Investigation of the functional pathogenesis of mild cognitive impairment by localisation-based locus coeruleus resting-state fMRI.

Dementia as one of the most prevalent diseases urges for a better understanding of the central mechanisms responsible for clinical symptoms, and necessitates improvement of actual diagnostic capabilities. The brainstem nucleus locus coeruleus (LC) is a promising target for early diagnosis because of its early structural alterations and its relationship to the functional disturbances in the patients. In this study, we applied our improved method of localisation-based LC resting-state fMRI to investigate the differences in central sensory signal processing when comparing functional connectivity (fc) of a patient group with mild cognitive impairment (MCI, n = 28) and an age-matched healthy control group (n = 29). MCI and control participants could be differentiated in their Mini-Mental-State-Examination (MMSE) scores (p < .001) and LC intensity ratio (p = .010). In the fMRI, LC fc to anterior cingulate cortex (FDR p < .001) and left anterior insula (FDR p = .012) was elevated, and LC fc to right temporoparietal junction (rTPJ, FDR p = .012) and posterior cingulate cortex (PCC, FDR p = .021) was decreased in the patient group. Importantly, LC to rTPJ connectivity was also positively correlated to MMSE scores in MCI patients (p = .017). Furthermore, we found a hyperactivation of the left-insula salience network in the MCI patients. Our results and our proposed disease model shed new light on the functional pathogenesis of MCI by directing to attentional network disturbances, which could aid new therapeutic strategies and provide a marker for diagnosis and prediction of disease progression.

DNA methylation of miR-200 clusters promotes epithelial to mesenchymal transition in human conjunctival epithelial cells.

Epithelial to mesenchymal transition (EMT) contributes to fibrosis associated pathologies including scarring of different ocular tissues. Recently targeting EMT is seen as an appropriate therapeutic approach for different fibrosis related eye diseases such as macular degeneration or glaucoma surgery related fibrosis. Nevertheless, for ocular surface diseases, target genes specific for particular cell type or condition are still undefined. This study aimed to expose the complex regulatory mechanisms that trigger EMT in human conjunctival epithelial (HCjE) cells. EMT was induced by prolonged treatment with two TGF-ß isoforms, TGF-ß1 and TGF-ß2, and their combination. TGF-ß1 showed the strongest potential for initiating EMT in HCjE cells, reflected on morphological changes, cell migration and the levels of mRNA expression of different epithelial (CDH1, OCLN, DSP) and mesenchymal (CDH2, FN1, VIM, SNAI1, ZEB2, TWIST1) marker genes. Co-treatment with the DNA demethylating agent 5-Azacytidine (5-AzaC) was capable of stopping the transition of HCjE cells towards a mesenchymal phenotype, based on morphological features, reduced cell mobility and mRNA and protein expression levels of epithelial and mesenchymal marker genes. An EMT qRT-PCR-based array revealed that EMT induced considerable alterations in gene expression, with downregulation of the majority of epithelial marker genes and upregulation of genes specific for the mesenchymal state. The major effect of 5-AzaC treatment was observed as a suppression of mesenchymal marker genes, suggesting the involvement of upstream negative regulator(s) whose promoter demethylation and subsequent expression will in turn promote EMT switch off. The expression level of miRNAs potentially important for EMT induction was determined using qRT-PCR-based array which pointed at members of miR-200 family as main regulators of EMT process in HCjE cells. 5-AzaC treatment induced increased expression of miR-200a, -200b, -200c and miR-141 towards the control level, indicating important role of DNA methylation in their regulation. The DNA methylation status of both miR-200 family clusters, analyzed with high-resolution melting (HRM) and bisulfite sequencing (Bis-Seq), revealed that TGF-ß1-induced EMT was accompanied by increase in promoter CpG methylation of both miR-200 loci, which was reverted after 5-AzaC treatment. In conclusion, our results indicate that DNA demethylation of promoters of miR-200 loci is critically important for stopping and reverting the EMT in human conjunctival epithelial cells, suggesting the potential for the development of novel epigenetic-based therapeutic strategies for treating conjunctival conditions associated with EMT.

Absence of PARP-1 affects Cxcl12 expression by increasing DNA demethylation.

Poly [ADP-ribose] polymerase 1 (PARP-1) has an inhibitory effect on C-X-C motif chemokine 12 gene (Cxcl12) transcription. We examined whether PARP-1 affects the epigenetic control of Cxcl12 expression by changing its DNA methylation pattern. We observed increased expression of Cxcl12 in PARP-1 knock-out mouse embryonic fibroblasts (PARP1-/-) in comparison to wild-type mouse embryonic fibroblasts (NIH3T3). In the Cxcl12 gene, a CpG island is present in the promoter, the 5' untranslated region (5' UTR), the first exon and in the first intron. The methylation state of Cxcl12 in each cell line was investigated by methylation-specific PCR (MSP) and high resolution melting analysis (HRM). Both methods revealed strong demethylation in PARP1-/- compared to NIH3T3 cells in all four DNA regions. Increased expression of the Ten-eleven translocation (Tet) genes in PARP1-/- cells indicated that TETs could be important factors in Cxcl12 demethylation in the absence of PARP-1, accounting for its increased expression. Our results showed that PARP-1 was a potential upstream player in (de)methylation events that modulated Cxcl12 expression.

Meniscal pathologies on MRI correlate with increased bone tracer uptake in SPECT/CT.

OBJECTIVES: To assess the relationship of subchondral bone tracer uptake (BTU) on SPECT/CT and meniscal pathologies on MRI in patients with painful knees. METHODS: Twenty-five patients who had MRI and SPECT/CT within 3 months without knee surgery or grade ≥3 cartilage lesions were prospectively included. Maximum values of each subchondral femorotibial area were quantified and a ratio was calculated in relation to a femoral shaft reference region, which represented the BTU background activity. Meniscal lesions were graded (intact/degeneration/tear) and meniscal extrusion (no/yes) was assessed using MRI by two musculoskeletal radiologists blinded to the SPECT/CT findings. One-tailed Spearman correlations served for statistics (p < 0.05). RESULTS: Knees with meniscal degeneration or tear showed a significantly higher BTU in the medial femorotibial compartment (p = 0.045) when compared to intact menisci. Meniscal degeneration was associated with an increased BTU in the lateral femorotibial compartment; however, this was not statistically significant (p = 0.143). Patients with an extruded meniscus showed significantly higher BTU compared to a non-extruded meniscus (p < 0.020). CONCLUSIONS: Medial femorotibial BTU in SPECT/CT was associated with meniscal pathologies. Highest BTU was found in patients with meniscal tears. SPECT/CT appears to be a useful imaging modality to identify patients with overloading or early osteoarthritis. KEY POINTS: • Meniscal degeneration and tears correlate significantly with increased BTU using SPECT/CT. • Medial meniscus extrusion is associated with an increased BTU in SPECT/CT. • SPECT/CT allows detection of overloading and early osteoarthritis.

Do Chondral Lesions of the Knee Correlate with Bone Tracer Uptake by Using SPECT/CT?

PURPOSE: To evaluate the correlation of bone tracer uptake as determined with single photon emission computed tomography (SPECT)/computed tomography (CT) and the size and severity of chondral lesions detected with magnetic resonance (MR) imaging of the knee. MATERIALS AND METHODS: MR imaging and SPECT/CT images of 63 knee joints in 63 patients (mean age ± standard deviation, 49.2 years ± 12.7) with chondral or osteochondral lesions were prospectively collected and retrospectively analyzed after approval by the ethics committee. Chondral lesions were graded on MR images by using a modified Noyes grading scale (grade 0, intact; grade 1, fibrillations; grade 2, <50% defect; grade 3, >50% defect; and grade 4, grade three plus subchondral changes) and measured in two dimensions. Technetium 99m hydroxymethane diphosphonate SPECT/CT bone tracer uptake was volumetrically quantified by using validated software. Maximum values of each subchondral area (patellofemoral or medial and lateral femorotibial) were quantified, and a ratio was calculated in relation to a reference region in the femoral shaft, which represented the bone tracer uptake background activity. Grades and sizes of chondral lesions and bone tracer uptake were correlated by using an independent t test and analysis of variance (P < .05). RESULTS: Bone tracer uptake was low (mean relative uptake, 1.64 ± 0.95) in knees without any present chondral lesion. In knees with grade 3 and 4 chondral lesions, the relative ratio was significantly higher (3.62 ± 2.18, P = .002) than in knees with grade 1 and 2 lesions (2.95 ± 2.07). The larger the diameter of the chondral lesion, the higher the bone tracer uptake. Higher grades of chondral lesions (grades 3 and 4) larger than 4 cm(2) (4.96 ± 2.43) showed a significantly higher bone tracer uptake than smaller lesions (<1 cm(2), 2.72 ± 1.43 [P = .011]; and 1-4 cm(2), 3.28 ± 2.15 [P = .004]). CONCLUSION: SPECT/CT findings significantly correlate with the degree and size of chondral lesions on MR images. Grade 3 and 4 chondral lesions of the knee, as well as larger lesions, correlate with a high bone tracer uptake.

CXCL12 protects pancreatic ß-cells from oxidative stress by a Nrf2-induced increase in catalase expression and activity.

Due to intrinsically low levels of antioxidant enzyme expression and activity, insulin producing pancreatic ß-cells are particularly susceptible to free radical attack. In diabetes mellitus, which is accompanied by high levels of oxidative stress, this feature of ß-cells significantly contributes to their damage and dysfunction. In light of the documented pro-survival effect of chemokine C-X-C Ligand 12 (CXCL12) on pancreatic ß-cells, we examined its potential role in antioxidant protection. We report that CXCL12 overexpression enhanced the resistance of rat insulinoma (Rin-5F) and primary pancreatic islet cells to hydrogen peroxide (H2O2). CXCL12 lowered the levels of DNA damage and lipid peroxidation and preserved insulin expression. This effect was mediated through an increase in catalase (CAT) activity. By activating downstream p38, Akt and ERK kinases, CXCL12 facilitated Nrf2 nuclear translocation and enhanced its binding to the CAT gene promoter, inducing constitutive CAT expression and activity that was essential for protecting ß-cells from H2O2.

Effect of high tibial osteotomy on joint loading in symptomatic patients with varus aligned knees: a study using SPECT/CT.

PURPOSE: The purpose was to prospectively evaluate the outcome, in particular the SPECT/CT bone tracer uptake (BTU) after high tibial osteotomy (HTO) due to symptomatic varus malalignment. It was the hypothesis that the BTU after HTO decreases in the medial compartment, clinical outcome and the degree of correction correlates with BTU and asymptomatic patients after HTO reveals a significantly decreased BTU in the medial subchondral areas. METHODS: Twenty-two consecutive patients with 23 knees undergoing medial opening-wedge HTO for medial compartment overloading were assessed pre- and postoperatively (12 and/or 24 months) using Tc-99m-HDP-SPECT/CT including our 4D-SPECT/CT protocol. BTU was quantified and localized to specific biomechanically relevant joint areas. Maximum absolute and relative values (mean ± standard deviation, median and range) for each area were recorded. Pre- and postoperative mechanical alignment was measured. At 24 months after HTO, the WOMAC score was used. RESULTS: A significant decrease of BTU in the medial subchondral zones after HTO was found (preoperatively to 12 and 24 months postoperatively, p < 0.01). BTU normalized in all asymptomatic patients within 24 months. This decrease was partly seen in the lateral compartments, but significantly higher in the medial compartments (p < 0.0001). A significant increase of the BTU was noted in zones directly adjacent to the plate or within the osteotomy zone (p < 0.01). Decreased BTU was observed in osteotomy zones at 24 months postoperatively following higher uptake values at 12 months postoperatively. The average valgus correction of the tibiofemoral angle was 5.9° ± 2.8°. Less stiffness correlated significantly with a higher decrease in BTU (p < 0.05). Higher postoperative BTU significantly correlated with more pain (p < 0.05). No statistical significant associations between BTU and alignment correction were found. CONCLUSION: In patients with medial compartment, overloading due to varus malalignment HTO led to a significant decrease in BTU in the medial joint compartments. SPECT/CT BTU patterns and intensity in these patients pre- to 12 and 24 months postoperatively were seen. These correlated significantly with pain and stiffness. Hence, SPECT/CT could be used for assessment of adequate correction and healing after HTO. SPECT/CT could be further used to identify the optimal individualized correction for each patient and clinical scenario. CLINICAL EVIDENCE: Diagnostic prospective study, Level II.

Computational approaches in the estimation of radiobiological damage for human-malignant cells irradiated with clinical proton and carbon beams.

PURPOSE: The use of Monte Carlo (MC) simulations capable of reproducing radiobiological effects of ionising radiation on human cell lines is of great importance, especially for cases involving protons and heavier ion beams. In the latter, huge uncertainties can arise mainly related to the effects of the secondary particles produced in the beam-tissue interaction. This paper reports on a detailed MC study performed using Geant4-based approach on three cancer cell lines, the HTB-177, CRL-5876 and MCF-7, that were previously irradiated with therapeutic proton and carbon ion beams. METHODS: A Geant4-based approach used jointly with analytical calculations has been developed to provide a more realistic estimation of the radiobiological damage produced by proton and carbon beams in tissues, reproducing available data obtained from in vitro cell irradiations. The MC "Hadrontherapy" Geant4 application and the Local Effect Model: LEM I, LEM II and LEM III coupled with the different numerical approaches: RapidRusso (RR) and RapidScholz (RS) were used in the study. RESULTS: Experimental survival curves are compared with those evaluated using the highlighted Geant4 MC-based approach via chi-square statistical analysis, for the combinations of radiobiological models and numerical approaches, as outlined above. CONCLUSION: This study has presented a comparison of the survival data from MC simulations to experimental survival data for three cancer cell lines. An overall best level of agreement was obtained for the HTB-177 cells.

In vitro validation of helium ion irradiations as a function of linear energy transfer in radioresistant human malignant cells.

PURPOSE: Based on considerable interest to enlarge the experimental database of radioresistant cells after their irradiation with helium ions, HTB140, MCF-7 and HTB177 human malignant cells are exposed to helium ion beams having different linear energy transfer (LET). MATERIALS AND METHODS: The cells are irradiated along the widened 62 MeV/u helium ion Bragg peak, providing LET of 4.9, 9.8, 23.4 and 36.8 keV/µm. Numerical simulations with the Geant4 toolkit are used for the experimental design. Cell survival is evaluated and compared with reference γ-rays. DNA double strand breaks are assessed via γ-H2AX foci. RESULTS: With the increase of LET, surviving fractions at 2 Gy decrease, while RBE (2 Gy, γ) gradually increase. For HTB140 cells, above the dose of 4 Gy, a slight saturation of survival is observed while the increase of RBE (2 Gy, γ) remains unaffected. With the increase of LET the increase of γ-H2AX foci is revealed at 0.5 h after irradiation. There is no significant difference in the number of foci between the cell lines for the same LET. From 0.5 to 24 h, the number of foci drops reaching its residual level. For each time point, there are small differences in DNA DSB among the three cell lines. CONCLUSION: Analyses of data acquired for the three cell lines irradiated by helium ions, having different LET, reveal high elimination capacity and creation of a large number of DNA DSB with respect to γ-rays, and are between those reported for protons and carbon ions.

A Comparison of Immersive vs. Non-Immersive Virtual Reality Exercises for the Upper Limb: A Functional Near-Infrared Spectroscopy Pilot Study with Healthy Participants.

Functional near-infrared spectroscopy (fNIRS) allows for a reliable assessment of oxygenated blood flow in relevant brain regions. Recent advancements in immersive virtual reality (VR)-based technology have generated many new possibilities for its application, such as in stroke rehabilitation. In this study, we asked whether there is a difference in oxygenated hemoglobin (HbO2) within brain motor areas during hand/arm movements between immersive and non-immersive VR settings. Ten healthy young participants (24.3 ± 3.7, three females) were tested using a specially developed VR paradigm, called "bus riding", whereby participants used their hand to steer a moving bus. Both immersive and non-immersive conditions stimulated brain regions controlling hand movements, namely motor cortex, but no significant differences in HbO2 could be found between the two conditions in any of the relevant brain regions. These results are to be interpreted with caution, as only ten participants were included in the study.

Geant4-DNA simulation of human cancer cells irradiation with helium ion beams.

PURPOSE: This study aimed to develop a computational environment for the accurate simulation of human cancer cell irradiation using Geant4-DNA. New cell geometrical models were developed and irradiated by alpha particle beams to induce DNA damage. The proposed approach may help further investigation of the benefits of external alpha irradiation therapy. METHODS: The Geant4-DNA Monte Carlo (MC) toolkit allows the simulation of cancer cell geometries that can be combined with accurate modelling of physical, physicochemical and chemical stages of liquid water irradiation, including radiolytic processes. Geant4-DNA is used to calculate direct and non-direct DNA damage yields, such as single and double strand breaks, produced by the deposition of energy or by the interaction of DNA with free radicals. RESULTS: In this study, the "molecularDNA" example application of Geant4-DNA was used to quantify early DNA damage in human cancer cells upon irradiation with alpha particle beams, as a function of linear energy transfer (LET). The MC simulation results are compared to experimental data, as well as previously published simulation data. The simulation results agree well with the experimental data on DSB yields in the lower LET range, while the experimental data on DSB yields are lower than the results obtained with the "molecularDNA" example in the higher LET range. CONCLUSION: This study explored and demonstrated the possibilities of the Geant4-DNA toolkit together with the "molecularDNA" example to simulate the helium beam irradiation of cancer cell lines, to quantify the early DNA damage, or even the following DNA damage response.

Is there a link between heart rate variability and cognitive decline? A cross-sectional study on patients with mild cognitive impairment and cognitively healthy controls.

BACKGROUND: Given that, up to date, there is no effective strategy to treat dementia, a timely start of interventions in a prodromal stage such as mild cognitive impairment (MCI) is considered an important option to lower the overall societal burden. Although autonomic functions have been related to cognitive performance, both aspects have rarely been studied simultaneously in MCI. OBJECTIVE: The aim of the present study was to investigate cardiac autonomic control in older adults with and without MCI. METHODS: Cardiac autonomic control was assessed by means of heart rate variability (HRV) at resting state and during cognitive tasks in 22 older adults with MCI and 29 healthy controls (HCs). Resting HRV measurement was performed for 5 minutes during a sitting position. Afterwards, participants performed three PC-based tasks to probe performance in executive functions and language abilities (i.e., Stroop, N-back, and a verbal fluency task). RESULTS: Participants with MCI showed a significant reduction of HRV in the frequency-domain (high frequency power) and nonlinear indices (SD2, D2, and DFA1) during resting state compared to HCs. Older individuals with MCI exhibited decreases in RMSSD and increases in DFA1 from resting state to Stroop and N-back tasks, reflecting strong vagal withdrawal, while this parameter remained stable in HCs. CONCLUSION: The results support the presence of autonomic dysfunction at the early stage of cognitive impairment. Heart rate variability could help in the prediction of cognitive decline as a noninvasive biomarker or as a tool to monitor the effectiveness of therapy and prevention of neurodegenerative diseases.

ANTECEDENTES: Como não existe até o momento uma estratégia eficaz para tratar a demência de comprometimento cognitivo leve (MCI, na sigla em inglês), as intervenções em um estágio prodrômico são consideradas uma opção. Embora as funções autonômicas tenham sido relacionadas ao desempenho cognitivo, ambos os aspectos raramente foram estudados simultaneamente no MCI. OBJETIVO: Investigar o controle autonômico cardíaco em idosos com e sem MCI. MéTODOS: O controle autonômico cardíaco foi avaliado por meio da variabilidade da frequência cardíaca (HRV, na sigla em inglês) em repouso e durante tarefas cognitivas, em 22 idosos com MCI e 29 controles saudáveis (HCs, na sigla em inglês). A medida da HRV de repouso foi realizada por 5 minutos na posição sentada. Os participantes realizaram três tarefas executadas em computador para testar o desempenho em funções executivas e habilidades de linguagem (o teste de cores e palavras - Stroop, Tarefa N-back auditiva e uma tarefa de fluência verbal). RESULTADOS: Em pacientes com MCI, observou-se uma redução significativa da HRV no domínio da frequência (potência de alta frequência) e índices não lineares (SD2, D2 e DFA1) durante o estado de repouso em comparação com os HCs. Indivíduos mais velhos com MCI exibiram diminuições em RMSSD e aumentos em DFA1 do estado de repouso para Stroop e tarefas N-back, refletindo forte recessão vagal, enquanto este parâmetro permaneceu estável em HC. CONCLUSãO: Observou-se disfunção autonômica na fase inicial da neurodegeneração. A HRV pode ajudar na previsão do declínio cognitivo, como um biomarcador não invasivo, ou como uma ferramenta para monitorar a eficácia da terapia e prevenção de doenças neurodegenerativas.

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

The Role of the Precuneus in Human Spatial Updating in a Real Environment Setting-A cTBS Study.

As we move through an environment, we update positions of our body relative to other objects, even when some objects temporarily or permanently leave our field of view-this ability is termed egocentric spatial updating and plays an important role in everyday life. Still, our knowledge about its representation in the brain is still scarce, with previous studies using virtual movements in virtual environments or patients with brain lesions suggesting that the precuneus might play an important role. However, whether this assumption is also true when healthy humans move in real environments where full body-based cues are available in addition to the visual cues typically used in many VR studies is unclear. Therefore, in this study we investigated the role of the precuneus in egocentric spatial updating in a real environment setting in 20 healthy young participants who underwent two conditions in a cross-over design: (a) stimulation, achieved through applying continuous theta-burst stimulation (cTBS) to inhibit the precuneus and (b) sham condition (activated coil turned upside down). In both conditions, participants had to walk back with blindfolded eyes to objects they had previously memorized while walking with open eyes. Simplified trials (without spatial updating) were used as control condition, to make sure the participants were not affected by factors such as walking blindfolded, vestibular or working memory deficits. A significant interaction was found, with participants performing better in the sham condition compared to real stimulation, showing smaller errors both in distance and angle. The results of our study reveal evidence of an important role of the precuneus in a real-environment egocentric spatial updating; studies on larger samples are necessary to confirm and further investigate this finding.

A Link between Handgrip Strength and Executive Functioning: A Cross-Sectional Study in Older Adults with Mild Cognitive Impairment and Healthy Controls.

Older adults with amnestic mild cognitive impairment (aMCI) who in addition to their memory deficits also suffer from frontal-executive dysfunctions have a higher risk of developing dementia later in their lives than older adults with aMCI without executive deficits and older adults with non-amnestic MCI (naMCI). Handgrip strength (HGS) is also correlated with the risk of cognitive decline in the elderly. Hence, the current study aimed to investigate the associations between HGS and executive functioning in individuals with aMCI, naMCI and healthy controls. Older, right-handed adults with amnestic MCI (aMCI), non-amnestic MCI (naMCI), and healthy controls (HC) conducted a handgrip strength measurement via a handheld dynamometer. Executive functions were assessed with the Trail Making Test (TMT A&B). Normalized handgrip strength (nHGS, normalized to Body Mass Index (BMI)) was calculated and its associations with executive functions (operationalized through z-scores of TMT B/A ratio) were investigated through partial correlation analyses (i.e., accounting for age, sex, and severity of depressive symptoms). A positive and low-to-moderate correlation between right nHGS (rp (22) = 0.364; p = 0.063) and left nHGS (rp (22) = 0.420; p = 0.037) and executive functioning in older adults with aMCI but not in naMCI or HC was observed. Our results suggest that higher levels of nHGS are linked to better executive functioning in aMCI but not naMCI and HC. This relationship is perhaps driven by alterations in the integrity of the hippocampal-prefrontal network occurring in older adults with aMCI. Further research is needed to provide empirical evidence for this assumption.

TET-mediated DNA hydroxymethylation is negatively influenced by the PARP-dependent PARylation.

BACKGROUND: Poly(ADP-ribosyl)ation (PARylation), a posttranslational modification introduced by PARP-1 and PARP-2, has first been implicated in DNA demethylation due to its role in base excision repair. Recent evidence indicates a direct influence of PARP-dependent PARylation on TET enzymes which catalyse hydroxymethylation of DNA-the first step in DNA demethylation. However, the exact nature of influence that PARylation exerts on TET activity is still ambiguous. In our recent study, we have observed a negative influence of PARP-1 on local TET-mediated DNA demethylation of a single gene and in this study, we further explore PARP-TET interplay. RESULTS: Expanding on our previous work, we show that both TET1 and TET2 can be in vitro PARylated by PARP-1 and PARP-2 enzymes and that TET1 PARylation negatively affects the TET1 catalytic activity in vitro. Furthermore, we show that PARylation inhibits TET-mediated DNA demethylation at the global genome level in cellulo. CONCLUSIONS: According to our findings, PARP inhibition can positively influence TET activity and therefore affect global levels of DNA methylation and hydroxymethylation. This gives a strong rationale for future examination of PARP inhibitors' potential use in the therapy of cancers characterised by loss of 5-hydroxymethylcytosine.

Structural and functional brain alterations in patients with myasthenia gravis.

Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described. However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients. Eleven myasthenia gravis patients (age: 70.64 ± 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 ± 8.98; 11 males). Most of the patients (n = 10, 0.91%) received cholinesterase inhibitors. Structural brain changes were determined by applying voxel-based morphometry using high-resolution T1-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels. Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, P = 0.034, d = 1.466), verbal episodic memory (P = 0.003, d = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, P = 0.003, d = 1.200). Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (P = 0.001, d = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions. Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.

Chronic, Mild Vestibulopathy Leads to Deficits in Spatial Tasks that Rely on Vestibular Input While Leaving Other Cognitive Functions and Brain Volumes Intact.

OBJECTIVES: In this study, based on the known vestibulo-hippocampal connections, we asked whether mild chronic vestibulopathy leads only to vestibular-related deficits or whether there are effects on hippocampal function, structure, and cognition in general. In more detail, we assessed whether chronic vestibulopathy leads to (a) deficits in vestibular tasks without cognitive demand (balancing), (b) deficits in spatial cognitive tasks that require vestibular input (path integration, rotational memory), (c) deficits in spatial cognitive tasks that do not rely on vestibular input, (d) deficits in general cognitive function, and (e) atrophy in the brain. METHODS: A total of 15 patients with chronic uni- or bilateral vestibulopathy (56.8 ± 10.1 years; 4 females) were included in this study and were age- and gender-matched by the control participants (57.6 ± 10.5) in a pairwise manner. Given their clinical symptoms and their deficits of the vestibulo-ocular reflex (VOR) the patients could be classified as being mildly affected. All participants of the underwent the following tests: clinical balance (CBT), triangle completion (TCT) for path integration, rotational memory (RM), the visuo-spatial subset of the Berlin intelligence structure test (BIS-4) and d2-R for attention and concentration, and a structural MRI for gray matter analysis using voxel-based morphometry (VBM). RESULTS: Compared to the healthy controls, the vestibulopathy patients performed significantly worse in terms of CBT, TCT, and RM but showed no differences in terms of the BIS-4 and d2-R. There were also no significant volumetric gray matter differences between the two groups. CONCLUSIONS: This study provides evidence that both non-cognitive and cognitive functions that rely on vestibular input (balancing, path integration, rotational memory) are impaired, even in mild chronic vestibulopathy, while other cognitive functions, which rely on visual input (visuo-spatial memory, attention), are unimpaired in this condition, together with an overall intact brain structure. These findings may reflect a segregation between vestibular- and visual-dependent processes in the medial temporal lobe on the one hand and a structure-function dissociation on the other.

Age-Related Differences in Cardiac Autonomic Control at Resting State and in Response to Mental Stress.

Our goal was to investigate age-related differences in cardiac autonomic control by means of heart rate variability (HRV). For this purpose, 30 healthy older and 34 younger adults were studied during three different conditions: (i) during resting state, (ii) during the execution of two cognitive tasks, and (iii) during the subsequent recovery phase. Mean heart rate and HRV parameters were higher in younger compared to older participants during all three conditions. While the mean heart rate was higher in older adults during the cognitive tasks compared to the resting state, it did not change in younger adults. In contrast, the change in HRV during the three conditions did not differ between age groups. Our results suggest decreased parasympathetic activity reflecting declined cardiac autonomic control with aging. In conclusion, HRV analysis could support the assessment of normal age-related alterations in cardiac autonomic control at resting state and in response to cognitive demands.

Multimodal measurement approach to identify individuals with mild cognitive impairment: study protocol for a cross-sectional trial.

INTRODUCTION: The diagnosis of mild cognitive impairment (MCI), that is, the transitory phase between normal age-related cognitive decline and dementia, remains a challenging task. It was observed that a multimodal approach (simultaneous analysis of several complementary modalities) can improve the classification accuracy. We will combine three noninvasive measurement modalities: functional near-infrared spectroscopy (fNIRS), electroencephalography and heart rate variability via ECG. Our aim is to explore neurophysiological correlates of cognitive performance and whether our multimodal approach can aid in early identification of individuals with MCI. METHODS AND ANALYSIS: This study will be a cross-sectional with patients with MCI and healthy controls (HC). The neurophysiological signals will be measured during rest and while performing cognitive tasks: (1) Stroop, (2) N-back and (3) verbal fluency test (VFT). Main aims of statistical analysis are to (1) determine the differences in neurophysiological responses of HC and MCI, (2) investigate relationships between measures of cognitive performance and neurophysiological responses and (3) investigate whether the classification accuracy can be improved by using our multimodal approach. To meet these targets, statistical analysis will include machine learning approaches.This is, to the best of our knowledge, the first study that applies simultaneously these three modalities in MCI and HC. We hypothesise that the multimodal approach improves the classification accuracy between HC and MCI as compared with a unimodal approach. If our hypothesis is verified, this study paves the way for additional research on multimodal approaches for dementia research and fosters the exploration of new biomarkers for an early detection of nonphysiological age-related cognitive decline. ETHICS AND DISSEMINATION: Ethics approval was obtained from the local Ethics Committee (reference: 83/19). Data will be shared with the scientific community no more than 1 year following completion of study and data assembly. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04427436, registered on 10 June 2020, https://clinicaltrials.gov/ct2/show/study/NCT04427436.