Publications by authors named "Bastian Cheng"

77 Publications

Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial.

Eur J Neurol 2021 Mar 3. Epub 2021 Mar 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background And Purpose: The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD.

Methods: This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale.

Results: Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS.

Conclusions: Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD.
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http://dx.doi.org/10.1111/ene.14797DOI Listing
March 2021

Association of lipid levels with motor and cognitive function and decline in advanced Parkinson's disease in the Mark-PD study.

Parkinsonism Relat Disord 2021 Feb 17;85:5-10. Epub 2021 Feb 17.

German Center of Cardiovascular Research (DZHK); Partner Site Hamburg/Lübeck/Kiel, Hamburg, Germany; Department of General and Interventional Cardiology, University Heart and Vascular Center, Hamburg, Germany.

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.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.007DOI Listing
February 2021

Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Analysis of the WAKE-UP Trial.

Front Neurol 2020 4;11:623881. Epub 2021 Feb 4.

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

Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30). Here, 85% of all patients ( = 140) and 95% of middle cerebral artery (MCA) occlusion patients ( = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth ( = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (β = 2.161; 95% CI 0.96-3.36; = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), -value for interaction was 0.11. While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.
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http://dx.doi.org/10.3389/fneur.2020.623881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890254PMC
February 2021

Safety and efficacy of intravenous thrombolysis in stroke patients on prior antiplatelet therapy in the WAKE-UP trial.

Neurol Res Pract 2020 20;2:40. Epub 2020 Nov 20.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial.

Methods: WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0-1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase.

Results: Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years,  <  0.001), and more frequently had a history of hypertension, atrial fibrillation, diabetes, hypercholesterolemia, and previous stroke or transient ischaemic attack. Rates of symptomatic intracranial hemorrhage and hemorrhagic transformation on follow-up imaging did not differ between patients with and without antiplatelet treatment. Patients on prior antiplatelet treatment were less likely to achieve a favorable outcome (37.3% vs. 52.6%,  = 0.014), but there was no interaction of prior antiplatelet treatment with intravenous alteplase concerning favorable outcome ( = 0.355). Intravenous alteplase was associated with higher rates of favorable outcome in patients on prior antiplatelet treatment with an adjusted odds ratio of 2.106 (95% CI 1.047-4.236).

Conclusions: Treatment benefit of intravenous alteplase and rates of post-treatment hemorrhagic transformation were not modified by prior antiplatelet intake among MRI-selected patients with unknown onset stroke. Worse functional outcome in patients on antiplatelets may result from a higher load of cardiovascular co-morbidities in these patients.
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http://dx.doi.org/10.1186/s42466-020-00087-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678217PMC
November 2020

Symptoms and probabilistic anatomical mapping of lacunar infarcts.

Neurol Res Pract 2020 3;2:21. Epub 2020 Aug 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: The anatomical distribution of acute lacunar infarcts has mainly been studied for supratentorial lesions. In addition, little is known about the association with distinct stroke symptoms, not summarized as classical lacunar syndromes. We aimed to describe the spatial lesion distribution of acute supra- and infratentorial lacunar infarcts and their association with stroke symptoms in patients eligible for thrombolysis.

Methods: All patients enrolled in the WAKE-UP trial (efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in wake-up stroke) were screened for lacunar infarcts on diffusion-weighted imaging (DWI). The relationship between the anatomical distribution of supra- and infratentorial lacunar infarcts, their demographic characteristics and acute stroke symptoms, defined by the National Institutes of Health Stroke Scale (NIHSS) score, were correlated and compared.

Results: Maps of lesion distribution from 224 lacunar infarct patients (76 [33.9%] females, mean age [standard deviation] of 63.4 [11.5] years) were generated using computational image mapping methods. Median infarct volume was 0.73 ml (interquartile range [IQR] 0.37-1.15 ml). Median NIHSS sum score on hospital arrival was 4 (IQR 3-6). 165 (73.7%) patients had lacunar infarcts in the supratentorial deep white or grey matter, while 59 (26.3%) patients had infratentorial lacunar infarcts. Patients with supratentorial lacunar infarcts presented with a significantly lower occurrence of deficits in the NIHSS items gaze ( < 0.001) and dysarthria ( = 0.008), but had more often a paresis of the left arm ( = 0.009) and left leg ( = 0.068) compared to patients with infratentorial infarcts.

Conclusions: The anatomical lesion distribution of lacunar infarcts reveals a distinct pattern and supports an association of localization with different stroke symptoms.

Trial Registration: NCT01525290.
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http://dx.doi.org/10.1186/s42466-020-00068-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650076PMC
August 2020

White matter integrity and structural brain network topology in cerebral small vessel disease: The Hamburg city health study.

Hum Brain Mapp 2021 Apr 8;42(5):1406-1415. Epub 2020 Dec 8.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Cerebral small vessel disease is a common finding in the elderly and associated with various clinical sequelae. Previous studies suggest disturbances in the integration capabilities of structural brain networks as a mediating link between imaging and clinical presentations. To what extent cerebral small vessel disease might interfere with other measures of global network topology is not well understood. Connectomes were reconstructed via diffusion weighted imaging in a sample of 930 participants from a population based epidemiologic study. Linear models were fitted testing for an association of graph-theoretical measures reflecting integration and segregation with both the Peak width of Skeletonized Mean Diffusivity (PSMD) and the load of white matter hyperintensities of presumed vascular origin (WMH). The latter were subdivided in periventricular and deep for an analysis of localisation-dependent correlations of cerebral small vessel disease. The median WMH volume was 0.6 mL (1.4) and the median PSMD 2.18 mm /s x 10 (0.5). The connectomes showed a median density of 0.880 (0.030), the median values for normalised global efficiency, normalised clustering coefficient, modularity Q and small-world propensity were 0.780 (0.045), 1.182 (0.034), 0.593 (0.026) and 0.876 (0.040) respectively. An increasing burden of cerebral small vessel disease was significantly associated with a decreased integration and increased segregation and thus decreased small-worldness of structural brain networks. Even in rather healthy subjects increased cerebral small vessel disease burden is accompanied by topological brain network disturbances. Segregation parameters and small-worldness might as well contribute to the understanding of the known clinical sequelae of cerebral small vessel disease.
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http://dx.doi.org/10.1002/hbm.25301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927298PMC
April 2021

Linking cortical atrophy to white matter hyperintensities of presumed vascular origin.

J Cereb Blood Flow Metab 2020 Dec 1:271678X20974170. Epub 2020 Dec 1.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

We examined the relationship between white matter hyperintensities (WMH) and cortical neurodegeneration in cerebral small vessel disease (CSVD) by investigating whether cortical thickness is a remote effect of WMH through structural fiber tract connectivity in a population at increased risk of CSVD. We measured cortical thickness on T1-weighted images and segmented WMH on FLAIR images in 930 participants of a population-based cohort study at baseline. DWI-derived whole-brain probabilistic tractography was used to define WMH connectivity to cortical regions. Linear mixed-effects models were applied to analyze the relationship between cortical thickness and connectivity to WMH. Factors associated with cortical thickness (age, sex, hemisphere, region, individual differences in cortical thickness) were added as covariates. Median age was 64 [IQR 46-76] years. Visual inspection of surface maps revealed distinct connectivity patterns of cortical regions to WMH. WMH connectivity to the cortex was associated with reduced cortical thickness ( = 0.009) after controlling for covariates. This association was found for periventricular WMH ( = 0.001) only. Our results indicate an association between WMH and cortical thickness via connecting fiber tracts. The results imply a mechanism of secondary neurodegeneration in cortical regions distant, yet connected to subcortical vascular lesions, which appears to be driven by periventricular WMH.
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http://dx.doi.org/10.1177/0271678X20974170DOI Listing
December 2020

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Higher white matter hyperintensity lesion load is associated with reduced long-range functional connectivity.

Brain Commun 2020 20;2(2):fcaa111. Epub 2020 Jul 20.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.

Cerebral small vessel disease is a common disease in the older population and is recognized as a major risk factor for cognitive decline and stroke. Small vessel disease is considered a global brain disease impacting the integrity of neuronal networks resulting in disturbances of structural and functional connectivity. A core feature of cerebral small vessel disease commonly present on neuroimaging is white matter hyperintensities. We studied high-resolution resting-state EEG, leveraging source reconstruction methods, in 35 participants with varying degree of white matter hyperintensities without clinically evident cognitive impairment in an observational study. In patients with increasing white matter lesion load, global theta power was increased independently of age. Whole-brain functional connectivity revealed a disrupted network confined to the alpha band in participants with higher white matter hyperintensities lesion load. The decrease of functional connectivity was evident in long-range connections, mostly originating or terminating in the frontal lobe. Cognitive testing revealed no global cognitive impairment; however, some participants revealed deficits of executive functions that were related to larger white matter hyperintensities lesion load. In summary, participants without clinical signs of mild cognitive impairment or dementia showed oscillatory changes that were significantly related to white matter lesion load. Hence, oscillatory neuronal network changes due to white matter lesions might act as biomarker prior to clinically relevant behavioural impairment.
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http://dx.doi.org/10.1093/braincomms/fcaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585696PMC
July 2020

Clinical Characteristics and Outcome of Patients With Hemorrhagic Transformation After Intravenous Thrombolysis in the WAKE-UP Trial.

Front Neurol 2020 28;11:957. Epub 2020 Aug 28.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome. We performed a analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0-1 at 90 days. Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28-3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05-1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01-1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00-1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57-5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01-1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93-6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05-0.86]), while HI was not. Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window.
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http://dx.doi.org/10.3389/fneur.2020.00957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483750PMC
August 2020

Structural brain networks and functional motor outcome after stroke-a prospective cohort study.

Brain Commun 2020 10;2(1):fcaa001. Epub 2020 Jan 10.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.

The time course of topological reorganization that occurs in the structural connectome after an ischaemic stroke is currently not well understood. We aimed to determine the evolution of structural brain networks in stroke patients with motor deficits and relate changes in their global topology to residual symptom burden and functional impairment. In this prospective cohort study, ischaemic stroke patients with supratentorial infarcts and motor symptoms were assessed longitudinally by advanced diffusion MRI and detailed clinical testing of upper extremity motor function at four time points from the acute to the chronic stage. For each time point, structural connectomes were reconstructed, and whole-hemisphere global network topology was quantified in terms of integration and segregation parameters. Using non-linear joint mixed-effects regression modelling, network evolution was related to lesion volume and clinical outcome. Thirty patients were included for analysis. Graph-theoretical analysis demonstrated that, over time, brain networks became less integrated and more segregated with decreasing global efficiency and increasing modularity. Changes occurred in both stroke and intact hemispheres and, in the latter, were positively associated with lesion volume. Greater change in topology was associated with larger residual symptom burden and greater motor impairment 1, 3 and 12 months after stroke. After ischaemic stroke, brain networks underwent characteristic changes in both ipsi- and contralesional hemispheres. Topological network changes reflect the severity of damage to the structural network and are associated with functional outcome beyond the impact of lesion volume.
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http://dx.doi.org/10.1093/braincomms/fcaa001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425342PMC
January 2020

Altered topology of large-scale structural brain networks in chronic stroke.

Brain Commun 2019 4;1(1):fcz020. Epub 2019 Oct 4.

Department of Neurology, University Medical Center Hamburg-Eppendorf, D20246 Hamburg, Germany.

Beyond disruption of neuronal pathways, focal stroke lesions induce structural disintegration of distant, yet connected brain regions via retrograde neuronal degeneration. Stroke lesions alter functional brain connectivity and topology in large-scale brain networks. These changes are associated with the degree of clinical impairment and recovery. In contrast, changes of large scale, structural brain networks after stroke are less well reported. We therefore aimed to analyse the impact of focal lesions on the structural connectome after stroke based on data from diffusion-weighted imaging and probabilistic fibre tracking. In total, 17 patients (mean age 64.5 ± 8.4 years) with upper limb motor deficits in the chronic stage after stroke and 21 healthy participants (mean age 64.9 ± 10.3 years) were included. Clinical deficits were evaluated by grip strength and the upper extremity Fugl-Meyer assessment. We calculated global and local graph theoretical measures to characterize topological changes in the structural connectome. Results from our analysis demonstrated significant alterations of network topology in both ipsi- and contralesional, primarily unaffected, hemispheres after stroke. Global efficiency was significantly lower in stroke connectomes as an indicator of overall reduced capacity for information transfer between distant brain areas. Furthermore, topology of structural connectomes was shifted toward a higher degree of segregation as indicated by significantly higher values of global clustering and modularity. On a level of local network parameters, these effects were most pronounced in a subnetwork of cortico-subcortical brain regions involved in motor control. Structural changes were not significantly associated with clinical measures. We propose that the observed network changes in our patients are best explained by the disruption of inter- and intrahemispheric, long white matter fibre tracts connecting distant brain regions. Our results add novel insights on topological changes of structural large-scale brain networks in the ipsi- and contralesional hemisphere after stroke.
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http://dx.doi.org/10.1093/braincomms/fcz020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425306PMC
October 2019

Network Localisation of White Matter Damage in Cerebral Small Vessel Disease.

Sci Rep 2020 06 8;10(1):9210. Epub 2020 Jun 8.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Cerebral small vessel disease (CSVD) is a widespread condition associated to stroke, dementia and depression. To shed light on its opaque pathophysiology, we conducted a neuroimaging study aiming to assess the location of CSVD-induced damage in the human brain network. Structural connectomes of 930 subjects of the Hamburg City Health Study were reconstructed from diffusion weighted imaging. The connectome edges were partitioned into groups according to specific schemes: (1) connection to grey matter regions, (2) course and length of underlying streamlines. Peak-width of skeletonised mean diffusivity (PSMD) - a surrogate marker for CSVD - was related to each edge group's connectivity in a linear regression analysis allowing localisation of CSVD-induced effects. PSMD was associated with statistically significant decreases in connectivity of most investigated edge groups except those involved in connecting limbic, insular, temporal or cerebellar regions. Connectivity of interhemispheric and long intrahemispheric edges as well as edges connecting subcortical and frontal brain regions decreased most severely with increasing PSMD. In conclusion, MRI findings of CSVD are associated with widespread impairment of structural brain network connectivity, which supports the understanding of CSVD as a global brain disease. The pattern of regional preference might provide a link to clinical phenotypes of CSVD.
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http://dx.doi.org/10.1038/s41598-020-66013-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280237PMC
June 2020

Effect of Balloon Guide Catheter Utilization on the Incidence of Sub-angiographic Peripheral Emboli on High-Resolution DWI After Thrombectomy: A Prospective Observational Study.

Front Neurol 2020 7;11:386. Epub 2020 May 7.

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Thrombus fragmentation causing distal emboli is a feared complication during mechanical thrombectomy (MT). We aimed to investigate the impact of procedural parameters and thrombus properties on the incidence of peripheral emboli after MT for large vessel occlusions (LVO). We performed a prospective analysis of patients with LVO stroke successfully treated with MT, defined as a score of 2b, 2c, or 3 on the thrombolysis in cerebral infarction (TICI) scale. A follow-up MRI including high-resolution diffusion-weighted imaging (DWI) was performed within 24 h following MT. The primary endpoint was the number and volume of peripheral emboli, classified as punctuate DWI lesions distant to the diffusion-restricted core lesion. Further analysis included the influence of baseline characteristics, procedural and outcome parameters, and thrombus properties on peripheral emboli. Thirty-seven patients with successful MT met the inclusion criteria. Use of a balloon guide catheter (BGC) and TICI were the only independent predictors for a reduced number of peripheral emboli. The use of a BGC led to a significant reduction in the number and volume of peripheral emboli, with a median number/volume of peripheral emboli of 4.5/287 μl (IQR 1.25-8.25/76-569 μl) vs. 12/938 μl (IQR 4-19/242-1,836 μl). In cases where BGC was not employed, the number of peripheral emboli increased with decreasing TICI scores. BGC-aided MT reduces the number of peripheral emboli in successful but incomplete reperfusion (TICI 2b and 2c). The effectiveness of this strategy therefore goes above and beyond that which can be demonstrated by the TICI score alone.
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http://dx.doi.org/10.3389/fneur.2020.00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221024PMC
May 2020

Ischemic lesion water homeostasis after thrombectomy for large vessel occlusion stroke within the anterior circulation: The impact of age.

J Cereb Blood Flow Metab 2021 Jan 4;41(1):45-52. Epub 2020 Apr 4.

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The effect of age on lesion pathophysiology in the context of thrombectomy has been poorly investigated. We aimed to investigate the impact of age on ischemic lesion water homeostasis measured with net water uptake (NWU) within a multicenter cohort of patients receiving thrombectomy for anterior circulation large vessel occlusion (LVO) stroke. Lesion-NWU was quantified in multimodal CT on admission and 24 h for calculating Δ-NWU as their difference. The impact of age and procedural parameters on Δ-NWU was analyzed. Multivariable regression analysis was performed to identify significant predictors for Δ-NWU. Two hundred and four patients with anterior circulation stroke were included in the retrospective analysis. Comparison of younger and elderly patients showed no significant differences in NWU on admission but significantly higher Δ-NWU ( = 0.005) on follow-up CT in younger patients. In multivariable regression analysis, higher age was independently associated with lowered Δ-NWU (95% confidence interval: -0.59 to -0.16,  < 0.001). Although successful recanalization (TICI ≥ 2b) significantly reduced Δ-NWU progression by 6.4% ( < 0.001), younger age was still independently associated with higher Δ-NWU ( < 0.001). Younger age is significantly associated with increased brain edema formation after thrombectomy for LVO stroke. Younger patients might be particularly receptive targets for future adjuvant neuroprotective drugs that influence ischemic edema formation.
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http://dx.doi.org/10.1177/0271678X20915792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747157PMC
January 2021

Different Mismatch Concepts for Magnetic Resonance Imaging-Guided Thrombolysis in Unknown Onset Stroke.

Ann Neurol 2020 06 20;87(6):931-938. Epub 2020 Apr 20.

Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

Objective: To explore the prevalence of the perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch and response to intravenous thrombolysis in the WAKE-UP trial.

Methods: We performed a prespecified post hoc analysis of ischemic stroke patients screened for DWI-fluid-attenuated inversion recovery (FLAIR) mismatch in WAKE-UP who underwent PWI. We defined PWI-DWI mismatch as ischemic core volume < 70ml, mismatch volume > 10ml, and mismatch ratio > 1.2. Primary efficacy end point was a modified Rankin Scale score of 0-1 at 90 days, adjusted for age and symptom severity.

Results: Of 1,362 magnetic resonance imaging-screened patients, 431 underwent PWI. Of these, 57 (13%) had a double mismatch, 151 (35%) only a DWI-FLAIR mismatch, and 54 (13%) only a PWI-DWI mismatch. DWI-FLAIR mismatch was more prevalent than PWI-DWI mismatch (48%, 95% confidence interval [CI] = 43-53% vs 26%, 95% CI = 22-30%; p < 0.0001). Screening for either one of the mismatch profiles resulted in a yield of 61% (95% CI = 56-65%). Prevalence of PWI-DWI mismatch was similar in patients with (27%) or without (24%) DWI-FLAIR mismatch (p = 0.52). In an exploratory analysis in the small subgroup of 208 randomized patients with PWI, PWI-DWI mismatch status did not modify the treatment response (p for interaction = 0.73).

Interpretation: Evaluating both the DWI-FLAIR and PWI-DWI mismatch patterns in patients with unknown time of stroke onset will result in the highest yield of thrombolysis treatment. The treatment benefit of alteplase in patients with a DWI-FLAIR mismatch seems to be driven not merely by the presence of a PWI-DWI mismatch, although this analysis was underpowered. ANN NEUROL 2020;87:931-938.
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http://dx.doi.org/10.1002/ana.25730DOI Listing
June 2020

Sub-angiographic peripheral emboli in high resolution DWI after endovascular recanalization.

J Neurol 2020 May 29;267(5):1401-1406. Epub 2020 Jan 29.

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background And Aim: To analyze the incidence of peripheral emboli after successful mechanical thrombectomy (MT) of intracranial large vessel occlusions (LVO).

Methods: We performed a prospective analysis of patients with intracranial LVO who underwent successful MT and received a 1.5 T MRI including diffusion-weighted imaging (DWI) in standard- and high-resolution as well as susceptibility-weighted imaging (SWI) on the day following the intervention. Reperfusion grade was assessed on post-thrombectomy digital subtraction angiography (DSA) using the expanded thrombolysis in cerebral infarction (eTICI) scale. Punctuate DWI lesions distal to the DWI core lesion were classified as peripheral emboli. DWI lesions outside the primary affected vascular territory were classified as emboli into new territories. Additionally, SWI and post-thrombectomy DSA were analyzed and correlated to findings on DWI.

Results: Twenty-eight patients undergoing successful MT met the inclusion criteria. In 26/28 patients (93%), a total of 324 embolic lesions were detected in DWI representing 2.1% of the cumulated ischemic core volume. 151 peripheral emboli were detected in standard-resolution DWI, 173 additional emboli were uncovered in high-resolution DWI. Eight out of nine patients with an eTICI 3 reperfusion had embolic lesions (29 DWI lesions). 9.6% (31/324) of peripheral emboli were observed in vascular territories not affected by the LVO. SWI lesions were observed in close proximity to 10.2% (33/324) of DWI lesions.

Conclusions: Peripheral emboli are frequent after MT even after complete reperfusion. These emboli occur rather in the vascular territory of the occluded vessel than in other territories. A large proportion of peripheral emboli is only detected by high-resolution DWI.
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http://dx.doi.org/10.1007/s00415-020-09719-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184052PMC
May 2020

Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial.

Stroke 2020 01 30;51(1):209-215. Epub 2019 Oct 30.

From the Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum (B.C., A.N., C.G., G.T.), University Medical Center Hamburg-Eppendorf, Germany.

Background and Purpose- Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods- FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results- FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 (=0.169) and shift analysis (=0.086) but reached significance for mRS score of 0 to 2 (=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions- In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.
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http://dx.doi.org/10.1161/STROKEAHA.119.027390DOI Listing
January 2020

Low-Frequency Brain Oscillations Track Motor Recovery in Human Stroke.

Ann Neurol 2019 12 30;86(6):853-865. Epub 2019 Oct 30.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: The majority of patients with stroke survive the acute episode and live with enduring disability. Effective therapies to support recovery of motor function after stroke are yet to be developed. Key to this development is the identification of neurophysiologic signals that mark recovery and are suitable and susceptible to interventional therapies. Movement preparatory low-frequency oscillations (LFOs) play a key role in cortical control of movement. Recent animal data point to a mechanistic role of motor cortical LFOs in stroke motor deficits and demonstrate neuromodulation intervention with therapeutic benefit. Their relevance in human stroke pathophysiology is unknown.

Methods: We studied the relationship between movement-preparatory LFOs during the performance of a visuomotor grip task and motor function in a longitudinal (<5 days, 1 and 3 months) cohort study of 33 patients with motor stroke and in 19 healthy volunteers.

Results: Acute stroke-lesioned brains fail to generate the LFO signal. Whereas in healthy humans, a transient occurrence of LFOs preceded movement onset at predominantly contralateral frontoparietal motor regions, recordings in patients revealed that movement-preparatory LFOs were substantially diminished to a level of 38% after acute stroke. LFOs progressively increased at 1 and 3 months. This re-emergence closely tracked the recovery of motor function across several movement qualities including grip strength, fine motor skills, and synergies and was frequency band specific.

Interpretation: Our results provide the first human evidence for a link between movement-preparatory LFOs and functional recovery after stroke, promoting their relevance for movement control. These results suggest that it may be interesting to explore targeted, LFOs-restorative brain stimulation therapy in human stroke patients. ANN NEUROL 2019;86:853-865.
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http://dx.doi.org/10.1002/ana.25615DOI Listing
December 2019

Analysis of Outcome of Intravenous Thrombolysis in Infarcts of Infratentorial Localization in the WAKE-UP Trial.

Front Neurol 2019 11;10:983. Epub 2019 Sep 11.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

In WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke), patients with an acute stroke of unknown onset time were randomized to treatment with intravenous alteplase or placebo, guided by MRI. In this exploratory secondary analysis we compared clinical and imaging data, as well as treatment effects and safety of intravenous thrombolysis between patients with infra- vs. supratentorial stroke. Forty-eight out of 503 randomized patients (9.5%) presented with a stroke involving the cerebellum or brainstem. Patients with infratentorial stroke were younger compared to patients with supratentorial stroke (mean age 60 vs. 66 years), more frequently male (85 vs. 62%), and less severely affected (median NIHSS 4.5 vs. 6.0). There was no heterogeneity for treatment effect between supratentorial (OR 1.67 95% CI 1.11-2.51) and infratentorial (OR 1.31 95% CI 0.41-4.22) sub-groups (test for interaction = 0.70). In patients with infratentorial stroke, favorable outcome [a score of 0-1 on the modified Rankin scale (mRS) at 90 days] was observed in 12/22 patients (54.5%) in the alteplase group and in 13/25 patients (52.0%) in the placebo group ( = 0.59). The primary safety endpoint (death or mRS 4-6 at day 90) occurred in three patients of the alteplase group (13.6%) and three patients in the placebo group (12.0%); = 0.74. WAKE-UP was underpowered for demonstrating treatment effect in subgroup analyses however, based on our current results, there is no evidence to recommend withholding MRI-guided thrombolysis in patients with unknown onset stroke of infratentorial localization.
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http://dx.doi.org/10.3389/fneur.2019.00983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749039PMC
September 2019

Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis.

J Cereb Blood Flow Metab 2020 09 11;40(9):1838-1848. Epub 2019 Sep 11.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.
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http://dx.doi.org/10.1177/0271678X19874338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446560PMC
September 2020

Cortical thickness and cognitive performance in asymptomatic unilateral carotid artery stenosis.

BMC Cardiovasc Disord 2019 06 25;19(1):154. Epub 2019 Jun 25.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: We investigated changes of cortical thickness and its association with cognitive performance in patients with high-grade carotid artery stenosis without ischemic brain lesions.

Methods: We studied 25 patients with unilateral carotid artery stenosis ≥50% and 25 age-matched controls. All subjects underwent T1-weighted MRI, and cortical thickness was measured in 33 regions of interest in each hemisphere, as well as in brain regions belonging to the vascular territory of the middle cerebral artery (MCA). General linear mixed models were fitted to the dependent variable cortical thickness. Cognitive assessment comprised the Stroop Test and Trail Making Test B.

Results: In the linear mixed model, presence of carotid stenosis had no effect on cortical thickness. There was a significant interaction of stenosis and region with a trend towards lower cortical thickness in the MCA region on the side of carotid stenosis. Patients with carotid stenosis performed significantly worse on the Stroop test than controls, but there was no correlation with cortical thickness.

Conclusion: In patients with carotid stenosis without ischemic brain lesions, neither a clear pattern of reduced cortical thickness nor an association of cortical thickness with cognitive function was observed. Our data do not support the hypothesized association of cortical thinning and cognitive impairment in carotid stenosis.
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http://dx.doi.org/10.1186/s12872-019-1127-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593546PMC
June 2019

Stroke Lesion Segmentation in FLAIR MRI Datasets Using Customized Markov Random Fields.

Front Neurol 2019 24;10:541. Epub 2019 May 24.

Department of Radiology, University of Calgary, Calgary, AB, Canada.

Robust and reliable stroke lesion segmentation is a crucial step toward employing lesion volume as an independent endpoint for randomized trials. The aim of this work was to develop and evaluate a novel method to segment sub-acute ischemic stroke lesions from fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) datasets. After preprocessing of the datasets, a Bayesian technique based on Gabor textures extracted from the FLAIR signal intensities is utilized to generate a first estimate of the lesion segmentation. Using this initial segmentation, a customized voxel-level Markov random field model based on intensity as well as Gabor texture features is employed to refine the stroke lesion segmentation. The proposed method was developed and evaluated based on 151 multi-center datasets from three different databases using a leave-one-patient-out validation approach. The comparison of the automatically segmented stroke lesions with manual ground truth segmentation revealed an average Dice coefficient of 0.582, which is in the upper range of previously presented lesion segmentation methods using multi-modal MRI datasets. Furthermore, the results obtained by the proposed technique are superior compared to the results obtained by two methods based on convolutional neural networks and three phase level-sets, respectively, which performed best in the ISLES 2015 challenge using multi-modal imaging datasets. The results of the quantitative evaluation suggest that the proposed method leads to robust lesion segmentation results using FLAIR MRI datasets only as a follow-up sequence.
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http://dx.doi.org/10.3389/fneur.2019.00541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542951PMC
May 2019

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions.

Clin Neuroradiol 2020 Sep 3;30(3):511-516. Epub 2019 Jun 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI).

Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions.

Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011).

Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.
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http://dx.doi.org/10.1007/s00062-019-00800-5DOI Listing
September 2020

Characterization of White Matter Hyperintensities in Large-Scale MRI-Studies.

Front Neurol 2019 26;10:238. Epub 2019 Mar 26.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

White matter hyperintensities of presumed vascular origin (WMH) are a common finding in elderly people and a growing social malady in the aging western societies. As a manifestation of cerebral small vessel disease, WMH are considered to be a vascular contributor to various sequelae such as cognitive decline, dementia, depression, stroke as well as gait and balance problems. While pathophysiology and therapeutical options remain unclear, large-scale studies have improved the understanding of WMH, particularly by quantitative assessment of WMH. In this review, we aimed to provide an overview of the characteristics, research subjects and segmentation techniques of these studies. We performed a systematic review according to the PRISMA statement. One thousand one hundred and ninety-six potentially relevant articles were identified via PubMed search. Six further articles classified as relevant were added manually. After applying a catalog of exclusion criteria, remaining articles were read full-text and the following information was extracted into a standardized form: year of publication, sample size, mean age of subjects in the study, the cohort included, and segmentation details like the definition of WMH, the segmentation method, reference to methods papers as well as validation measurements. Our search resulted in the inclusion and full-text review of 137 articles. One hundred and thirty-four of them belonged to 37 prospective cohort studies. Median sample size was 1,030 with no increase over the covered years. Eighty studies investigated in the association of WMH and risk factors. Most of them focussed on arterial hypertension, diabetes mellitus type II and Apo E genotype and inflammatory markers. Sixty-three studies analyzed the association of WMH and secondary conditions like cognitive decline, mood disorder and brain atrophy. Studies applied various methods based on manual (3), semi-automated (57), and automated segmentation techniques (75). Only 18% of the articles referred to an explicit definition of WMH. The review yielded a large number of studies engaged in WMH research. A remarkable variety of segmentation techniques was applied, and only a minority referred to a clear definition of WMH. Most addressed topics were risk factors and secondary clinical conditions. In conclusion, WMH research is a vivid field with a need for further standardization regarding definitions and used methods.
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http://dx.doi.org/10.3389/fneur.2019.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443932PMC
March 2019

Somatosensory Deficits After Ischemic Stroke.

Stroke 2019 05;50(5):1116-1123

From the Department of Neurology (S.S.K., E.S., B.C., C.G., G.T.), University Medical Center Hamburg-Eppendorf, Germany.

Background and Purpose- About 50% to 80% of stroke survivors present with somatosensory deficits. Somatosensory deficits because of an ischemic stroke are determined by the infarct location. However, a detailed understanding of the long-term effect of lesions on somatosensory performance is lacking. Methods- This prospective observational study enrolled 101 ischemic stroke patients. For voxel-based lesion-symptom mapping, magnetic resonance imaging fluid-attenuated inversion recovery imaging infarct lesions were segmented within 5 days after stroke. Standardized tests such as the National Institutes of Health Stroke Scale and the Rivermead Assessment of Somatosensory Performance were performed during acute stage, after 3 and 12 months. This included bilateral testing for multiple tactile and proprioceptive somatosensory modalities (pressure, light touch, sharp-dull discrimination, temperature discrimination, sensory extinction, 2-point discrimination, and joint position and movement sense). We further study the association of acute somatosensory deficit with functional outcome 12 months after stroke assessed by the modified Rankin Scale using univariate and multiple linear regression analysis also including acute motor deficit assessed by the arm research action test. Results- Sixty patients (59.4%) showed impairment in at least one somatosensory modality. Light touch was most frequently affected (38.7%), whereas temperature was least frequently affected (21.8%). After 3 months, significant recovery was observed in all somatosensory modalities, with only minor additional improvements after 12 months. Voxel-based lesion-symptom mapping revealed significant associations of lesions in the primary and secondary somatosensory and insular cortex with somatosensory deficits. Acute somatosensory deficit was associated with functional outcome at 12 months. However, including the acute motor deficit, somatosensory deficit was no longer an independent predictor of functional outcome. Conclusions- Our study confirms that somatosensory deficits are frequent in acute ischemic stroke but largely recover over time. Infarct lesions in the primary and secondary somatosensory cortex and insula show a robust association with somatosensory impairment. Long-term disability is influenced by somatosensory deficits but driven by motor symptoms.
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http://dx.doi.org/10.1161/STROKEAHA.118.023750DOI Listing
May 2019

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial.

JAMA Neurol 2019 06;76(6):641-649

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment.

Objective: To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts.

Design, Setting, And Participants: This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information.

Main Outcomes And Measures: The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms.

Results: Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93).

Conclusions And Relevance: While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.
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http://dx.doi.org/10.1001/jamaneurol.2019.0351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563546PMC
June 2019

Dynamics of brain perfusion and cognitive performance in revascularization of carotid artery stenosis.

Neuroimage Clin 2019 13;22:101779. Epub 2019 Mar 13.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Introduction: There is evidence suggesting a detrimental effect of asymptomatic carotid artery stenosis on cognitive function even in the absence of ischemic cerebral lesions. Hypoperfusion has been suggested as pathophysiological mechanism causing cognitive impairment. We aimed to assess cognitive performance and cerebral perfusion changes in patients with carotid artery stenosis without ischemic lesions by arterial spin labeling (ASL) and contrast enhanced (CE) perfusion MRI before and after revascularization therapy.

Methods: 17 asymptomatic patients with unilateral high-grade (≥70%) carotid artery stenosis without evidence of structural brain lesions underwent ASL and CE perfusion MRI and cognitive testing (MMSE, DemTect, Clock-Drawing Test, Trail-Making Test, Stroop Test) before and 6-8 weeks after revascularization therapy by endarterectomy or stenting. Multiparametric perfusion maps (ASL: cerebral blood flow (ASL-CBF), bolus arrival time (ASL-BAT); CE: cerebral blood flow (CE-CBF), mean transit time (CE-MTT), cerebral blood volume (CE-CBV)) were calculated and analyzed by vascular territory. Relative perfusion values were calculated.

Results: Multivariate analysis revealed a significant impact of revascularization therapy on all perfusion measures analyzed. At baseline post-hoc testing showed significant hypoperfusion in MCA borderzones as assessed by ASL-CBF, ASL-BAT, CE-MTT and CE-CBV. All perfusion alterations normalized after revascularization. We did not observe any significant correlation of cognitive test results with perfusion parameters. There was no significant change in cognitive performance after revascularization.

Conclusion: We found evidence of traceable perfusion alterations in patients with high grade carotid artery stenosis in the absence of structural brain lesions, which proved fully reversible after revascularization therapy. In this cohort of asymptomatic patients we did not observe an association of hypoperfusion with cognitive performance.
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http://dx.doi.org/10.1016/j.nicl.2019.101779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431743PMC
January 2020

Prefrontal-Premotor Pathways and Motor Output in Well-Recovered Stroke Patients.

Front Neurol 2019 14;10:105. Epub 2019 Feb 14.

Defitech Chair of Clinical Neuroengineering, Center for Neuroprosthetics and Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Geneva, Switzerland.

Structural brain imaging has continuously furthered our knowledge how different pathways of the human motor system contribute to residual motor output in stroke patients. Tract-related microstructure of pathways between primary and premotor areas has been found to critically influence motor output. The motor network is not restricted in connectivity to motor and premotor areas but these brain regions are densely interconnected with prefrontal regions such as the dorsolateral (DLPFC) and ventrolateral (VLPFC) prefrontal cortex. So far, the available data about the topography of such direct pathways and their microstructural properties in humans are sparse. To what extent prefrontal-premotor connections might also relate to residual motor outcome after stroke is still an open question. The present study was designed to address this issue of structural connectivity of prefrontal-premotor pathways in 26 healthy, older participants (66 ± 10 years old, 15 male) and 30 well-recovered chronic stroke patients (64 ± 10 years old, 21 males). Probabilistic tractography was used to reconstruct direct fiber tracts between DLPFC and VLPFC and three premotor areas (dorsal and ventral premotor cortex and the supplementary motor area). Direct connections between DLPFC/VLPFC and the primary motor cortex were also tested. Tract-related microstructure was estimated for each specific tract by means of fractional anisotropy and alternative diffusion metrics. These measures were compared between the groups and related to residual motor outcome in the stroke patients. Direct prefrontal-premotor trajectories were successfully traceable in both groups. Similar in gross anatomic topography, stroke patients presented only marginal microstructural alterations of these tracts, predominantly of the affected hemisphere. However, there was no clear evidence for a significant association between tract-related microstructure of prefrontal-premotor connections and residual motor functions in the present group of well-recovered stroke patients. Direct prefrontal-motor connections between DLPFC/VLPFC and the primary motor cortex could not be reconstructed in the present healthy participants and stroke patients.
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http://dx.doi.org/10.3389/fneur.2019.00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382735PMC
February 2019