From Alzheimer's disease to vascular dementia: Different roads leading to cognitive decline.

La Caixa Foundation Predoctoral Fellowship, Grant/Award Numbers: ID 100010434, LCF/BQ/DI22/11940002; Instituto de Salud Carlos III, Grant/Award Number: CPII21/00007; European Regional Development Fund; Spanish Ministry for Science, Innovation and Universities, Grant/Award Numbers: PID2022-140616OB-I00, MCIN/AEI/ 10.13039/501100011033; Pro-CNIC Foundation; Severo Ochoa Center of Excellence, Grant/Award Number: CEX2020-001041-S; Leducq Foundation for Cardiovascular Research, Grant/Award Number: TNE-19CVD01andTNE-21CVD04; European Union (Fondo Social Europeo) Plus)S

Insights from thrombi retrieved in stroke due to large vessel occlusion

The recent advances of endovascular procedures to treat stroke due to large cerebral vessel occlusion have made it possible to analyze the retrieved thrombus material. Analysis of cerebral thrombi is emerging as a relevant opportunity to complement the diagnostic workup of etiology, to develop new lytic approaches and to optimize the acute treatment of stroke due to large vessel occlusion. Nonetheless, retrieved thrombi are frequently discarded since their informative potential is often neglected and standards are missing. This review provides an overview of the current knowledge and expanding research relating to thrombus composition analysis in large vessel occlusions. We first discuss the heterogeneity of thrombogenic factors that underlie the thrombotic formation in stroke and its implications to identify stroke etiology and thrombus age. Further, we show that understanding structural characteristics of thrombus is pivotal for the development of new-targeted lytic therapies as well as to improve, through thrombus modeling, the development of thrombectomy devices. Finally, we discuss the on-going attempts to identify a signature of thrombus composition indirectly through imaging and peripheral blood biomarkers, which might in future assist treatment decision-making as well as secondary prevention. Thrombus analysis might contribute to the advancement and optimization of personalized stroke treatments

Leukocytes, Collateral Circulation, and Reperfusion in Ischemic Stroke Patients Treated With Mechanical Thrombectomy

Background and Purpose- Peripheral immune cells are activated after stroke and may in turn influence the fate of ischemic brain tissue, thus exerting a dual role in ischemic stroke. We evaluated the contribution of neutrophil and lymphocyte counts to hemorrhagic complications and functional outcome in stroke patients treated with mechanical thrombectomy (MT) with varying degrees of collateral circulation and reperfusion. Methods- We retrospectively analyzed 433 consecutive ischemic stroke patients treated with MT. Neutrophil and lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) were collected before MT and 1 day after symptom onset. Outcome measures included categories of hemorrhagic transformation, symptomatic intracerebral hemorrhage, 3-month functional dependence (modified Rankin Scale, 3-6), and mortality. Patients were categorized according to their baseline collateral status and the degree of reperfusion after MT. Results- Neutrophil counts and NLR increased, whereas lymphocyte counts decreased after MT (P<0.001), and changes in neutrophils and NLR at day 1 were significantly greater in patients with poor reperfusion. Neutrophil counts and NLR were significantly higher already at admission in patients with poor 3-month outcome. In adjusted analysis, the impact of neutrophilia on poor functional outcome was more substantial in patients with good collaterals achieving successful reperfusion (aOR, 3.09 per quartile; 95% CI, 1.95-4.90), whereas admission lymphopenia (aOR, 4.08 per decreasing quartile; 95% CI, 1.56-10.64) and higher NLR (aOR, 3.76 per quartile; 95% CI, 1.44-9.79) predicted subsequent symptomatic intracerebral hemorrhage in patients with poor collaterals and successful reperfusion. Conclusions- In patients treated with MT, neutrophil and lymphocyte counts are dynamic parameters associated with hemorrhagic complications and long-term outcome. The extent of collateral circulation and the success of brain reperfusion influence the strength of these associations and highlight the dual role of leukocytes in acute stroke

Treatment Challenges of a Primary Vertebral Artery Aneurysm Causing Recurrent Ischemic Strokes

Background. Extracranial vertebral artery aneurysms are a rare cause of embolic stroke; surgical and endovascular therapy options are debated and long-term complication may occur. Case Report. A 53-year-old man affected by neurofibromatosis type 1 (NF1) came to our attention for recurrent vertebrobasilar embolic strokes, caused by a primary giant, partially thrombosed, fusiform aneurysm of the left extracranial vertebral artery. The aneurysm was treated by endovascular approach through deposition of Guglielmi Detachable Coils in the proximal segment of the left vertebral artery. Six years later the patient presented stroke recurrence. Cerebral angiography and Color Doppler Ultrasound well characterized the unique hemodynamic condition developed over the years responsible for the new embolic event: the aneurysm had been revascularized from its distal portion by reverse blood flow coming from the patent vertebrobasilar axis. A biphasic Doppler signal in the left vertebral artery revealed a peculiar behavior of the blood flow, alternately directed to the aneurysm and backwards to the basilar artery. Surgical ligation of the distal left vertebral artery and excision of the aneurysm were thus performed. Conclusion. This is the first described case of NF1-associated extracranial vertebral artery aneurysm presenting with recurrent embolic stroke. Complete exclusion of the aneurysm from the blood circulation is advisable to achieve full resolution of the embolic source

AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1β (Interleukin-1β)

Background and Purpose- Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD-a member of the AP-1 (activated protein-1) family of transcription factors-was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods- WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti-IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results- In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti-IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions- JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β

TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing

AIMS Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target. METHODS 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome. RESULTS Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age. CONCLUSIONS This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population

TNF-\u3b1 antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing

Aims: Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target.Methods: 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-alpha neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- alpha were assessed in patients with ischemic stroke and correlated with age and outcome.Results: Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-alpha displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-alpha plasma levels which correlated with worsened short-term neurological outcome as well as with age.Conclusions: This study identifies TNF-alpha as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population

Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101(+)CD62L(lo) mature and CD177(hi)CD101(lo)CD62L(lo) and CD177(lo)CD101(lo)CD62L(hi) immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62L(lo) neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62L(lo) neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.Bacigaluppi and colleagues report that the accumulation of atypical mature and immature neutrophil subsets and a dysregulated emergency granulopoiesis response in aged mice and humans affect the outcome of stroke