Publications by authors named "Ulrike Grittner"

169 Publications

Cervical Spine Injuries with Acute Traumatic Spinal Cord Injury - Spinal Surgery Adverse Events and Their Association with Neurological and Functional Outcome.

Spine (Phila Pa 1976) 2021 May 21. Epub 2021 May 21.

Treatment Centre for Spinal Cord Injuries, Trauma Hospital Berlin, Germany Spinal Cord Injury Research (Neuroparaplegiology), Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany Medical Management, Trauma Hospital Berlin, Germany University of the German Social Accident Insurance (HGU), Bad Hersfeld, Germany Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany Berlin Institute of Health, Berlin, Germany Controlling, Trauma Hospital Berlin, Germany Clinic for Trauma Surgery and Orthopaedics, Trauma Hospital Berlin, Germany Berlin Institute of Health, QUEST - Center for Transforming Biomedical Research, Berlin, Germany.

Study Design: Monocenter case-control study.

Objective: Effects of spinal surgical adverse events (SSAE) on clinical and functional outcome, length of stay, and treatment costs after traumatic cervical spinal cord injury (SCI).

Summary Of Background Data: Traumatic SCI is a challenge for primary care centers because of the emergency setting and complex injury patterns. SSAE rates of up to 15% are reported for spine fractures without SCI. Little is known about SSAE after traumatic SCI and their outcome relevance.

Methods: Acute traumatic cervical SCI patients were enrolled from 2011-2017. Cases with and without SSAE were compared regarding neurological recovery, functional outcome, secondary complications, mortality, length of stay and treatment costs. Adjusted logistic regression and generalized estimating equation models were calculated for the endpoints ASIA impairment scale (AIS)-conversion and dysphagia. All analyses were run in the total and in a propensity score matched sample.

Results: At least one SSAE occurred in 37 of 165 patients (22.4%). Mechanical instability and insufficient spinal decompression were the most frequent SSAE with 13 (7.9%) or 11 (6.7%) cases, respectively. The regression models adjusted for demographic, injury, and surgery characteristics demonstrated a reduced probability for AIS-conversion related to SSAE [OR (95%CI) 0.14 (0.03-0.74)] and additionally to single-sided ventral or dorsal surgical approach [0.12 (0.02-0.69)] in the matched sample. Furthermore, SSAE were associated with higher risk for dysphagia in the matched [4.77 (1.31-17.38)] and the total sample [5.96 (2.07-17.18)]. Primary care costs were higher in cases with SSAE [Median (IQR) 97,300 (78,200-112,300)] EUR compared to cases without SSAE [52,300 (26,700-91,200)] EUR.

Conclusions: SSAE are an important risk factor after acute traumatic cervical SCI with impact on neurological recovery, functional outcome, and healthcare costs. Reducing SSAE is a viable means to protect the limited intrinsic capacity for recovery from SCI.Level of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000004124DOI Listing
May 2021

Applying time series analyses on continuous accelerometry data-A clinical example in older adults with and without cognitive impairment.

PLoS One 2021 13;16(5):e0251544. Epub 2021 May 13.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Stroke Research Berlin (CSB), Berlin, Germany.

Introduction: Many clinical studies reporting accelerometry data use sum score measures such as percentage of time spent in moderate to vigorous activity which do not provide insight into differences in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we present an improved functional data analysis approach to model activity patterns and circadian rhythms from accelerometer data. As a use case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV).

Methods: Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data.

Results: Information on 48 HOV (mean age 65 SD 6 years) and 18 patients with MCI (mean age 70, SD 8 years) were available for this analysis. MCI patients displayed slightly lower activity in the morning hours (minimum relative activity at 6:05 am: -41.3%, 95% CI -64.7 to -2.5%, p = 0.031) and in the evening (minimum relative activity at 21:40 am: -48.4%, 95% CI -68.5 to 15.4%, p = 0.001) as compared to HOV after adjusting for age and sex.

Discussion: Using a novel approach of FoSR, we found timeframes with lower activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry.

Clinical Trials: Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, ClinicalTrial.gov identifier: NCT01782391. Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment, ClinicalTrial.gov identifier: NCT01782365.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251544PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118312PMC
May 2021

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

J Neuroinflammation 2021 May 1;18(1):105. Epub 2021 May 1.

Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG) NMOSD.

Methods: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG patients over a median observation period of 4.25 years.

Results: In patients with AQP4-IgG NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG, but not MOG-IgG patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG, but not MOG-IgG patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG NMOSD. Patients with AQP4-IgG NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75 age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG NMOSD.

Conclusion: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG NMOSD in phases of clinical remission.
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http://dx.doi.org/10.1186/s12974-021-02138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088712PMC
May 2021

Characteristics and patient-reported outcomes associated with dropout in severely affected oncological patients: an exploratory study.

BMC Med Res Methodol 2021 Apr 20;21(1):77. Epub 2021 Apr 20.

Berlin Institute of Health at Charité -Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Background: Patient-reported outcome measures (PROMs) are commonly-used surrogates for clinical outcomes in cancer research. When researching severe diseases such as cancer, it is difficult to avoid the problem of incomplete questionnaires from drop-outs or missing data from patients who pass away during the observation period. The aim of this exploratory study was to explore patient characteristics and the patient-reported outcomes associated with the time-to-dropout.

Methods: In an Oncological Social Care Project (OSCAR) study, the condition of the participants was assessed four times within 12 months (t0: baseline, t1: 3 months, t2: 6 months, and t3: 12 months) by validated PROMs. We performed competing-risk regressions based on Fine and Gray's proportional sub-distribution hazards model for exploring factors associated with time-to-dropout. Death was considered a competing risk.

Results: Three hundred sixty-two participants were analyzed in the study. 193 (53.3%) completed a follow-up after 12 months, 67 (18.5%) patients dropped out, and 102 patients (28.2%) died during the study period. Poor subjective social support was related to a higher risk of drop-out (SHR = 2.10; 95%CI: 1.01-4.35). Lower values in health-related quality of life were related to drop-out and death. The sub-scales global health status/QoL, role functioning, physical functioning, and fatigue symptom in the EORTC QLQ-C30 were key characteristics of early drop-out.

Conclusion: Severely affected cancer patients with poor social support and poor quality of life seem more likely to drop out of studies than patients with higher levels of social support and a better quality of life. This should be considered when planning studies to assess advanced cancer patients. Methods of close continued monitoring should be actively used when patient experiences a substantial deterioration in their health-related quality of life and symptoms during the study. Results for such studies have to be interpreted with caution in light of specific drop-out mechanisms.

Trial Registration: OSCAR study was registered to the German Clinical Trials Register (DRKS-ID: DRKS00013640 ). Registered 29 December 2017.
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http://dx.doi.org/10.1186/s12874-021-01259-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059010PMC
April 2021

Estimating perceived parental substance use disorder: Using register data to adjust for non-participation in survey research.

Addict Behav 2021 08 8;119:106897. Epub 2021 Mar 8.

Centre for Alcohol and Drug Research, Aarhus University, Denmark.

Aims: To estimate the prevalence of parental substance use disorder (PSUD) in the general population based on young adults' reports adjusted for non-participation using register-based indicators of PSUD.

Design: A national sample survey study combined with a retrospective register-based study. Setting Denmark. Participants 10,414 young people (aged 15-25 years) invited to two national sample surveys in 2014 and 2015 (5,755 participants and 4,659 non-participants).

Measurements: A crude prevalence of PSUD was calculated based on participants' reports. Parental data from medical, mortality, prescription, and treatment registers (from the young adults' birth until the time of the surveys) were used to estimate a register-based prevalence of PSUD for both participants and non-participants. Differences between participants and non-participants were analysed using bivariate comparisons. Inverse probability weighting was used to adjust for bias due to non-participation. The crude prevalence of PSUD based on survey data was adjusted using the ratio of incidence proportion of the register-based PSUD compared with the survey-based PSUD.

Findings: A total of 731 (12.7%) of the 5,755 survey participants reported PSUD. Register-based PSUD was more common among non-participants (856/4,659; 18.4%) compared with participants (738/5,755; 12.8%, OR = 1.53, 95% CI 1.38-1.70). The adjusted estimate of the survey-based PSUD increased by 2.5 percentage points, from 12.7% to 15.2%.

Conclusions: In the absence of register data, youth-reported PSUD is likely to underestimate the number of young people experiencing PSUD.
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http://dx.doi.org/10.1016/j.addbeh.2021.106897DOI Listing
August 2021

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): Safety analyses of a randomized clinical trial.

Int J Stroke 2021 Apr 7:17474930211006286. Epub 2021 Apr 7.

Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background And Aim: To report the six-month safety analyses among patients enrolled in the "Physical Fitness Training in Subacute Stroke-PHYS-STROKE" trial and identify underlying risk factors associated with serious adverse events.

Methods: We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5-45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training.

Results: Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81).

Conclusions: Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials.

Data Access Statement: The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.
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http://dx.doi.org/10.1177/17474930211006286DOI Listing
April 2021

Tomoelastography for Longitudinal Monitoring of Viscoelasticity Changes in the Liver and in Renal Allografts after Direct-Acting Antiviral Treatment in 15 Kidney Transplant Recipients with Chronic HCV Infection.

J Clin Med 2021 Feb 1;10(3). Epub 2021 Feb 1.

Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

Besides the liver, hepatitis C virus (HCV) infection also affects kidney allografts. The aim of this study was to longitudinally evaluate viscoelasticity changes in the liver and in kidney allografts in kidney transplant recipients (KTRs) with HCV infection after treatment with direct-acting antiviral agents (DAAs). Fifteen KTRs with HCV infection were treated with DAAs (daclatasvir and sofosbuvir) for 3 months and monitored at baseline, end of treatment (EOT), and 3 (FU1) and 12 (FU2) months after EOT. Shear-wave speed (SWS) and loss angle of the complex shear modulus (φ), reflecting stiffness and fluidity, respectively, were reconstructed from multifrequency magnetic resonance elastography data with tomoelastography post-processing. After virus elimination by DAAs, hepatic stiffness and fluidity decreased, while kidney allograft stiffness and fluidity increased compared with baseline (hepatic stiffness change at FU1: -0.14 m/s, < 0.01, and at FU2: -0.11 m/s, < 0.05; fluidity at FU1: -0.05 rad, = 0.04 and unchanged at FU2: = 0.20; kidney allograft stiffness change at FU1: +0.27 m/s, = 0.01, and at FU2: +0.30 m/s, < 0.01; fluidity at FU1 and FU2: +0.06 rad, = 0.02). These results suggest the restoration of mechanically sensitive structures and functions in both organs. Tomoelastography can be used to monitor the therapeutic results of HCV treatment non-invasively on the basis of hepatic and renal viscoelastic parameters.
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http://dx.doi.org/10.3390/jcm10030510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867050PMC
February 2021

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

JAMA 2021 02;325(5):454-466

Klinik für Neurologie, Klinikum Frankfurt (Oder), Germany.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment.

Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke.

Design, Setting, And Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only).

Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794).

Main Outcomes And Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability.

Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04).

Conclusions And Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.
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http://dx.doi.org/10.1001/jama.2020.26345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856548PMC
February 2021

Blinding in electric current stimulation in subacute neglect patients with current densities of 0.8 A/m: a cross-over pilot study.

BMC Res Notes 2021 Jan 25;14(1):35. Epub 2021 Jan 25.

QUEST Center for Transforming Biomedical Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Objective: Neglect after stroke is a disabling disorder and its rehabilitation is a major challenge. Transcranial direct current stimulation (tDCS) seems to be a promising adjuvant technique to improve standard care neglect therapy. Since electric fields are influenced by age-related factors, higher current densities are probably needed for effective treatment in aged stroke patients. Validation of treatment efficacy requires sham-controlled experiments, but increased current densities might comprise blinding. Therefore, a pilot study was conducted to test sham adequacy when using current density of 0.8 A/m. Whether especially neglect patients who mainly suffer from perceptual and attentional deficits are able to differentiate beyond chance active from sham tDCS was investigated in a randomized cross-over design (active/sham stimulation) in 12 early subacute patients with left-sided hemineglect. Stimulation (0.8 A/m) was performed simultaneous to standard care neglect therapy.

Results: Odds ratio of correct guessing an atDCS condition compared to wrongly judge an atDCS condition as sham was 10.00 (95%CI 0.65-154.40, p = 0.099). However, given the small sample size and high OR, although likely somewhat overestimated, results require careful interpretation and blinding success in neglect studies with current densities of 0.8 A/m should be further confirmed.
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http://dx.doi.org/10.1186/s13104-020-05421-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836170PMC
January 2021

Towards a tractography-based risk stratification model for language area associated gliomas.

Neuroimage Clin 2021 25;29:102541. Epub 2020 Dec 25.

Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Cluster of Excellence: "Matters of Activity. Image Space Material", Humboldt University, Berlin, Germany.

Objectives: Injury to major white matter pathways during language-area associated glioma surgery often leads to permanent loss of neurological function. The aim was to establish standardized tractography of language pathways as a predictor of language outcome in clinical neurosurgery.

Methods: We prospectively analyzed 50 surgical cases of patients with left perisylvian, diffuse gliomas. Standardized preoperative Diffusion-Tensor-Imaging (DTI)-based tractography of the 5 main language tracts (Arcuate Fasciculus [AF], Frontal Aslant Tract [FAT], Inferior Fronto-Occipital Fasciculus [IFOF], Inferior Longitudinal Fasciculus [ILF], Uncinate Fasciculus [UF]) and spatial analysis of tumor and tracts was performed. Postoperative imaging and the resulting resection map were analyzed for potential surgical injury of tracts. The language status was assessed preoperatively, postoperatively and after 3 months using the Aachen Aphasia Test and Berlin Aphasia Score. Correlation analyses, two-step cluster analysis and binary logistic regression were used to analyze associations of tractography results with language outcome after surgery.

Results: In 14 out of 50 patients (28%), new aphasic symptoms were detected 3 months after surgery. The preoperative infiltration of the AF was associated with functional worsening (cc = 0.314; p = 0.019). Cluster analysis of tract injury profiles revealed two areas particularly related to aphasia: the temporo-parieto-occipital junction (TPO; temporo-parietal AF, middle IFOF, middle ILF) and the temporal stem/peri-insular white matter (middle IFOF, anterior ILF, temporal UF, temporal AF). Injury to these areas (TPO: OR: 23.04; CI: 4.11 - 129.06; temporal stem: OR: 21.96; CI: 2.93 - 164.41) was associated with a higher-risk of persisting aphasia.

Conclusions: Tractography of language pathways can help to determine the individual aphasia risk profile pre-surgically. The TPO and temporal stem/peri-insular white matter were confirmed as functional nodes particularly sensitive to surgical injuries.
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http://dx.doi.org/10.1016/j.nicl.2020.102541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785953PMC
December 2020

Impact of COMT val158met on tDCS-induced cognitive enhancement in older adults.

Behav Brain Res 2021 03 4;401:113081. Epub 2021 Jan 4.

Department of Neurology, University Medicine Greifswald, Greifswald, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Department of Neurology, NeuroCure Clinical Research Center, Berlin, Germany; German Centre for Neurodegenerative Diseases (DZNE) Standort Greifswald, Greifswald, Germany. Electronic address:

Background: Previous studies suggest that genetic polymorphisms and aging modulate inter-individual variability in brain stimulation-induced plasticity. However, the relationship between genetic polymorphisms and behavioral modulation through transcranial direct current stimulation (tDCS) in older adults remains poorly understood.

Objective: Link individual tDCS responsiveness, operationalized as performance difference between tDCS and sham condition, to common genetic polymorphisms in healthy older adults.

Methods: 106 healthy older participants from five tDCS-studies were re-invited to donate blood for genotyping of apoliproprotein E (APOE: ε4 carriers and ε4 non-carriers), catechol-O-methyltransferase (COMT: val/val, val/met, met/met), brain-derived neurotrophic factor (BDNF: val/val, val/met, met/met) and KIdney/BRAin encoding gene (KIBRA: C/C, C/T, T/T). Studies had assessed cognitive performance during tDCS and sham in cross-over designs. We now asked whether the tDCS responsiveness was related to the four genotypes using a linear regression models.

Results: We found that tDCS responsiveness was significantly associated with COMT polymorphism; i.e., COMT val carriers (compared to met/met) showed higher tDCS responsiveness. No other significant associations emerged.

Conclusion: Using data from five brain stimulation studies conducted in our group, we showed that only individual variation of COMT genotypes modulated behavioral response to tDCS. These findings contribute to the understanding of inherent factors that explain inter-individual variability in functional tDCS effects in older adults, and might help to better stratify participants for future clinical trials.
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http://dx.doi.org/10.1016/j.bbr.2020.113081DOI Listing
March 2021

Community care coordination for stroke survivors: results of a complex intervention study.

BMC Health Serv Res 2020 Dec 19;20(1):1143. Epub 2020 Dec 19.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

Background: Outpatient follow-up care for stroke survivors is often inadequate and mostly self-organized by the patients themselves. In the German health care system, there are no standard care programs for patients after they are discharged from the hospital to support them with their multifaceted and heterogeneous health care needs. The objective of this complex intervention study was to evaluate the effectiveness of a post-stroke care coordination program in comparison to standard care in the first year after a stroke.

Methods: Patients aged 55 and older who had survived a stroke or a transient ischemic attack (TIA) within the last 6 months before enrollment were included. Participants received care coordination either by telephone or face-to-face for up to 1 year. Patients' health insurance claims data were used to measure outcomes. The control group consisted of stroke survivors receiving standard care and was constructed by exact matching based on six criteria. Outcome measures were health services utilization, rate of recurrent events, readmissions and accompanying costs, and mortality. Outcomes were tested using different multiple models.

Results: In total, N = 361 patients were included in the analyses. Intervention participants had seen an outpatient neurologist more often (OR = 4.75; 95% CI: 2.71-8.31) and were readmitted to a hospital less frequently (IRR = 0.42; 95% CI: 0.29-0.61), resulting in lower hospital costs (IQR = €0-1910 in the intervention group, IQR = €0-4375 in the control group). There were no substantial group differences in the rate of recurrent events and mortality.

Conclusion: This study showed the beneficial potential of care coordination for a vulnerable patient population: the utilization rate of important health services was increased, and the rate of hospital readmissions decreased as a result. Future research should focus on the risk of recurrent strokes and the long-term effects of improved care.

Trial Registration: DRKS00017526 on DRKS - German Clinical Trials Register (retrospectively registered: 21 June 2019).
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http://dx.doi.org/10.1186/s12913-020-05993-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749985PMC
December 2020

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

Mov Disord 2021 04 14;36(4):1005-1010. Epub 2020 Dec 14.

CENTOGENE GmbH, Rostock, Germany.

Background: Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants.

Methods: Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing.

Results: Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers.

Conclusions: The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28416DOI Listing
April 2021

Cognitive training and brain stimulation in prodromal Alzheimer's disease (AD-Stim)-study protocol for a double-blind randomized controlled phase IIb (monocenter) trial.

Alzheimers Res Ther 2020 11 7;12(1):142. Epub 2020 Nov 7.

Department of Neurology, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.

Background: Given the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer's disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stimulation (tDCS) to be an effective method to boost cognitive performance, especially when applied in combination with cognitive training in healthy older adults. So far, no studies combining tDCS concurrent with an intense multi-session cognitive training in prodromal AD populations have been conducted.

Methods: The AD-Stim trial is a monocentric, randomized, double-blind, placebo-controlled study, including a 3-week tDCS-assisted cognitive training with anodal tDCS over left DLPFC (target intervention), compared to cognitive training plus sham (control intervention). The cognitive training encompasses a letter updating task and a three-stage Markov decision-making task. Forty-six participants with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) will be randomized block-wise to either target or control intervention group and participate in nine interventional visits with additional pre- and post-intervention assessments. Performance in the letter updating task after training and anodal tDCS compared to sham stimulation will be analyzed as primary outcome. Further, performance on the second training task and transfer tasks will be investigated. Two follow-up visits (at 1 and 7 months post-training) will be performed to assess possible maintenance effects. Structural and functional magnetic resonance imaging (MRI) will be applied before the intervention and at the 7-month follow-up to identify possible neural predictors for successful intervention.

Significance: With this trial, we aim to provide evidence for tDCS-induced improvements of multi-session cognitive training in participants with SCD and MCI. An improved understanding of tDCS effects on cognitive training performance and neural predictors may help to develop novel approaches to counteract cognitive decline in participants with prodromal AD.

Trial Registration: ClinicalTrials.gov , NCT04265378 . Registered on 07 February 2020. Retrospectively registered. Protocol version: Based on BB 004/18 version 1.2 (May 17, 2019).

Sponsor: University Medicine Greifswald.
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http://dx.doi.org/10.1186/s13195-020-00692-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648990PMC
November 2020

Inter-individual and age-dependent variability in simulated electric fields induced by conventional transcranial electrical stimulation.

Neuroimage 2021 01 1;224:117413. Epub 2020 Oct 1.

Department of Neurology, Universitätsmedizin Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE) Standort Greifswald, Greifswald, Germany. Electronic address:

Variations in head and brain anatomy determine the strength and distribution of electrical fields in humans and may account for inconsistent behavioral and neurophysiological results in transcranial electrical stimulation (tES) studies. However, it is insufficiently understood which anatomical features contribute to the variability of the modelled electric fields, and if their impact varies across age groups. In the present study, we tested the associations of global head anatomy, indexed by extra- and intra-cranial volumes, with electric field measures, comparing young and older adults. We modelled six "conventional" electrode montages typically used in tES studies using SimNIBS software in 40 individuals (20 young, 20 older adults; 20-35, 64-79 years). We extracted individual electric field strengths and focality values for each montage to identify tissue volumes that account for variability of the induced electric fields in both groups. Linear mixed models explained most of the inter-individual variability of the overall induced field strength in the brain, but not of field focality. Higher absolute head volume and relative volume of skin, skull and cerebrospinal fluid (CSF) were associated with lower overall electric field strengths. Additionally, we found interactions of age group with head volume and CSF, indicating that this relationship was mitigated in the older group. Our results demonstrate the importance to adjust brain stimulation not only according to brain atrophy, but also to additional parameters of head anatomy. Future studies need to elucidate the mechanisms underlying individual variability of tES effects in young and older adults, and verify the usefulness of the proposed models in terms of neurophysiology and behavior in empirical studies.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117413DOI Listing
January 2021

Temporal Trends in Pharmacological Stroke Prevention in Patients with Acute Ischemic Stroke and Known Atrial Fibrillation.

J Stroke Cerebrovasc Dis 2020 Dec 10;29(12):105266. Epub 2020 Sep 10.

Department of Neurology, Universitätsklinikum Würzburg, Germany. Electronic address:

Introduction: Oral anticoagulation (OAC) substantially reduces stroke risk in patients with atrial fibrillation (AF) at risk for stroke. Whether non-vitamin K-dependent oral anticoagulants (NOACs) improve OAC use in stroke prevention requires investigation.

Methods: To investigate temporal trends of OAC use in patients with known AF pre-stroke, we retrospectively analyzed records of 6,803 stroke patients admitted in 2003-2004 (n=1,496), 2008-2010 (n=1,638) or 2013-2015 (n=3,669) to the Charité-Universitätsmedizin Berlin, Germany. Adjusted regression models were used to identify factors associated with OAC use.

Results: Of 1,209 AF patients (mean age 79 years, 55.9% female) with given indication for OAC according to the CHADS/CHADS-VASc score, 484 (40.0%) were anticoagulated prior to the index stroke, 458 (37.9%) received antiplatelets and 236 (19.5%) had no antithrombotic medication. Compared to 2003-2004 and 2008-2010, there was a higher rate of pre-admission OAC in 2013-2015 (28.2% vs. 49.6%, p<0.001). After adjustment for possible confounders, factors associated with OAC pre-admission were young age (OR 0.74 per decade [95%CI 0.64-0.85]), previous stroke/TIA (OR 1.29 [95%CI 1.00-1.67]), absence of heart failure (OR 0.63 [95%CI 0.47-0.85]) and admission in 2013-2015 (OR 2.45 [95%CI 1.91-3.15]). Prescription of OAC at hospital discharge increased from 2003-2010 compared to 2013-2015 (45.2% vs. 69.5%, p < 0.001).

Conclusions: Irrespective of temporal trends and despite given indication, more than half of all patients with known AF were not anticoagulated prior to the index stroke. In the NOAC era, there was an increase in OAC intake pre-stroke and a higher rate of OAC prescription at hospital discharge in stroke survivors with known AF.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105266DOI Listing
December 2020

International time trends in sudden unexpected infant death, 1969-2012.

BMC Pediatr 2020 08 11;20(1):377. Epub 2020 Aug 11.

Institute for Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Luisenstr. 57, 10117, Berlin, Germany.

Background: Sudden unexpected infant death (SUID) - including sudden infant death syndrome (SIDS) - continues to be a major contributor to infant mortality worldwide. Our objective was to analyse time trends and to identify country-clusters.

Methods: The National Statistical Offices of 52 countries provided the number of deaths and live births (1969-2012). We calculated infant mortality rates per 1000 live births for SUID, SIDS, and all-cause mortality. Overall, 29 countries provided sufficient data for time course analyses of SUID. To sensitively model change over time, we smoothed the curves of mortality rates (1980-2010). We performed a hierarchical cluster analysis to identify clusters of time trends for SUID and SIDS, including all-cause infant mortality.

Results: All-cause infant mortality declined from 28.5 to 4.8 per 1000 live births (mean 12.4; 95% confidence interval 12.0-12.9) between 1969 and 2012. The cluster analysis revealed four country-clusters. Clusters 1 and 2 mostly contained countries showing the typical peak of SUID mortality during the 1980s. Cluster 1 had higher SUID mortality compared to cluster 2. All-cause infant mortality was low in both clusters but higher in cluster 1 compared to cluster 2. Clusters 3 and 4 had low rates of SUID without a peak during the 1980s. Cluster 3 had the highest all-cause infant mortality of all clusters. Cluster 4 had an intermediate all-cause infant mortality. The time trends of SUID and SIDS mortality were similar.

Conclusions: The country-specific time trends in SUID varied considerably. The identification of country-clusters may promote research into how changes in sleep position, smoking, immunisation, or other factors are related to our findings.
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http://dx.doi.org/10.1186/s12887-020-02271-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418369PMC
August 2020

Evaluation of left ventricular function in patients with acute ischaemic stroke using cine cardiovascular magnetic resonance imaging.

ESC Heart Fail 2020 10 15;7(5):2572-2580. Epub 2020 Jul 15.

Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Aims: Heart failure (HF) is frequent in patients with acute ischaemic stroke (AIS) and associated with higher morbidity and mortality. Assessment of cardiac function in AIS patients using cardiovascular MRI (CMR) may help to detect HF. We report the rate of systolic and diastolic dysfunction in a cohort of patients with AIS using CMR and compare cine real-time (CRT) sequences with the reference of segmented cine steady-state free precession sequences.

Methods And Results: Patients with AIS without known atrial fibrillation were prospectively enrolled in the HEart and BRain Interfaces in Acute Ischemic Stroke (HEBRAS) study (NCT02142413) and underwent CMR at 3 Tesla within 7 days after AIS. Validity of CRT sequences was determined in 50 patients. A total of 229 patients were included in the analysis (mean age 66 years; 35% women; HF 2%). Evaluation of cardiac function was successful in 172 (75%) patients. Median time from stroke onset to CMR was 82 h (interquartile range 56-111) and 54 h (interquartile range 31-78) from cerebral MRI to CMR. Systolic dysfunction was observed in 43 (25%) and diastolic dysfunction in 102 (59%) patients. Diagnostic yield was similar using CRT or segmented cine imaging (no significant difference in left ventricular ejection fraction, myocardial mass, time to peak filling rate, and peak filling rate ratio E/A). Intraobserver and interobserver agreement was high (κ = 0.78-1.0 for all modalities).

Conclusions: Cardiovascular MRI at 3 Tesla is an appropriate method for the evaluation of cardiac function in a selected cohort of patients with AIS. Systolic and diastolic dysfunction is frequent in these patients. CRT imaging allows reliable assessment of systolic and diastolic function.
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http://dx.doi.org/10.1002/ehf2.12833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524103PMC
October 2020

Spermidine intake is associated with cortical thickness and hippocampal volume in older adults.

Neuroimage 2020 11 3;221:117132. Epub 2020 Jul 3.

Department of Neurology, University Medicine Greifswald, Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE) Standort Greifswald, Greifswald, Germany. Electronic address:

Background: The natural polyamine spermidine, known to be important for cellular function, decreases during aging. Previous research has demonstrated beneficial impact of spermidine intake on memory functions in both animal models and humans, suggesting that spermidine may be a preventive approach to delay age-related cognitive decline and possibly even Alzheimer's disease (AD). However, the association of spermidine intake with brain health in humans is still unknown. In this study, we aimed to determine the association between dietary spermidine intake and structural brain measures in older individuals with subjective cognitive decline (SCD) and healthy controls (HC).

Methods: Dietary spermidine intake and adherence to Mediterranean Diet (MeDi) were assessed by a self-reported food frequency questionnaire in 90 older adults with SCD and 47 HC. Processing of structural MRI data yielded global brain volumes, hippocampal volume, mean and regional cortical thickness, and cortical thickness in a template encompassing AD-vulnerable regions. In exploratory analyses, the association between spermidine intake and structural brain measures was assessed using adjusted and unadjusted linear regression models. Additionally, we tested for differential associations as a function of group. Mediation analyses were performed to examine whether dietary spermidine intake mediates the associations between adherence to MeDi and structural brain measures.

Results: Higher spermidine intake was associated with larger hippocampal volume (standardized β ​= ​0.262, p ​= ​0.002), greater mean cortical thickness (standardized β ​= ​0.187, p ​= ​0.031), and greater cortical thickness in AD-vulnerable brain regions (standardized β ​= ​0.176, p ​= ​0.042), the parietal (standardized β ​= ​0.202, p ​= ​0.020), and temporal lobes (standardized β ​= ​0.217, p ​= ​0.012). No significant differential effect emerged between older adults with SCD and HC. Moreover, a substantial mediating effect of dietary spermidine intake on the associations between adherence to MeDi and structural brain measures was observed.

Conclusion: Higher dietary spermidine intake was positively associated with several structural brain measures, irrespective of the presence of SCD, and substantially mediated the relationship of adherence to MeDi and structural brain measures. Our data suggest that higher spermidine intake might be a promising dietary approach to preserve brain health in older adults, a hypothesis currently tested in an interventional trial.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117132DOI Listing
November 2020

Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots.

Int J Mol Sci 2020 Jun 27;21(13). Epub 2020 Jun 27.

CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany.

Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay's longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the "under treatment" versus "not under treatment" conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients.
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http://dx.doi.org/10.3390/ijms21134577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369829PMC
June 2020

[Support for General Practitioners in the Care of Patients with Complex Needs: A Questionnaire Survey of General Practitioners in Berlin].

Gesundheitswesen 2020 Jun 18. Epub 2020 Jun 18.

Institut für Allgemeinmedizin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin.

Objectives: Because of demographic changes, new models of care are important for supporting general practitioners in the care of patients with complex needs. This study addresses the question of the type of support that is requested by general practitioners working in Berlin.

Methods: All general practitioners working in Berlin (n=2354) were asked between August and September 2018 to return a questionnaire by post which has been developed for this study. Questions addressed support needs as well as support models within the practice (delegation, substitution) and outside the practice (social worker, navigator, community care points). Data were analysed descriptively and by exploratory multivariate analysis to show the influence of practice and doctor characteristics on the preference of support models (age, gender, location of the practice, type of practice, working hours).

Results: A total of 557 questionnaires (response rate 23.7%) were included in the analysis. Need for support was seen particularly for administrative, coordinative and organisational tasks and for advice on social issues. The majority of the study participants approved delegation and substitution. In their view, it was conceivable to get support from professionals or institutions outside their practice, such as mobile care services, community care points, social workers or navigators. Particularly younger and female doctors working in group practices were open for cooperative care models integrating other health professions.

Conclusions: There is unused potential for delegation and cooperation within existing structures. Further research should investigate the acceptance and feasibility of different support models.
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http://dx.doi.org/10.1055/a-1173-9225DOI Listing
June 2020

Tumor-associated macrophages in classical Hodgkin lymphoma: hormetic relationship to outcome.

Sci Rep 2020 06 10;10(1):9410. Epub 2020 Jun 10.

Institute for Pathology, Unfallkrankenhaus Berlin, Berlin, Germany.

Commonly attributed to the prevalence of M2 macrophages, tumor-associated macrophages (TAM) are linked to poor outcome in Hodgkin lymphoma (HL). MYC is supposed to control the expression of M2-specific genes in macrophages, and deficiency in MYC-positive macrophages inhibits tumor growth in mouse models. To verify this hypothesis for HL, seventy-six samples were subjected to immunohistochemical double staining using CD68 or CD163 macrophage-specific antibodies and a reagent detecting MYC. For each cell population, labelled cells were grouped according to low, intermediate and high numbers and related to disease-free survival (DFS) and overall survival (OS). MYC+ cells accounted for 21% and 18% of CD68+ and CD163+ cells, respectively. Numbers of MYC- macrophages were significantly higher in EBV+ cases while no differences were observed for MYC+ macrophages between EBV+ and EBV- cases. Cases with highest numbers of macrophages usually showed worst DFS and OS. In most scenarios, intermediate numbers of macrophages were associated with better outcome than very low or very high numbers. Our observations are reminiscent of the "hormesis hypothesis" and suggest that a relative lack of TAM may allow HL growth while macrophages display an inhibitory effect with increasing numbers. Above a certain threshold, TAM may again support tumor growth.
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http://dx.doi.org/10.1038/s41598-020-66010-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287068PMC
June 2020

The Effect of Scan Length on the Assessment of BOLD Delay in Ischemic Stroke.

Front Neurol 2020 5;11:381. Epub 2020 May 5.

Center for Stroke Research, Charité - Universitätsmedizin Berlin, Berlin, Germany.

To evaluate the impact of resting-state functional MRI scan length on the diagnostic accuracy, image quality and lesion volume estimation of BOLD delay maps used for brain perfusion assessment in acute ischemic stroke. Sixty-three acute ischemic stroke patients received a 340 s resting-state functional MRI within 24 h of stroke symptom onset. BOLD delay maps were calculated from the full scan and four shortened versions (68 s, 136 s, 204 s, 272 s). The BOLD delay lesions on these maps were compared in terms of spatial overlap and volumetric agreement with the lesions derived from the full scans and with time-to-maximum (Tmax) lesions derived from DSC-MRI in a subset of patients (n = 10). In addition, the interpretability and quality of these maps were compared across different scan lengths using mixed models. Shortened BOLD delay scans showed a small volumetric bias (ranging from 0.05 to 5.3 mL; between a 0.13% volumetric underestimation and a 7.7% overestimation relative to the mean of the volumes, depending on scan length) compared to the full scan. Decreased scan length was associated with decreased spatial overlap with both the BOLD delay lesions derived from the full scans and with Tmax lesions. Only the two shortest scan lengths (68 and 136 s) were associated with substantially decreased interpretability, decreased structure clarity, and increased noisiness of BOLD delay maps. BOLD delay maps derived from resting-state fMRI scans lasting 272 and 204 s provide sufficient diagnostic quality and adequate assessment of perfusion lesion volumes. Such shortened scans may be helpful in situations where quick clinical decisions need to be made.
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http://dx.doi.org/10.3389/fneur.2020.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214917PMC
May 2020

Is there an association between social determinants and care dependency risk? A multi-state model analysis of a longitudinal study.

Res Nurs Health 2020 06 20;43(3):230-240. Epub 2020 Apr 20.

Institute of Medical Sociology and Rehabilitation Science, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

Despite a growing body of knowledge about the morbidities and functional impairment that frequently lead to care dependency, the role of social determinants is not yet well understood. The purpose of this study was to examine the effect of social determinants on care dependency onset and progression. We used data from the Berlin Initiative Study, a prospective, population-based cohort study including 2,069 older participants living in Berlin. Care dependency was defined as requiring substantial assistance in at least two activities of daily living for 90 min daily (level 1) or 3+ hours daily (level 2). Multi-state time to event regression modeling was used to estimate the effects of social determinants (partnership status, education, income, and sex), morbidities, and health behaviors, characteristics, and conditions. During the study period, 556 participants (27.5%) changed their status of care dependency. Participants without a partner at baseline were at a higher risk to become care-dependent than participants with a partner (hazard ratio [HR], 95% confidence interval [CI]: 1.24 (1.02-1.51)). After adjustment for other social determinants, morbidities and health behaviors, characteristics, and conditions the risk decreased to a HR of 1.19 (95% CI: 0.79-1.79). Results indicate that older people without a partner may tend to be at higher risk of care dependency onset but not at higher risk of care dependency progression. Clinicians should inquire about and consider patients' partnership status as they evaluate care needs.
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http://dx.doi.org/10.1002/nur.22022DOI Listing
June 2020

Confounding adjustment performance of ordinal analysis methods in stroke studies.

PLoS One 2020 16;15(4):e0231670. Epub 2020 Apr 16.

Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: In stroke studies, ordinal logistic regression (OLR) is often used to analyze outcome on the modified Rankin Scale (mRS), whereas the non-parametric Mann-Whitney measure of superiority (MWS) has also been suggested. It is unclear how these perform comparatively when confounding adjustment is warranted.

Aims: Our aim is to quantify the performance of OLR and MWS in different confounding variable settings.

Methods: We set up a simulation study with three different scenarios; (1) dichotomous confounding variables, (2) continuous confounding variables, and (3) confounding variable settings mimicking a study on functional outcome after stroke. We compared adjusted ordinal logistic regression (aOLR) and stratified Mann-Whitney measure of superiority (sMWS), and also used propensity scores to stratify the MWS (psMWS). For comparability, OLR estimates were transformed to a MWS. We report bias, the percentage of runs that produced a point estimate deviating by more than 0.05 points (point estimate variation), and the coverage probability.

Results: In scenario 1, there was no bias in both sMWS and aOLR, with similar point estimate variation and coverage probabilities. In scenario 2, sMWS resulted in more bias (0.04 versus 0.00), and higher point estimate variation (41.6% versus 3.3%), whereas coverage probabilities were similar. In scenario 3, there was no bias in both methods, point estimate variation was higher in the sMWS (6.7%) versus aOLR (1.1%), and coverage probabilities were 0.98 (sMWS) versus 0.95 (aOLR). With psMWS, bias remained 0.00, with less point estimate variation (1.5%) and a coverage probability of 0.95.

Conclusions: The bias of both adjustment methods was similar in our stroke simulation scenario, and the higher point estimate variation in the MWS improved with propensity score based stratification. The stratified MWS is a valid alternative for adjusted OLR only when the ratio of number of strata versus number of observations is relatively low, but propensity score based stratification extends the application range of the MWS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162480PMC
July 2020

Impact of 3-Day Combined Anodal Transcranial Direct Current Stimulation-Visuospatial Training on Object-Location Memory in Healthy Older Adults and Patients with Mild Cognitive Impairment.

J Alzheimers Dis 2020 ;75(1):223-244

Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Berlin, Germany.

Background: Associative object-location memory (OLM) is known to decline even in normal aging, and this process is accelerated in patients with mild cognitive impairment (MCI). Given the lack of curative treatment for Alzheimer's disease, activating cognitive resources during its preclinical phase might prevent progression to dementia.

Objective: To evaluate the effects of anodal transcranial direct current stimulation (atDCS) combined with an associative episodic memory training on OLM in MCI patients and in healthy elderly (HE).

Methods: In a single-blind cross-over design, 16 MCI patients and 32 HE underwent a 3-day visuospatial OLM training paired with either 20 min or 30 s (sham) atDCS (1 mA, right temporoparietal cortex). Effects on immediate (training success) and long-term memory (1-month) were investigated by conducting Mixed Model analyses. In addition, the impact of combined intervention on within-session (online) and on between-session (offline) performance were explored.

Results: OLM training+atDCS enhanced training success only in MCI patients, but not HE (difference n.s.). Relative performance gain was similar in MCI patients compared to HE under atDCS. No beneficial effect was found after 1-month. Exploratory analyses suggested a positive impact on online, but a negative effect on offline performance in MCI patients. In both groups, exploratory post-hoc analyses indicated an association between initially low-performers and greater benefit from atDCS.

Conclusion: Cognitive training in MCI may be enhanced by atDCS, but further delineation of the impact of current brain state, as well as temporal characteristics of multi-session atDCS-training application, may be needed to induce longer-lasting effects.
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http://dx.doi.org/10.3233/JAD-191234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306891PMC
May 2021

Clinical decision-making on spinal cord injury-associated pneumonia: a nationwide survey in Germany.

Spinal Cord 2020 Aug 18;58(8):873-881. Epub 2020 Feb 18.

Department of Neurology with Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

Study Design: Survey study.

Objectives: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP.

Setting: All departments for SCI-care in Germany.

Methods: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of 'clinically defined pneumonia' were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART).

Results: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38-81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7-41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/β-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/β-lactamase inhibitors with fluoroquinolones or carbapenems.

Conclusions: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP.
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http://dx.doi.org/10.1038/s41393-020-0435-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223654PMC
August 2020

Impact of COPD and anemia on motor and cognitive performance in the general older population: results from the English longitudinal study of ageing.

Respir Res 2020 Feb 3;21(1):40. Epub 2020 Feb 3.

Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on cognitive and motor performance in the general older population and assess potential interaction.

Methods: The English Longitudinal Study of Aging is a population-based cohort study including measurements of lung-function and HB levels together with cognitive and motor performance testing. Data were collected from 5709 participants including three measurement time over eight years. COPD was defined using lung-function-parameters and clinical symptoms. HB was assessed continuously and low HB was defined using clinical anemia cutoffs. Linear mixed-effects regression models were used to quantify the associations of COPD and HB with outcome measures, both individually and in combination.

Results: Participants with both low HB and COPD demonstrated worse motor performance compared to individuals with only one exposure, resulting in up to 1 s (95%CI, 0.04-1.8) longer time needed to complete the five times sit to stand task than what would be expected based on purely additive effects. Additionally in individuals with COPD, the time to complete the motor-performance task per unit decrease in continuous HB levels was longer than in participants without COPD after full adjustment for confounding (up to 1.38 s/unit HB level, 95% CI: 0.65-2.11).

Conclusion: In persons with COPD low HB levels may contribute to low motor-performance in a supra additive fashion. Further studies should re-evaluate whether earlier treatment of lower HB in these individuals might be beneficial.
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http://dx.doi.org/10.1186/s12931-020-1305-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998076PMC
February 2020

Bariatric Surgery and Brain Health-A Longitudinal Observational Study Investigating the Effect of Surgery on Cognitive Function and Gray Matter Volume.

Nutrients 2020 Jan 2;12(1). Epub 2020 Jan 2.

Department of Neurology, University of Greifswald, 17489 Greifswald, Germany.

Dietary modifications leading to weight loss have been suggested as a means to improve brain health. In morbid obesity, bariatric surgery (BARS)-including different procedures, such as vertical sleeve gastrectomy (VSG), gastric banding (GB), or Roux-en-Y gastric bypass (RYGB) surgery-is performed to induce rapid weight loss. Combining reduced food intake and malabsorption of nutrients, RYGB might be most effective, but requires life-long follow-up treatment. Here, we tested 40 patients before and six months after surgery (BARS group) using a neuropsychological test battery and compared them with a waiting list control group. Subsamples of both groups underwent structural MRI and were examined for differences between surgical procedures. No substantial differences between BARS and control group emerged with regard to cognition. However, larger gray matter volume in fronto-temporal brain areas accompanied by smaller volume in the ventral striatum was seen in the BARS group compared to controls. RYGB patients compared to patients with restrictive treatment alone (VSG/GB) had higher weight loss, but did not benefit more in cognitive outcomes. In sum, the data of our study suggest that BARS might lead to brain structure reorganization at long-term follow-up, while the type of surgical procedure does not differentially modulate cognitive performance.
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http://dx.doi.org/10.3390/nu12010127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019777PMC
January 2020

A Multilevel Analysis of Regional and Gender Differences in the Drinking Behavior of 23 Countries.

Subst Use Misuse 2020 26;55(5):772-786. Epub 2019 Dec 26.

Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

: Drinking behavior differs not only among countries, but also among regions within a country. However, the extent of such variation and the interplay between gender and regional differences in drinking have not been explored and are addressed in this study. : Data stem from 105,061 individuals from 23 countries of the GENACIS data set. The outcomes were heavy drinking (10/20 g or more of pure ethanol per day for women/men), and risky single occasion drinking (RSOD) (5+ drinks per occasion) at least monthly. Analyses used binary logistic mixed models. Variance at specific levels was measured by the intra-class correlation coefficient (ICC). Gender differences in outcomes were measured using gender ratios. : Country-level ICC was 0.13 (95% CI: 0.09-0.18) for heavy drinking and 0.16 (95% CI: 0.10-0.26) for RSOD. Within-country regional-level ICC for heavy drinking and RSOD was 0.02 (95% CI: 0.009-0.05; 0.01-0.04, respectively), implying that 2% of variation in heavy drinking and RSOD was explained by regional variation. Variance in drinking indicators was larger for women compared to men across countries. Gender ratios were higher in low- and middle-income countries. : Regional variations in risky drinking were more often present in low- to middle-income countries as well as in a few higher-income countries, and could be due to cultural and demographic differences. Variations in gender differences were larger on the country level than on the regional level, with lower-income countries showing larger differences. These results can help to better identify specific high-risk groups for prevention strategies.
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http://dx.doi.org/10.1080/10826084.2019.1702700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125004PMC
June 2021