Incidence and Risk Factors for New and Recurrent Infarcts in Adults With Sickle Cell Disease.

BACKGROUND: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults. METHODS AND RESULTS: This observational study included adults with sickle cell disease and no history of stroke. Magnetic resonance imaging scans of the brain completed at baseline and >1 year later were reviewed by 3 radiologists for baseline SCIs and new or progressive infarcts on follow-up magnetic resonance imaging. Stroke risk factors were abstracted from the medical chart. Time-to-event analysis was utilized for progressive infarcts. Median age was 24.1 years; 45.3% of 95 participants had SCIs on baseline magnetic resonance imaging. Progressive infarcts were present in 17 participants (17.9%), and the median follow-up was 2.1 years. Incidence of new infarcts was 11.95 per 100 patient-years (6.17-20.88) versus 3.74 per 100 patient-years (1.21-8.73) in those with versus without prior SCI. Multivariable Cox regression showed that baseline SCI predicts progressive infarcts (hazard ratio, 3.46 [95% CI, 1.05-11.39]; P=0.041); baseline hypertension was also associated with progressive infarcts (hazard ratio, 3.23 [95% CI, 1.16-9.51]; P=0.025). CONCLUSIONS: Selecting individuals with SCIs and hypertension for stroke prevention trials in sickle cell disease may enrich the study population with those at highest risk for infarct recurrence.

Corrigendum: Academic performance of children with sickle cell disease in the United States: a meta-analysis.

[This corrects the article DOI: 10.3389/fneur.2021.786065.].

Silent cerebral infarcts in patients with atrial fibrillation: Clinical implications of an imaging-adjusted CHA2DS2-VASc score.

BACKGROUND: The CHA2DS2-VASc score does not include silent infarcts on neuroimaging in stroke risk estimation for patients with atrial fibrillation (AF). The inclusion of silent infarcts into CHA2DS2-VASc scoring and its impact on stroke prophylaxis recommendations in patients with AF has not been previously studied. The present study sought to quantify the prevalence of silent infarcts in patients with AF and describe potential changes in management based on magnetic resonance imaging (MRI) findings. METHODS: Participants from the Mayo Clinic Study of Aging with AF and brain MRI were included. Silent infarcts were identified. "Standard" CHA2DS2-VASc scores were calculated for each subject based on clinical history alone and "imaging-adjusted" CHA2DS2-VASc scores based on evidence of cerebral infarction on MRI. Standard and imaging-adjusted scores were compared. RESULTS: One hundred and forty-seven participants (average age 77, 28% female) were identified with AF, MRI, and no clinical history of stroke. Overall, 41 (28%) patients had silent infarcts on MRI, corresponding with a 2-point increase in CHA2DS2-VASc score. Of these participants, only 39% (16/41) with silent infarct were on anticoagulation despite having standard CHA2DS2-VASc scores supportive of anticoagulation. After incorporating silent infarcts, 13% (19/147) would have an indication for periprocedural bridging compared to 0.6% (1/147) at baseline. CONCLUSIONS: Incorporation of silent infarcts into the CHA2DS2-VASc score may change the risk- -benefit ratio of anticoagulation. It may also increase the number of patients who would benefit from periprocedural bridging. Future research should examine whether an anticoagulation strategy based on imaging-adjusted CHA2DS2-VASc scores could result in a greater reduction of stroke and cognitive decline.

Brain Magnetic Resonance Imaging and Angiography in Children with Sickle Cell Anaemia in Uganda in a Cross-Sectional Sample.

OBJECTIVE: Children with sickle cell anaemia (SCA) are highly susceptible to cerebrovascular injury. We performed brain magnetic resonance imaging and angiography (MRI-MRA) in Ugandan children with SCA to identify structural cerebrovascular abnormalities and examine their relationship to standardized clinical assessments. METHODS: A sub-sample (n=81) was selected from a cross-sectional study of children attending SCA clinic, including 52 (64.2%) with and 29 (35.8%) without clinically detected abnormalities. Clinical evaluation included assessment for prior stroke, cognitive testing and cerebral arterial transcranial doppler (TCD) flow velocity. MRI-MRA scans were interpreted by at least two neuroradiologists. RESULTS: Mean age was 6.5±2.7 years, with 39 (48.1%) female. Mean haemoglobin was 7.3±0.9 g/dl. Overall, 13 (16.0%) were malnourished. Infarcts and/or stenoses were detected in 55 (67.9%) participants, with stenoses primarily in the anterior circulation. Infarcts were seen in those with normal 17/29 (58.6%) or abnormal 34/52 (65.4%) clinical testing (p=0.181). Neither abnormal MRI nor MRA was associated with age, sex, haemoglobin, or malnutrition. Abnormal MRA was highly associated with infarcts (p<0.0001). Participants with abnormal imaging had two-fold higher proportion of stroke on exam and/or impaired cognition. Stroke on exam was strongly associated with an imaging abnormality after adjusting for age, sex, malnutrition, and haemoglobin (OR 11.8, 95%CI 1.87-74.2). CONCLUSION: Over half of these SCA children had cerebrovascular infarcts and/or arterial stenoses. Cerebrovascular disease was frequently undetectable by clinical assessments. While rarely available in under-resourced settings, MRI-MRA brain imaging is an important tool for defining SCA cerebrovascular disease and for assessing impact of clinical intervention trials.

Academic Performance of Children With Sickle Cell Disease in the United States: A Meta-Analysis.

Background: Students with sickle cell disease are at risk for poor academic performance due to the combined and/or interactive effects of environmental, psychosocial, and disease-specific factors. Poor academic performance has significant social and health consequences. Objective: To study academic achievement and attainment in children with sickle cell disease in the United States. Design: Medline, Embase, SCOPUS, CINAHL, ERIC, and PsycINFO were searched for peer-reviewed articles. Studies of children (ages 5-18) diagnosed with sickle cell disease of any genotype reporting academic achievement (standardized tests of reading, math, and spelling) or attainment (grade retention or special education) outcomes were included. Outcomes were analyzed using a random effects model. Achievement scores were compared to within study controls or normative expectations. Prevalence of grade retention and special education services were compared to national (United States) estimates for Black students. Age at assessment and overall IQ were evaluated separately for association with reading and mathematics scores. Subgroup analyses of reading and math scores were analyzed by cerebral infarct status (no cerebrovascular accident, silent infarct, stroke). Results: There were 44 eligible studies. Students with sickle cell disease scored 0.70, 0.87, and 0.80 (p < 0.001) SD below normative expectations on measures of reading, mathematics, and spelling, respectively. Compared to unaffected sibling and/or healthy controls (k = 8, n = 508), reading and math scores were 0.40 (p = 0.017) and 0.36 (p = 0.033) SD below expectations. Grade retention was approximately 10 times higher in students with sickle cell disease than Black students nationally. Intellectual functioning explained 97.3 and 85.8% of the variance in reading and mathematics performance, respectively (p < 0.001). Subgroup analyses revealed significant differences in reading (p = 0.034) and mathematics (p < 0.001) based on infarct status, with lower performance associated with presence of a silent infarct or stroke. Conclusion: Students with sickle cell disease demonstrate notable academic difficulties and are at high risk for grade retainment. Development of academic interventions and increased access to school support services are needed for this vulnerable population. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020179062.

Tamoxifen offers long-term neuroprotection after hippocampal silent infarct in male rats.

Silent infarcts (SI) are a cerebral small vessel disease characterized by small subcortical infarcts. These occur in the absence of typical ischemia symptoms but are linked to cognitive decline and dementia. While there are no approved treatments for SI, recent results from our laboratory suggest that tamoxifen, a selective estrogen receptor modulator, is a viable candidate. In the present study, we induced SI in the dorsal hippocampal CA1 region of rats and assessed the effects of systemic administration of tamoxifen (5 mg/kg, twice) 21 days after injury on cognitive and pathophysiological measures, including cell loss, apoptosis, gliosis and estrogen receptors (ERs). We found that tamoxifen protected against the SI-induced cognitive dysfunction on the hippocampal-dependent, place recognition task, cell and ER loss, and increased apoptosis and gliosis in the CA1. Exploratory data analyses using a scatterplot matrix and principal component analysis indicated that SI-tamoxifen rats were indistinguishable from sham controls while they differed from SI rats, who were characterized by enhanced cell loss, apoptosis and gliosis, lower ERs, and recognition memory deficit. Supervised machine learning using support vector machine (SVM) determined predictors of progression from the early ischemic state to the dementia-like state. It showed that caspase-3 and ERα in the CA1 and exploration proportion were reliable and accurate predictors of this progression. Importantly, tamoxifen ameliorated SI-induced effects on all three of these variables, providing further evidence for its viability as a candidate treatment for SI and prevention of associated dementia.

Low Rates of Cerebral Infarction after Hematopoietic Stem Cell Transplantation in Patients with Sickle Cell Disease at High Risk for Stroke.

Hematopoietic stem cell transplantation (HSCT) can be curative for sickle cell disease (SCD). SCD patients with cerebrovascular disease are often referred for HSCT. The objective of this study was to describe neurologic outcomes after HSCT in patients with pre-existing SCD and cerebrovascular comorbidity. Patients with SCD treated with HSCT at a single center between 1996 and 2019 were identified. Patients with cerebral ischemia and/or vasculopathy before undergoing HSCT were included. Patients with graft failure were excluded. The cohort was divided into 3 groups: symptomatic stroke, vasculopathy without symptomatic stroke, and isolated silent cerebral infarction (SCI). Magnetic resonance imaging/angiography and neurologic assessments pre- and post-HSCT were analyzed to assess outcomes. In a cohort of 44 patients, there were 25 with symptomatic infarction, 10 with vasculopathy, and 9 with isolated SCI. Post-HSCT ischemic injury (2 symptomatic strokes, 2 SCIs) was identified in 4 patients, all with previous symptomatic infarction. Within this group (n = 25), the post-HSCT incidence of subsequent symptomatic infarction was 1.6 events/100 patient-years, and SCIs occurred at a rate of 2.2 events/100 patient-years. No patient had progression of vasculopathy post-HSCT. Our data show a low incidence of new ischemic injury after successful HSCT for SCD. Patients with a history of both symptomatic stroke and vasculopathy are at greatest risk for post-HSCT ischemic injury.

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury 24 h after hippocampal silent infarct in male Sprague-Dawley rats.

Silent infarcts (SI) are subcortical cerebral infarcts occurring in the absence of typical ischemia symptoms and are linked to cognitive decline and dementia development. There are no approved treatments for SI. One potential treatment is tamoxifen, a selective estrogen receptor modulator. It is critical to establish whether treatments effectively target the early consequences of SI to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 h later against cognitive deficits and injury responses including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). SI led to subtle cognitive impairment on the object place task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but increased apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI increased ERα and decreased ERß in the hippocampus, which were mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that SI rats given tamoxifen were indistinguishable from controls. Further, SI rats were significantly different from all other groups, an effect associated with low levels of ERα and increased apoptosis, gliosis, inflammation, ERß, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI 24 h after injury. Tamoxifen mitigates apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

Hippocampal silent infarct leads to subtle cognitive decline that is associated with inflammation and gliosis at twenty-four hours after injury in a rat model.

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of clinical symptoms commonly associated with ischemia and are linked to dementia development. Little is known about the pathophysiology underlying the cognitive dysfunction associated with SI, and few studies have examined the early cellular responses and neurobiological underpinnings. We induced SI in adult male Sprague-Dawley rats using an infusion of endothelin-1 in the CA1 dorsal hippocampus. Twenty-four hours later, we assessed cognition using the hippocampal-dependent object place recognition task. We also examined whether the resulting cognitive effects were associated with common markers of ischemia, specifically cell and synapse loss, gliosis, and inflammation, using histology and immunohistochemistry. Hippocampal SI led to subtle cognitive impairment on the object place recognition task 24 -hs post-injury. This was characterized by a significant difference in exploration proportion relative to a pre-injury baseline and a positive association between time spent with both the moved and unmoved objects. SI did not result in any detectable cell or synaptophysin loss, but did increase apoptosis, gliosis and inflammation in the CA1. Principal component analysis indicated the main variables associated with hippocampal SI included increased time spent with the unmoved object, gliosis, apoptosis and inflammation as well as decreased exploration proportion and CA1 cells. Our data demonstrate that hippocampal SI can lead to cognitive dysfunction 24 -hs after injury. Further, this appears to be driven by early degenerative processes including apoptosis, gliosis and inflammation, suggesting that these may be targets for early interventions treating hippocampal SI and its cognitive consequences.

Patient risk factors associated with embolic stroke volumes after revascularization.

OBJECTIVE: Previous research has shown that subclinical, microembolic infarcts result in long-term cognitive changes. Whereas both carotid endarterectomy (CEA) and carotid artery stenting (CAS) have potential for microembolic events, CAS has been shown to have a larger volume of infarct. We have previously shown that large-volume infarction is associated with long-term memory deterioration. The purpose of this study was to identify independent risk factors that trend toward higher embolic volumes in both procedures. METHODS: A total of 162 patients who underwent carotid revascularization procedures were prospectively recruited at two separate institutions. Preoperative and postoperative brain magnetic resonance images were compared to identify procedure-related microinfarcts. A novel semiautomated approach was used to define volumes of infarcts for each patient. Patient-related factors including comorbidities, symptomatic status, and medications were analyzed. Tweedie regression analysis was used to identify risk factors associated with procedure-related infarct volume. Variables with an unadjusted P value of ≤ .05 were included in the multivariate analysis. RESULTS: There were 80 CAS and 82 CEA procedures performed and analyzed for the data set; 81% of CAS patients had procedure-related new infarcts with a mean volume of 388.15 ± 927.90 mm3 compared with 30% of CEA patients with a mean volume of 74.80 ± 225.52 mm3. In the CAS cohort, increasing age (adjusted coefficient ± standard error, 0.06 ± 0.02; P < .01) and obesity (1.14 ± 0.35; P < .01) were positively correlated with infarct volume, whereas antiplatelet use (-1.11 ± 0.33; P < .001) was negatively correlated with infarct volume. For the CEA group, diabetes (adjusted coefficient ± standard error, 1.69 ± 0.65; P < .01) was identified as the only risk factor positively correlated with infarct volume, whereas increasing age (-0.10 ± 0.05; P = .03) was negatively correlated with infarct volume. CONCLUSIONS: Risk factors for CAS- or CEA-related infarct volumes are identified in our study. Although the result warrants further validation, this study showed that advanced age, obesity, and diabetes independently predicted volume of microinfarcts related to CAS and CEA. These data provide valuable information for patient factor-based risk stratification and preoperative consultation for each procedure.

Why, Who, When, and How? Rationale for Considering Allogeneic Stem Cell Transplantation in Children with Sickle Cell Disease.

Considering the progress made in the management of sickle cell disease during the past 30 years, along with the excellent results obtained with hematopoietic stem cell transplantation (SCT), it is important to reexamine why, who, when and how to recommend allogeneic SCT in children with sickle cell disease. While sickle cell disease has a low risk of death in children and a high risk for morbidity during aging, SCT carries an early risk of death, graft-vs-host disease and infertility. Nevertheless, SCT offers at least 95% chance of cure with low risk of chronic graft-vs-host disease when a matched-sibling donor is available and the risks of infertility can be reduced by ovarian, sperm or testis cryopreservation. Thus, all available therapies such as hydroxyurea, transfusions and SCT should be presented to the parents, providers, and affected children and discussed with them from infancy. Furthermore, the use of these therapies should be adjusted to the severity of the disease and to local availabilities in order to choose the treatment offering the best benefit/risk ratio.

Rationale, design, and baseline participant characteristics in the MRI and cognitive substudy of the cardiovascular outcomes for people using anticoagulation strategies trial.

BACKGROUND: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. AIMS: The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a sample of consenting COMPASS participants without contraindications to MRI. METHODS: COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in individuals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy; biomarker and genetic samples at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. RESULTS: Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23-28). CONCLUSIONS: The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.

Serum Levels of S100b and NSE Proteins in Patients with Non-Transfusion-Dependent Thalassemia as Biomarkers of Brain Ischemia and Cerebral Vasculopathy.

Patients with non-transfusion-dependent thalassemia (NTDT) are at risk of developing brain ischemia. Transcranial Doppler (TCD) has been established as a useful screening tool of cerebrovascular disease in patients with sickle cell disease. Proteins neuron specific enolase (NSE) and S100B are biomarkers that reflect CNS injury. The purpose of this study is to evaluate cerebral vessel vasculopathy and brain damage in NTDT patients using non-invasive methods as TCD and measurement serum levels of NSE and S100B. We included in our study 30 patients with NTDT, aged between 8 and 62 years old (mean: 29.4, median: 32) who presented in our Unit for regular follow-up. We performed in all patients a non-imaging TCD examination and have measured serum S100, NSE and lactate dehydrogenase (LDH) levels. We investigated the possible correlation between TCD results and S100B, NSE and LDH levels as well as between NSE-LDH and S100B-LDH levels by regression analysis. We found a statistically significant relationship for both NSE, S100B with LDH. We also found a statistically significant relationship for S100B and time-averaged mean velocity (TAMV)/peak velocity of left middle cerebral artery (MCA), NSE and pulsatility index (PI)/resistive index (RI) of the left posterior cerebral artery (PCA). TCD results correlated with biomarkers for brain ischemia. This finding enhances the role of TCD as a screening tool for brain ischemia in patients with NTDT.