Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217 = 15.29, ORp-tau205 = 5.05 and ORp-tau231 = 3.86) and Braak staging (ORp-tau217 = 14.29, ORp-tau205 = 5.27 and ORp-tau231 = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.

Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy.

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.

Plasma p-tau181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau.

INTRODUCTION: We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). METHODS: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. RESULTS: Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

Differentiating Between Healthy Control Participants and Those with Mild Cognitive Impairment Using Volumetric MRI Data.

OBJECTIVE: To determine whether volumetric measures of the hippocampus, entorhinal cortex, and other cortical measures can differentiate between cognitively normal individuals and subjects with mild cognitive impairment (MCI). METHOD: Magnetic resonance imaging (MRI) data from 46 cognitively normal subjects and 50 subjects with MCI as part of the Boston University Alzheimer's Disease Center research registry and the Alzheimer's Disease Neuroimaging Initiative were used in this cross-sectional study. Cortical, subcortical, and hippocampal subfield volumes were generated from each subject's MRI data using FreeSurfer v6.0. Nominal logistic regression models containing these variables were used to identify subjects as control or MCI. RESULTS: A model containing regions of interest (superior temporal cortex, caudal anterior cingulate, pars opercularis, subiculum, precentral cortex, caudal middle frontal cortex, rostral middle frontal cortex, pars orbitalis, middle temporal cortex, insula, banks of the superior temporal sulcus, parasubiculum, paracentral lobule) fit the data best (R2 = .7310, whole model test chi-square = 97.16, p < .0001). CONCLUSIONS: MRI data correctly classified most subjects using measures of selected medial temporal lobe structures in combination with those from other cortical areas, yielding an overall classification accuracy of 93.75%. These findings support the notion that, while volumes of medial temporal lobe regions differ between cognitively normal and MCI subjects, differences that can be used to distinguish between these two populations are present elsewhere in the brain.

Left ventricular perforation with catheter decompression.

Thoracostomy tube placement is one of the more common procedures performed in the Emergency Department, most commonly for treatment of pneumothorax or hemothorax but occasionally for drainage of empyema or pleural effusion. Thoracostomy may be a life-saving procedure with a wide range of complication rates reported, ranging from 19.4-37%, most commonly extrathoracic placement. Most recent meta-analyses showed a relatively stable complication rate of 19% over the past three decades with the vast majority being benign in nature. We present a case with the rare complication of thoracostomy in which of a small-caliber thoracostomy tube was placed in the left ventricle. Although thoracotomy was performed to remove the catheter, the patient remained virtually asymptomatic and had an uneventful course.

Concomitant Infection With Epstein-Barr Virus and Cytomegalovirus Infection Leading to Portal Vein Thrombosis.

BACKGROUND: Portal vein thrombosis (PVT) is well recognized as a complication of hepatic cirrhosis and is likely to be suspected in patients with hypercoagulable syndromes, however, it is rarely recognized as a possibility in otherwise healthy patients with Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection. We report a case of a healthy 27-year-old man with fever and weight loss who was found to have PVT in the setting of acute EBV and CMV infection. CASE REPORT: A 27-year-old man with no known medical history presented to the emergency department (ED) for fever for 18 days. Patient reported daily high fevers associated with chills, night sweats, generalized myalgia, nausea with appetite loss, and unquantified weight loss. Vital signs showed temperature of 100.5°F. Patient reported discomfort upon palpation of abdomen on physical examination. There was no lymphadenopathy, cardiac murmur, rash, or jaundice. Laboratory tests revealed titers diagnostic of acute EBV and CMV infection with elevated liver function tests and leukocytosis with lymphocyte predominance (white blood cell count 15,400/µL; 43% atypical lymphocytes). Computed tomography of the abdomen/pelvis with i.v. contrast showed a filling defect in the anterior portal vein. The patient was admitted with the ED diagnosis of PVT secondary to viral infection and was initiated on anticoagulation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although rarely considered, CMV has been associated with PVT in up to 6% of cases, and EBV infection has been implicated as well. Emergency physicians should be aware of this potentially serious complication of these common viral infections and consider imaging modalities to rule out thrombosis, if appropriate.

Failure to detect an association between self-reported traumatic brain injury and Alzheimer's disease neuropathology and dementia.

INTRODUCTION: Recent research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status. METHODS: The sample included 4761 autopsy participants (453 with remote TBI with loss of consciousness; 2822 with AD neuropathologic changes) from National Alzheimer's Coordinating Center. RESULTS: Self-reported TBI did not predict AD neuropathologic changes (P > .10). Reported TBI was not associated with baseline or change in dementia severity or cognitive function in participants with or without autopsy-confirmed AD. DISCUSSION: Self-reported TBI with loss of consciousness may not be an independent risk factor for clinical or pathological AD. Research that evaluates number and severity of TBIs is needed to clarify the neuropathological links between TBI and dementia documented in other large clinical databases.

Vitamin B12 deficiency-induced neuropathy secondary to prolonged recreational use of nitrous oxide.

A 24-year-old female, otherwise healthy, presented to the Emergency Department (ED) with difficulty walking and bilateral leg pain. The patient was a recreational nitrous oxide (NO2) user, also known as "whippets" or simply nitrous. Neurologic examination demonstrated an unsteady gait and positive Romberg sign along with normal deep tendon reflexes and normal muscle strength in upper and lower extremities. Laboratory results demonstrated macrocytic erythropoiesis, reduced B12, elevated homocysteine, and elevated methylmalonic acid. Outpatient MRI later demonstrated degeneration of the posterior spinal column. The patient was empirically treated in the ED with intramuscular B12 and admitted to the evaluation unit for pain control and Physical Therapy (PT) evaluation. Emergency Medicine (EM) physicians should be aware of this condition because NO2 is used both recreationally and in medicine. With the popularity of recreational nitrous oxide, many emergency patients have experience with this drug. As in our case report, the toxic effects can be profound and mimic other emergent conditions like stroke. Emergency physicians should have a higher index of suspicion for the toxic effects of this common drug. Elderly, vegetarians and patients with Irritable Bowel Disease are at higher risk and may even experience toxicity from nitrous oxide used therapeutically during routine anesthesia.

Screening Utility of the King-Devick Test in Mild Cognitive Impairment and Alzheimer Disease Dementia.

The King-Devick (K-D) test is a 1 to 2 minute, rapid number naming test, often used to assist with detection of concussion, but also has clinical utility in other neurological conditions (eg, Parkinson disease). The K-D involves saccadic eye and other eye movements, and abnormalities thereof may be an early indicator of Alzheimer disease (AD)-associated cognitive impairment. No study has tested the utility of the K-D in AD and we sought to do so. The sample included 206 [135 controls, 39 mild cognitive impairment (MCI), and 32 AD dementia] consecutive subjects from the Boston University Alzheimer's Disease Center registry undergoing their initial annual evaluation between March 2013 and July 2015. The K-D was administered during this period. Areas under the receiver operating characteristic curves generated from logistic regression models revealed the K-D test distinguished controls from subjects with cognitive impairment (MCI and AD dementia) [area under the curve (AUC)=0.72], MCI (AUC=0.71) and AD dementia (AUC=0.74). K-D time scores between 48 and 52 seconds were associated with high sensitivity (>90.0%) and negative predictive values (>85.0%) for each diagnostic group. The K-D correlated strongly with validated attention, processing speed, and visual scanning tests. The K-D test may be a rapid and simple effective screening tool to detect cognitive impairment associated with AD.

Intracardiac Venous Stent Migration: Emergency Department Presentation of a Catastrophic Complication.

BACKGROUND: Venous stents are commonly placed to ensure patency in patients with chronic peripheral venous insufficiency. Although serious complications are uncommon, peripheral venous stent placement can have some potentially life-threatening complications. One of the most feared, and certainly the most dramatic, complication is stent migration. CASE REPORT: We report on a 55-year-old woman with transvenous migration of an infrarenal inferior vena cava stent into the right atrium and through the intra-atrial septum. The patient expired in the emergency department (ED). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: There are several potentially life-threatening post-surgical complications after an endovascular procedure, some of which occur shortly after the patient is discharged from the recovery unit. Frequently, these patients present to the ED for initial evaluation. Although details of the procedure performed and the surgical intervention might not be available immediately, emergency physicians should consider stent migration when a patient presents in extremis shortly after an endovascular procedure.

STEMI notification by EMS predicts shorter door-to-balloon time and smaller infarct size.

BACKGROUND: Emergency medical services (EMS) transportation is associated with shorter door-to-balloon (DTB) time in patients with ST-segment elevation myocardial infarction (STEMI). In addition to EMS transportation, prehospital notification of STEMI by EMS to receiving hospital might be able to further shorten DTB time. We evaluated the impact of STEMI notification on DTB time as well as infarct size. METHODS: We performed a retrospective analysis of consecutive patients with anterior wall STEMI who underwent emergent coronary angiography. We excluded patients who presented with cardiac arrest and those who were transferred from non-percutaneous coronary intervention-capable hospitals. Mode of transportation were categorized into the 3 groups: (1) EMS transport with STEMI notification, (2) EMS transport without STEMI notification, and (3) self-transport. Baseline characteristics, laboratory data, left ventricular ejection fraction (LVEF), and DTB time were compared among the 3 groups. RESULTS: A total of 148 patients were included in the final analysis. Of the 148 patients, 56 patients arrived by EMS transport with STEMI notification, 56 patients arrived by EMS transport without STEMI notification, and 36 patients arrived by self-transport. Patients who arrived by EMS transport with STEMI notification had the shortest DTB time among the 3 groups. Patients who arrived by EMS transport with STEMI notification had smaller infarct size, as indicated by lower peak creatine kinase value and higher LVEF, compared with those who arrived by EMS transport without STEMI notification. CONCLUSION: Emergency medical services transport with STEMI notification was associated with shorter DTB time and smaller infarct size in patients with anterior wall STEMI.

Teaching residents to teach: A pilot study for an innovative online curriculum.

Introduction: Resident-as-teacher (RAT) curricula have improved teaching behavior, ability, and confidence among resident participants. However, there are limited data on the appropriate format, length, and content. With teaching being a core residency competency and residents delivering one-third of student teaching in the clinical setting, properly training residents in clinical teaching is essential. We created a formal, scalable, asynchronous RAT curriculum. We report the pilot implementation of this curriculum along with feasibility, user acceptability, and preliminary knowledge outcomes. Methods: In this pilot pre-post interventional study, senior emergency medicine residents completed a formalized online education curriculum during their "teach month." The curriculum consisted of three online modules completed weekly over a 4-week rotation. Topics included adult learning, assessment and feedback, and group teaching. Several surveys were sent to residents before and after curriculum implementation. The surveys rated satisfaction and asked several education-specific knowledge questions to assess learning. Ratings were analyzed using means and confidence intervals (95%). Knowledge questions were graded and then analyzed by ANOVA and Fisher's LSD test. Results: After the online modules were completed, the intervention group residents' mean score on knowledge questions was significantly higher than that prior to the curriculum and significantly higher than that the control group (previous graduated residents; 6.00 vs. 2.70, p = 0.0001; and 6.00 vs. 3.00, p = 0.0003, respectively). This score was maintained 3 months after completing the online modules. Intervention group residents were more satisfied with the online education resources than the control group (p = 0.048). Conclusions: Residents participating in a formalized online curriculum during their teach month demonstrate a high comprehension of education concepts and increased satisfaction with the provided educational resources and report high satisfaction with the teach month. Our pilot study suggests that a short online education-focused curriculum is an effective method of providing RAT training and may be applicable to clinical teachers across specialties and experience levels.

Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease.

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease.

BACKGROUND AND OBJECTIVES: Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors. METHODS: The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3, Consortium to Establish a Registry for Alzheimer's Disease score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes. RESULTS: Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (ß = -0.93, 95% CI -1.35, -0.51, Bayes factor [BF] 130.75), working memory (ß = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (ß = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (ß = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (ß = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (ß = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (ß = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (ß = 0.45, 95% CI 0.01, 0.89, BF 0.33). DISCUSSION: In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome.

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Predictors of H1N1 vaccination in pregnancy.

The purpose of this review was to determine factors that influence a pregnant woman's acceptance of the H1N1 vaccine with the use of the Health Belief Model (HBM). A self-administered questionnaire based on the HBM was used in a cross-sectional study of postpartum women during the 2009 H1N1 epidemic. Overall, 212 postpartum women were approached and agreed to participate; of these women, 25.5% had received an H1N1 vaccination. Perceived barriers to vaccination (P = .001) and perceived severity of infection (P = .018) were independent predictors of vaccination. The total predictive utility of the full model that incorporated HBM dimensions, age, race, care provider, and education level was moderate (area under the curve, -0.86). The addressing of perceived barriers (such as fear of side-effects), an explanation of the safety of the vaccine for the fetus, and the stressing of complications that are associated with H1N1 infection in pregnancy may increase the rate of vaccination.

Calculated decisions: Canadian Syncope Risk Score.

A review of the uses and evidence for the Canadian Syncope Risk Score, which predicts 30-day serious adverse events in patients presenting with syncope.