Repetitive transcranial magnetic stimulation in the treatment of mild cognitive impairment due to cerebral small vessel disease

Introduction. Mild cognitive impairment (MCI) negatively affects patients quality of life and is a risk factor for dementia. One of the main causes of MCI is cerebral small vessel disease (CSVD). The previously established link between decreased activity in the supplementary motor area (SMA) and cognitive impairment in patients with CSVD makes it possible to consider repetitive transcranial magnetic stimulation (rTMS) of the SMA with functional magnetic resonance imaging (fMRI)-assisted positioning as a promising method for treating MCI caused by CSVD. The aim of the study was to evaluate the efficacy and tolerability of fMRI-guided rTMS of the SMA in patients with MCI caused by CSVD. Materials and methods. Twenty patients were randomly assigned to the intervention (SMA stimulation; n = 10) and the control (vertex stimulation; n = 10) groups. All patients underwent 10 sessions of high-frequency rTMS. The MoCA scale, trail making test, Tower of London test, and copying and delayed recall in the ReyOsterrieth complex figure test were used to assess treatment effect. Testing was conducted before, immediately after and 3 months post rTMS. Results. The intervention group demonstrated a significant improvement in the MoCA, the Tower of London test and delayed recall in the ReyOsterrieth complex figure test immediately after rTMS. Statistically significant improvement in the MoCA and the Tower of London test results was maintained after 3 months. No statistically significant improvements were found in the control group. Groups were comparable in the incidence of headache during and in the 24-hour period after the stimulation session, and in unpleasant sensations during the session. Conclusion. fMRI-guided rTMS of the SMA is an effective and promising treatment method for MCI caused by CSVD, with effects lasting three or more months, and good tolerability.

Regression-Based Normative Data for Independent and Cognitively Active Spanish Older Adults: Free and Cued Selective Reminding Test, Rey–Osterrieth Complex Figure Test and Judgement of Line Orientation

The aim of this work was to develop normative data for neuropsychological tests for the assessment of independent and cognitively active Spanish older adults over 55 years of age. Methods: regression-based normative data were calculated from a sample of 103 nondepressed independent community-dwelling adults aged 55 or older (66% women). The raw data for the Free and Cued Selective Reminding Test (FCSRT), the Rey–Osterrieth Complex Figure Test (ROCF) and the Judgement of Line Orientation Test (JLO) were regressed on age, sex and education. The model predicting the FCSRT delayed-recall (FCSRT-Del) scores also included the FCSRT immediate-recall (FCSRT-Imm) scores. The model predicting the ROCF immediate-recall (ROCF-Imm) scores included the ROCF copy-trial (ROCF-C) scores, and the model predicting the ROCF delayed-recall (ROCF-Del) scores included both the ROCF-C and the ROCF-Imm scores. In order to identify low scores, z-scores were used to determine the discrepancy between the observed and the predicted scores. The base rates of the low scores for both the SABIEX normative data and the published normative data obtained from the general population were compared. Results: the effects of the different sociodemographic variables (age, sex and education) varied throughout the neuropsychological measures. Despite finding similar proportions of low scores between the normative data sets, the agreement was irrelevant or only fair-to-good. Conclusions: the normative data obtained from the general population might not be sensitive enough to identify low scores in cognitively active older adults, incorrectly classifying them as cognitively normal compared to the less active population.

Analysis of the Proteomes of Primary, De Novo Acute Myeloid Leukemia Cells from Adults

Introduction: Proteins, despite being the primary effectors of cellular processes, are often studied only indirectly through analysis of the transcriptome. However, it is clear that the relationship between mRNA expression and protein expression is approximate at best. In Acute Myeloid Leukemia (AML), the genome and transcriptome have been thoroughly characterized, but the proteome has been less well studied. Here, we present a deep-scale study of the proteomes of 44 primary AML bone marrow samples representing a wide range of AML across the spectrum of cytogenetic risk, common mutations, and driver fusions. Methods: Bone marrow samples were collected at presentation from 44 adult patients with de novo AML as part of an institutional banking protocol, and buffy coat cells were immediately cryopreserved without further manipulation. Cryovials were thawed in the presence of the cell permeable serine protease inhibitor diisopropyl fluorophosphate (DFP) to inactivate the abundant neutrophil serine proteases (ELANE, CTSG, PRTN3, and PRSS57), and further processed for nano-liquid chromatography mass spectrometry in the presence of an extensive cocktail of protease inhibitors. Both label-free quantification (LFQ) and tandem-mass-tag (TMT) deep-scale proteomics were performed on these 44 patient samples, as well as 3 lineage-depleted bone marrow samples from healthy adult donors. Matching RNA-seq and exome sequencing data were available for the same samples as part of The Cancer Genome Atlas (TCGA) AML project. Results: 10,651 and 6,679 unique proteins were detected in the TMT and LFQ experiments, respectively. Correlations between measurements derived from the independent proteomic platforms (i.e. TMT and LFQ) is higher (mean Spearman correlation, 0.60, Figure 1A) than correlation between proteomic (TMT) and transcriptomic measurements from bulk RNA-seq data (Spearman 0.43, Figure 1B). Quality checks of the proteomic data strongly supported the reliability of quantification of protein measurements; for example, the mean ratio of beta globin protein (HBB) to alpha globin (HBA1) was 1.2 +/- 0.25 (Figure 1C), and several proteins known to be dysregulated by specific AML-initiating fusion proteins (for PML-RARA, HGF and RARA; for RUNX1-RUNX1T1, RUNX1T1; and for CBFB-MYH11, MYH11) were detected in the expected samples (Figure 1D). Globally, 1,364 proteins were differentially expressed in the AML samples (corrected p-value <0.05, fold change ≥ 1.5) compared to the lineage-depleted, healthy bone marrow samples. Globally overexpressed proteins were enriched for ribosomal RNA modification, mitochondrial protein import, nuclear export, and the mitochondrial electron transport chain, among others. These overexpressed proteins include 61 cell surface proteins that could potentially represent therapeutic targets (overexpressed on average in 82% of AML samples, range 25-97%). Globally downregulated proteins in AML samples were enriched for glycogen metabolism and protein groups associated with mature neutrophils (reflecting the expected maturation block in AML), among others. 771 of the 1364 differentially expressed proteins (56.5%) showed only minimal variability in mRNA expression levels (fold change of <1.1 between AML and normal marrow CD34 cell mRNA) that could not explain dysregulated protein expression. Several protein complexes likewise showed coordinated differential expression in the proteomic data, but no change in the transcriptome, including the THO complex (Figure 1E) and the phosphorylase kinase complex (Figure 1F), among others, indicating the presence of posttranscriptional regulation of the levels of many proteins in AML samples. Conclusion: We have created a deep-scale proteomic database from a set of well-characterized AML samples, allowing for a proteogenomic study of AML. We have identified many examples of post-transcriptional regulation of key metabolic pathways that may be relevant for better understanding AML cell metabolism and therapeutic vulnerabilities. Additional studies linking patterns of protein dysregulation with a variety of AML covariates are underway. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Cortical Hyper-Connectivity in a Stroke Patient with Rotated Drawing

In the present case report, we investigated the cortical networks of a patient (DDA) affected by right parietal stroke who showed a constructional phenomenon, in which when coping and recalling from memory a complex figure, the model was reproduced rotated of 90° along the vertical axis. Previous studies suggested that rotation on copy is associated with visuospatial impairments and abnormalities in parietal cortex, whereas rotation on recall might be related to executive deficits and dysfunction of frontal regions. Here, we computed the DDA’s resting-state functional connectivity (FC) derived from cortical regions of the dorsal attention (DAN) and the frontal portion of the executive-control network (fECN), which are involved in the control of visuospatial attention and multiple executive functions, respectively. We observed that, as compared to a control group of right stroke patients without drawing rotation, DDA exhibited selective increased FC of the DAN and fECN, but not of task-irrelevant language network, within the undamaged hemisphere. These patterns might reflect a pathological communication in such networks leading to impaired attentional and executive operations required to reproduce the model in the correct orientation. Notably, such enhancement of FC was not detected in a patient with a comparable neuropsychological profile as DDA, yet without rotated drawing, suggesting that network-specific modulations in DDA might be ascribed to the constructional phenomenon of rotated drawing.

White Matter Correlates of Hostility and Aggression in the Visuospatial Function Network in Patients With Schizophrenia

Background: Violent acts in patients with schizophrenia are often associated with their hostility and aggression levels. Poor visuospatial processing has been suggested as a possible risk factor of violence in schizophrenia. However, studies investigating the relationship between hostility, aggression, and the visuospatial function have been lacking. Here, we aimed to investigate brain dysconnectivity associated with hostility and aggression in schizophrenia, particularly focusing on the visuospatial function network.Methods: Eighty-eight participants with schizophrenia and 42 healthy controls were enrolled. The visuospatial function network regions of interest were analyzed using Tract-Based Spatial Statistics. The hostility item from the Positive and Negative Syndrome Scale (PANSS), aggressive, and agitated behavior item from the Scale for the Assessment of Positive Symptoms (SAPS), and the Rey Complex Figure Test (R-CFT) were measured.Results: Among the participants with schizophrenia, the SAPS aggressive and agitated behavior scores were significantly correlated with fractional anisotropies (FAs) of the white matter regions in the splenium of the corpus callosum (CC), left posterior thalamic radiations (PTR), and left posterior corona radiata (PCR). Exploratory correlational analysis revealed significant negative correlations between FAs of the splenium of the CC and R-CFT copy and immediate recall scores. In addition, three regions including CC, PTR, and PCR that significantly correlated with the aggression scores showed significant correlations with the total PANSS scores.Conclusion: Our main finding suggests that aggression of patients with schizophrenia may be associated with poor visuospatial ability and underlying white matter dysconnectivity. These may help enhance understanding aggression in patients with schizophrenia.

Does daytime sleepiness alter visual memory in schoolchildren aged 9 to 11 at different times during the school semester?

Daytime sleepiness could reduce the memorization of children who are in school. Thus, the aim of this study was to study the effect of daytime sleepiness on the visual memory of schoolchildren at different times during the school semester. Individuals of both genders (n = 88) aged 9 to 11 years and regularly enrolled at the Mariana Amália Municipal School were selected. Data collection occurred in two moments: at the beginning and end of the academic semester. A semi-structured questionnaire was used to collect sociodemographic information, the Epworth Sleepiness Scale to assess sleepiness and the Rey-Osterrieth complex figure, object recall, scrambling figures and addition of dictated numbers for memory analysis tests. The data revealed that there is no direct relationship between sleepiness and impaired memory by the tests used in any of the analyzed moments. However, children showed lower visuospatial memory efficiency at the beginning of the school semester, indicating that they may have greater difficulty in memory retention. Lastly, there was an abnormality in the degree of sleepiness at the end of the school semester and the female gender showed efficiency in immediate and late memory.