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Background and purposeDuring the COVID-19 outbreak, the presence of extensive white matter microhemorrhages was detected by brain MRIs. The goal of this study was to investigate the origin of this atypical hemorrhagic complication.MethodsBetween March 17 and May 18, 2020, 80 patients with severe COVID-19 infections were admitted for acute respiratory distress syndrome to intensive care units at the University Hospitals of Strasbourg for whom a brain MRI for neurologic manifestations was performed. 19 patients (24%) with diffuse microhemorrhages were compared to 18 control patients with COVID-19 and normal brain MRI.ResultsThe first hypothesis was hypoxemia. The latter seemed very likely since respiratory failure was longer and more pronounced in patients with microhemorrhages (prolonged endotracheal intubation (p = 0.0002), higher FiO2 (p = 0.03), increased use of extracorporeal membrane oxygenation (p = 0.04)). A relevant hypothesis, the role of microangiopathy, was also considered, since patients with microhemorrhages presented a higher increase of the D-Dimers (p = 0.01) and a tendency to more frequent thrombotic events (p = 0.12). Another hypothesis tested was the role of kidney failure, which was more severe in the group with diffuse microhemorrhages (higher creatinine level [median of 293 µmol/L versus 112 µmol/L, p = 0.04] and more dialysis were introduced in this group during ICU stay [12 versus 5 patients, p = 0.04]).ConclusionsBlood–brain barrier dysfunction secondary to hypoxemia and high concentration of uremic toxins seems to be the main mechanism leading to critical illness-associated cerebral microbleeds, and this complication remains to be frequently described in severe COVID-19 patients.

Primary CNS Vasculitis (PCNSV) is a rare, diverse, and polymorphic CNS blood vessel inflammatory condition. Due to its rarity, clinical variability, heterogeneous imaging results, and lack of definitive laboratory markers, PCNSV diagnosis is challenging. This retrospective cohort analysis identified patients with histological diagnosis of PCNSV. Demographic data, clinical presentation, neuroimaging studies, and histopathologic findings were recorded. We enrolled 56 patients with a positive biopsy of CNS vasculitis. Most patients had cerebral hemisphere or brainstem symptoms. Most brain MRI lesions were bilateral, diffuse discrete to confluent white matter lesions. Frontal lobe lesions predominated, followed by inferior cerebellar lesions. Susceptibility-weighted imaging (SWI) hemorrhages in 96.4% (54/56) of patients, either solitary microhemorrhages or a combination of micro and macrohemorrhages. Contrast-enhanced T1-WIs revealed parenchymal enhancement in 96.3% (52/54 patients). The most prevalent pattern of enhancement observed was dot-linear (87%), followed by nodular (61.1%), perivascular (25.9%), and patchy (16.7%). Venulitis was found in 19 of 20 individuals in cerebral DSA. Hemorrhages in SWI and dot-linear enhancement pattern should be incorporated as MINOR diagnostic criteria to diagnose PCNSV accurately within an appropriate clinical context. Microhemorrhages in SWI and venulitis in DSA, should be regarded as a potential marker for PCNSV.

Background Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. Methods CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. Results CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels ( p  < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r  = 0.37, p  < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% ( p  < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood–brain barrier (BBB) by 34% ( p  < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) ( p  < 0.01) and increased sodium fluorescein permeability ( p  < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group ( p  < 0.0001). Conclusions CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

Diffuse axonal injury (DAI) is caused by acceleration‐deceleration forces during trauma that shear white matter tracts. Susceptibility‐weighted MRI (SWI) identifies microbleeds that are considered the radiologic hallmark of DAI and are used in clinical prognostication. However, this assumption is limited by a lack of systematic radiologic‐pathologic correlation studies. Here, we performed ex vivo SWI on three brains from patients who died after severe TBI and assessed axonal injury around SWI microbleeds using immunohistochemistry to the amyloid‐beta precursor protein. Axonal injury was present in 64% of microbleeds, indicating a heterogeneous injury response in the white matter.

INTRODUCTION Increased white matter hyperintensity (WMH) volume is a common but non‐specific finding in AD. This study investigates the effect of baseline WMH volume and APOE ε4 on magnetic resonance imaging (MRI)‐visible hemorrhagic lesion emergence. METHODS We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post‐baseline MRI. We examined age, sex, amyloid, WMH, APOEε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero‐ and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short‐term risk, irrespective of APOE genotype. Trial Registration: NCT02008357 Highlights Elevated baseline white matter lesion volume is related to the risk of ARIA‐H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA‐H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA‐H emergence.

Intestinal dysbiosis and gut-derived toxins in chronic kidney diseases (CKD) are associated with vascular injury. This study examined the relationship between gut dysbiosis and cerebral microhemorrhages (CMH) in young and aged CKD mice (3 vs. 16 months of age) in both sexes. CKD was induced in C57BL/6J mice using a nephrotoxic adenine diet. Serum creatinine, trimethylamine N-oxide (TMAO), indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured. CMH was quantified via brain histology, and gut microbial sequencing was analyzed from fecal pellets. Creatinine and uremic toxins were elevated in both young and aged CKD mice compared with controls, and microbial populations were altered by age, sex and CKD status. Age was the most significant factor in microbial variance, with higher levels of IS and pCS in aged CKD mice. Aged male mice had significantly higher creatinine, TMAO and IS than aged females. Males had higher CMH counts than females, and aged CKD males had the highest CMH burden. Age modified the relationship between uremic toxins and CMH burden, with creatinine, TMAO and IS correlating with increased CMH in aged animals. In conclusion, gut dysbiosis in CKD is modulated by sex and age, and gut-derived uremic toxins including TMAO and IS may contribute to vascular injury and CMH development.

INTRODUCTION Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti‐amyloid immunotherapies, termed amyloid‐related imaging abnormalities (ARIA‐H). They are also observed in treatment‐naïve older adults. This study explored relationships with modifiable and non‐modifiable risk factors. METHODS This cross‐sectional study included 1414 cognitively unimpaired, treatment‐naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were investigated using regression analyses and structural equation modeling. RESULTS CMHs were observed in 8.3% of participants and SS in 1.3%. Significant risk factors for CMHs included age and hypertension. Higher education attainment appeared to have a protective effect. Elevated amyloid is a risk factor, particularly when adjusting for APOE ε4 status in individuals aged 70 or younger. DISCUSSION Increasing age and hypertension are significant risk factors of CMHs. Higher educational attainment may offer a protective effect. Highlights Of the 1414 participants from the CHARIOT‐PRO SubStudy (CPSS), CMHs were present in 118 (8.3%), and SS was present in 18 (1.3%). Age and hypertension were identified as significant risk factors for CMHs, and the latter had a stronger association with the presence of CMHs among female participants. Having a bachelor's degree or higher was found to be protective. Elevated brain amyloid burden, particularly when adjusted for APOE ε4 carrier status, was identified as a risk factor in individuals aged 70 years and below.

INTRODUCTION Cerebral microhemorrhages (CMHs) are detectable by magnetic resonance imaging (MRI). CMHs in deep brain regions are linked to hypertensive vasculopathy, while those in lobar regions with amyloid beta (Aβ) deposition in blood vessels. This study aims to determine the association between anti‐thrombotic treatment and CMH prevalence among cognitively asymptomatic adults, and to assess the role of Aβ markers, apolipoprotein E (APOE) ε4 carrier status, and cardiovascular risk factors in CMH development. METHODS Using baseline data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, we examined CMH presence via 3T MRI, along with medication use, APOE ε4 carrier status, medical history, and blood pressure. RESULTS Our analysis showed a significantly higher prevalence of CMHs in the A4 cohort (17.3%) compared to the LEARN cohort (2.6%). DISCUSSION Factors such as male sex, age, Aβ markers, and APOE ε4 status were significantly associated with higher CMH prevalence in the A4 cohort. However, anti‐thrombotic treatment did not show association with overall CMHs. Highlights Male sex, age > 75, amyloid beta (Aβ) burden, and apolipoprotein E (APOE) ε4 homozygosity are significantly associated with higher prevalence of CMHs (cerebral microhemorrhages) in a cohort of cognitively asymptomatic individuals. Male sex, age > 75, Aβ burden, and APOE ε4 homozygosity are significantly associated with higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals. Anti‐platelet or anti‐coagulant usage were not associated with an increased prevalence of CMHs in either brain location or overall, in a cohort of cognitively asymptomatic individuals. History of a lipid disorder is associated with a higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals.

Cerebral microhemorrhages (CMH) are the pathological substrate for MRI-demonstrable cerebral microbleeds, which are associated with cognitive impairment and stroke. Aging and hypertension are the main risk factors for CMH. In this study, we investigated the development of CMH in a mouse model of aging and hypertension. Hypertension was induced in aged (17-month-old) female and male C57BL/6J mice via angiotensin II (Ang II), a potent vasoconstrictor. We investigated the vascular origin of CMH using three-dimensional images of 1-mm thick brain sections. We examined Ang II-induced CMH formation with and without telmisartan, an Ang II type 1 receptor (AT1R) blocker. To evaluate the effect of microglia and perivascular macrophages on CMH formation, mice were treated with PLX3397, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, to achieve microglial and macrophage depletion. Iba-1 and CD206 labeling were used to study the relative contributions of microglia and macrophages, respectively, on CMH formation. CMH quantification was performed with analysis of histological sections labeled with Prussian blue. Vessels surrounding CMH were primarily of capillary size range (< 10 μm in diameter). Ang II-infused mice exhibited elevated blood pressure (p < 0.0001) and CMH burden (p < 0.001). CMH burden was significantly correlated with mean arterial pressure in mice with and without Ang II (r = 0.52, p < 0.05). Ang II infusion significantly increased Iba-1 immunoreactivity (p < 0.0001), and CMH burden was significantly correlated with Iba-1 in mice with and without Ang II (r = 0.32, p < 0.05). Telmisartan prevented elevation of blood pressure due to Ang II infusion and blocked Ang II-induced CMH formation without affecting Iba-1 immunoreactivity. PLX3397 treatment reduced Iba-1 immunoreactivity in Ang II-infused mice (p < 0.001) and blocked Ang II-induced CMH (p < 0.0001). No significant association between CMH burden and CD206 reactivity was observed. Our findings demonstrate Ang II infusion increases CMH burden. CMH in this model appear to be capillary-derived and Ang II-induced CMH are largely mediated by blood pressure. In addition, microglial activation may represent an alternate pathway for CMH formation. These observations emphasize the continuing importance of blood pressure control and the role of microglia in hemorrhagic cerebral microvascular disease.

Objective To investigate the associations between cerebral microhemorrhages (CMH) and cognitive decline across the Alzheimer’s dementia continuum. Methods Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, we studied 619 participants, categorized into 221 cognitively normal (CN) participants, 281 patients with mild cognitive impairment (MCI), and 117 patients with Alzheimer’s disease (AD). CMH prevalence and distribution were determined using T2-weighted magnetic resonance imaging (MRI), focusing on the frontal, occipital, and parietal subcortical regions of interest (ROIs).Clinical dementia rating scale sum of boxes (CDR-SB) and mini-mental state examination (MMSE) were used for diagnosis and composite cognitive scores regarding visuospatial abilities, language, memory, and executive functions were used as outcome variables. Age, gender, and APOE ε4 positivity status were used as covariates. Results The AD group displayed significantly elevated tau and P-tau levels compared to MCI and CN groups ( p  < 0.001). APOE ε4 positivity was 67.5% in the AD group, surpassing the 50.2% in MCI and 29% in CN individuals ( p  < 0.001). Cognitive assessments revealed that the AD group’s CDR-SB score and MMSE both significantly differed from these scores in the MCI and CN groups ( p  < 0.001). Overall, CMH prevalence was 27.7%, with a predominant distribution in the frontal subcortical ROIs. MCI subjects with CMH showed notably diminished ADNI Visuospatial Composite Scores compared to those without CMH. Age significantly predicted CMH in CN and MCI ( p  < 0.05). In AD participants, APOE ε4 heterozygotes ( p  = 0.02) and homozygotes ( p  = 0.01) hadincreased CMH likelihood. Conclusion CMHs are significantly associated with cognitive decline in patients with MCI. This association is more prominent in regard to the decline in visuospatial abilities.