Search

Structural disconnectome analyses have provided valuable insights into how a stroke lesion results in widespread network disturbances and how these relate to deficits, recovery patterns, and outcomes. Previous analyses have primarily focused on patients with relatively mild to moderate deficits. However, outcomes vary among survivors of severe strokes, and the mechanisms of recovery remain poorly understood. This study assesses the association between lesion-induced network disconnection and outcome after severe stroke. Thirty-eight ischaemic stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Lesion information was integrated with normative connectome data to infer individual disconnectome profiles on a localized regional and region-to-region pathway level. Ordinal logistic regressions were computed to link disconnectome information to the modified Rankin Scale after 3-6 months. Disconnections of ipsilesional frontal, parietal, and temporal cortical brain areas were significantly associated with a worse motor outcome after a severe stroke, adjusted for the initial deficit, lesion volume, and age. The analysis of the underlying pathways mediating this association revealed location-specific results: For frontal, prefrontal, and temporal brain areas, the association was primarily driven by relatively sparse intrahemispheric disconnections. In contrast, the ipsilesional primary motor cortex, the dorsal premotor cortex, and various parietal brain regions showed a remarkable involvement of either frontoparietal intrahemispheric or additionally interhemispheric disconnections. These results indicate that localized disconnection of multiple regions embedded in the structural frontoparietal network correlates with worse outcomes after severe stroke. Specifically, primary motor and parietal cortices might gain particular importance as they structurally link frontoparietal networks of both hemispheres. These data shed novel light on the significance of distinct brain networks for recovery after a severe stroke., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Novel deep brain stimulation (DBS) systems allow directional and short-pulse stimulation to potentially improve symptoms and reduce side effects. The aim of this study was to investigate the effect of short-pulse and directional stimulation, in addition to a combination of both, in the ventral intermediate thalamus (VIM)/posterior subthalamic area (PSA) on tremor and stimulation-induced side effects in patients with essential tremor., Materials and Methods: We recruited 11 patients with essential tremor and VIM/PSA-DBS. Tremor severity (Fahn-Tolosa-Marin), ataxia (International Cooperative Ataxia Rating Scale), and paresthesia (visual analog scale) were assessed with conventional omnidirectional and directional stimulation with pulse width of 60 μs and 30 μs., Results: All stimulation conditions reduced tremor. The best directional stimulation with 60 μs reduced more tremor than did most other stimulation settings. The best directional stimulation, regardless of pulse width, effectively reduced stimulation-induced ataxia compared with the conventional stimulation (ring 60 μs) or worst directional stimulation with 60 μs. All new stimulation modes reduced occurrence of paresthesia, but only the best directional stimulation with 30 μs attenuated paresthesia compared with the conventional stimulation (ring 60 μs) or worst directional stimulation with 60 μs. The best directional stimulation with 30 μs reduced tremor, ataxia, and paresthesia compared with conventional stimulation in most patients. Correlation analyses indicated that more anterior stimulation sites are associated with stronger ataxia reduction with directional 30 μs than with conventional 60 μs stimulation., Conclusion: Directional and short-pulse stimulation, and a combination of both, revealed beneficial effects on stimulation-induced adverse effects., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

We consider globally coupled networks of identical oscillators, located on the surface of a sphere with interaction time delays, and show that the distance-dependent time delays play a key role for the spiral chimeras to occur as a generic state in different systems of coupled oscillators. For the phase oscillator system, we analyze the existence and stability of stationary solutions along the Ott-Antonsen invariant manifold to find the bifurcation structure of the spiral chimera state. We demonstrate via an extensive numerical experiment that the time-delay-induced spiral chimeras are also present for coupled networks of the Stuart-Landau and Van der Pol oscillators in the same parameter regime as that of phase oscillators, with a series of evenly spaced band-type regions. It is found that the spiral chimera state occurs as a consequence of a resonant-type interplay between the intrinsic period of an individual oscillator and the interaction time delay as a topological structure property.

Brain imaging has significantly contributed to our understanding of the cerebellum being involved in recovery after non-cerebellar stroke. Due to its connections with supratentorial brain networks, acute stroke can alter the function and structure of the contralesional cerebellum, known as crossed cerebellar diaschisis (CCD). Data on the spatially precise distribution of structural CCD and their implications for persistent deficits after stroke are notably limited. In this cross-sectional study, structural MRI and clinical data were analyzed from 32 chronic stroke patients, at least 6 months after the event. We quantified lobule-specific contralesional atrophy, as a surrogate of structural CCD, in patients and healthy controls. Volumetric data were integrated with clinical scores of disability and motor deficits. Diaschisis-outcome models were adjusted for the covariables age, lesion volume, and damage to the corticospinal tract. We found that structural CCD was evident for the whole cerebellum, and particularly for lobules V and VI. Lobule VI diaschisis was significantly correlated with clinical scores, that is, volume reductions in contralesional lobule VI were associated with higher levels of disability and motor deficits. Lobule V and the whole cerebellum did not show similar diaschisis-outcome relationships across the spectrum of the clinical scores. These results provide novel insights into stroke-related cerebellar plasticity and might thereby promote lobule VI as a key area prone to structural CCD and potentially involved in recovery and residual motor functioning., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Guanidino compounds such as dimethylarginines (SDMA, ADMA) and L-homoarginine ((L-)hArg) can interfere with bioavailability and function of the main NO-donor L-arginine (L-Arg). High ADMA and SDMA but low L-hArg concentrations have been associated with cardio- and cerebrovascular events and mortality in adults. The role of guanidino compounds in paediatric patients remains less clear. We, therefore, compared guanidino compound levels in plasma samples of 57 individuals with chronic kidney disease (CKD) and 141 individuals without CKD from the age of 0 to 17 years, including patients with different comorbidities by correlation and regression analyses. We found highest hArg, SDMA and ADMA concentrations in neonates (Kruskal-Wallis, p < 0.001 for all). From the age of 1 year on, hArg levels increased, whereas SDMA und ADMA levels further decreased in children. SDMA and ADMA are higher in children with CKD independent of GFR (mean factor 1.92 and 1.38, respectively, p < 0.001 for both), and SDMA is strongly correlated with creatinine concentration in children with CKD (Spearman's rho 0.74, p < 0.001). We provide guanidino compound levels in a large sample covering all paediatric age groups for the first time. Our data can be used to assess the role of guanidino compounds such as hArg in disease states, i.e. cerebro- and cardiovascular disorders in childhood and adolescence., (© 2023. The Author(s).)

Homoarginine is associated with cardio- and cerebrovascular morbidity and mortality. However, the underlying pathomechanisms remain elusive. Here, we evaluated the association of homoarginine with adverse events (i.e., death, stroke, and myocardial infarction) and carotid intima-media thickness (cIMT) in stroke patients. In the prospective bioMARKers in STROKE (MARK-STROKE) cohort, patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled. Plasma homoarginine concentrations were analyzed and associated with clinical phenotypes in cross-sectional (374 patients) and prospective (273 patients) analyses. Adjustments for possible confounders were evaluated. A two-fold increase in homoarginine was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission, cIMT, and prevalent atrial fibrillation (mean factor -0.68 [95% confidence interval (CI): -1.30, -0.07], -0.14 [95% CI: -0.22, -0.05]; and odds ratio 0.57 [95% CI: 0.33, 0.96], respectively). During the follow-up (median 284 [25th, 75th percentile: 198, 431] days), individuals with homoarginine levels in the highest tertile had fewer incident events compared with patients in the lowest homoarginine tertile independent of traditional risk factors (hazard ratio 0.22 [95% CI: 0.08, 0.63]). A lower prevalence of atrial fibrillation and a reduced cIMT pinpointed potential underlying pathomechanisms.

Connectivity studies have significantly extended the knowledge on motor network alterations after stroke. Compared to interhemispheric or ipsilesional networks, changes in the contralesional hemisphere are poorly understood. Data obtained in the acute stage after stroke and in severely impaired patients are remarkably limited. This exploratory, preliminary study aimed to investigate early functional connectivity changes of the contralesional parieto-frontal motor network and their relevance for the functional outcome after severe motor stroke. Resting-state functional imaging data were acquired in 19 patients within the first 2 weeks after severe stroke. Nineteen healthy participants served as a control group. Functional connectivity was calculated from five key motor areas of the parieto-frontal network on the contralesional hemisphere as seed regions and compared between the groups. Connections exhibiting stroke-related alterations were correlated with clinical follow-up data obtained after 3-6 months. The main finding was an increase in coupling strength between the contralesional supplementary motor area and the sensorimotor cortex. This increase was linked to persistent clinical deficits at follow-up. Thus, an upregulation in contralesional motor network connectivity might be an early pattern in severely impaired stroke patients. It might carry relevant information regarding the outcome which adds to the current concepts of brain network alterations and recovery processes after severe stroke., (© 2023. The Author(s).)

The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut-brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease., (© 2023. The Author(s).)

Blood neurofilament light chain (NfL) is an easily accessible, highly sensitive and reliable biomarker for neuroaxonal damage. Currently, its role in Parkinson's disease (PD) remains unclear. Here, we demonstrate that blood NfL can distinguish idiopathic PD from atypical parkinsonian syndromes (APS) with high sensitivity and specificity. In cross-sectional studies, some found significant correlations between blood NfL with motor and cognitive function, whereas others did not. In contrast, prospective studies reported very consistent associations between baseline blood NfL with motor progression and cognitive worsening. Amongst PD subtypes, especially postural instability and gait disorder (PIGD) subtype, symptoms and scores are reliably linked with blood NfL. Different non-motor PD comorbidities have also been associated with high blood NfL levels suggesting that the neuroaxonal damage of the autonomic nervous system as well as serotonergic, cholinergic and noradrenergic neurons is quantifiable. Numerous absolute NfL cutoff levels have been suggested in different cohort studies; however, validation across cohorts remains weak. However, age-adjusted percentiles and intra-individual blood NfL changes might represent more valid and consistent parameters compared with absolute NfL concentrations. In summary, blood NfL has the potential as biomarker in PD patients to be used in clinical practice for prediction of disease severity and especially progression., (© 2023. The Author(s).)

Cortical thickness analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to uncover hidden aspects of stroke-related alterations in cortical microstructure, going beyond cortical thickness as a surrogate for cortical macrostructure. We re-analysed clinical and imaging data of 42 well-recovered chronic stroke patients from 2 independent cohorts (mean age 64 years, 4 left-handed, 71% male, 16 right-sided strokes) and 33 healthy controls of similar age and gender. Cortical fractional anisotropy and cortical thickness values were obtained for six key sensorimotor areas of the contralesional hemisphere. The regions included the primary motor cortex, dorsal and ventral premotor cortex, supplementary and pre-supplementary motor areas, and primary somatosensory cortex. Linear models were estimated for group comparisons between patients and controls and for correlations between cortical fractional anisotropy and cortical thickness and clinical scores. Compared with controls, stroke patients exhibited a reduction in fractional anisotropy in the contralesional ventral premotor cortex ( P = 0.005). Fractional anisotropy of the other regions and cortical thickness did not show a comparable group difference. Higher fractional anisotropy of the ventral premotor cortex, but not cortical thickness, was positively associated with residual grip force in the stroke patients. These data provide novel evidence that the contralesional ventral premotor cortex might constitute a key sensorimotor area particularly susceptible to stroke-related alterations in cortical microstructure as measured by diffusion MRI and they suggest a link between these changes and residual motor output after stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The spiral chimera state shows a remarkable spatiotemporal pattern in a two-dimensional array of oscillators for which the coherent spiral arms coexist with incoherent cores. In this work, we report on an asymmetric spiral chimera having incoherent cores of different sizes on the spherical surface of identical phase oscillators with nonlocal coupling. This asymmetric spiral chimera exhibits a strongly symmetry-broken state in the sense that not only the coherent and incoherent domains coexist, but also their incoherent cores are nonidentical, although the underlying coupling structure is symmetric. On the basis of analyses along the Ott-Antonsen invariant manifold, the bifurcation conditions of asymmetric spiral chimeras are derived, which reveals that the asymmetric spiral chimera state emerges via a supercritical symmetry-breaking bifurcation from the symmetric spiral chimera. For the coupling function composed of two Legendre modes, rigorous stability analyses are carried out to present a complete stability diagram for different types of spiral chimeras, including the stationary symmetric and asymmetric spiral chimeras as well as breathing asymmetric spiral chimera. For the general coupling scheme the asymmetric spiral chimera occurs as a result of competition between the odd and even Legendre modes of the coupling function. Our theoretical findings are verified by using extensive numerical simulations of the model system.

Imaging studies have evidenced that contralesional cortices are involved in recovery after motor stroke. Cortical thickness (CT) analysis has proven its potential to capture the changes of cortical anatomy, which have been related to recovery and treatment gains under therapy. An open question is whether CT obtained in the acute phase after stroke might inform correlational models to explain outcome variability. Data of 38 severely impaired (median NIH Stroke Scale 9, interquartile range: 6-13) acute stroke patients of 2 independent cohorts were reanalyzed. Structural imaging data were processed via the FreeSurfer pipeline to quantify regional CT of the contralesional hemisphere. Ordinal logistic regression models were fit to relate CT to modified Rankin Scale as an established measure of global disability after 3-6 months, adjusted for the initial deficit, lesion volume, and age. The data show that CT of contralesional cortices, such as the precentral gyrus, the superior frontal sulcus, and temporal and cingulate cortices, positively relates to the outcome after stroke. This work shows that the baseline cortical anatomy of selected contralesional cortices can explain the outcome variability after severe stroke, which further contributes to the concept of structural brain reserve with respect to contralesional cortices to promote recovery., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Low levels of the endogenous amino acid L-homoarginine are a risk factor for cardiovascular morbidity and mortality. For individual risk prediction, commercially available test systems are mandatory. This study aims at formulating sex- and age-specific reference intervals of serum L-homoarginine determined with an ELISA., Methods: We determined reference intervals for serum L-homoarginine stratified by age and sex in a sample of 1285 healthy participants of the Study of Health in Pomerania (SHIP)-TREND cohort after exclusion of participants with cardiovascular diseases, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes, chronic kidney disease stages III or IV, or body mass index &gt;25 kg/m2. Serum L-homoarginine was determined applying a commercially available ELISA., Results: The reference cohort included 836 women (median age 41, 25th and 75th percentiles are 32 and 50 years) and 449 men (median age 38, 25th, and 75th percentiles are 30 and 49 years). The median serum concentration of L-homoarginine was 1.93 (25th 1.49; 75th 2.60) µmol/L in women and 2.02 (25th 1.63; 75th 2.61) µmol/L in men (P = 0.04). The reference intervals (2.5th to 97.5th percentile) were 0.89-5.29 µmol/L for women and 1.09-3.76 µmol/L for men. The L-homoarginine serum concentration declined over age decades in both sexes and a notable interaction with sex hormone intake in women was observed., Conclusions: The novelty of our study is that we determined reference intervals specific for the L-isomer being lower than those previously reported for homoarginine in SHIP and thus might be helpful in identifying individuals suitable for oral L-homoarginine supplementation., Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: R. Wesemann is managing director of WESAMIN GmbH & Co. KG, Winsen, Germany, responsible for the development and production of the DLD Diagnostika ELISA kit for L-homoarginine. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: C.-u.Choe received honoraria from Zambon GmbH. Research Funding: This work was funded in part by a grant from the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., E. Schwedhelm, T. Ittermann, N. Friedrich). The SHIP-TREND study is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania (T. Ittermann, N. Friedrich). C.-u.Choe was supported by an Else Kröner Exzellenzstipendium from the Else Kröner-Fresenius Stiftung. Expert Testimony: None declared. Patents: None declared., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Effective high density lipoprotein cholesterol (HDL-C) is a measure of HDL functionality. We evaluated if HDL-C is associated with carotid intima-media thickness (cIMT) and incident major adverse cardiovascular events (MACE) in patients with acute ischemic stroke from two prospective cohort studies., Methods: In the MARK-STROKE cohort, 299 patients with acute ischemic stroke or TIA were included. Outcome was available in 219 patients during a median follow-up of 294 days. In CIRCULAS, 382 acute ischemic stroke patients were included and a 90-day follow-up was available in 213 patients. HDL-C was calculated based on symmetric dimethylarginine (SDMA) and HDL cholesterol concentrations. Main outcome was incident MACE (death, stroke, and myocardial infarction) and the main measure was cIMT., Results: In both studies, HDL-C was inversely associated with cIMT in linear regression analysis adjusted for age, sex and creatinine. In MARK-STROKE, the adjusted hazard for MACE was significantly reduced for patients with one unit increase (mg/dL) of HDL-C (hazard ratio 0.95 [95% confidence interval (CI): 0.92, 0.99]). In the CIRCULAS cohort, stroke patients with higher HDL-C had less incident MACE during 90 days of follow-up (odds ratio: 0.97 [95% CI: 0.94, 0.99] for one unit increase). Neither SDMA nor HDL cholesterol predicted outcome., Conclusions: Our findings imply a protective role of biologically effective HDL after acute cerebral ischemia for secondary events and emphasize the relevance of lipoprotein functionality in these patients., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The concept of brain reserve capacity positively influencing the process of recovery after stroke has been continuously developed in recent years. Global measures of brain health have been linked with a favourable outcome. Numerous studies have evidenced that the cerebellum is involved in recovery after stroke. However, it remains an open question whether characteristics of cerebellar anatomy, quantified directly after stroke, might have an impact on subsequent outcome after stroke. Thirty-nine first-ever ischaemic non-cerebellar stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Structural images were used for volumetric analyses of distinct cerebellar regions. Ordinal logistic regression analyses were conducted to associate cerebellar volumes with functional outcome 3-6 months after stroke, operationalized by the modified Rankin Scale. Larger volumes of cerebellar lobules IV, VI, and VIIIB were positively correlated with favourable outcome, independent of the severity of initial impairment, age, and lesion volume ( P < 0.01). The total cerebellar volume did not exhibit a significant structure-outcome association. The present study reveals that pre-stroke anatomy of distinct cerebellar lobules involved in motor and cognitive functioning might be linked to outcome after acute non-cerebellar stroke, thereby promoting the emerging concepts of structural brain reserve for recovery processes after stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Diabetes is associated with incidence and prevalence of Parkinson's disease (PD). Furthermore, glycated hemoglobin (HbA1c) levels have been linked with motor function and progression., Objectives: We evaluated the relationship between prevalent diabetes and HbA1c levels with serum neurofilament light chain (NfL) levels as marker of neuroaxonal damage., Methods: NfL concentrations were analyzed with Simoa in serum of 195 PD patients with available HbA1c values. Motor (MDS-UPDRS III, Hoehn & Yahr [H&Y]) and cognitive (Montreal Cognitive Assessment [MoCA]) function was assessed and vascular comorbidities were documented from medical records., Results: PD patients with prevalent diabetes had higher serum NfL levels and lower MoCA scores independent of age, body mass index (BMI), and vascular risk factors. Furthermore, diabetes was associated with higher H&Y stages in unadjusted and age/BMI-adjusted models. Higher HbA1c levels were associated with increased NfL in unadjusted and age/BMI-adjusted models., Conclusions: In PD patients, diabetes and high HbA1c are associated with increased neuroaxonal damage and cognitive impairment. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

Homoarginine is an endogenous amino acid whose levels are reduced in patients with renal, cardio- and cerebrovascular disease. Moreover, low homoarginine concentrations independently predict morbidity and mortality in these patients. Besides endogenous synthesis, homoarginine is also a constituent of the human diet. The objective of the present study was to analyze the kinetics of orally supplemented homoarginine in human plasma by means of a pharmacometric approach. We developed a pharmacometric model to evaluate different dosing regimens, especially the regimen of 125 mg once weekly, based on a previous clinical study (n = 20). The model was adapted to account for differences in baseline homoarginine plasma concentrations between healthy and diseased individuals. A novel dosing regimen of 25 mg once daily led to higher attainment of homoarginine reference concentrations using clinical trial simulations. With 25 mg/day, the trough concentration of only 6% of the older and 3.8% of the younger population was predicted to be below the target concentration of 2.0-4.1 µmol/L. In synopsis, the new dosing regimen recapitulates the kinetics of homoarginine in healthy individuals optimally., (© 2022. The Author(s).)

The aim of this study was to assess the effects of novel stimulation algorithms of deep brain stimulation (short pulse and directional stimulation) in the ventrointermediate thalamus and posterior subthalamic area (VIM/PSA-DBS) on tremor in Parkinson's disease (PD) and to compare the effects with those in essential tremor (ET). We recruited six PD patients (70.8 ± 10.4 years) and seven ET patients (64.4 ± 9.9 years) with implanted VIM/PSA-DBS in a stable treatment condition (> 3 months postoperatively). Tremor severity and ataxia were assessed in four different stimulation conditions in a randomized order: DBS switched off (STIM OFF), omnidirectional stimulation with 60 µs (oDBS60), omnidirectional stimulation with 30 µs (oDBS30), directional stimulation at the best segment with 60 µs (dDBS60). In both patient groups, all three DBS stimulation modes reduced the total tremor score compared to STIM OFF, whereas stimulation-induced ataxia was reduced by oDBS30 and partially by dDBS60 compared to oDBS60. Tremor reduction was more pronounced in PD than in ET due to a limited DBS effect on intention and action-specific drawing tremor in ET. In PD and ET tremor, short pulse or directional VIM/PSA-DBS is an effective and well tolerated therapeutic option.Trial registration: The study was registered in the DRKS (ID DRKS00025329, 18.05.2021, German Clinical Trials Register, DRKS-Deutsches Register Klinischer Studien)., (© 2022. The Author(s).)

Introduction: The preoperative evaluation of Parkinson's Disease (PD) patients for subthalamic nucleus deep brain stimulation (STN-DBS) includes the assessment of the neuropsychological status of the patient. A widely used preoperative test is the Mattis Dementia rating scale (MDRS). However, the Montreal cognitive assessment (MoCA) has also been proven to be a sensitive, time-sparing tool with high diagnostic validity in PD. We evaluate the utility of the MoCA as a preoperative screening test for PD patients undergoing bilateral STN-DBS., Methods: In this single-centre, retrospective study, we analysed pre- and postoperative assessments of MoCA, MDRS, Movement disorder society-Unified PD Rating Scale-motor examination, PD Questionnaire-39 and levodopa equivalent daily dose. Longitudinal outcome changes were analysed using paired t-test, Pearson's correlation coefficient, linear regression and CHAID (chi-square automatic interaction detector) regression tree model., Results: Clinical motor and cognitive scores of 59 patients (61.05±7.73 years, 24 females) were analysed. The MoCA, but not the MDRS, identified significant postoperative cognitive decline in PD patients undergoing STN-DBS. The preoperative MoCA score correlated with postoperative quality of life improvement, whereas the MDRS did not. PD patients with a MoCA score ≤ 23 points had a significant decline of quality of life after DBS surgery compared to patients > 23 points., Conclusion: This study identifies the MoCA as an alternative test within the preoperative evaluation of PD patients for the detection of neuropsychological deficits and prediction of the postoperative improvement of quality of life., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: E. Gülke received travel and attendance grants from Abbvie, Abbott, Medtronic and Bial. M. Alsalem reported no financial disclosures. M. Kirsten received travel and attendance grants from Abbott and Abbvie. E. Vetorazzi reported no fincancial disclosures. C. Choe received personal fees from Pfizer. U.Hidding reported no financial disclosures. S. Zittel received research support from Merz Pharmeceuticals and honoraria from Brainlab AG. C. Buhmann served on the scientific advisory boards for Bial and Zambon and received honoraria for lectures from Abbvie, Bial, GE Healthcare, Grünenthal, TAD and UCB. M. Schaper reported no financial disclosures. A. Gulberti received travel reimbursements from Medtronic. C.K.E. Moll served as medico-scientific consultant to Abbott. W. Hamel received lecture fees and honoraria for serving on advisory boards and travel grants from Boston Scientific, Medtronic, and Abbott. J. Koeppen reported no financial disclosures. C. Gerloff reports honoraria from Bayer Healthcare, Boehringer Ingelheim, Acticor Biotech, Sanofi Aventis Amgene, and Prediction Bioscience. M. Pötter-Nerger received lecture fees from Abbott and Licher, and served as consultant for Medtronic, Boston scientific, Abbott and Abbvie. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

In humans and mice, L-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to cardiovascular disease (CVD), specifically myocardial infarction (MI) and heart failure (HF). The underlying molecular and regulatory mechanisms, however, remain unclear. To identify potential pathways of cardiac AGAT metabolism, we sequenced microRNA (miRNA) in left ventricles of wild-type (wt) compared to AGAT-deficient (AGAT -/- ) mice. Using literature search and validation by qPCR, we identified eight significantly regulated miRNAs in AGAT -/- mice linked to atherosclerosis, MI and HF: miR-30b, miR-31, miR-130a, miR-135a, miR-148a, miR-204, miR-298, and let-7i. Analysis of Gene Expression Omnibus (GEO) data confirmed deregulation of these miRNAs in mouse models of MI and HF. Quantification of miRNA expression by qPCR in AGAT -/- mice supplemented with creatine or hArg revealed that miR-30b, miR-31, miR-130a, miR-148a, and miR-204 were regulated by creatine, while miR-135a and miR-298 showed a trend of regulation by hArg. Finally, bioinformatics-based target prediction showed that numerous AGAT-dependent genes previously linked to CVD are likely to be regulated by the identified miRNAs. Taken together, AGAT deficiency and hArg/creatine supplementation are associated with cardiac miRNA expression which may influence cardiac (dys)function and CVD., (© 2022. The Author(s).)

Ischemic stroke leads to excitability changes of the motor network as probed by means of transcranial magnetic stimulation (TMS). There is still limited data that shows to what extent structural alterations of the motor network might be linked to excitability changes. Previous results argue that the microstructural state of specific corticofugal motor tracts such as the corticospinal tract associate with cortical excitability in chronic stroke patients. The relationship between changes of cortical anatomy after stroke, as operationalized by means of decreases or increases in local cortical thickness (CT), has scarcely been addressed. In the present study, we re-analyzed TMS data and recruitment curve properties of motor evoked potentials and CT data in a group of 14 well-recovered chronic stroke patients with isolated supratentorial subcortical lesions. CT data of the stroke patients were compared to CT data of 17 healthy controls. Whole-brain and region-of-interest based analyses were conducted to relate CT data to measures of motor cortical excitability and clinical data. We found that stroke patients exhibited significantly reduced CT not only in the ipsilesional primary motor cortex but also in numerous secondary motor and non-motor brain regions, particularly in the ipsilesional hemisphere including areas along the central sulcus, the inferior frontal sulcus, the intraparietal sulcus, and cingulate cortices. We could not detect any significant relationship between the extent of CT reduction and stroke-related excitability changes of the motor network or clinical scores., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Graterol Pérez, Guder, Choe, Gerloff and Schulz.)

The PIGD (postural instability / gait difficulty) subtype of Parkinson´s disease (PD) is associated with faster cognitive and motor decline. So far, there are no quantifiable biomarkers to aid clinical subtyping. Neurofilament light chain (NfL) is a highly specific marker of neuro-axonal damage and can be assessed in blood. Here, we investigated if serum NfL concentrations are associated with PIGD subtype and PIGD scores in PD patients at advanced disease stages. Furthermore, we evaluated if serum NfL is associated with motor and cognitive function assessed with MDS-UPDRS part III and Montreal cognitive assessment (MoCA). Serum NfL levels were analyzed with Single Molecule Assays (Simoa) in blood of 223 PD patients from the bioMARKers in Parkinson's Disease (MARK-PD) study. Serum NfL concentrations were higher in PIGD patients independent of age, sex and disease duration. In linear regression analysis, serum NfL levels were associated with MoCA, MDS-UPDRS III and PIGD scores in unadjusted models, but remained significant after adjustment only with PIGD scores. In conclusion, increased serum NfL levels were associated with PIGD subtype and PIGD scores in patients with advanced PD., (© 2022. The Author(s).)

Background and Purpose: The aim of this study was to examine whether sphingosine-1-phosphate (S1P) levels in patients with acute stroke are associated with stroke severity and outcome., Methods: In a prospective stroke cohort (MARK-STROKE), 374 patients with acute ischemic stroke or transient ischemic attack were enrolled (mean age: 67.9±13.0 years, sex: 64.7% male), and serum-S1P at admission was analyzed with tandem mass spectrometry. In addition to cross-sectional analyses, 79 adverse events (death, stroke, myocardial infarction, rehospitalization) were recorded in 270 patients during follow-up. Regression analyses were adjusted for age, sex, low-density lipoprotein cholesterol, and vascular risk factors. Results were validated in an independent stroke cohort with 219 patients with acute ischemic stroke (CIRCULAS)., Results: Low serum-S1P was associated with higher National Institutes of Health Stroke Scale score at admission and with anterior circulation nonlacunar infarcts determined by multivariate regression analyses. During a follow-up of 294±170 days, patients with S1P in the lowest tertile (<1.33 µmol/L) had more adverse events (Kaplan-Meier analysis, P =0.048 for trend). In adjusted Cox regression analysis, the lowest S1P tertile was associated with a worse outcome after stroke (hazard ratio, HR 0.51 [95% confidence interval 0.28-0.92]). Results were confirmed in an independent cohort, ie, low S1P levels were associated with higher National Institutes of Health Stroke Scale, larger infarct volumes and worse outcome after 90 days (β-coefficient: -0.03, P =0.026; β-coefficient: -0.099, P =0.009 and odds ratio 0.52 [0.28-0.96], respectively)., Conclusions: Our findings imply a detrimental role of low S1P levels in acute stroke and therefore underpin the therapeutic potential of S1P-mimics.

Introduction: Serum neurofilament light chain (NfL) levels are associated with disease severity in early Parkinson's disease (PD). We assessed the association of serum NfL with motor and cognitive function and decline in advanced PD patients., Methods: NfL concentrations were analyzed with single molecule array (Simoa) assay in serum of 289 PD patients with advanced disease from the single-center prospective observational biobank study Biomarkers in Parkinson's disease (MARK-PD). Motor and cognitive symptoms were assessed with MDS-UPDRS III, Hoehn&Yahr stages and Montreal Cognitive Assessment (MoCA) at baseline and during 520 [364, 674] days of follow-up., Results: Serum NfL concentrations were associated with Hoehn&Yahr stages. During follow-up, baseline NfL levels were associated with time to cognitive decline in adjusted Cox regression models (hazard ratio: 3.23; 95% CI [1.16, 9.00], P < 0.025). Serum NfL was associated with NT-proBNP in adjusted models linking neuronal and cardiac damage in advanced PD patients., Conclusion: In advanced PD patients, serum NfL concentrations are associated with motor function, cognitive decline and subclinical cardiac damage., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Treatment with sphingosine-1-phosphate (S1P) agonists confers neuroprotective effects in animal models of Parkinson's disease (PD)., Objectives: We assessed the association of serum S1P levels with motor and cognitive symptoms in patients with PD., Methods: S1P concentrations were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) in serum of 196 PD patients and in 196 age- and sex-matched controls. Motor (Unified Parkinson's disease rating scale III [UPDRS III], Hoehn and Yahr) and cognitive (Montreal Cognitive Assessment [MoCA]) function were assessed at baseline. Follow-up data was available from 64 patients (median [interquartile range], 513 [381-677] days)., Results: S1P levels were lower in PD patients compared with controls, that is 1.75 (1.38-2.07) and 1.90 (1.59-2.18) μmol/L, respectively (P = 0.001). In PD patients, lower S1P concentrations were associated with higher UPDRS III scores and Hoehn and Yahr stage. In the follow-up cohort, S1P concentrations below the median were associated with faster motor decline (hazard ratio: 4.78 [95% CI, 1.98, 11.50]), but not with cognitive worsening., Conclusions: Our observations reveal an association of S1P with PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltransferase. Low hArg concentrations are associated with cardiovascular morbidity and predict mortality in patients with PH. We therefore aimed to investigate the survival and cardiac outcome of AGAT knockout ( Agat -/- ) mice under hypoxia and a possible rescue of the phenotype. Methods: Agat -/- mice and wild-type (WT) littermates were subjected to normoxia or normobaric hypoxia (10% oxygen) for 4 weeks. A subgroup of Agat -/- mice was supplemented with 1% creatine from weaning. Survival, hematocrit, blood lactate and glucose, heart weight-to-tibia length (HW/TL) ratio, hArg plasma concentration, and Agat and Gamt expression in lung, liver, and kidneys were evaluated. Results: After 6 h of hypoxia, blood lactate was lower in Agat -/- -mice as compared to normoxia ( p < 0.001). Agat -/- mice died within 2 days of hypoxia, whereas Agat -/- mice supplemented with creatine and WT mice survived until the end of the study. In WT mice, hematocrit (74 ± 4 vs. 55 ± 2%, mean ± SD, p < 0.001) and HW/TL (9.9 ± 1.3 vs. 7.3 ± 0.7 mg/mm, p < 0.01) were higher in hypoxia, while hArg plasma concentration (0.25 ± 0.06 vs. 0.38 ± 0.12 μmol/L, p < 0.01) was lower. Agat and Gamt expressions were differentially downregulated by hypoxia in lung, liver, and kidneys. Conclusion: Agat and Gamt are downregulated in hypoxia. Agat -/- mice are nonviable in hypoxia. Creatine rescues the lethal phenotype, but it does not reduce right ventricular hypertrophy of Agat -/- mice in hypoxia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hannemann, Cordts, Seniuk, Choe, Schmidt-Hutten, Duque Escobar, Weinberger, Böger and Schwedhelm.)

Trimethyllysine (TML) is involved in the generation of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO) by gut microbiota. In clinical studies, elevated TML levels predicted major adverse cardiovascular events (MACE) in patients with acute or stable coronary artery disease (CAD). In contrast to cardiovascular patients, the role of TML in patients with acute cerebral ischemia is unknown. Here, we evaluated circulating TML levels in 374 stroke patients from the prospective biomarkers in stroke (MARK-STROKE) study. Compared with 167 matched healthy controls, acute ischemic stroke patients had lower median TML plasma concentrations, i.e. 0.71 vs. 0.47 µmol/L (p < 0.001) and this difference persisted after adjusting for age and sex. TML plasma concentrations were associated with age, serum creatinine, glucose, cholesterol and lysine. Patients with prevalent arterial hypertension, atrial fibrillation or a history of myocardial infarction had increased TML levels, but this observation was not independent of age, sex and GFR. In 274 patients, follow-up data were available. During a median follow-up of 284 [25th-75th percentile: 198, 431] days, TML was not associated with incident MACE (stroke, myocardial infarction, death). In summary, our data suggests a different role of TML in acute ischemic stroke compared with CAD patients.

Objectives: In prospective cohort studies different blood lipid fractions have been identified as risk factors of Parkinson's disease (PD). However, data relating lipoproteins to disease phenotypes and progression in advanced PD patients are sparse. Therefore, we assessed the most common lipoproteins in a case-control design and evaluated their associations with motor and cognitive function and decline in PD patients., Methods: Triglycerides, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein a (Lp(a)) were analyzed in 294 PD patients of the MARK-PD study cohort and 588 controls matched for age, sex and cardiovascular risk factors. In PD patients, motor (MDS-UPDRS III, Hoehn-Yahr stage) and cognitive function (MoCA) were examined. In a sub-cohort (n = 98 patients), baseline lipid levels were correlated with motor and cognitive disease progression during a follow-up period of 523 ± 199 days., Results: At baseline, HDL-C levels were lower in PD patients compared to matched controls after adjustment. We observed a very weak association of Lp(a) levels with UDPRS III scores. In cross-sectional analyses, no other lipid fraction revealed a significant and consistent association with motor or cognitive function. During follow-up, no lipid fraction level was associated with motor or cognitive progression., Conclusion: In advanced PD, there is no strong and consistent association of lipid levels with motor or cognitive function and decline., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Major complications affecting the central nervous system (CNS) present a challenge after allogeneic stem cell transplantation (allo-SCT)., Methods: Incidence, risk factors, and outcome were retrospectively analyzed in 888 patients in a monocentric study., Results: Cumulative incidence (CI) of major CNS complications at 1 year was 14.8% (95%CI 12.3%-17.2%). Median follow-up is 11 months. CNS complications were documented in 132 patients: in 36 cases, classified metabolic; 26, drug-related neurotoxicity (14 attributed to cyclosporine A, 4 to antilymphocyte globulin); 11, cerebrovascular (ischemic n = 8, bleeding n = 3); 9, infections; 9, psychiatric; and 9, malignant. The cause of CNS symptoms remained unclear for 37 patients (28%). Multivariate analysis demonstrated an association of CNS complication with patient age (P < .001). The estimated OS of patients with any CNS complication was significantly lower than in patients without neurological complications (P < .001), and the CI of non-relapse mortality (NRM) was higher for patients with CNS complication (P < .001). A significant negative impact on survival can only be demonstrated for metabolic CNS complications and CNS infections (NRM, P < .0001 and P = .0003, respectively), and relapse (P < .0001)., Conclusion: CNS complications after allo-SCT are frequent events with a major contribution to morbidity and mortality. In particular, the situations of unclear neurological complications need to be clarified by intensive research., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: We assessed if cardiac blood markers are associated with motor and cognitive function in patients with Parkinson's disease (PD)., Methods: High-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were evaluated in 285 PD patients. Furthermore, N-terminal pro-B-type natriuretic peptide levels were analyzed in 570 age, sex and cardiovascular risk factor matched healthy controls. Motor (UPDRS, Hoehn &Yahr) and cognitive function (Montreal Cognitive Assessemtn) were assessed at baseline in all 285 patients and after 1 year in 101 patients., Results: N-terminal pro-B-type natriuretic peptide were significantly increased in 285 PD patients compared with 570 matched healthy controls. In PD patients, increased high-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide levels were associated with worse motor function at baseline and also with motor decline after 1 year. N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I were inversely associated with cognitive function at baseline only in unadjusted models., Conclusions: Subclinical cardiac microdamage is associated with motor severity in PD patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

We consider two diffusively coupled populations of identical oscillators, where the oscillators in each population are coupled with a common dynamic environment. Existence and stability of a variety of stationary states are analyzed on the basis of the Ott-Antonsen reduction method, which reveals that the chimera state occurs under the diffusive coupling scheme. Furthermore, we find an exotic symmetry-breaking behavior, the so-called the heterosynchronous state, in which each population exhibits in-phase coherence, while the order parameters of two populations rotate at different phase velocities. The chimera and heterosynchronous states emerge from bistabilities of distinct states for decoupled population and occur as a unique continuation for weak diffusive couplings. The heterosynchronous state is caused by an indirect coupling scheme via dynamic environments and could occur for a finite-size system as well, even for the system that consists of one oscillator per population.

L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood. Here, we report the first analysis of heart transcriptome variation using microarrays in an AGAT-deficient (AGAT -/- ) mouse model to evaluate AGAT-, creatine- and HA-dependent gene regulation. Our data revealed significant differences of gene expression between AGAT -/- and wild-type (WT) mice, affecting cardiac energy metabolism (Fbp2, Ucp2), cardiac hypertrophy and fibrosis (Nppa, Ctgf), immune response (Fgl2), and the conduction system of the heart (Dsc2, Ehd4, Hcn2, Hcn4, Scn4a, Scn4b). All of these genes being expressed on WT level in creatine-supplemented mice. Using in silico analysis based on the GEO database we found that most of these candidate genes (Ctgf, Dsc2, Fbp2, Fgl2, Hcn2, Nppa)  revealed significant alterations in a WT mouse model of myocardial infarction underlining a pathophysiological relationship between AGAT metabolism and cardiovascular disease.

l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT -/- ) mice and AGAT -/- mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT -/- and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism ( Ivd , Lcmt2 ), creatine metabolism ( Slc6a8 ), cerebral myelination ( Bcas1 ) and neuronal excitability ( Kcnip3 ). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8 . Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.