Methylation and Expression of Mutant FUS in Motor Neurons Differentiated From Induced Pluripotent Stem Cells From ALS Patients.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease leading to degeneration of motor neurons (MNs). Epigenetic modification of gene expression is increasingly recognized as potential disease mechanism. In the present study we generated motor neurons from induced pluripotent stem cells from ALS patients carrying a mutation in the fused in sarcoma gene (FUS) and analyzed expression and promoter methylation of the FUS gene and expression of DNA methyltransferases (DNMTs) compared to healthy control cell lines. While mutant FUS neural progenitor cells (NPCs) did not show a difference in FUS and DNMT expression compared to healthy controls, differentiated mutant FUS motor neurons showed significantly lower FUS expression, higher DNMT expression and higher methylation of the proximal FUS gene promoter. Immunofluorescence revealed perceived proximity of cytoplasmic FUS aggregates in ALS MNs together with 5-methylcytosin (5-mC). Targeting disturbed methylation in ALS may therefore restore transcriptional alterations and represent a novel therapeutic strategy.

Accuracy of registration techniques and vascular imaging modalities in fusion imaging for aortic endovascular interventions: a phantom study.

BACKGROUND: This study aimed to assess the error of different registration techniques and imaging modalities for fusion imaging of the aorta in a standardized setting using a anthropomorphic body phantom. MATERIALS AND METHODS: A phantom with the 3D printed vasculature of a patient suffering from an infrarenal aortic aneurysm was constructed. Pulsatile flow was generated via an external pump. CTA/MRA of the phantom was performed, and a virtual 3D vascular model was computed. Subsequently, fusion imaging was performed employing 3D-3D and 2D-3D registration techniques. Accuracy of the registration was evaluated from 7 right/left anterior oblique c-arm angulations using the agreement of centerlines and landmarks between the phantom vessels and the virtual 3D virtual vascular model. Differences between imaging modalities were assessed in a head-to-head comparison based on centerline deviation. Statistics included the comparison of means ± standard deviations, student's t-test, Bland-Altman analysis, and intraclass correlation coefficient for intra- and inter-reader analysis. RESULTS: 3D-3D registration was superior to 2D-3D registration, with the highest mean centerline deviation being 1.67 ± 0.24 mm compared to 4.47 ± 0.92 mm. The highest absolute deviation was 3.25 mm for 3D-3D and 6.25 mm for 2D-3D registration. Differences for all angulations between registration techniques reached statistical significance. A decrease in registration accuracy was observed for c-arm angulations beyond 30° right anterior oblique/left anterior oblique. All landmarks (100%) were correctly positioned using 3D-3D registration compared to 81% using 2D-3D registration. Differences in accuracy between CT and MRI were acceptably small. Intra- and inter-reader reliability was excellent. CONCLUSION: In the realm of registration techniques, the 3D-3D method proved more accurate than did the 2D-3D method. Based on our data, the use of 2D-3D registration for interventions with high registration quality requirements (e.g., fenestrated aortic repair procedures) cannot be fully recommended. Regarding imaging modalities, CTA and MRA can be used equivalently.

EEG microstate periodicity explained by rotating phase patterns of resting-state alpha oscillations.

Spatio-temporal patterns in electroencephalography (EEG) can be described by microstate analysis, a discrete approximation of the continuous electric field patterns produced by the cerebral cortex. Resting-state EEG microstates are largely determined by alpha frequencies (8-12 Hz) and we recently demonstrated that microstates occur periodically with twice the alpha frequency. To understand the origin of microstate periodicity, we analyzed the analytic amplitude and the analytic phase of resting-state alpha oscillations independently. In continuous EEG data we found rotating phase patterns organized around a small number of phase singularities which varied in number and location. The spatial rotation of phase patterns occurred with the underlying alpha frequency. Phase rotors coincided with periodic microstate motifs involving the four canonical microstate maps. The analytic amplitude showed no oscillatory behaviour and was almost static across time intervals of 1-2 alpha cycles, resulting in the global pattern of a standing wave. In n=23 healthy adults, time-lagged mutual information analysis of microstate sequences derived from amplitude and phase signals of awake eyes-closed EEG records showed that only the phase component contributed to the periodicity of microstate sequences. Phase sequences showed mutual information peaks at multiples of 50 ms and the group average had a main peak at 100 ms (10 Hz), whereas amplitude sequences had a slow and monotonous information decay. This result was confirmed by an independent approach combining temporal principal component analysis (tPCA) and autocorrelation analysis. We reproduced our observations in a generic model of EEG oscillations composed of coupled non-linear oscillators (Stuart-Landau model). Phase-amplitude dynamics similar to experimental EEG occurred when the oscillators underwent a supercritical Hopf bifurcation, a common feature of many computational models of the alpha rhythm. These findings explain our previous description of periodic microstate recurrence and its relation to the time scale of alpha oscillations. Moreover, our results corroborate the predictions of computational models and connect experimentally observed EEG patterns to properties of critical oscillator networks.

Drug safety profiles in geriatric patients with Parkinson's disease using the FORTA (Fit fOR The Aged) classification: results from a mono-centric retrospective analysis.

To reduce potentially inappropriate medications, the FORTA (Fit fOR The Aged) concept classifies drugs in terms of their suitability for geriatric patients with different labels, namely A (indispensable), B (beneficial), C (questionable), and D (avoid). The aims of our study were to assess the medication appropriateness in PD inpatients applying the FORTA list and drug-drug interaction software, further to assess the adequacy of FORTA list for patients with PD. We retrospectively collected demographic data, comorbidities, laboratory values, and the medication from the discharge letters of 123 geriatric inpatients with PD at the university hospital of Hannover Medical School. Patients suffered on average from 8.2 comorbidities. The majority of the medication was labeled A (60.6% of PD-specific and 40.9% of other medication) or B (22.3% of PD-specific and 26.9% of other medication). Administered drugs labeled with D were amantadine, clozapine, oxazepam, lorazepam, amitriptyline, and clonidine. Overall, 545 interactions were identified, thereof 11.9% severe interactions, and 1.7% contraindicated combinations. 81.3% of patients had at least one moderate or severe interaction. The FORTA list gives rational recommendations for PD-specific and other medication, especially for general practitioners. Considering the demographic characteristics and the common multimorbidity of geriatric PD patients, this study underlines the importance of awareness, education, and preventive interventions to increase drug safety.

Association of Motor and Cognitive Symptoms with Health-Related Quality of Life and Caregiver Burden in a German Cohort of Advanced Parkinson's Disease Patients.

Parkinson's disease (PD) is a chronic progressive movement disorder with severe reduction in patients' health-related quality of life (HR-QoL). Motor and cognitive symptoms are especially linked with decreased PD patients' HR-QoL. However, the relationship of these symptoms to caregiver burden is relatively unclear. Influence of the Montreal Cognitive Assessment scale (MoCA) as a cognitive screening tool and Movement Disorders Society Unified Parkinson's disease Rating Scale MDS-UPDRS symptoms in relation to patients' HR-QoL and caregivers` burden was analyzed. PD patients (n = 124) completed MDS-UPDRS, MoCA, and the PD questionnaire 8 (PDQ-8) as a measure of quality of life. Caregivers (n = 78) were assessed by the PD caregiver burden inventory (PDCB). PDQ-8 and PDCB scores were regressed on MDS-UPDRS subscales and MoCA subscores. PDQ-8 correlated with attention (R 2 0.1282; p < 0.001) and executive (R 2 0.0882; p 0.001) MoCA subscores and all parts of the MDS-UPDRS. PDCB correlated most strongly with MDS-UPDRS part III motor symptoms (R 2 0.2070; p < 0.001) and the MoCA attention subscore (R 2 0.1815; p < 0.001). While all facets of PD symptoms assessed by the MDS-UPDRS relate to PD patients' quality of life, motor symptoms are the most relevant factor for the prediction of caregiver burden. In addition, patients' attentional symptoms seem to affect not only them, but also their caregivers. These findings show the potential of a detailed analysis of MDS-UPDRS and MoCA performance in PD patients.

Rapid study assessment in follow-up whole-body computed tomography in patients with multiple myeloma using a dedicated bone subtraction software.

OBJECTIVES: The diagnostic reading of follow-up low-dose whole-body computed tomography (WBCT) examinations in patients with multiple myeloma (MM) is a demanding process. This study aimed to evaluate the diagnostic accuracy and benefit of a novel software program providing rapid-subtraction maps for bone lesion change detection. METHODS: Sixty patients (66 years ± 10 years) receiving 120 WBCT examinations for follow-up evaluation of MM bone disease were identified from our imaging archive. The median follow-up time was 292 days (range 200-641 days). Subtraction maps were calculated from 2-mm CT images using a nonlinear deformation algorithm. Reading time, correctly assessed lesions, and disease classification were compared to a standard reading software program. De novo clinical reading by a senior radiologist served as the reference standard. Statistics included Wilcoxon rank-sum test, Cohen's kappa coefficient, and calculation of sensitivity, specificity, positive/negative predictive value, and accuracy. RESULTS: Calculation time for subtraction maps was 84 s ± 24 s. Both readers reported exams faster using subtraction maps (reader A, 438 s ± 133 s; reader B, 1049 s ± 438 s) compared to PACS software (reader A, 534 s ± 156 s; reader B, 1486 s ± 587 s; p < 0.01). The course of disease was correctly classified by both methods in all patients. Sensitivity for lesion detection in subtraction maps/conventional reading was 92%/80% for reader A and 88%/76% for reader B. Specificity was 98%/100% for reader A and 95%/96% for reader B. CONCLUSION: A software program for the rapid-subtraction map calculation of follow-up WBCT scans has been successfully tested and seems suited for application in clinical routine. Subtraction maps significantly facilitated reading of WBCTs by reducing reading time and increasing sensitivity. KEY POINTS: • A novel algorithm has been successfully applied to generate motion-corrected bone subtraction maps of whole-body low-dose CT scans in less than 2 min. • Motion-corrected bone subtraction maps significantly facilitate the reading of follow-up whole-body low-dose CT scans in multiple myeloma by reducing reading time and increasing sensitivity.

Caregiver burden and health-related quality of life in idiopathic dystonia patients under botulinum toxin treatment: a cross-sectional study.

Dystonia is a chronic movement disorder that is associated with a reduction in health-related quality of life (HR-QoL) and restriction of activities of daily living. Botulinum neurotoxin (BT) improves disease-specific HR-QoL by reducing abnormal movements, postures, and pain. We examined the burden of the corresponding primary caregiver as a potential important factor for disease management and HR-QoL of dystonia patients under treatment with BT. 114 patients with focal, segmental, or generalized dystonia were recruited, together with 93 corresponding caregivers, whose burden was investigated using the Caregiver Burden Inventory. In addition, all participants were assessed for cognitive impairment, depression, anxiety, alexithymia, and HR-QoL. Only a small proportion of caregivers suffered from caregiver burden. Despite BT therapy, patients' HR-QoL was decreased compared to the age-matched general German population. Psychological symptoms, notably anxiety, and depression correlated significantly with reduced HR-QoL. Our data imply that caregiver burden emerged to be an issue in subgroups of dystonia patients. Furthermore, HR-QoL of dystonia patients is reduced even under optimized BT treatment in a specialized center.

Validating the Parkinson's disease caregiver burden questionnaire (PDCB) in German caregivers of advanced Parkinson's disease patients.

BACKGROUND: Advanced Parkinson's disease (PD) may place a high burden on patients and their caregivers. Understanding the determinants of caregiver burden is of critical importance. This understanding requires the availability of adequate assessment tools. Recently, the Parkinson's disease caregiver burden questionnaire (PDCB) has been developed as a PD-specific measure of caregiver burden. However, the PDCB has only been evaluated in a sample of Australian caregivers of patients at a less advanced stage of the disease. OBJECTIVE: We tested whether a German translation of the PDCB qualifies as an adequate measure of caregiver burden in a German sample of caregivers of advanced patients with PD. METHODS: We collected PDCB data from 65 caregivers of advanced patients with PD. Reliability of the scale was assessed and compared against the original version. To validate the German version of the PDCB, we examined the correlations with the caregiver burden inventory (CBI), the short form 36 health survey (SF-36), the Parkinson's disease quality of life questionnaire 39 (PDQ-39), disease duration, and the amount of caregiving time. RESULTS: The total PDCB score proved to be reliable and to be significantly related to CBI and SF-36 scores. PDCB scores also increased with increasing amounts of caregiving time. CONCLUSIONS: The German version of the PDCB appears to be an adequate measure of caregiver burden in caregivers of advanced PD patients.

Multimodal Elimination for Intoxication with a Lethal Dose of Organic Mercury.

We here report on a case of massive organic mercury intoxication in a 40-year-old man that resulted in progressive multiorgan failure. We treated the patient intravenously and enterally with the chelating agent (RS)-2,3-bis(sulfanyl) propane-1-sulfonic acid (DMPS) in addition to hemodialysis. The patient was treated for 6 weeks and could successfully be weaned from mechanical ventilation and hemodialysis. He awoke and was sent to rehabilitation, but unfortunately died 7 months later from refractory status epilepticus. Autopsy revealed severe brain atrophy consistent with organ damage from massive mercury intoxication. The present case illustrates that bimodal DMPS application is sufficient for detoxification from lethal mercury levels, with an associated chance for weaning of organ support and survival to discharge. The case further reminds us of intoxication as a cause of multiorgan dysfunction. We propose to immediately initiate combined parenteral and enteral detoxification in cases of methyl mercury intoxication, especially in cases of high doses.

Altered glutamate response and calcium dynamics in iPSC-derived striatal neurons from XDP patients.

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder endemic to Panay Island (Philippines). Patients present with generalizing dystonia and parkinsonism. Genetic changes surrounding the TAF1 (TATA-box binding protein associated factor 1) gene have been associated with XDP inducing a degeneration of striatal spiny projection neurons. There is little knowledge about the pathophysiology of this disorder. Our objective was to generate and analyze an in-vitro model of XDP based on striatal neurons differentiated from induced pluripotent stem cells (iPSC). We generated iPSC from patient and healthy control fibroblasts (3 affected, 3 controls), followed by directed differentiation of the cultures towards striatal neurons. Cells underwent characterization of immunophenotype as well as neuronal function, glutamate receptor properties and calcium dynamics by whole-cell patch-clamp recordings and calcium imaging. Furthermore, we evaluated expression levels of AMPA receptor subunits and voltage-gated calcium channels by quantitative real-time PCR. We observed no differences in basic electrophysiological properties. Application of the AMPA antagonist NBQX led to a more pronounced reduction of postsynaptic currents in XDP neurons. There was a higher expression of AMPA receptor subunits in patient-derived neurons. Basal calcium levels were lower in neurons derived from XDP patients and cells with spontaneous calcium transients were more frequent. Our data suggest altered glutamate response and calcium dynamics in striatal XDP neurons.