Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.
Introduction: Prior studies of critically ill patients found that non-whites are less likely to pursue comfort measures only status (CMOs). We sought to identify determinants of CMOs in a large multi-ethnic cohort study of intracerebral hemorrhage (ICH). Methods: We analyzed cases enrolled from 2010 to 2015 in the Ethnic/Racial Variations of ICH (ERICH) study, a multi-center study in the USA. Clinical, demographic and radiologic data on non-traumatic ICH patients were prospectively collected. Univariate and multivariate logistic regression was used to evaluate the association between ethnicity/race and CMOs after adjustment for potential confounders. Results: 2705 ICH cases were included in this study (mean age 62 (14), female sex 1119 [41%]). Of these, 912 were black (34%), 893 Hispanic (33%) and 900 white (33%). CMOs patients comprised 276 (10%), 64 (7%), 79 (9%) and 133 (15%) of the entire cohort and the black, Hispanic and white cohorts, respectively (p<0.001) (Table 1). In multivariate analysis, black patients were half as likely as white patients to be made CMO (OR 0.50, 95% CI 0.34-0.75; p=0.001) and there was a trend for Hispanic patients to have CMOs less often than white patients (OR 0.72, 95% CI 0.49-1.06, p=0.093) (Table 2). Other factors associated with CMOs included age, premorbid modified Rankin Scale, dementia, admission Glasgow Coma Scale, ICH volume, intraventricular hematoma volume, lobar and brainstem bleeds and intubation. Conclusion: Black patients were less likely than white patients to be made CMO after controlling for potential confounders. Further investigation is warranted to understand the causes and implications of racial disparities in CMO decisions.
Background and Purpose— Human immunodeficiency virus (HIV) infection has been shown to increase both ischemic and hemorrhagic stroke risks, but there are limited data on the safety and outcomes of intravenous thrombolysis with tPA (tissue-type plasminogen activator) for acute ischemic stroke in HIV-infected patients. Methods— A retrospective chart review of intravenous tPA-treated HIV patients who presented with acute stroke symptoms was performed in 7 large inner-city US academic centers (various search years between 2000 and 2017). We collected data on HIV, National Institutes of Health Stroke Scale score, ischemic stroke risk factors, opportunistic infections, intravenous drug abuse, neuroimaging findings, and modified Rankin Scale score at last follow-up. Results— We identified 33 HIV-infected patients treated with intravenous tPA (mean age, 51 years; 24 men), 10 of whom were stroke mimics. Sixteen of 33 (48%) patients had an HIV viral load less than the limit of detection while 10 of 33 (30%) had a CD4 count <200/mm 3 . The median National Institutes of Health Stroke Scale score at presentation was 9, and mean time from symptom onset to tPA was 144 minutes (median, 159). The median modified Rankin Scale score for the 33-patient cohort was 1 and for the 23-patient actual stroke cohort was 2, measured at a median of 90 days poststroke symptom onset. Two patients had nonfatal hemorrhagic transformation (6%; 95% confidence interval, 1%–20%), both in the actual stroke group. Two patients had varicella zoster virus vasculitis of the central nervous system, 1 had meningovascular syphilis, and 7 other patients were actively using intravenous drugs (3 cocaine, 1 heroin, and 3 unspecified), none of whom had hemorrhagic transformation. Conclusions— Most HIV-infected patients treated with intravenous tPA for presumed and actual acute ischemic stroke had no complications, and we observed no fatalities. Stroke mimics were common, and thrombolysis seems safe in this group. We found no data to suggest an increased risk of intravenous tPA-related complications because of concomitant opportunistic infections or intravenous drug abuse.
May 7, 2019April 9, 2019Free AccessMotivation for Behavioral Change for Weight Loss in Obese Patients with Acute Stroke or TIA (P3.3-005)Hailey Orgass, Emily Daigle, Zachary King, Cora Ormseth, Sara Jasak, Emily Gilmore, Lauren Sansing, Hardik Amin, Walter Kernan, Guido Falcone, Kevin Sheth, and Jennifer DearbornAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P3.3-005 Letters to the Editor
The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented threat to all of us, regardless of age, nationality, or socioeconomic status. However, older patients are especially at risk for life-threatening respiratory, cardiovascular, and cerebral complications.1 As the COVID-19 pandemic continues to consume available global hospital resources, including in the United States, delirium prevention strategies may become an unintended casualty of scarce resource and personnel allocation.2 A significant consequence of these realities is an anticipated surge of delirium incidence and duration in hospitalized patients, regardless of COVID-19 status, due to increased risk factors and barriers to implementation of evidence-based delirium prevention guidelines.3, 4 An increase in delirium will result in both inadvertent harm to individuals and also exacerbation of hospital resource shortages.3, 4 Our goals are to highlight this insidious complication and pose pragmatic recommendations for minimizing the risk and duration of delirium in all patients during the COVID-19 pandemic. Even in the absence of drastic environmental modifications resulting from isolation and personal protective equipment (PPE) shortages, up to 50% to 70% of critically ill patients, and 10% to 15% of hospitalized general medical patients, develop delirium.3, 5 Compared with non-delirious patients, delirious patients are more likely to consume more hospital staff time and precious life-support resources, stay longer, and develop in-hospital complications. Higher rates of delirium will also likely result in more patients discharged to a facility and readmitted to the hospital.6 Such complications would greatly stress an already chaotic healthcare system during the COVID-19 pandemic. Delirium is not inevitable; rather, it is preventable in approximately 30% to 40% of cases.3 Unfortunately, the COVID-19 management issues outlined in Table 1 bring to light potential barriers to our typical nonpharmacologic prevention strategies such as the Assess, Prevent, and Manage Pain, Both Spontaneous Awakening Trials and Spontaneous Breathing Trials, Choice of analgesia and sedation, Delirium: Assess, Prevent, and Manage, Early mobility and Exercise, and Family engagement and empowerment (ABCDEF) bundle in the intensive care unit (ICU)7 or the Hospital Elder Life Program.8 These interventions target risk factors for delirium including inadequate pain management, overuse of sedation and time on mechanical ventilation, restraints, social isolation from loved ones, immobility, and sleep disruption.7, 8 Delirium prevention programs are even more crucial in the era of COVID-19 and cannot be allowed to wither despite the challenges of integrating delirium prevention with COVID-19 care. Visitors are now prohibited for all hospitalized patients, with rare exceptions.9 Because we know that caregivers play pivotal roles in delirium prevention by reducing isolation, providing daytime stimulation to maintain sleep-wake cycles, and advocating for patient needs,10 excluding them is likely to exacerbate rates of delirium, posttraumatic stress disorder, and depression. For this reason, we posit that caregivers, even if family members or friends, are essential healthcare workers because they can prevent these poor clinical outcomes.11 We believe that a designated caregiver should be allowed to accompany a non-COVID patient with cognitive impairment or delirium during hospitalization, provided the caregiver passes the hospital health screen and wears a mask. Patients hospitalized with COVID-19 face additional challenges (outlined in Table 1). Those who are critically ill, requiring ICU-level care, are most at risk of developing delirium. Those who improve may be transferred out of the ICU still delirious. Tests often occur late at night to ensure adequate time for equipment sterilization, disrupting sleep and causing disorientation for vulnerable patients. In addition to being isolated from visitors, these patients also have minimal contact with staff, including nursing and rehabilitation services, largely to preserve PPE and reduce exposure. Although created with the intention of minimizing contagion, policies that increase isolation and immobility for hospitalized patients, combined with acute illness, produce a high-risk environment for delirium.3 We propose several strategies for delirium prevention adapted during this critical time that require minimal effort to implement and do not increase risk of exposure to healthcare workers (Table 1). We highlight meaningful steps that can occur outside patient rooms, as well as low-tech ways for improving communication that is hindered by PPE. We also propose ways to integrate technology into the workflow to reduce the isolation felt between patients and family members. Mitigating delirium during this chaotic time is possible with interdisciplinary teamwork and flexibility of roles. Some might think that infection with the SARS-CoV-2 virus has created a new reality in the field of healthcare that would allow us to triage delirium "off the table" as a priority. We believe the opposite is true. A focus on delirium during the COVID-19 pandemic is more important than ever. Millions of people are at risk for delirium as a complementary and exacerbating factor of COVID-19. Doubling down on established protocols and guidelines for delirium prevention and management will help with our ventilator and hospital bed shortage. Delirium prevention tenets are not antithetical to the precautions needed to care for patients in a pandemic. Rather, these principles center on the humanistic qualities that inspired many of us to enter medicine in the first place. While faced with unprecedented social isolation, preventing delirium in our patients is something we must all embrace. The authors have declared no conflicts of interest for this article. Sara C. LaHue drafted the article. All the authors made substantial contributions to the conception and design, revised the article critically for important intellectual content, and approved the final version to be published. No sponsor to report.
The continued harm of Black individuals in the US by law enforcement officers calls for reform of both law enforcement officers and structural racism embedded in communities.To examine the association between county characteristics and racial and ethnic disparities in legal intervention injuries.This retrospective, cross-sectional study was conducted among 27 671 patients presenting to California hospitals from January 1, 2016, to December 31, 2019, with legal intervention injuries (defined as any injury sustained as a result of an encounter with any law enforcement officer) as identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes.Legal intervention injuries were classified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision external cause of injury code Y35. Expected injury counts were calculated for each county by multiplying statewide median rates of injury per capita for each age-racial and ethnic group, and then observed to expected injury ratios were measured. The association between county injury ratio, percentage of Black individuals, and residential segregation (measured using an index of dissimilarity) was modeled, stratifying by race and ethnicity.A total of 27 671 patients (24 159 male patients [87.3%]; 1734 Asian and Pacific Islander [6.3%], 5049 Black [18.2%], 11 250 Hispanic [40.7%], and 9638 White [34.8%]; mean [SD] age, 34.2 [12.5] years) presented with legal intervention injuries in California from 2016 to 2019. Observed to expected injury ratios ranged from 0 to 7 for Black residents and from 0 to 5 for White residents. High observed to expected injury ratios for Black residents (408 observed vs 60 expected; ratio = 7) were clustered around San Francisco Bay Area counties and corresponded with a higher proportion of Black residents. High observed to expected injury ratios for White residents (57 observed vs 11 expected; ratio = 5) clustered around rural northern California counties and corresponded with higher mean percentage of residents with income below the federal poverty level and fewer urban areas.This study suggests that residential segregation may be associated with increased legal intervention injury rates for Black residents of California counties with a large percentage of Black residents. Reform efforts to address racial and ethnic disparities in these injuries should carefully consider and address the legacy of discriminatory policies that has led to segregated communities in California and the United States.
