Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have ...functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived 14C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function.
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•Nuclear-bomb-test-derived 14C in human hippocampal neurons reveals adult neurogenesis•One-third of hippocampal neurons are subject to exchange•The annual turnover rate is 1.75% within the renewing fraction in adult humans•The extent of adult neurogenesis is comparable in middle-aged humans and mice
14C dating shows that in the human hippocampus neurons are continually added throughout adulthood at a rate of 700 new neurons per day, implicating neurogenesis in human cognitive plasticity.
Background: Intracerebral hemorrhage (ICH) accounts for up to 15% of all strokes and
is characterized by high rates of mortality and morbidity. The post-ICH brain injury can be distinguished
in 1) ...primary, which are caused by disruption and mechanical deformation of brain tissue
due to hematoma growth and 2) secondary, which are induced by microglia activation, mitochondrial
dysfunction, neurotransmitter and inflammatory mediator release. Although these events typically
lead to necrosis, the occurrence of programmed cell death has also been reported after ICH.
Methods: We reviewed recent publications describing advance in pre- and clinic ICH research.
Results: At present, treatment of ICH patients is based on oral anticoagulant reversal, management
of blood pressure and other medical complications. Several pre-clinical studies showed promising
results and demonstrated that anti-oxidative and anti-inflammatory treatments reduced neuronal cell
death, however, to date, all of these attempts have failed in randomized controlled clinical trials.
Yet, the time frame of administration may be crucial in translation from animal to clinical studies.
Furthermore, the latest pre-clinical research points toward the existence of other, apoptosisunrelated
forms kinds of programmed cell death.
Conclusion: Our review summarizes current knowledge of pathways leading to programmed cell
death after ICH in addition to data from clinical trials. Some of the pre-clinical results have not yet
demonstrated clinical confirmation, however they significantly contribute to our understanding of
post-ICH pathology and can contribute to development of new therapeutic approaches, decreasing
mortality and improving ICH patients’ quality of life.
BACKGROUND AND PURPOSE:This study aims to assess the number of patients with acute ischemic cerebrovascular events seeking in-patient medical emergency care since the implementation of social ...distancing measures in the coronavirus disease 2019 (COVID-19) pandemic.
METHODS:In this retrospective multicenter study, data on the number of hospital admissions due to acute ischemic stroke or transient ischemic attack and numbers of reperfusion therapies performed in weeks 1 to 15 of 2020 and 2019 were collected in 4 German academic stroke centers. Poisson regression was used to test for a change in admission rates before and after the implementation of extensive social distancing measures in week 12 of 2020. The analysis of anonymized regional mobility data allowed for correlations between changes in public mobility as measured by the number and length of trips taken and hospital admission for stroke/transient ischemic attack.
RESULTS:Only little variation of admission rates was observed before and after week 11 in 2019 and between the weeks 1 and 11 of 2019 and 2020. However, reflecting the impact of the COVID-19 pandemic, a significant decrease in the number of admissions for transient ischemic attack was observed (−85%, −46%, −42%) in 3 of 4 centers, while in 2 of 4 centers, stroke admission rates decreased significantly by 40% and 46% after week 12 in 2020. A relevant effect on reperfusion therapies was found for 1 center only (thrombolysis, −60%; thrombectomy, −61%). Positive correlations between number of ischemic events and mobility measures in the corresponding cities were identified for 3 of 4 centers.
CONCLUSIONS:These data demonstrate and quantify decreasing hospital admissions due to ischemic cerebrovascular events and suggest that this may be a consequence of social distancing measures, in particular because hospital resources for acute stroke care were not limited during this period. Hence, raising public awareness is necessary to avoid serious healthcare and economic consequences of undiagnosed and untreated strokes and transient ischemic attacks.
Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and ...spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
In light of an aging population with increased cardiovascular comorbidity, the use of oral anticoagulation (OAC) is steadily expanding. A variety of pharmacological alternatives to vitamin K ...antagonists (VKA) have emerged over recent years (direct oral anticoagulants, DOAC, i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) which show a reduced risk for the occurrence of intracerebral hemorrhage (ICH). Yet, in the event of ICH under OAC (OAC-ICH), hematoma characteristics are similarly severe and clinical outcomes likewise substantially limited in both patients with VKA- and DOAC-ICH, which is why optimal acute hemostatic treatment in all OAC-ICH needs to be guaranteed. Currently, International Guidelines for the hemostatic management of patients with OAC-ICH are updated as several relevant large-sized observational studies and recent trials have established treatment approaches for both VKA- and DOAC-ICH. While the management of VKA-ICH is mainly based on the immediate reversal of elevated levels of international normalized ratio using prothrombin complex concentrates, hemostatic management of DOAC-associated ICH is challenging requiring specific antidotes, notably idarucizumab and andexanet alfa. This review will provide an overview of the latest studies and trials on hemostatic reversal agents and timing and summarizes the effects on hemorrhage progression and clinical outcomes in patients with OAC-ICH.
Stroke-associated immunosuppression and inflammation are increasingly recognized as factors triggering infections and thus potentially influencing outcome after stroke. Several studies have ...demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes for patients with ischemic stroke or intracerebral hemorrhage. Thus far, in patients with subarachnoid hemorrhage the association between NLR and outcome is insufficiently established. The authors sought to investigate the association between NLR on admission and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH).
This observational study included all consecutive aSAH patients admitted to a German tertiary center over a 5-year period (2008-2012). Data regarding patient demographics and clinical, laboratory, and in-hospital measures, as well as neuroradiological data, were retrieved from institutional databases. Functional outcome was assessed at 3 and 12 months using the modified Rankin Scale (mRS) score and categorized into favorable (mRS score 0-2) and unfavorable (mRS score 3-6). Patients' radiological and laboratory characteristics were compared between aSAH patients with favorable and those with unfavorable outcome at 3 months. In addition, multivariate analysis was conducted to investigate parameters independently associated with favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cutoff for NLR to discriminate between favorable and unfavorable outcome in these patients. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on outcome measures.
Overall, 319 patients with aSAH were included. Patients with unfavorable outcome at 3 months were older, had worse clinical status on admission (Glasgow Coma Scale score and Hunt and Hess grade), greater amount of subarachnoidal and intraventricular hemorrhage (modified Fisher Scale grade and Graeb score), and higher rates of infectious complications (pneumonia and sepsis). A significantly higher NLR on admission was observed in patients with unfavorable outcome according to mRS score (median IQR NLR 5.8 3.0-10.0 for mRS score 0-2 vs NLR 8.3 4.5-12.6 for mRS score 3-6; p < 0.001). After adjustments, NLR on admission remained a significant predictor for unfavorable outcome in SAH patients (OR 95% CI 1.014 1.001-1.027; p = 0.028). In ROC analysis, an NLR of 7.05 was identified as the best cutoff value to discriminate between favorable and unfavorable outcome (area under the curve = 0.614, p < 0.001, Youden's index = 0.211; mRS score 3-6: 94/153 61.4% for NLR ≥ 7.05 vs 67/166 40.4% for NLR < 7.05; p < 0.001). Subanalysis of patients with NLR levels ≥ 7.05 vs < 7.05, performed using 2 propensity score-matched cohorts (n = 133 patients in each group), revealed an increased proportion of patients with unfavorable functional outcome at 3 months in patients with NLR ≥ 7.05 (mRS score 3-6 at 3 months: NLR ≥ 7.05 82/133 61.7% vs NLR < 7.05 62/133 46.6%; p = 0.014), yet without differences in mortality at 3 months (NLR ≥ 7.05 37/133 27.8% vs NLR < 7.05 27/133 20.3%; p = 0.131).
Among aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. Whether the impact of NLR on functional outcome is related to preexisting comorbidities or represents independent causal relationships in the context of stroke-associated immunosuppression should be investigated in future studies.
Summary Space-occupying, malignant middle cerebral artery (MCA) infarctions are still one of the most devastating forms of ischaemic stroke, with a mortality of up to 80% in untreated patients. An ...early diagnosis is essential and depends on CT and MRI to aid the prediction of a malignant course. Several pharmacological strategies have been proposed but the efficacy of these approaches has not been supported by adequate evidence from clinical trials and, until recently, treatment of malignant MCA infarctions has been a major unmet need. Over the past 3 years, results from randomised controlled trials and their pooled analyses have provided evidence that an early hemicraniectomy leads to a substantial decrease in mortality at 6 and 12 months and is likely to improve functional outcome. Hemicraniectomy is now in routine use for the clinical management of malignant MCA infarction in patients younger than 60 years of age. However, there are still important questions about the individual indication for decompressive surgery, particularly with regard to the ideal timing of hemicraniectomy, a potential cut-off age for the procedure, the hemisphere affected, and ethical considerations about functional outcome in surviving patients.
Objective
Oral anticoagulation treatment (OAT) resumption is a therapeutic dilemma in intracerebral hemorrhage (ICH) care, particularly for lobar hemorrhages related to amyloid angiopathy. We sought ...to determine whether OAT resumption after ICH is associated with long‐term outcome, accounting for ICH location (ie, lobar vs nonlobar).
Methods
We meta‐analyzed individual patient data from: (1) the multicenter RETRACE study (n = 542), (2) a U.S.‐based single‐center ICH study (n = 261), and (3) the Ethnic/Racial Variations of Intracerebral Hemorrhage study (n = 209). We determined whether, within 1 year from ICH, OAT resumption was associated with: (1) mortality, (2) favorable functional outcome (modified Rankin Scale = 0–3), and (3) stroke incidence. We separately analyzed nonlobar and lobar ICH cases using propensity score matching and Cox regression models.
Results
We included 1,012 OAT‐related ICH survivors (633 nonlobar and 379 lobar). Among nonlobar ICH survivors, 178/633 (28%) resumed OAT, whereas 86/379 (23%) lobar ICH survivors did. In multivariate analyses, OAT resumption after nonlobar ICH was associated with decreased mortality (hazard ratio HR = 0.25, 95% confidence interval CI = 0.14–0.44, p < 0.0001) and improved functional outcome (HR = 4.22, 95% CI = 2.57–6.94, p < 0.0001). OAT resumption after lobar ICH was also associated with decreased mortality (HR = 0.29, 95% CI = 0.17–0.45, p < 0.0001) and favorable functional outcome (HR = 4.08, 95% CI = 2.48–6.72, p < 0.0001). Furthermore, OAT resumption was associated with decreased all‐cause stroke incidence in both lobar and nonlobar ICH (both p < 0.01).
Interpretation
These results suggest novel evidence of an association between OAT resumption and outcome following ICH, regardless of hematoma location. These findings support conducting randomized trials to explore risks and benefits of OAT resumption after ICH. Ann Neurol 2017;82:755–765
BACKGROUND AND PURPOSE—This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), ...vitamin K antagonist (VKA)- and non–VKA oral anticoagulant-associated ICH.
METHODS—Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume.
RESULTS—A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non–VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0–3; APT, 48/202 23.8% versus no APT, 187/587 31.9%; P=0.030) and higher mortality (APT, 103/202 51.0% versus no APT, 237/587 40.4%; P=0.009), whereas no significant differences were present in primary spontaneous ICH and non–VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 7.4–61.4 versus 15.7 5.7–44.5 mL; P=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 1.20–2.70; P=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients.
CONCLUSIONS—APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.
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