Distinct neuroinflammatory patterns between cerebral microbleeds and microinfarcts in cerebral amyloid angiopathy.

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA.

Multimodal and serial MRI monitors brain peri-hematomal injury and repair mechanisms after experimental intracerebral hemorrhage.

The peri-hematomal area (PHA) emerges as a key but puzzling interface where edematous and neuroinflammatory events co-occur after intracerebral hemorrhage (ICH), while being considered either as deleterious or protective. We aimed at unraveling the pathogeny and natural history of PHA over time after experimental ICH. Male and female rats were longitudinally followed up to day 7 using multimodal brain MRI. MRI measures were compared to neuropathological and behavioural results. While the peak of PHA volume at day 3 was predictive for spontaneous locomotor deficit without sex-effect, its drop at day 7 fitted with locomotor recovery and hematoma resorption. The PHA highest water density was observed at onset despite microvascular hypoperfusion, taken over by blood-brain barrier (BBB) leakage at day 3. Water density dropped at day 7, when vascular integrity was normalized, and the highest number of reactive astrocytes, microglial cells, and siderophages found. This study shows that the PHA with edematous component is hematoma-driven at onset and BBB-driven at day 3, but this excess neuroinflammation enabled PHA volume reduction and significant hematoma resorption as soon as day 7. Therapeutic interventions should consider this pathogeny, and be monitored by multimodal MRI in preclinical ICH models.

Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Study.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.

Impact of prodromal symptoms on the prognosis of patients with basilar artery occlusion treated with mechanical thrombectomy.

INTRODUCTION: Even with reperfusion therapies, the prognosis of patients with basilar artery occlusion (BAO) related stroke remains poor. We aimed to test the hypothesis that the presence of prodromal symptoms, an easily available anamnestic data, is a key determinant of poor functional outcome. PATIENTS AND METHODS: Data from patients with BAO treated in Lille, France, with mechanical thrombectomy (MT) between 2015 and 2021 were prospectively collected. The presence of prodromal symptoms was defined by previous transient neurological deficit or gradual progressive clinical worsening preceding a secondary sudden clinical worsening. We compared the characteristics of patients with and without prodromal symptoms. We built multivariate logistic regression models to study the association between the presence of prodromal symptoms and functional (mRS 0-3 and mortality), and procedural (successful recanalization and early reocclusion) outcomes. RESULTS: Among the 180 patients, 63 (35%) had prodromal symptoms, most frequently a vertigo. Large artery atherosclerosis was the predominant cause of stroke (41.3%). The presence of prodromal symptoms was an independent predictor of worse 90-day functional outcome (mRS 0-3: 25.4% vs 47.0%, odds ratio (OR) 0.39; 95% confidence interval (CI) 0.16-0.86) and 90-day mortality (OR 2.17; 95% CI 1.02-4.65). Despite similar successful recanalization rate, the proportion of early basilar artery reocclusion was higher in patients with prodromal symptoms (23.8% vs 5.6%, p = 0.002). DISCUSSION AND CONCLUSION: More than one third of BAO patients treated with MT had prodromal symptoms, especially patients with large-artery atherosclerosis. Clinicians should systematically screen for prodromal symptoms given the poor related functional outcome and increased risk of early basilar artery reocclusion.

Long-term headache after spontaneous intracerebral haemorrhage.

BACKGROUND: Though headache is commonly observed after stroke and may affect survivors' quality of life, it has rarely been studied after spontaneous intracerebral haemorrhage (ICH). In a cohort of ICH survivors, we assessed the long-term prevalence and determinants of headache. METHODS: We screened consecutive ICH survivors enrolled in the prospective, single-centre Prognosis of Intracerebral Haemorrhage study for headache 1, 3, and 6 years after ICH, according to the International Headache Society's criteria. Depressive and anxiety symptoms severity was measured at 1-year follow-up. Variables associated with the presence of headache 1 year after ICH were analyzed using univariate and multivariable models. RESULTS: Among the 146 patients included in this study, 31 (21%), 25 (19%), and 14 (20%) patients reported headache at 1-, 3-, and 6-year follow-up, respectively. In an age-adjusted model, patients with headache at ICH onset (adjusted odds ratio [aOR] 2.75; 95% CI 1.02-7.42) and previous history of headache (aOR 4.60; 95% CI 1.74-12.1) were associated with headache at 1-year follow-up. Patients with headache were more likely to report depressive and anxiety symptoms at 1-year follow-up (both p < 0.02). CONCLUSIONS: One in five ICH survivors suffered from headache and patients who reported headache at ICH onset were especially at risk.

Diffusion-Weighted Imaging Lesion Reversal in Older Patients With Stroke Treated With Mechanical Thrombectomy.

BACKGROUND: Diffusion-weighted imaging lesion reversal (DWIR) is frequently observed after mechanical thrombectomy for acute ischemic stroke, but little is known about age-related differences and impact on outcome. We aimed to compare, in patients <80 versus ≥80 years old, (1) the effect of successful recanalization on DWIR and (2) the impact of DWIR on functional outcome. METHODS: We retrospectively analyzed data of patients treated for an anterior circulation acute ischemic stroke with large vessel occlusion in 2 French hospitals, who underwent baseline and 24-hour follow-up magnetic resonance imaging, with baseline DWI lesion volume ≥10 cc. The percentage of DWIR (DWIR%), was calculated as follows: DWIR%=(DWIR volume/baseline DWI volume)×100. Data on demographics, medical history, and baseline clinical and radiological characteristics were collected. RESULTS: Among 433 included patients (median age, 68 years), median DWIR% after mechanical thrombectomy was 22% (6-35) in patients ≥80, and 19% (interquartile range, 10-34) in patients <80 (P=0.948). In multivariable analyses, successful recanalization after mechanical thrombectomy was associated with higher median DWIR% in both ≥80 (P=0.004) and <80 (P=0.002) patients. In subgroup analyses performed on a minority of subjects, collateral vessels status score (n=87) and white matter hyperintensity volume (n=131) were not associated with DWIR% (P>0.2). In multivariable analyses, DWIR% was associated with increased rates of favorable 3-month outcomes in both ≥80 (P=0.003) and <80 (P=0.013) patients; the effect of DWIR% on outcome was not influenced by the age group (P interaction=0.185) Conclusions: DWIR might be an important and nonage-dependent effect of arterial recanalization, as it seems to beneficially impact 3-month outcomes of both younger and older subjects treated with mechanical thrombectomy for acute ischemic stroke and large vessel occlusion.

Intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a dramatic condition caused by the rupture of a cerebral vessel and the entry of blood into the brain parenchyma. ICH is a major contributor to stroke-related mortality and dependency: only half of patients survive for 1 year after ICH, and patients who survive have sequelae that affect their quality of life. The incidence of ICH has increased in the past few decades with shifts in the underlying vessel disease over time as vascular prevention has improved and use of antithrombotic agents has increased. The pathophysiology of ICH is complex and encompasses mechanical mass effect, haematoma expansion and secondary injury. Identifying the causes of ICH and predicting the vital and functional outcome of patients and their long-term vascular risk have improved in the past decade; however, no specific treatment is available for ICH. ICH remains a medical emergency, with prevention of haematoma expansion as the key therapeutic target. After discharge, secondary prevention and management of vascular risk factors in patients remains challenging and is based on an individual benefit-risk balance evaluation.

Acute Microbleeds and Microinfarcts Within the Perihematomal Area After Intracerebral Hemorrhage.

BACKGROUND: To further our understanding of the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and related injury, we provided a postmortem neuropathological examination of acute microvascular lesions (microbleeds and microinfarcts) within the perihematomal area. METHODS: We included all consecutive cases (2005-2019) from the Lille University Hospital brain bank of ICH patients who died within the first month. Paraffin-embedded tissue sections from the perihematomal area were processed for several stainings and immunolabelings to investigate the presence of acute microbleeds and microinfarcts in the perihematomal area and to characterize surrounding neuronal and systemic inflammatory reaction (macrophages and neutrophils). RESULTS: We included 14 ICH cases (median age, 78 years; 10 females). Acute microbleeds were observed in the perihematomal area in 12/14 patients (86%, ranging from 1 through >10) and microinfarcts in 5/14 (36%, ranging from 1 through 4). Microbleeds were observed whatever the delay from ICH onset to death was, while most cases with acute microinfarcts were observed between day 3 and day 7 (n=3/5). Both lesions were characterized by an abundant accumulation of systemic inflammatory cells and necrotic areas. CONCLUSIONS: Acute microbleeds and microinfarcts might contribute to the propagation of secondary brain tissue damages after ICH. Our examinations also question the potential role of massive systemic inflammatory cells recruitment in the genesis of these microvascular injuries.

Early reocclusion after successful mechanical thrombectomy for large artery occlusion-related stroke.

BACKGROUND AND PURPOSE: Despite initial successful recanalization after mechanical thrombectomy (MT), some patients with large artery occlusion (LAO)-related stroke will experience an early reocclusion of the injured vessel which may worsen their prognosis. We aimed to investigate the prevalence, associated factors and prognosis of early reocclusion after successful MT in a large prospective cohort of stroke patients with LAO. METHODS: We included patients from the Lille reperfusion registry with LAO-related stroke involving M1 segment, internal carotid artery terminus or tandem ICA-M1 occlusion, with successful recanalization after MT and available 24 h imaging follow-up. Early reocclusion was defined as internal carotid artery terminus or M1 occlusion on 24 h magnetic resonance imaging (MRI) or computed tomography (CT) vascular imaging. Multivariable logistic regression models were used to investigate factors associated with early reocclusion and its impact on outcomes. RESULTS: Between 2015 and 2020, 62 of 1015 included patients experienced an early reocclusion (6.1%). Age (odds ratio (OR) per 15 years decrease: 1.38 (1.05-1.81)) antiplatelet use (OR: 0.41 (0.19-0.89)), several device passes (OR: 2.13 (1.18-3.83)), atherosclerosis cause (OR: 2.38 (1.19-4.78)), and early clinical worsening (OR: 2.45 (1.18-5.07)) were independently associated with early reocclusion. Early reocclusion was independently associated with poor prognosis (OR: 7.15 (3.49-14.65)) and mortality (OR: 2.05 (1.07-3.91)) at 3 months. CONCLUSION: Six percent of patients with LAO-related stroke and initial successful recanalization experienced early reocclusion. This event is associated with a 7-fold increased risk of poor functional outcome and a 2-fold increased risk of mortality. Further efforts are warranted to refine early detection of patients at risk of reocclusion and to improve their management.

The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid ß in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484).

Intracerebral Hemorrhage-Induced Cognitive Impairment in Rats Is Associated With Brain Atrophy, Hypometabolism, and Network Dysconnectivity.

The mechanisms underlying intracerebral hemorrhage (ICH)-related cognitive impairment (CI) remain unclear. Long-term structural and functional changes were investigated in the brains of healthy male and female Wistar rats after experimental ICH. Following double injection of autologous blood, rats underwent short-term (onset, 3 and 7 days) and long-term (3 and 6 months) radiological assessment and behavioral tests exploring spontaneous locomotion, anxiety-like behavior and working memory, spatial recognition memory and visual recognition memory. Volumetric and metabolic changes in brain areas were examined by 7Tesla-MRI and [18F] FDG-PET, respectively. Brain connectomic disorders and maladaptive processes were seeked through brain metabolic connectivity analysis and atrophy-related network analysis. From an initial hematoma mean volume of 23.35 ± 9.50 mm3, we found early spontaneous locomotor recovery and significant spontaneous blood resorption (≈ 40% of the initial lesion) from days 0 to 7. After 3 and 6 months, ICH rats exhibited CI in several domains as compared to the sham group (working memory: 58.1 ± 1.2 vs. 70.7 ± 1.2%, p < 0.001; spatial recognition memory: 48.7 ± 1.9 vs. 64 ± 1.8%, p < 0.001 and visual recognition memory: 0.14 ± 0.05 vs. 0.33 ± 0.04, p = 0.013, in female only). Rats that experienced ICH had remote and concomitant cerebral atrophy and hypometabolism of ipsilateral striatum, thalamus, limbic system and cortical areas (temporal and parietal lobes). Interestingly, both structural and metabolic deterioration was found in the limbic system connected to the affected site, but remotely from the initial insult. On the other hand, increased activity and functional connectivity occurred in the contralateral hemisphere. These connectomics results showed that both maladaptative and compensation processes coexist in the rat brain following ICH, even at young age and in a disease-free setting. These radiological findings deepen our understanding of ICH-related CI and may serve as biomarkers in the view of future therapeutic intervention.

Unusual Histopathological Findings in Mechanically Removed Stroke Thrombi - A Multicenter Experience.

Background: Several studies have investigated the histopathology of mechanically retrieved thrombi from stroke patients. Thrombi with unusual components constitute about 1-2% of all stroke thrombi in clinical practice. Knowledge about these rare components is limited. Objectives: To characterize the histopathology of unusual stroke thrombi from a real-world setting with relation to clinical presentation, patient characteristics and procedural aspects of mechanical thrombectomy. Methods: One-thousand and eight thrombi retrieved from stroke patients with mechanical thrombectomy at three different hospitals were retrospectively reviewed for unusual histological components. Fifteen thrombi were included in the study for further histopathological analysis. Clinical data and data on procedural aspects were collected. Results: We identified six cases with large amounts of extracellular DNA, of which three were calcified. All six cases except one received anticoagulant therapy. We describe two types of calcifications that differ with respect to general calcification morphology, von Kossa staining pattern, macrophage immunophenotype and presence of multinucleated giant cells. Cholesterol-rich (n = 3), adipocyte-like pattern-rich (n = 2), collagen-rich (n = 2) and myxomatous (n = 1) thrombi were also identified and are discussed with regard to pathogenesis and clinical and intervention characteristics. Finally, a thrombus with parts of a vascular wall is described. Suggestions for future studies are made and clinical and technical aspects of the management for these rare but important patients are discussed. Conclusion: In our retrospective multicenter study, we characterized stroke thrombi histopathologically and found subgroups of thrombi defined by presence of rarely seen components. These defined subgroups showed relation to underlying cardiovascular disease, patient characteristics, and mechanical thrombectomy technique. Knowledge about these components may increase our understanding of stroke pathophysiology and influence interventional procedures.

Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. METHODS: We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. RESULTS: A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%-37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%-33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding (P=0.01), a higher total dose of heparin (P=0.02), a prolonged procedure (P=0.03), absence of protamine reversion (P=0.04), higher final activated partial thromboplastin time (P=0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio (P=0.007), and lower final closure time with adenosine-diphosphate (P=0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03-1.73] for every 5 minutes of fluoroscopy time; P=0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08-1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P=0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. CONCLUSIONS: One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02972008.

Protecting the Brain, From the Heart: Safely Mitigating the Consequences of Thrombosis in Intracerebral Hemorrhage Survivors With Atrial Fibrillation.

Optimal antithrombotic management after intracerebral hemorrhage remains one of the central unresolved issues for patients who survive, especially for those patients with atrial fibrillation. Given the observational nature of the studies regarding anticoagulation resumption after intracerebral hemorrhage, there is uncertainty regarding resumption of oral anticoagulation therapy and its timing. There is limited high-quality evidence to guide clinical practice, leading to significant practice variation and uncertainty for patients and providers. Here, we aim to provide the key elements to guide clinicians in their individual decision: whether or not to start or resume anticoagulation in patients with a history of intracerebral hemorrhage.

Brain Peri-Hematomal Area, a Strategic Interface for Blood Clearance: A Human Neuropathological and Transcriptomic Study.

BACKGROUND: Enhancing the blood clearance process is a promising therapeutic strategy for intracerebral hemorrhage (ICH). We aimed to investigate the kinetic of this process after ICH in human brain tissue through the monocyte-macrophage scavenger receptor (CD163)/HO-1 (hemoxygenase-1) pathway. METHODS: We led a cross-sectional post-mortem study including 22 consecutive ICH cases (2005-2019) from the Lille Neurobank. Cases were grouped according to the time of death: ≤72 hours, 4 to 7 days, 8 to 15 days, 16 to 90 days, and >90 days after ICH onset. Paraffin-embedded tissue was extracted from 4 strategic areas, including hematoma core and peri-hematomal area to perform histological investigations. Additionally, we extracted RNA from the peri-hematomal area of 6 cases to perform transcriptomic analysis. RESULTS: We included 19 ICH cases (median age: 79 [71-89] years; median delay ICH-death: 13 [5-41] days). The peri-hematomal area concentrated most of reactive microglia, CD163/HO-1 and iron deposits as compared with other brain areas. We found a surge in the blood clearance process from day 8 to day 15 after ICH onset. Transcriptomic analysis showed that HO-1 was the most upregulated gene (2.81±0.39, adjusted P=1.11×10-10) and CD163 the sixth (1.49±0.29, adjusted P=1.68×10-5). We also identified several upregulated genes that exert a beneficial role in terminating inflammation and enhancing tissue repair. CONCLUSIONS: We provide histological and transcriptomic-based evidence in humans for the key role of peri-hematomal area in endogenous blood clearance process through the CD163/HO-1 pathway, especially from day 8 after ICH and favored by an anti-inflammatory environment. Our findings contribute to identify innovative therapeutic strategies for ICH.

Neutrophil extracellular traps (NETs) infiltrate haematoma and surrounding brain tissue after intracerebral haemorrhage: A post-mortem study.

AIMS: Because of their prothrombotic and neuroinflammatory effects, neutrophils and neutrophil extracellular traps (NETs) represent interesting therapeutic targets for spontaneous intracerebral haemorrhage (sICH). We investigated the presence, spatial and temporal distribution of NETs in a human sICH post-mortem study. METHODS: From 2005 to 2019, all sICH patients who came to autopsy within the first month after stroke were included and grouped according to the timing of death: 72 h, 4-7 days, 8-15 days and >15 days after ICH onset. Paraffin-embedded tissue was extracted from four strategic areas: haematoma, peri-haematomal area, ipsilateral surrounding brain tissue and a control contralateral area. Myeloperoxidase and histone H3 citrulline were immunolabelled to detect neutrophils and NETs respectively. RESULTS: Neutrophils were present in the brains of the 14 cases (4 men, median age: 78 years) and NETs were found in 7/14 cases. Both neutrophils and NETs were detected within the haematoma but also in the surrounding tissue. The appearance of neutrophils and NETs was time-dependent, following a two-wave pattern: during the first 72 h and between 8 and 15 days after ICH onset. Qualitative examination showed that neutrophils and NETs were mainly located around dense fibrin fibres within the haematoma. CONCLUSIONS: These observations provide evidence for NETs infiltration in the brain of patients who die from sICH. NETs might interact with early haemostasis within the haematoma core, and with the surrounding neuroinflammatory response. These findings open research perspectives for NETs in the treatment of sICH injuries.

Cerebral microbleeds: from depiction to interpretation.

Cerebral microbleeds (CMBs) are defined as hypointense foci visible on T2*-weighted and susceptible-weighted MRI sequences. CMBs are increasingly recognised with the widespread use of MRI in healthy individuals as well as in the context of cerebrovascular disease or dementia. They can also be encountered in major critical medical conditions such as in patients requiring extracorporeal mechanical oxygenation. The advent of MRI-guided postmortem neuropathological examinations confirmed that, in the context of cerebrovascular disease, the vast majority of CMBs correspond to recent or old microhaemorrhages. Detection of CMBs is highly influenced by MRI parameters, in particular field strength, postprocessing methods used to enhance T2* contrast and three dimensional sequences. Despite recent progress, harmonising imaging parameters across research studies remains necessary to improve cross-study comparisons. CMBs are helpful markers to identify the nature and the severity of the underlying chronic small vessel disease. In daily clinical practice, presence and numbers of CMBs often trigger uncertainty for clinicians especially when antithrombotic treatments and acute reperfusion therapies are discussed. In the present review, we discuss those clinical dilemmas and address the value of CMBs as diagnostic and prognostic markers for future vascular events.

[Sporadic cerebral amyloid angiopathy]. / Angiopathie amyloïde cérébrale de forme sporadique.

Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease caused by vascular deposits of Aß-amyloid peptides in the walls of cortical and leptomeningeal vessels. Advancing age is the strongest known clinical risk factor for developing CAA. This devastating disease occurs frequently in elderly people, and is a frequent cause of symptomatic lobar intracerebral hemorrhage (ICH), cognitive impairment and transient focal neurological episodes. Typical cerebral MRI findings include lobar intracerebral hemorrhages and neuroimaging biomarkers of CAA (lobar cerebral microbleeds, cortical superficial siderosis, white matter hyperintensities, dilated perivascular spaces and microinfarcts). In the absence of direct neuropathological examination, the most commonly used criteria for CAA diagnosis are the modified Boston criteria based on clinical and MRI data. To date, no specific treatment is available to prevent bleeding or cognitive decline. Thus, management is mainly based on strict blood pressure control. Anticoagulation should usually be avoided in patients with a diagnosis of CAA and symptomatic lobar ICH. The risk/benefit ratio evaluation at individual level of antiplatelet agents is also required.