Chloe Nobuhara

All Publications

• The Surgical Residency of Tomorrow: A Case for Authenticity. Journal of the American College of Surgeons Klaris, G. E., Branch, R., Wang, L., Nobuhara, C. K., Spain, D. A. 2025

  View details for DOI 10.1097/XCS.0000000000001698

  View details for PubMedID 41263774

• Surgical stabilization of flail sternum and bilateral chest wall injury in an octogenarian after horse trampling injury. Trauma surgery & acute care open Tai, J. W., Ko, B., Adams, M. E., Nobuhara, C. K., Knight, A. W., Forrester, J. D. 2025; 10 (4): e001999

  View details for DOI 10.1136/tsaco-2025-001999

  View details for PubMedID 41158727

  View details for PubMedCentralID PMC12557740

• The Role of Sleep Apnea in Postoperative Neurocognitive Disorders Among Older Noncardiac Surgery Patients: A Prospective Cohort Study. Anesthesia and analgesia Devinney, M. J., Spector, A. R., Wright, M. C., Thomas, J., Avasarala, P., Moretti, E. W., Dominguez, J. E., Smith, P. J., Whitson, H. E., Veasey, S. C., Mathew, J. P., Berger, M. 2025; 140 (1): 99-109

  Abstract

  Obstructive sleep apnea is associated with increased dementia risk, yet its role in postoperative neurocognitive disorders is unclear. Here, we studied whether the severity of untreated obstructive sleep apnea is associated with the severity of postoperative neurocognitive disorder.In this single-center prospective cohort study, older noncardiac surgery patients aged 60 years and above underwent preoperative home sleep apnea testing, and pre- and postoperative delirium assessments and cognitive testing. Sleep apnea severity was determined using the measured respiratory event index (REI). Global cognitive change from before to 6 weeks (and 1 year) after surgery was used to measure postoperative neurocognitive disorder severity. Postoperative changes in individual cognitive domain performance along with subjective cognitive complaints and/or deficits in instrumental activities of daily living were used to measure postoperative neurocognitive disorder incidence.Of 96 subjects who completed home sleep apnea testing, 58 tested positive for sleep apnea. In univariable analyses, sleep apnea severity was not associated with increased postoperative neurocognitive disorder severity at 6 weeks (global cognitive change ; [95% confidence interval [CI], -0.02 to 0.03]; P = .79) or 1-year after surgery (; [95% CI, -0.02 to 0.03]; P = .70). Adjusting for age, sex, baseline cognition, and surgery duration, sleep apnea severity remained not associated with increased postoperative neurocognitive disorder severity at 6 weeks (; [95% CI, -0.02 to 0.04]; P = .40) or 1-year after surgery (; [95% CI, -0.02 to 0.04]; P = .55). In a multivariable analysis, sleep apnea severity was not associated with postoperative neurocognitive disorder (either mild or major) incidence at 6 weeks (odds ratio [OR] = 0.89, [95% CI, 0.59-1.14]; P = .45) or 1-year postoperatively (OR = 1.01, [95% CI, 0.81-1.24]; P = .90). Sleep apnea severity was also not associated with postoperative delirium in univariable analyses (delirium incidence OR = 0.88, [95% CI, 0.59-1.10]; P = .37; delirium severity ; [95% CI, -0.02 to 0.03]; P = .79) or in multivariable analyses (delirium incidence OR = 1.07, [95% CI, 0.81-1.38]; P = .74; delirium severity OR = 0.95, [95% CI, 0.81-1.10]; P = .48).In this older noncardiac surgery cohort, untreated sleep apnea was not associated with increased incidence or severity of postoperative neurocognitive disorder or delirium.

  View details for DOI 10.1213/ANE.0000000000007269

  View details for PubMedID 39688967

• Resident-Applicant Buddy Program Increases Applicant Interest and Program Transparency. Journal of surgical education Shearer, J., Ngongoni, R. F., Yelorda, K., Nobuhara, C., Lin, D. T., Gahagan, J., Dua, M., Spain, D. A., Liebert, C. A. 2024; 81 (11): 1792-1797

  Abstract

  Resident-Applicant Buddy Programs (RABPs) are a new initiative designed to improve resident recruitment. This study aims to evaluate the impact and perceived value of RABPs and to identify areas for improvement for future recruitment cycles.Anonymous online survey study of RABP participants with mixed-methods approach to evaluate participants' experience and perceived impact of the program. The survey queried demographics, Likert responses, and open-ended responses. Qualitative thematic analysis of open-ended responses was performed with inductive coding in an iterative fashion by 2 raters.This study was conducted at a general surgery residency program at a tertiary academic institution during 2022-2023 recruitment cycle.Of 125 RABP participants (n = 39 residents and n = 86 interviewed applicants), surveys from n = 45 participants (n = 19 residents, 66%; n = 26 applicants, 30%) were completed and analyzed.Applicants were predominantly female (65%) and first-generation physicians (69%). Buddy pairings were 65% gender concordant and 48% race/ethnicity concordant. Many applicants (60%) participated in RABPs at other institutions. Buddies connected for a mean (SD) of 52 (28) minutes. Majority of applicants agreed the program decreased stress/apprehension about interviewing (70%, 4.0 [1.1]), helped understand resident life at the program (91%, 4.3 [1.0]), and increased desire to match in the program (65%, 4.0 [1.1]). Residents agreed they enjoyed participation (89%, 4.5 [0.7]), the program should be continued (100%, 4.8 [0.4]), and desired to participate again (100%, 4.8 [0.4]). Thematic analysis revealed applicants valued the program as an approachable source of information, illumination of program culture, aid in interview preparation, and connection between applicant and program. Applicants appreciated the intentionality of the program to create a RABP.RABP decreased applicants' stress, improved understanding of resident life, and for the majority, increased desire to match at the program. Resident engagement and desire for ongoing participation in the RABP was high. Overall, RABPs can increase applicant interest and program transparency.

  View details for DOI 10.1016/j.jsurg.2024.08.010

  View details for PubMedID 39321695

• Initial Multivisceral Resection for Retroperitoneal Liposarcoma Does Not Predict Improved Outcomes After Recurrence Sun, B. J., Yue, T. M., Nobuhara, C. K., Castro, S., Agolia, J. P., Lee, B. SPRINGER. 2024: S42

  View details for Web of Science ID 001185577500086

• Regional vs General Anesthesia and Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Nobuhara, C., Devinney, M., Berger, M. 2022; 327 (17): 1707-+

  View details for DOI 10.1001/jama.2022.3538

  View details for Web of Science ID 000793675300025

  View details for PubMedID 35503352

• Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY Berger, M., Browndyke, J. N., Wright, M., Nobuhara, C., Reese, M., Acker, L., Bullock, W., Colin, B. J., Devinney, M. J., Moretti, E. W., Moul, J. W., Ohlendorf, B., Laskowitz, D. T., Waligorska, T., Shaw, L. M., Whitson, H. E., Cohen, H. J., Mathew, J. P., MADCO-PC Investigators 2022; 9 (2): 155-170

  Abstract

  Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aβ levels after non-cardiac, non-neurologic surgery in older adults.Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis.There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aβ over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aβ42 changes over this interval (p > 0.05 for each).Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aβ, tau or p-tau-181p levels or the p-tau-181p/Aβ or tau/Aβ ratios).clinicaltrials.gov (NCT01993836).

  View details for DOI 10.1002/acn3.51499

  View details for Web of Science ID 000749251400001

  View details for PubMedID 35104057

  View details for PubMedCentralID PMC8862419

• A Historical Cohort in Kidney Transplantation: 55-Year Follow-Up of 72 HLA-Identical, Donor-Recipient Pairs. Journal of clinical medicine Shaw, B. I., Villani, V., Kesseli, S. J., Nobuhara, C., Samoylova, M. L., Moris, D., Collins, B. H., McElroy, L. M., Poh, M., Knechtle, S. J., Barbas, A. S., Seigler, H. F. 2021; 10 (23)

  Abstract

  The impact of HLA matching on graft survival has been well characterized in renal transplantation, with a higher degree of matching associated with superior graft survival. Additionally, living donor grafts are known to confer superior survival compared to those from deceased donors. The purpose of this study is to report our multi-decade institutional experience and outcomes for patients who received HLA-identical living donor grafts, which represent the most favorable scenario in kidney transplantation. We conducted a retrospective analysis of these graft recipients performed at a Duke University Medical Center between the years of 1965 and 2002. The recipients demonstrated excellent graft and patient survival outcomes, superior to a contemporary cohort, with median patient and graft survival of 24.2 and 30.9 years, respectively, among Duke recipients vs. 16.1 and 16.0 years in a cohort derived from national data. This study offers a broad perspective on the importance of HLA matching and graft type, and demonstrates a historical best-case-scenario in renal transplantation.

  View details for DOI 10.3390/jcm10235505

  View details for PubMedID 34884207

  View details for PubMedCentralID PMC8658388

• HLA Loci and Recurrence of Focal Segmental Glomerulosclerosis in Pediatric Kidney Transplantation. Transplantation direct Shaw, B. I., Ochoa, A., Chan, C., Nobuhara, C., Gbadegesin, R., Jackson, A. M., Chambers, E. T. 2021; 7 (10): e748

  Abstract

  Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation accounts for the majority of allograft failures in children with primary FSGS. Although current research focuses on FSGS pathophysiology, a common etiology and mechanisms of disease recurrence remain elusive.We performed a retrospective review of the Scientific Registry of Transplant Recipients to determine the association of specific HLA recurrence of FSGS. Kidney transplants recipients under the age of 19 who were diagnosed with FSGS, who were transplanted after January 1, 2000, and who had complete HLA data were included in the study. We performed simple logistic regression on all HLA A, B, C, DR, and DQ represented in the dataset and FSGS recurrence and then determined those associated with recurrence using the Benjamini-Hochberg method for multiple comparisons. For those HLAs that were associated with recurrence, we further determined the effect of matching recipient and donor HLA with recurrence.HLA DR7, DR53, DQ2, DR52, and DQ7 were associated with increased or decreased risk of recurrent disease after transplantation. We identified a risk haplotype consisting of HLA-DR7, DR53, and DQ2 that was consistently associated with an increased risk of recurrence (odds ratio 1.91; 95% confidence interval, 1.44-2.54, P < 0.001). We also found that donor/recipient concordance for HLA-DQ7 was associated with a decreased risk of recurrence (odds ratio 0.42; 95% confidence interval, 0.37-0.53, P = 0.009).HLA profiles may be used for risk stratification of recurrence of FSGS in pediatric kidney transplant recipients and deserves further study.

  View details for DOI 10.1097/TXD.0000000000001201

  View details for PubMedID 34476293

  View details for PubMedCentralID PMC8405131

• Immune Thrombocytopenia Associated with Hepatitis B Virus and Autoimmune Hepatitis and Recovery of Platelet Count following Liver Transplantation. Case reports in transplantation Nobuhara, C., Cardona, D. M., Arcasoy, M. O., Berg, C. L., Barbas, A. S. 2021; 2021: 8484106

  Abstract

  Immune thrombocytopenia is a consumptive coagulopathy that can be either idiopathic or associated with infectious or autoimmune etiologies. Here, we present a case of immune thrombocytopenia in the setting of acute liver failure due to coexisting diagnoses of hepatitis B virus and autoimmune hepatitis. Our patient underwent orthotopic liver transplantation and recovered hemostatic platelet counts after treatment with romiplostim, a thrombopoietin receptor agonist, 51 days after transplantation. To our knowledge, this is the first case report of immune thrombocytopenia secondary to both hepatitis B virus and autoimmune hepatitis in a patient with acute liver failure.

  View details for DOI 10.1155/2021/8484106

  View details for PubMedID 34567820

  View details for PubMedCentralID PMC8457963

• Cellular Therapies in Solid Organ Allotransplantation: Promise and Pitfalls. Frontiers in immunology Shaw, B. I., Ord, J. R., Nobuhara, C., Luo, X. 2021; 12: 714723

  Abstract

  Donor specific transfusions have been the basis of tolerance inducing protocols since Peter Medawar showed that it was experimentally feasible in the 1950s. Though trials of cellular therapies have become increasingly common in solid organ transplantation, they have not become standard practice. Additionally, whereas some protocols have focused on cellular therapies as a method for donor antigen delivery-thought to promote tolerance in and of itself in the correct immunologic context-other approaches have alternatively focused on the intrinsic immunosuppressive properties of the certain cell types with less emphasis on their origin, including mesenchymal stem cells, regulatory T cells, and regulatory dendritic cells. Regardless of intent, all cellular therapies must contend with the potential that introducing donor antigen in a new context will lead to sensitization. In this review, we focus on the variety of cellular therapies that have been applied in human trials and non-human primate models, describe their efficacy, highlight data regarding their potential for sensitization, and discuss opportunities for cellular therapies within our current understanding of the immune landscape.

  View details for DOI 10.3389/fimmu.2021.714723

  View details for PubMedID 34526991

  View details for PubMedCentralID PMC8435835

• Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study. Journal of neuroinflammation Vasunilashorn, S. M., Ngo, L. H., Dillon, S. T., Fong, T. G., Carlyle, B. C., Kivisäkk, P., Trombetta, B. A., Vlassakov, K. V., Kunze, L. J., Arnold, S. E., Xie, Z., Inouye, S. K., Libermann, T. A., Marcantonio, E. R. 2021; 18 (1): 103

  Abstract

  Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation.We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). The integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine the correlation between biofluids.Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline.In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

  View details for DOI 10.1186/s12974-021-02145-8

  View details for PubMedID 33931093

  View details for PubMedCentralID PMC8088047

• Risk of Spinal Hematoma After Lumbar Puncture JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Nobuhara, C., Berger, M. 2021; 325 (8): 787-+

  View details for DOI 10.1001/jama.2020.24601

  View details for Web of Science ID 000621957400030

  View details for PubMedID 33620394

• Machine Learning to Develop and Internally Validate a Predictive Model for Post-operative Delirium in a Prospective, Observational Clinical Cohort Study of Older Surgical Patients. Journal of general internal medicine Racine, A. M., Tommet, D., D'Aquila, M. L., Fong, T. G., Gou, Y., Tabloski, P. A., Metzger, E. D., Hshieh, T. T., Schmitt, E. M., Vasunilashorn, S. M., Kunze, L., Vlassakov, K., Abdeen, A., Lange, J., Earp, B., Dickerson, B. C., Marcantonio, E. R., Steingrimsson, J., Travison, T. G., Inouye, S. K., Jones, R. N. 2021; 36 (2): 265-273

  Abstract

  Our objective was to assess the performance of machine learning methods to predict post-operative delirium using a prospective clinical cohort.We analyzed data from an observational cohort study of 560 older adults (≥ 70 years) without dementia undergoing major elective non-cardiac surgery. Post-operative delirium was determined by the Confusion Assessment Method supplemented by a medical chart review (N = 134, 24%). Five machine learning algorithms and a standard stepwise logistic regression model were developed in a training sample (80% of participants) and evaluated in the remaining hold-out testing sample. We evaluated three overlapping feature sets, restricted to variables that are readily available or minimally burdensome to collect in clinical settings, including interview and medical record data. A large feature set included 71 potential predictors. A smaller set of 18 features was selected by an expert panel using a consensus process, and this smaller feature set was considered with and without a measure of pre-operative mental status.The area under the receiver operating characteristic curve (AUC) was higher in the large feature set conditions (range of AUC, 0.62-0.71 across algorithms) versus the selected feature set conditions (AUC range, 0.53-0.57). The restricted feature set with mental status had intermediate AUC values (range, 0.53-0.68). In the full feature set condition, algorithms such as gradient boosting, cross-validated logistic regression, and neural network (AUC = 0.71, 95% CI 0.58-0.83) were comparable with a model developed using traditional stepwise logistic regression (AUC = 0.69, 95% CI 0.57-0.82). Calibration for all models and feature sets was poor.We developed machine learning prediction models for post-operative delirium that performed better than chance and are comparable with traditional stepwise logistic regression. Delirium proved to be a phenotype that was difficult to predict with appreciable accuracy.

  View details for DOI 10.1007/s11606-020-06238-7

  View details for PubMedID 33078300

  View details for PubMedCentralID PMC7878663

• Autoantibodies against the prion protein in individuals with PRNP mutations. Neurology Frontzek, K., Carta, M., Losa, M., Epskamp, M., Meisl, G., Anane, A., Brandel, J. P., Camenisch, U., Castilla, J., Haïk, S., Knowles, T., Lindner, E., Lutterotti, A., Minikel, E. V., Roiter, I., Safar, J. G., Sanchez-Valle, R., Žáková, D., Hornemann, S., Aguzzi, A. 2020; 95 (14): e2028-e2037

  Abstract

  To determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease.In this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) PRNP mutation carriers vs controls and (2) asymptomatic vs symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts.We found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as PRNP codon 129 polymorphism.Pathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated.NCT02837705.

  View details for DOI 10.1212/WNL.0000000000009183

  View details for PubMedID 32098855

  View details for PubMedCentralID PMC7682844

• Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease. BMC medicine Vallabh, S. M., Minikel, E. V., Williams, V. J., Carlyle, B. C., McManus, A. J., Wennick, C. D., Bolling, A., Trombetta, B. A., Urick, D., Nobuhara, C. K., Gerber, J., Duddy, H., Lachmann, I., Stehmann, C., Collins, S. J., Blennow, K., Zetterberg, H., Arnold, S. E. 2020; 18 (1): 140

  Abstract

  Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population.We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months.CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

  View details for DOI 10.1186/s12916-020-01608-8

  View details for PubMedID 32552681

  View details for PubMedCentralID PMC7302371

• A protocol to reduce self-reported pain scores and adverse events following lumbar punctures in older adults JOURNAL OF NEUROLOGY Nobuhara, C. K., Bullock, W., Bunning, T., Colin, B., Cooter, M., Devinney, M. J., Ferrandino, M. N., Gadsden, J., Garrigues, G., Habib, A. S., Moretti, E., Moul, J., Ohlendorf, B., Sandler, A., Scheri, R., Sharma, B., Thomas, J. P., Young, C., Mathew, J. P., Berger, M., MADCO-PC Investigator Team, INTUIT Investigator Team 2020; 267 (7): 2002-2006

  Abstract

  Lumbar punctures (LPs) are important for obtaining CSF in neurology studies but are associated with adverse events and feared by many patients. We determined adverse event rates and pain scores in patients prospectively enrolled in two cohort studies who underwent LPs using a standardized protocol and 25 g needle.Eight hundred and nine LPs performed in 262 patients age ≥ 60 years in the MADCO-PC and INTUIT studies were analyzed. Medical records were monitored for LP-related adverse events, and patients were queried about subjective complaints. We analyzed adverse event rates, including headaches and pain scores.There were 22 adverse events among 809 LPs performed, a rate of 2.72% (95% CI 1.71-4.09%). Patient hospital stay did not increase due to adverse events. Four patients (0.49%) developed a post-lumbar puncture headache (PLPH). Twelve patients (1.48%) developed nausea, vasovagal responses, or headaches that did not meet PLPH criteria. Six patients (0.74%) reported lower back pain at the LP site not associated with muscular weakness or paresthesia. The median pain score was 1 [0, 3]; the mode was 0 out of 10.The LP protocol described herein may reduce adverse event rates and improve patient comfort in future studies.

  View details for DOI 10.1007/s00415-020-09797-1

  View details for Web of Science ID 000520898400001

  View details for PubMedID 32198714

  View details for PubMedCentralID PMC7336280

• The Role of Inflammation after Surgery for Elders (RISE) study: Study design, procedures, and cohort profile. Alzheimer's & dementia (Amsterdam, Netherlands) Hshieh, T. T., Vasunilashorn, S. M., D'Aquila, M. L., Arnold, S. E., Dickerson, B. C., Fong, T. G., Jones, R. N., Marcantonio, E. R., Schmitt, E. M., Xu, G., Gou, Y., Chen, F., Kunze, L. J., Vlassakov, K. V., Abdeen, A. R., Lange, J. K., Earp, B. E., Touroutoglou, A., Carlyle, B. C., Kivisakk-Webb, P., Travison, T. G., Dillon, S. T., Libermann, T. A., Inouye, S. K. 2019; 11: 752-762

  Abstract

  The Role of Inflammation after Surgery for Elders study correlates novel inflammatory markers measured in blood, cerebrospinal fluid (CSF) assays, and [11C]-PBR28 positron-emission tomography imaging.This study involved a prospective cohort design with patients who underwent elective hip and knee arthroplasty under spinal anesthesia. Sixty-five adults participated with their family members. Inflammatory biomarker assays were measured preoperatively on day 1 and postoperatively at one month.On average, participants were 75 years old, and 72% were female. 54% underwent total knee arthroplasty, and 46% underwent total hip arthroplasty. The mean Modified Mini-Mental State (3MS) Examination score was 89.3; four patients (6%) scored ≤77 points. Plasma assays were completed in 63 (97%) participants, cerebrospinal fluid assays in 61 (94%), and PET imaging in 44 (68%).This complex study presents an innovative effort to correlate peripheral and central inflammatory biomarkers before and after major surgery in older adults. Strengths include collecting concurrent blood, cerebrospinal fluid, and positron-emission tomography with detailed clinical characterization of delirium, cognition, and functional status.

  View details for DOI 10.1016/j.dadm.2019.09.004

  View details for PubMedID 31737775

  View details for PubMedCentralID PMC6849121

• Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development. Proceedings of the National Academy of Sciences of the United States of America Vallabh, S. M., Nobuhara, C. K., Llorens, F., Zerr, I., Parchi, P., Capellari, S., Kuhn, E., Klickstein, J., Safar, J. G., Nery, F. C., Swoboda, K. J., Geschwind, M. D., Zetterberg, H., Arnold, S. E., Minikel, E. V., Schreiber, S. L. 2019; 116 (16): 7793-7798

  Abstract

  Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by the addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test-retest reliability (mean coefficient of variation, 13% in samples collected 8-11 wk apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, and will facilitate development of prion disease therapeutics with this mechanism of action.

  View details for DOI 10.1073/pnas.1901947116

  View details for PubMedID 30936307

  View details for PubMedCentralID PMC6475435

• Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain. Frontiers in neuroscience DeVos, S. L., Corjuc, B. T., Oakley, D. H., Nobuhara, C. K., Bannon, R. N., Chase, A., Commins, C., Gonzalez, J. A., Dooley, P. M., Frosch, M. P., Hyman, B. T. 2018; 12: 267

  Abstract

  Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

  View details for DOI 10.3389/fnins.2018.00267

  View details for PubMedID 29740275

  View details for PubMedCentralID PMC5928393

• Biomarkers in Alzheimer's, Frontotemporal, Lewy Body, and Vascular Dementias. Focus (American Psychiatric Publishing) Koenig, A. M., Nobuhara, C. K., Williams, V. J., Arnold, S. E. 2018; 16 (2): 164-172

  Abstract

  This article reviews the current evidence base for biomarkers of the most common causes of dementia in later life: Alzheimer's disease (AD), frontotemporal lobar degenerations, Lewy body dementias, and vascular cognitive impairment and dementia. Biomarkers are objectively measurable indicators of normal physiology, pathological processes, or response to an intervention. Ideally, they are sensitive, specific, easy to obtain, and closely reflect the underlying biological processes of interest. While such markers are well established and in broad clinical use for common disorders in general medicine (e.g., thallium stress tests for coronary artery disease or serum blood urea nitrogen and creatinine for renal failure), analogous, validated markers for AD or other common dementias are limited, although biomarkers in research settings and specialty dementia clinics are progressing toward clinical use. By way of introducing current and future biomarkers for dementias of later life, this article will benefit the practicing clinician by increasing awareness of the availability and utility of current and emerging biomarkers in dementia diagnosis and prognosis and for monitoring new disease-modifying therapeutics that arrive in the clinic over the coming decade.

  View details for DOI 10.1176/appi.focus.20170048

  View details for PubMedID 31975911

  View details for PubMedCentralID PMC6526853

• Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro. The American journal of pathology Nobuhara, C. K., DeVos, S. L., Commins, C., Wegmann, S., Moore, B. D., Roe, A. D., Costantino, I., Frosch, M. P., Pitstick, R., Carlson, G. A., Hock, C., Nitsch, R. M., Montrasio, F., Grimm, J., Cheung, A. E., Dunah, A. W., Wittmann, M., Bussiere, T., Weinreb, P. H., Hyman, B. T., Takeda, S. 2017; 187 (6): 1399-1412

  Abstract

  The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer-based tau uptake assay to assess blocking efficacy. The antibodies reduced tau uptake in an epitope-dependent manner: N-terminal (Tau13) and middomain (6C5 and HT7) antibodies successfully prevented uptake of tau species, whereas the distal C-terminal-specific antibody (Tau46) had little effect. Phosphorylation-dependent (40E8 and p396) and C-terminal half (4E4) tau antibodies also reduced tau uptake despite removing less total tau by immunodepletion, suggesting specific interactions with species involved in uptake. Among the seven antibodies evaluated, 6C5 most efficiently blocked uptake and subsequent aggregation. More important, 6C5 also blocked neuron-to-neuron spreading of tau in a unique three-chamber microfluidic device. Furthermore, 6C5 slowed down the progression of tau aggregation even after uptake had begun. Our results imply that not all antibodies/epitopes are equally robust in terms of blocking tau uptake of human AD-derived tau species.

  View details for DOI 10.1016/j.ajpath.2017.01.022

  View details for PubMedID 28408124

  View details for PubMedCentralID PMC5455060

• Characterization of TauC3 antibody and demonstration of its potential to block tau propagation. PloS one Nicholls, S. B., DeVos, S. L., Commins, C., Nobuhara, C., Bennett, R. E., Corjuc, D. L., Maury, E., Eftekharzadeh, B., Akingbade, O., Fan, Z., Roe, A. D., Takeda, S., Wegmann, S., Hyman, B. T. 2017; 12 (5): e0177914

  Abstract

  The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer's disease (AD), which is thought to be caused by the propagation of "seeding" competent soluble misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.

  View details for DOI 10.1371/journal.pone.0177914

  View details for PubMedID 28531180

  View details for PubMedCentralID PMC5439699

• Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients. Annals of neurology Takeda, S., Commins, C., DeVos, S. L., Nobuhara, C. K., Wegmann, S., Roe, A. D., Costantino, I., Fan, Z., Nicholls, S. B., Sherman, A. E., Trisini Lipsanopoulos, A. T., Scherzer, C. R., Carlson, G. A., Pitstick, R., Peskind, E. R., Raskind, M. A., Li, G., Montine, T. J., Frosch, M. P., Hyman, B. T. 2016; 80 (3): 355-67

  Abstract

  Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high-molecular-weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates.We have examined seeding and uptake properties of brain extracellular tau from various sources, including interstitial fluid (ISF) and CSF from an AD transgenic mouse model and postmortem ventricular and antemortem lumbar CSF from AD patients.We found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients, and its levels were significantly elevated compared to control subjects. HMW tau derived from CSF of AD patients was seed competent in vitro.These findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species, giving new insights into the role of CSF tau and biomarker development for AD. Ann Neurol 2016;80:355-367.

  View details for DOI 10.1002/ana.24716

  View details for PubMedID 27351289

  View details for PubMedCentralID PMC5016222

• Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain. Nature communications Takeda, S., Wegmann, S., Cho, H., DeVos, S. L., Commins, C., Roe, A. D., Nicholls, S. B., Carlson, G. A., Pitstick, R., Nobuhara, C. K., Costantino, I., Frosch, M. P., Müller, D. J., Irimia, D., Hyman, B. T. 2015; 6: 8490

  Abstract

  Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.

  View details for DOI 10.1038/ncomms9490

  View details for PubMedID 26458742

  View details for PubMedCentralID PMC4608380