production, and more recently reading. Recent studies suggest that predictive mechanisms in reading may be related to domain-general statistical learning (SL) abilities that support the extraction of regularities from sequential input. Both mechanisms have been discussed in relation to developmental dyslexia. Some suggest that SL is impaired in dyslexia with negative effects on the ability to make linguistic predictions. Others suggest that dyslexic readers rely to a greater extent on semantic and syntactic predictions to compensate for lower-level deficits. Here, we followed these two research questions in a single study. We therefore assessed the effects of semantic and syntactic prediction in reading and SL abilities in a population of university students with dyslexia and a group of typical readers using fMRI. The SL task was a serial reaction time (SRT) task that was performed inside and outside the scanner. The predictive reading task was performed in the scanner and used predictive versus nonpredictive semantic and syntactic contexts. Our results revealed distinct neural networks underlying semantic and syntactic predictions in reading, group differences in predictive processing in the left precentral gyrus and right anterior insula, and an association between predictive reading and SL, particularly in dyslexic readers. These findings contribute to our understanding of the interplay between SL, predictive processing, and compensation in dyslexia, providing new insights into the neural mechanisms that support reading. Show less

SARS-CoV-2 infection is a significant health concern that needs to be addressed not only during the initial phase of infection but also after hospitalization. This is the consequence of the various pathologies associated with long COVID-19, which are still being studied and researched. Lung fibrosis is an important complication after COVID-19, found in up to 71% of patients after discharge. Our research is based on scientific articles indexed in PubMed; in the selection process, we used the following keywords: "lung fibrosis", "fibrosis mediators", "fibrosis predictors", "COVID-19", "SARS-CoV-2 infection", and "long COVID-19". In this narrative review, we aimed to discuss the current understanding of the mechanisms of initiation and progression of post-COVID-19 lung fibrosis (PC-19-LF) and the risk factors for its occurrence. The pathogenesis of pulmonary fibrosis involves various mediators such as TGF-β, legumain, osteopontin, IL-4, IL-6, IL-13, IL-17, TNF-α, Gal-1, Gal-3, PDGF, and FGFR-1. The key cellular effectors involved in COVID-19 lung fibrosis are macrophages, epithelial alveolar cells, neutrophils, and fibroblasts. The main fibrosis pathways in SARS-CoV-2 infection include hypoxemia-induced fibrosis, macrophage-induced fibrosis, and viral-fibroblast interaction-induced fibrosis. Show less

It has been argued that university students with dyslexia compensate for their reading deficits by a neural re-organization of the typical reading network, where the lexical representations of words are (re-)structured according to semantic rather than orthographic information. To investigate the re-organization of neural word representations more directly, we used multivariate representational similarity analyses (RSA) to find out which brain regions of the reading network respond to orthographic and semantic similarity between 544 pairs of words and whether there were any differences between typical and dyslexic readers. In accordance with the re-organization hypothesis, we predicted greater similarity (i.e., correlation of neural dissimilarity matrices) in adult dyslexic than in typical readers in regions associated with semantic processing and weaker similarity in regions associated with orthographic processing. Our results did not confirm these predictions. First, we found sensitivity to semantic similarity in all three subparts of the fusiform gyrus (FG1, FG2, and FG3) bilaterally. Adults with dyslexia showed less (rather than more) sensitivity to semantic similarity in the posterior subpart of fusiform gyrus (FG1) in the left hemisphere. Second, in typical readers, sensitivity to orthographic information was not only found in the left fusiform gyrus (FG1, FG2, and FG3) but also in left inferior frontal gyrus (IFG). Adults with dyslexia, in contrast, did not show sensitivity to orthographic information in left IFG. However, they showed increased sensitivity to orthographic information in the right hemisphere FG1. Together, the results show abnormal orthographic processing in left IFG and right FG1 and reduced semantic information in left FG1. While we found evidence for compensatory re-organization in adult dyslexia, the present results do not support the hypothesis according to which adults with dyslexia rely more heavily on semantic information. Instead, they revealed atypical hemispheric organization of the reading network that is not restricted to the typical left language hemisphere. Show less

Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel. Show less

RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence. The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs) was examined with four substance dependence diagnoses (alcohol (AD), cocaine (CD), opioid (OD) or marijuana (MjD)] in 1,905 African Americans (AAs: 1,562 cases and 343 controls) and 1,332 European Americans (EAs: 981 cases and 351 controls). Analyses were performed using both χ2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses. Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003≤P(empirical)≤0.037). The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005≤P(empirical)≤0.019). This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P = 0.002) and non-significantly lower mRNA expression levels of RGS17 in CEU subjects (P = 0.185). No RGS20 SNPs were associated with any of the four dependence traits in either population. This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations. Show less