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2.
Eur Stroke J ; : 23969873241259561, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38872255

RESUMEN

BACKGROUND: Cirrhosis is associated with an increased risk of hemorrhagic stroke. Liver fibrosis, typically a silent condition, is antecedent to cirrhosis. The objective of this study was to test the hypothesis that elevated Fibrosis-4 (FIB-4) index, indicating a high probability of liver fibrosis, is associated with an increased risk of hemorrhagic stroke. METHODS: We performed a cohort analysis of the prospective United Kingdom Biobank cohort study. Participants 40-69 years old were enrolled between 2007 and 2010 and had available follow-up data until March 1, 2018. We excluded participants with prevalent hemorrhagic stroke or thrombocytopenia. High probability of liver fibrosis was defined as having a value >2.67 of the validated FIB-4 index. The primary outcome was hemorrhagic stroke (intracerebral or subarachnoid hemorrhage), defined based on hospitalization and death registry data. Secondary outcomes were intracerebral and subarachnoid hemorrhage, separately. We used Cox proportional hazards models to evaluate the association of FIB-4 index >2.67 with hemorrhagic stroke while adjusting for potential confounders including hypertension, alcohol use, and antithrombotic use. RESULTS: Among 452,994 participants (mean age, 57 years; 54% women), approximately 2% had FIB-4 index >2.67, and 1241 developed hemorrhagic stroke. In adjusted models, FIB-4 index >2.67 was associated with an increased risk of hemorrhagic stroke (HR, 2.0; 95% CI, 1.6-2.6). Results were similar for intracerebral hemorrhage (HR, 2.0; 95% CI, 1.5-2.7) and subarachnoid hemorrhage (HR, 2.2; 95% CI, 1.5-3.5) individually. CONCLUSIONS: Elevated FIB-4 index was associated with an increased risk of hemorrhagic stroke.

3.
Ann Neurol ; 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38874304

RESUMEN

OBJECTIVE: Approximately half of ischemic strokes (IS) in cancer patients are cryptogenic, with many presumed cardioembolic. We evaluated whether there were specific miRNA and mRNA transcriptome architectures in peripheral blood of IS patients with and without comorbid cancer, and between cardioembolic versus noncardioembolic IS etiologies in comorbid cancer. METHODS: We studied patients with cancer and IS (CS; n = 42), stroke only (SO; n = 41), and cancer only (n = 28), and vascular risk factor-matched controls (n = 30). mRNA-Seq and miRNA-Seq data, analyzed with linear regression models, identified differentially expressed genes in CS versus SO and in cardioembolic versus noncardioembolic CS, and miRNA-mRNA regulatory pairs. Network-level analyses identified stroke etiology-specific responses in CS. RESULTS: A total of 2,085 mRNAs and 31 miRNAs were differentially expressed between CS and SO. In CS, 122 and 35 miRNA-mRNA regulatory pairs, and 5 and 3 coexpressed gene modules, were associated with cardioembolic and noncardioembolic CS, respectively. Complement, growth factor, and immune/inflammatory pathways showed differences between IS etiologies in CS. A 15-gene biomarker panel assembled from a derivation cohort (n = 50) correctly classified 81% of CS and 71% of SO participants in a validation cohort (n = 33). Another 15-gene panel correctly identified etiologies for 13 of 13 CS-cardioembolic and 11 of 11 CS-noncardioembolic participants upon cross-validation; 11 of 16 CS-cryptogenic participants were predicted cardioembolic. INTERPRETATION: We discovered unique mRNA and miRNA transcriptome architecture in CS and SO, and in CS with different IS etiologies. Cardioembolic and noncardioembolic etiologies in CS showed unique coexpression networks and potential master regulators. These may help distinguish CS from SO and identify IS etiology in cryptogenic CS patients. ANN NEUROL 2024.

4.
bioRxiv ; 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38915621

RESUMEN

Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively impacting their translational relevance. Here we aimed to develop a minimally invasive thrombotic stroke model through magnetic particle delivery that does not require craniotomy, is amenable to reperfusion therapy, can be combined with in vivo imaging modalities, and can be performed in awake mice. We found that the model results in reproducible cortical infarcts within the middle cerebral artery (MCA) with cytologic and immune changes similar to that observed with more invasive distal MCA occlusion models. Importantly, the injury produced by the model was ameliorated by tissue plasminogen activator (tPA) administration. We also show that MCA occlusion in awake animals results in bigger ischemic lesions independent of day/night cycle. Magnetic particle delivery had no overt effects on physiologic parameters and systemic immune biomarkers. In conclusion, we developed a novel stroke model in mice that fulfills many requirements for modeling human stroke.

5.
Alzheimers Dement ; 20(7): 4572-4582, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38899570

RESUMEN

INTRODUCTION: Amyloid beta (Aß) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aß accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aß-induced neurovascular and cognitive dysfunction. METHODS: Tg2576 mice and wild-type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later. RESULTS: Treatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid. DISCUSSION: These findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution. HIGHLIGHTS: Amyloid beta (Aß) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aß. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aß and tPA reconstitution may be of therapeutic value.


Asunto(s)
Péptidos beta-Amiloides , Circulación Cerebrovascular , Modelos Animales de Enfermedad , Ratones Transgénicos , Activador de Tejido Plasminógeno , Animales , Activador de Tejido Plasminógeno/farmacología , Ratones , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Disfunción Cognitiva/tratamiento farmacológico , Cognición/efectos de los fármacos , Administración Intranasal , Enfermedad de Alzheimer/tratamiento farmacológico , Comportamiento de Nidificación/efectos de los fármacos , Masculino , Hiperemia/tratamiento farmacológico
6.
bioRxiv ; 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38853992

RESUMEN

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in systemic inflammation-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammatory response. In the acute phase, we identified novel molecular (e.g. upregulation of plasmalemma vesicle associated protein, a driver of endothelial permeability, and the pro-coagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small molecule BBB permeability, elevated levels of PAI-1, intra/perivascular fibrin/fibrinogen deposition and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor suggesting diffuse axonal injury, synapse degeneration and impaired neurotrophism. Our study serves as a standardized model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition. SIGNIFICANCE: The limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.

7.
Commun Biol ; 7(1): 321, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38480905

RESUMEN

Ubiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the ischemic periphery, wherein cells remain viable, however the identity of ubiquitinated proteins is unknown. Here, we employed a proteomics approach to identify these proteins in mice undergoing ischemic stroke. The data are available in a searchable web interface ( https://hochrainerlab.shinyapps.io/StrokeUbiOmics/ ). We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD95, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with elevated post-ischemic ubiquitination were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, whose aberrant activities are well-known to contribute to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered PSD-associated phosphorylation patterns, indicative of modified kinase activities following stroke. PSD-located CaMKII, PKC, and Cdk5 activities were decreased while Pyk2 activity was increased after stroke. Removal of ubiquitin restored kinase activities to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of ubiquitination in the regulation of essential kinases involved in ischemic injury.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratones , Animales , Homólogo 4 de la Proteína Discs Large , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Quinasa 2 de Adhesión Focal , Densidad Postsináptica , Fosfotransferasas , Ubiquitinación , Isquemia , Ubiquitina
8.
Hypertension ; 81(5): 991-1007, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38426329

RESUMEN

Elevated blood pressure is a well-established risk factor for age-related cognitive decline. Long linked to cognitive impairment on vascular bases, increasing evidence suggests a potential association of hypertension with the neurodegenerative pathology underlying Alzheimer disease. Hypertension is well known to disrupt the structural and functional integrity of the cerebral vasculature. However, the mechanisms by which these alterations lead to brain damage, enhance Alzheimer pathology, and promote cognitive impairment remain to be established. Furthermore, critical questions concerning whether lowering blood pressure by antihypertensive medications prevents cognitive impairment have not been answered. Recent developments in neurovascular biology, brain imaging, and epidemiology, as well as new clinical trials, have provided insights into these critical issues. In particular, clinical and basic findings on the link between neurovascular dysfunction and the pathobiology of neurodegeneration have shed new light on the overlap between vascular and Alzheimer pathology. In this review, we will examine the progress made in the relationship between hypertension and cognitive impairment and, after a critical evaluation of the evidence, attempt to identify remaining knowledge gaps and future research directions that may advance our understanding of one of the leading health challenges of our time.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Hipertensión , Humanos , Encéfalo , Antihipertensivos/uso terapéutico
9.
Stroke ; 55(3): 541-547, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38299346

RESUMEN

BACKGROUND: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood. METHODS: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. RESULTS: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL. CONCLUSIONS: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antihipertensivos , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/complicaciones , Hematoma/diagnóstico por imagen , Hematoma/epidemiología , Hematoma/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del Tratamiento
10.
Nat Immunol ; 25(2): 357-370, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38177281

RESUMEN

Cerebral ischemia triggers a powerful inflammatory reaction involving peripheral leukocytes and brain resident cells that contribute to both tissue injury and repair. However, their dynamics and diversity remain poorly understood. To address these limitations, we performed a single-cell transcriptomic study of brain and blood cells 2 or 14 days after ischemic stroke in mice. We observed a strong divergence of post-ischemic microglia, monocyte-derived macrophages and neutrophils over time, while endothelial cells and brain-associated macrophages showed altered transcriptomic signatures at 2 days poststroke. Trajectory inference predicted the in situ trans-differentiation of macrophages from blood monocytes into day 2 and day 14 phenotypes, while neutrophils were projected to be continuously de novo recruited from the blood. Brain single-cell transcriptomes from both female and male aged mice were similar to that of young male mice, but aged and young brains differed in their immune cell composition. Although blood leukocyte analysis also revealed altered transcriptomes after stroke, brain-infiltrating leukocytes displayed higher transcriptomic divergence than their circulating counterparts, indicating that phenotypic diversification occurs within the brain in the early and recovery phases of ischemic stroke. A portal ( https://anratherlab.shinyapps.io/strokevis/ ) is provided to allow user-friendly access to our data.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Masculino , Ratones , Animales , Células Endoteliales , Accidente Cerebrovascular/genética , Encéfalo , Monocitos , Microglía , Perfilación de la Expresión Génica , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
11.
BMJ Neurol Open ; 6(1): e000543, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38268753

RESUMEN

Background: Data regarding the prevalence and phenotype of cognitive impairment in non-alcoholic fatty liver disease (NAFLD) are limited. Objective: We assessed the prevalence and nature of cognitive deficits in people with NAFLD and assessed whether liver fibrosis, an important determinant of outcomes in NAFLD, is associated with worse cognitive performance. Methods: We performed a prospective cross-sectional study. Patients with NAFLD underwent liver fibrosis assessment with transient elastography and the following assessments: Cognitive Change Index, Eight-Item Informant Interview to Differentiate Aging and Dementia Questionnaire (AD8), Montreal Cognitive Assessment (MoCA), EncephalApp minimal hepatic encephalopathy test and a limited National Institutes of Health Toolbox battery (Flanker Inhibitory Control and Attention Test, Pattern Comparison Test and Auditory Verbal Learning Test). We used multiple linear regression models to examine the association between liver fibrosis and cognitive measures while adjusting for relevant covariates. Results: We included 69 participants with mean age 50.4 years (SD 14.4); 62% were women. The median liver stiffness was 5.0 kilopascals (IQR 4.0-6.9), and 25% had liver fibrosis (≥7.0 kilopascals). Cognitive deficits were common in people with NAFLD; 41% had subjective cognitive impairment, 13% had an AD8 >2, 32% had MoCA <26 and 12% had encephalopathy detected on the EncephalApp test. In adjusted models, people with liver fibrosis had modestly worse performance only on the Flanker Inhibitory Control and Attention Task (ß=-0.3; 95% CI -0.6 to -0.1). Conclusion: Cognitive deficits are common in people with NAFLD, among whom liver fibrosis was modestly associated with worse inhibitory control and attention.

12.
J Magn Reson Imaging ; 59(2): 431-449, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37141288

RESUMEN

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.


Asunto(s)
Encéfalo , Imagen por Resonancia Magnética , Animales , Humanos , Ciudad de Roma , Encéfalo/patología , Líquido Extracelular , Meninges
13.
Nat Neurosci ; 27(1): 63-77, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38049579

RESUMEN

Hypertension (HTN), a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In the present study, in a mouse model of HTN, we find that the neurovascular and cognitive dysfunction depends on interleukin (IL)-17, a cytokine elevated in individuals with HTN. However, neither circulating IL-17 nor brain angiotensin signaling can account for the dysfunction. Rather, IL-17 produced by T cells in the dura mater is the mediator released in the cerebrospinal fluid and activating IL-17 receptors on border-associated macrophages (BAMs). Accordingly, depleting BAMs, deleting IL-17 receptor A in brain macrophages or suppressing meningeal T cells rescues cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. Our data unveil a critical role of meningeal T cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction in a mouse model of HTN.


Asunto(s)
Disfunción Cognitiva , Hipertensión , Ratones , Animales , Interleucina-17 , Angiotensina II , Linfocitos T , Cloruro de Sodio Dietético
14.
JAMA Neurol ; 81(2): 163-169, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38147345

RESUMEN

Importance: Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage in older patients. Although other types of intracranial hemorrhage can occur in conjunction with CAA-related intracerebral hemorrhage, the association between CAA and other subtypes of intracranial hemorrhage, particularly in the absence of intracerebral hemorrhage, remains poorly understood. Objective: To determine whether CAA is an independent risk factor for isolated nontraumatic subdural hemorrhage (SDH). Design, Setting, and Participants: A population-based cohort study was performed using a 2-stage analysis of prospectively collected data in the UK Biobank cohort (discovery phase, 2006-2022) and the All of Us Research Program cohort (replication phase, 2018-2022). Participants included those who contributed at least 1 year of data while they were older than 50 years, in accordance with the diagnostic criteria for CAA. Participants with prevalent intracranial hemorrhage were excluded. Data were analyzed from October 2022 to October 2023. Exposure: A diagnosis of CAA, identified using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code. Main Outcomes and Measures: The outcome was an isolated nontraumatic SDH, identified using ICD-10-CM codes. Two identical analyses were performed separately in the 2 cohorts. First, the risk of SDH in patients with and without CAA was assessed using Cox proportional hazards models, adjusting for demographic characteristics, cardiovascular comorbidities, and antithrombotic medication use. Second, multivariable logistic regression was used to study the association between CAA and SDH. Results: The final analytical sample comprised 487 223 of the total 502 480 individuals in the UK Biobank cohort and 158 008 of the total 372 082 individuals in the All of Us cohort. Among the 487 223 participants in the discovery phase of the UK Biobank, the mean (SD) age was 56.5 (8.1) years, and 264 195 (54.2%) were female. There were 649 cases of incident SDH. Of the 126 participants diagnosed with CAA, 3 (2.4%) developed SDH. In adjusted Cox regression analyses, participants with CAA had an increased risk of having an SDH compared with those without CAA (hazard ratio [HR], 8.0; 95% CI, 2.6-24.8). Multivariable logistic regression analysis yielded higher odds of SDH among participants with CAA (odds ratio [OR], 7.6; 95% CI, 1.8-20.4). Among the 158 008 participants in the All of Us cohort, the mean (SD) age was 63.0 (9.5) years, and 89 639 (56.7%) were female. The findings were replicated in All of Us, in which 52 participants had CAA and 320 had an SDH. All of Us participants with CAA had an increased risk of having an SDH compared with those without CAA (HR, 4.9; 95% CI, 1.2-19.8). In adjusted multivariable logistic regression analysis, CAA was associated with higher odds of SDH (OR, 5.2; 95% CI, 0.8-17.6). Conclusions and Relevance: In 2 large, heterogeneous cohorts, CAA was associated with increased risk of SDH. These findings suggest that CAA may be a novel risk factor for isolated nontraumatic SDH.


Asunto(s)
Angiopatía Amiloide Cerebral , Salud Poblacional , Humanos , Femenino , Anciano , Persona de Mediana Edad , Masculino , Estudios de Cohortes , Hematoma Subdural/epidemiología , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/epidemiología , Hemorragia Cerebral/complicaciones , Imagen por Resonancia Magnética/efectos adversos
16.
Mol Neurodegener ; 18(1): 73, 2023 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-37789345

RESUMEN

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer's disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aß-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. METHODS: Tg2576 mice and WT littermates were transplanted with CD36-/- or CD36+/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36-/- BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. RESULTS: The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36-/- → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aß1-40, but not Aß1-42, was reduced in CD36-/- → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36-/- → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36-/- mice were able to more efficiently clear exogenous Aß1-40 injected into the neocortex or the striatum. CONCLUSIONS: CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aß. CD36 deletion in BAM also reduced brain Aß1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aß. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aß deposition and damage.


Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Disfunción Cognitiva , Humanos , Ratones , Animales , Especies Reactivas de Oxígeno , Ratones Transgénicos , Angiopatía Amiloide Cerebral/patología , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/patología , Macrófagos/metabolismo , Estrés Oxidativo , Disfunción Cognitiva/patología
17.
bioRxiv ; 2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37662420

RESUMEN

Ubiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the ischemic periphery, wherein cells remain viable, however the identity of ubiquitinated proteins is unknown. Here, we employed a proteomics approach to identify these proteins in mice undergoing ischemic stroke. The data are available in a searchable web interface ( https://hochrainerlab.shinyapps.io/StrokeUbiOmics/ ). We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD95, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with elevated post-ischemic ubiquitination were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, whose aberrant activities are well-known to contribute to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered PSD-associated phosphorylation patterns, indicative of modified kinase activities following stroke. PSD-located CaMKII, PKC, and Cdk5 activities were decreased while Pyk2 activity was increased after stroke. Removal of ubiquitin restored kinase activities to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of ubiquitination in the regulation of essential kinases involved in ischemic injury.

18.
Res Sq ; 2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37577565

RESUMEN

Apolipoprotein-E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4 we report that border associated macrophages (BAM), myeloid cells closely apposed to neocortical microvessels, are both the source and the target of the ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAM is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.

19.
Stroke ; 54(9): 2401-2408, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37462054

RESUMEN

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with an increased risk of ischemic stroke. Whether there are racial and ethnic disparities in the risk of ischemic stroke after ICH is poorly understood. We therefore aimed to test the hypothesis that non-Hispanic Black and Hispanic ICH patients have a higher risk of ischemic stroke compared with non-Hispanic White ICH patients. METHODS: We performed a retrospective cohort study using the Healthcare Cost and Utilization Project (HCUP) on all hospitalizations at all nonfederal hospitals in Florida from 2005 to 2018 and New York from 2006 to 2016. Race and ethnicity were coded as a single variable in HCUP. We included patients with an ICH, and without a prior or concomitant diagnosis of ischemic stroke, ascertained using validated International Classification of Diseases-Clinical Modification-9 and 10 diagnosis codes. Using Cox proportional hazard models, we studied the relationship between race and risk of ischemic stroke starting from the time of discharge from ICH hospitalization, after adjustment of demographics and vascular comorbidities. RESULTS: We included 91 342 patients with ICH-62% non-Hispanic White, 18% non-Hispanic Black, and 12% Hispanic patients. Non-Hispanic Black and Hispanic patients were younger and had a higher prevalence of cardiovascular comorbidities; however, atrial fibrillation was more prevalent among non-Hispanic White patients. During a median follow-up period of 4.4 years (interquartile range, 1.5-8.1), an incident ischemic stroke occurred in 3377 (6%) non-Hispanic White, 1323 (8%) non-Hispanic Black, and 844 (8%) Hispanic patients. In adjusted Cox models, the risk of an ischemic stroke was significantly higher among non-Hispanic Black patients (hazard ratio, 1.6 [95% CI, 1.5-1.8]) and Hispanic patients (hazard ratio, 1.4 [95% CI, 1.3-1.5]), compared with non-Hispanic White patients. Similar results were obtained in sensitivity analyses when using death as a competing risk and after excluding patients with atrial fibrillation and valvular heart disease. CONCLUSIONS: In a large heterogeneous cohort of patients with ICH, we found that non-Hispanic Black and Hispanic patients had a significantly higher risk of ischemic stroke compared with non-Hispanic White patients.


Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Estudios Retrospectivos , Hemorragia Cerebral/epidemiología , Etnicidad , Accidente Cerebrovascular/epidemiología , Factores de Riesgo
20.
Stroke ; 54(7): 1726-1734, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37226773

RESUMEN

BACKGROUND: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. METHODS: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4-6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. RESULTS: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15-2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06-1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11-1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. CONCLUSIONS: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes.


Asunto(s)
Molécula 1 de Adhesión Intercelular , Accidente Cerebrovascular , Humanos , Molécula 1 de Adhesión Intercelular/uso terapéutico , Estudios Prospectivos , Hemorragia Cerebral/complicaciones , Accidente Cerebrovascular/complicaciones , Hematoma/tratamiento farmacológico
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