Evaluation and Management of Buprenorphine Extended-Release Injection Thrombophlebitis: A Case Report.

INTRODUCTION: Buprenorphine extended-release subcutaneous injection (BUP-XR) is a medication used to treat opioid use disorder. It is a long-acting formulation of buprenorphine, which is a partial opioid agonist. Buprenorphine extended-release subcutaneous injection is injected into the subcutaneous space forming a depot that can last up to a month. The most common adverse effects of BUP-XR are injection site pain, erythema, and induration. CASE REPORT: A man in his late 30s presented to the emergency department 48 hours after BUP-XR injection with abdominal pain. He was found to have superficial venous thrombosis of an abdominal wall vessel extending near the deep venous system. He was subsequently started on apixaban for 30 days and cefadroxil for 7 days to reduce the risk of extension and infection. He fully recovered and has since restarted BUP-XR without further complications. CONCLUSIONS: Venous thrombosis is a rare but potentially life-threatening complication of BUP-XR. It is important for emergency and outpatient clinicians to be aware of adverse reactions associated with this medication. The patient was successfully treated with a 30-day course of apixaban and able to resume taking BUP-XR without further complications. Clinicians may want to consider supplementing BUP-XR with sublingual film after injection-related complications due to possible lower serum levels.

Factors Underlying Racial Disparity in Utilization of Hepatitis C-Viremic Kidneys in the United States.

Utilization of hepatitis C (HCV) viremic kidneys is increasing in the United States. We examined racial disparity in this utilization using UNOS/OPTN data (2014-2020) and mixed effects models adjusting for donor/recipient/center factors. Included in the study were 58,786 adults receiving a deceased donor kidney transplant from 191 centers. Two thousand six hundred thirteen (4%) received kidneys from HCV-viremic donors. Of these, 1598 (61%) were HCV seronegative and 1015 (49%) were HCV seropositive. Among seronegative recipients, before adjusting for waiting time and education, Blacks (OR 0.69, 95%CI (0.60, 0.80)), Hispanics (OR 0.63, 95%CI (0.51, 0.79)), and Asians (OR 0.69, 95%CI (0.53, 0.90)) were less likely than Whites to receive HCV-viremic kidneys. In final models, effect of race was attenuated. Notably, shorter waiting time (OR 0.65, 95%CI (0.63, 0.67)) and increasing educational level (grade school less likely compared to high school OR 0.67, 95% CI (0.49, 0.92) and college more likely than high school (OR 1.16 95% CI (1.02, 1.31)) were associated with receipt of HCV-viremic kidneys. Among HCV-seropositive recipients, recipient race was not independently associated with receipt of HCV-viremic kidneys; however, centers with larger populations of Black waitlisted patients were more likely to utilize HCV-viremic kidneys (OR 1.71, 95%CI (1.20, 2.45)) compared to other centers. Our results suggest recipient race does not independently determine who receives HCV-viremic kidneys; however, other underlying factors including waiting time, education (among seronegative), and center racial mix (among seropositive) contribute to the current differential distribution of HCV-viremic kidneys among races.

The Effects of Rental Assistance on Housing Stability, Quality, Autonomy, and Affordability.

Federal rental assistance is an important source of affordable housing for low income households, given a growing and severe affordable housing crisis. However, few studies have examined the extent to which rental assistance may improve housing access. This paper examines associations between rental assistance receipt and four dimensions of housing: quality, stability, autonomy and affordability. We draw on data from a longitudinal cohort study of low-income adults in New Haven, Connecticut and use Generalized Estimating Equations to examine associations between rental assistance receipt and housing measures. We find that participants receiving rental assistance had lower odds of reporting housing instability, low quality housing, lack of autonomy related to housing, and some measures of housing unaffordability compared to those not receiving assistance. The large and highly significant effects remain after adjusting for demographic variables and factors that can impact access to rental assistance.

Bivalirudin for the prevention of hepatic artery thrombosis in pediatric liver transplantation.

BACKGROUND: Early hepatic artery thrombosis (HAT) after liver transplantation is a serious complication that frequently results in graft loss and the need for retransplantation. Although studies have reported on various operative and endovascular treatment approaches, pharmacologic strategies for the prevention or management of HAT are not well defined. Patients with blood clotting disorders, those with a contraindication to heparin, and those who have previously developed HAT represent unique challenges in management. METHODS: We present the case of a 9-month-old male with a hypercoagulable state who developed early HAT after two liver transplants, despite the use of postoperative therapeutic heparin infusion. RESULTS AND CONCLUSION: The patient successfully underwent a third liver transplant using intraoperative and postoperative bivalirudin infusion, a direct thrombin inhibitor. Rotational thromboelastometry (ROTEM) was used to guide anticoagulation and blood product administration in the perioperative period. At 1.5 years post-transplant, the patient has good graft function with patent hepatic vasculature. This case demonstrates the innovative use of bivalirudin anticoagulant therapy and viscoelastic methodologies to improve outcomes in hypercoagulable liver transplant recipients.

Case report of lymph node activation mimicking cancer progression: A false positive F18 FDG PET CT after COVID-19 vaccination.

This case illustrates a false positive F18 FDG PET CT in the left axilla of a woman being treated for metastatic breast cancer after COVID-19 vaccination. Follow-up ultrasound of the axilla indicated no metastasis, indicating that the lymphadenopathy was likely due to an immune response following vaccination. This case report, in conjunction with prior studies of other vaccines with similar findings suggest that providers should be aware of potential false positive imaging following COVID-19 vaccination. In light of these findings, clinicians and imaging providers should record the date and side of the vaccination and inform patient of potential false positive results to reduce patient anxiety and unnecessary tests as COVID-19 vaccines become widely available.

COVID-19 outcomes in patients waitlisted for kidney transplantation and kidney transplant recipients.

The COVID-19 pandemic has brought unprecedented challenges to the transplant community. The reduction in transplantation volume during this time is partly due to concerns over potentially increased susceptibility and worsened outcomes of COVID-19 in immunosuppressed recipients. The consequences of COVID-19 on patients waitlisted for kidney transplantation, however, have not previously been characterized. We studied 56 waitlisted patients and 80 kidney transplant recipients diagnosed with COVID-19 between March 13 and May 20, 2020. Despite similar demographics and burden of comorbidities between waitlisted and transplant patients, waitlisted patients were more likely to require hospitalization (82% vs. 65%, P = .03) and were at a higher risk of mortality (34% vs. 16%, P = .02). Intubation was required in one third of hospitalized patients in each group, and portended a very poor prognosis. The vast majority of patients who died were male (84% waitlist, 100% transplant). Multivariate analysis demonstrated waitlist status, age, and male sex were independently associated with mortality. COVID-19 has had a dramatic impact on waitlisted patients, decreasing their opportunities for transplantation and posing significant mortality risk. Understanding the impact of COVID-19 on waitlist patients in comparison to transplant recipients may aid centers in weighing the risks and benefits of transplantation in the setting of ongoing COVID-19.

Simultaneous Living Donor Kidney Transplant and Laparoscopic Native Nephrectomy: An Approach to Kidney Transplant Candidates with Suspected Renal-Cell Carcinoma.

Introduction: Kidney transplant candidates are occasionally found during the pre-transplant evaluation to have a suspicious mass in a native kidney. Further work-up and management of such a mass may delay transplantation for several months, which may create logistic barriers to transplant, particularly if there are timing constraints of the donor. In this study, we report our experience with simultaneous living donor kidney transplant and laparoscopic native nephrectomy, where the indication for nephrectomy was a suspicious lesion. Methods: We performed a retrospective review of patients who underwent simultaneous kidney transplant and native nephrectomy using prospectively collected data. We analyzed relevant patient characteristics, surgical details, pathologic results, and long-term follow-up. Results: We identified 16 patients who underwent simultaneous living donor kidney transplantation and laparoscopic native nephrectomy at our institution between 2013 and 2018. Ten (62.5%) patients were found to have renal-cell carcinoma (RCC) on the final pathology. No patients had recurrent RCC, at a median follow-up of 4 years. Conclusion: For patients who are planning to undergo a living donor kidney transplant and are found to have a small mass that is suspicious for RCC, a simultaneous living donor kidney transplant and laparoscopic native nephrectomy is a possible approach in selected patients.

Kidney allograft recipients, immunosuppression, and coronavirus disease-2019: a report of consecutive cases from a New York City transplant center.

BACKGROUND: Kidney graft recipients receiving immunosuppressive therapy may be at heightened risk for coronavirus disease 2019 (Covid-19) and adverse outcomes. It is therefore important to characterize the clinical course and outcome of Covid-19 in this population and identify safe therapeutic strategies. METHODS: We performed a retrospective chart review of 73 adult kidney graft recipients evaluated for Covid-19 from 13 March to 20 April 2020. Primary outcomes included recovery from symptoms, acute kidney injury, graft failure and case fatality rate. RESULTS: Of the 73 patients screened, 54 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-39 with moderate to severe symptoms requiring hospital admission and 15 with mild symptoms managed in the ambulatory setting. Hospitalized patients were more likely to be male, of Hispanic ethnicity and to have cardiovascular disease. In the hospitalized group, tacrolimus dosage was reduced in 46% of patients and mycophenolate mofetil (MMF) therapy was stopped in 61% of patients. None of the ambulatory patients had tacrolimus reduction or discontinuation of MMF. Azithromycin or doxycycline was prescribed at a similar rate among hospitalized and ambulatory patients (38% versus 40%). Hydroxychloroquine was prescribed in 79% of hospitalized patients. Graft failure requiring hemodialysis occurred in 3 of 39 hospitalized patients (8%) and 7 patients died, resulting in a case fatality rate of 13% among Covid-19-positive patients and 18% among hospitalized Covid-19-positive patients. CONCLUSIONS: Data from our study suggest that a strategy of systematic triage to outpatient or inpatient care, early management of concurrent bacterial infections and judicious adjustment of immunosuppressive drugs rather than cessation is feasible in kidney transplant recipients with Covid-19.

Neuropraxia: An Underappreciated Morbidity of Liver Transplantation.

BACKGROUND: Peripheral nerve injuries can be devastating complications of surgery, potentially resulting in severe functional disability and decreased quality of life. Long surgeries with considerable tissue manipulation, for example, liver transplantation, may present increased risk; however, neuropraxia in transplantation has not been well investigated. MATERIALS AND METHODS: This is a retrospective study of all adult patients undergoing liver transplantation at a large academic center between January 2013 and December 2015. Descriptive analyses, logistic regressions, and forward selection procedures were used to determine the odds of developing neuropraxia and associated factors. RESULTS: Of the 283 liver recipients, the mean age was 55.8 y, 35.1% were female, 65.6% were Caucasian, 8.9% were African American, 16.7% were Hispanic, and mean model for end-stage liver disease sodium score at transplant was 24.2 ± 10.9. The underlying etiology was alcohol (26.2%), hepatitis C (34.8%), nonalcoholic steatohepatitis (13.1%), and other (14.2%). The incidence of neuropraxia after liver transplantation was 8.3% (n = 25), with 60% (n = 16) upper extremities, 82% left sided, and 84% male. There was no difference in age, race, body mass index, hypertension, diabetes, hyperlipidemia, or smoking in those with neuropraxia versus those without. In multivariate analysis, neuropraxia was significantly associated with male gender, lower model for end-stage liver disease score, and longer duration of surgery (P < 0.05). Symptoms lasted median 5 d, with a wide range up to 187 d. Neuropraxia-specific treatment (physical therapy or medications) was required in 32% (n = 9). CONCLUSIONS: Peripheral nerve injuries are an unexplored complication of liver transplantation. Although transient, a high number (8.2%) of patients developed neuropraxia, negatively affecting their ability for recovery. Exploration of mechanisms for minimizing risk and intraoperative detection and prevention should be considered to mitigate this complication.

Outcomes of lower extremity bypass surgery in patients with renal transplants.

OBJECTIVE: Outcomes of infrainguinal bypass surgery (IBS) in patients with renal transplants are largely undescribed. This study evaluated perioperative and long-term outcomes of IBS using autogenous and prosthetic conduits in a large population-based cohort of renal transplantation patients. METHODS: A retrospective review of all renal transplantation patients who underwent IBS between January 2007 and December 2011 in the United States Renal Data System was performed. Univariable, Kaplan-Meier, multivariable logistic, and Cox regression analyses were employed to evaluate 30-day postoperative (graft failure, limb loss, conduit infection, and death) and long-term (primary patency, primary assisted patency, secondary patency, limb salvage, and mortality) outcomes. RESULTS: There were 1048 IBSs performed (autogenous, 68%; prosthetic, 32%), predominantly for critical limb ischemia (70%). Of these, 480 (46%) were femoral-popliteal, 330 (31%) were femoral-tibial, and 238 (23%) were popliteal-tibial bypasses. Comparing autogenous vs prosthetic conduits, primary patency was 33% vs 28% (P = .22), primary assisted patency was 38% vs 31% (P = .13), secondary patency was 48% vs 53% (P = .67), limb salvage was 53% vs 63% (P = .73), and patient survival was 47% vs 51% (P = .88), all at 5 years. Risk-adjusted analyses demonstrated higher primary assisted patency (adjusted hazard ratio [aHR], 1.33; 95% confidence interval [CI], 1.06-1.66; P = .012), secondary patency (aHR, 1.33; 95% CI, 1.02-1.74; P = .034), and limb salvage (aHR, 1.35; 95% CI, 1.02-1.80; P = .037) for autogenous compared with prosthetic bypasses. There was no difference in mortality of patients who received autogenous vs prosthetic conduits. CONCLUSIONS: We have presented postoperative and long-term outcomes of IBS in renal transplantation patients. Autogenous bypasses outperform prosthetics with regard to primary assisted patency, secondary patency, and limb salvage. Given the modest survival advantage conferred by renal transplantation, maximum efforts should be made to create bypasses with autogenous conduits when it is feasible. These results should inform the patient's and surgeon's expectations in planning of IBS for these patients.

Meet your surgical team: The impact of a resident-led quality improvement project on patient satisfaction.

BACKGROUND: Patients often have an incomplete understanding of the levels of training and roles of the various surgical providers in teaching hospitals, leading to patient confusion and dissatisfaction. METHODS: Pre-intervention discharge surveys were administered to gastrointestinal surgery inpatients (10/2016-02/2017) to evaluate sentiments regarding their surgical team. During the intervention period (02/2017-05/2017), patients at admission received "facesheets" containing team member profiles, photos, training level, and roles. These patients were evaluated using the survey, and pre- and post-intervention scores compared. RESULTS: 153 pre- and 100 post-intervention surveys were collected. There was a significant increase in patients reporting it was important to know the surgical team members and that they knew team member roles (p ≤ 0.05). Scores in every domain of the satisfaction survey improved in the post-intervention period, although not reaching statistical significance. CONCLUSIONS: Improving how patients perceive their interactions with their surgical team has implications on patient satisfaction and hospital quality metrics.

Kidney offer acceptance at programs undergoing a Systems Improvement Agreement.

In the United States, the Centers for Medicare and Medicaid Services (CMS) use Systems Improvement Agreements (SIAs) to require transplant programs repeatedly flagged for poor-performance to improve performance or lose CMS funding for transplants. We identified 14 kidney transplant (KT) programs with SIAs and 28 KT programs without SIAs matched on waitlist volume and characterized kidney acceptance using SRTR data from 12/2006-3/2015. We used difference-in-differences linear regression models to identify changes in acceptance associated with an SIA independent of program variation and trends prior to the SIA. SIA programs accepted 26.9% and 22.1% of offers pre- and post-SIA, while non-SIA programs accepted 33.9% and 44.4% of offers in matched time periods. After adjustment for donor characteristics, time-varying waitlist volume, and secular trends, SIAs were associated with a 5.9 percentage-point (22%) decrease in kidney acceptance (95% CI: -10.9 to -0.8, P = .03). The decrease in acceptance post-SIA was more pronounced for KDPI 0-40 kidneys (12.3 percentage-point decrease, P = .007); reductions in acceptance of higher KDPI kidneys occurred pre-SIA. Programs undergoing SIAs substantially reduced acceptance of kidney offers for waitlisted candidates. Attempts to improve posttransplant outcomes might have the unintended consequence of reducing access to transplantation as programs adopt more restrictive organ selection practices.

Aggressive infrainguinal revascularization in renal transplant patients is justifiable.

While studies demonstrate poor outcomes of lower extremity revascularization in patients with end-stage renal disease, little is known about results in renal transplant patients. We analyzed 2-year primary patency and limb salvage outcomes and associated risk factors of transplant (n = 202) and nontransplant patients (n = 25 274) in the Vascular Quality Initiative database undergoing infrainguinal bypass from 2003 to 2016. Multivariable Cox regression analysis and coarsened exact matching with many-to-one were used. Transplant patients were more likely to have critical limb ischemia and revascularization of more distal arteries and to receive vein conduits. Primary patency was similar between transplant and nontransplant patients at 1 year (80.8% vs 77.5%) and 2 years (67.9% vs 63.7%, P = .079). Amputation-free survival was higher for nontransplant patients (1 year: 82.4% vs 75.3%, 2 years: 68.8% vs 58.2%, P = .0060), although overall survival was equivalent (2 years: 84.6% vs 87.2%, 4 years: 75.9% vs 79.6%, P = .35). Risk factors for primary patency loss included being female, critical limb ischemia, prior bypass, and distal bypass. Age, diabetes, prior contralateral amputation, critical limb ischemia, prosthetic conduit, and more distal bypass were associated with limb loss. This is the largest series of infrainguinal revascularization in transplant patients. Outcomes for transplant patients are not inferior, and aggressive approaches at limb salvage are justifiable in appropriately selected patients.

Carotid Revascularization in Asymptomatic Patients after Renal Transplantation.

BACKGROUND: In multiple studies, chronic renal insufficiency has been associated with increased risk of periprocedural stroke, cardiac complications, and death following carotid revascularization. Renal transplantation has been shown to reduce cardiovascular risk and improve survival; outcomes after carotid revascularization in renal transplant patients however are unknown. In this study, we evaluate periprocedural and long-term risks after carotid endarterectomy (CEA) and carotid artery stenting (CAS) in a cohort of renal transplant patients. METHODS: We studied all renal transplant patients in the United States Renal Data System who underwent CEA or CAS between January 2006 and December 2011. Patient outcomes were determined by linking with the Medicare database. Propensity score matched logistic and cox regression analyses were employed to evaluate perioperative stroke, myocardial infarction (MI), and death and long-term stroke and death. RESULTS: Of the 462 revascularizations for asymptomatic carotid artery stenosis between 2006 and 2011, 387 (84%) were CEA and 75 (16%) were CAS. The 2 groups did not differ in age, gender, sex, race, or baseline medical characteristics. There was no significant difference in perioperative stroke, MI, or death rates in the CEA cohort (4.7%, 4.4%, and 1.3%, respectively) compared with the CAS cohort (5.3%, 2.7%, and 4.0%, respectively). Stroke-free survival for CEA versus CAS was 93% vs. 92% at 1 year, 90% vs. 87% at 2 years, 88% vs. 87% at 3 years, and 84% vs. 82% at 4 years (P = 0.81). Overall patient survival for CEA versus CAS was 89% vs. 88% at 1 year, 77% vs. 75% at 2 years, 66% for both at 3 years, and 53% vs. 48% at 4 years (P = 0.68). In propensity score matched Cox regression analysis, there was no difference in risk of perioperative stroke or MI or in long-term stroke or death for CAS compared with CEA. CONCLUSIONS: This is the first study to evaluate outcomes following CEA and CAS in renal transplant patients. The incidence of perioperative complications in this group is higher than the maximum recommended by the Society of Vascular Surgery, and the benefits of revascularization may be outweighed by the excess periprocedural morbidity and reduced life expectancy of these patients.

Early hospital readmission for gastrointestinal-related complications predicts long-term mortality after pancreatectomy.

BACKGROUND: The purpose of this study was to investigate the prognostic significance of early (30-day) hospital readmission (EHR) on mortality after pancreatectomy. METHODS: Using a prospectively collected institutional database linked with a statewide dataset, we evaluated the association between EHR and overall mortality in all patients undergoing pancreatectomy at our tertiary institution (2005 to 2010). RESULTS: Of 595 pancreatectomy patients, EHR occurred in 21.5%. Overall mortality was 29.4% (median follow-up 22.7 months). Patients with EHR had decreased survival compared with those who were not readmitted (P = .011). On multivariate analysis adjusting for baseline group differences, EHR for gastrointestinal-related complications was a significant independent predictor of mortality (hazard ratio 2.30, P = .001). CONCLUSIONS: In addition to known risk factors, 30-day readmission for gastrointestinal-related complications following pancreatectomy independently predicts increased mortality. Additional studies are necessary to identify surgical, medical, and social factors contributing to EHR, as well as interventions aimed at decreasing postpancreatectomy morbidity and mortality.

Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease.

OBJECTIVES: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aß42 levels and t-tau/Aß42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. CONCLUSION: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.

Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis.

BACKGROUND: Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ∼10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aß42, tau, p-tau181). METHODS AND FINDINGS: Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aß42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aß42, and age. CONCLUSIONS/SIGNIFICANCE: Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential.

Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.

BACKGROUND: Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome. METHODS AND FINDINGS: CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aß42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively. CONCLUSIONS: Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aß42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.