Clinical Medicine
Soluble TREM2 levels associate with conversion from mild cognitive impairment to Alzheimer’s disease
Abstract
BACKGROUND Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) plays an important role in the clearance of pathological amyloid-β (Aβ) in Alzheimer’s disease (AD). This study aimed to explore sTREM2 as a central and peripheral predictor of the conversion from mild cognitive impairment (MCI) to AD.METHODS sTREM2 and Aβ1–42 levels in cerebrospinal fluid (CSF) and florbetapir-PET (AV45) images were analyzed for healthy control (HCs), patients with MCI, and patients with AD from the ADNI database. Peripheral plasma sTREM2 and Aβ1–42 levels were determined for our Neurology database of Ruijin Hospital for Alzheimer’s Disease (NRHAD) cohort, and patients with MCI were reevaluated at follow-up visits to assess for progression to AD. The association between CSF and plasma sTREM2 levels was analyzed in data from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) database.RESULTS The results showed that patients with MCI who had low levels of CSF sTREM2 and Aβ1–42 were more likely to develop AD. Among participants with positive Aβ deposition, as assessed by AV45 imaging, elevated CSF sTREM2 levels were associated with a decreased risk of MCI-to-AD conversion. Meanwhile, in the NRHAD cohort, individuals in the MCI group with high sTREM2 levels in plasma were at a greater risk for AD, whereas low Aβ1–42 with high sTREM2 levels in plasma were associated with a faster cognitive decline. In addition, CSF sTREM2 levels were highly correlated with plasma sTREM2 levels in the CABLE database.CONCLUSION These findings suggest that sTREM2 may be useful as a potential predictive biomarker of MCI-to-AD conversion.FUNDING This study was supported by grants from the National Natural Science Foundation of China (grant nos. 82001341, 82071415, 81873778, and 82201392); the Shanghai Sailing Program (grant no. 22YF1425100); and the China Postdoctoral Science Foundation funded project (grant no. 2021M702169).
Authors
Aonan Zhao, Yang Jiao, Guanyu Ye, Wenyan Kang, Lan Tan, Yuanyuan Li, Yulei Deng, Jun Liu, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Abstract
BACKGROUND. The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status), and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS. We observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen (EBNA) IgG levels, but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52). CONCLUSION. Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. TRIAL REGISTRATION. Long-term Impact of Infection with Novel Coronavirus (LIINC); NCT04362150 FUNDING. This work was supported by the National Institute of Allergy and Infectious Diseases NIH/NIAID 3R01AI141003-03S1 to TJ Henrich, R01AI158013 to M Gandhi and M Spinelli, K24AI145806 to P Hunt, and by the Zuckerberg San Francisco Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine. MJP is supported on K23 A137522 and received support from the UCSFBay Area Center for AIDS Research (P30-AI027763).
Authors
Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan M. Ryder, Amanda M. Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio E. Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, John Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich
Abstract
Chronic-pain is a debilitating illness that has become exceedingly widespread with currently limited treatments. Differences in the molecular signature of nociceptors, have been demonstrated between human and the commonly-used mouse model, suggesting functional differences in detection and transmission of noxious-stimuli. Therefore, direct understanding of pain-physiology in humans is required for pain treatment. This could be facilitated by studying humans carrying deleterious genetic mutations affecting pain sensation. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with several body-functions, in particular, noxious-heat detection and inflammatory-pain. Reports of adverse effects in human trials have hinder the clinical development of TRPV1 antagonists as novel pain relievers. Hence, studies on the functional roles of TRPV1, which currently rely mainly on evidences obtained from rodents, should be extended to humans. Here, we examined humans carrying a unique missense mutation in TRPV1, rendering the channel non-functional. The affected individual demonstrated lack of aversion towards capsaicin and elevated heat-pain threshold. Surprisingly, he showed elevated cold-pain threshold and extensive neurogenic inflammatory flare and pain-responses following application of the TRPA1 channel-activator, mustard-oil. Our study provides the first direct evidence for pain-related functional-changes linked to TRPV1 in humans, which is a prime target in the development of novel pain-relievers.
Authors
Ben Katz, Rachel Zaguri, Simon Edvardson, Channa Maayan, Orly Elpeleg, Shaya Lev, Elyad Davidson, Maximilian Peters, Shlomit Kfir-Erenfeld, Esther Berger, Shifa Ghazalin, Alexander M. Binshtok, Baruch Minke
Abstract
BACKGROUND. Sanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding for alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS, prevent brain atrophy and potentially delay cognitive decline. METHODS. In this phase 1/2, open-label study, subjects (n=22) affected with MPS IIIB were treated with tralesinidase alfa administered intracerebroventricularly (ICV). Subjects were monitored for drug exposure, total HS and HS non-reducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma, anti-drug antibody response, brain, spleen and liver volumes as measured by magnetic resonance imaging and cognitive development as measured by age-equivalent (AEq) scores. RESULTS. In the Part 1 dose escalation (30, 100, and 300 mg) phase, tralesinidase alfa 300 mg was necessary to achieve normalization of HS and HS-NRE in CSF and plasma. In Part 2, tralesinidase alfa 300 mg sustained HS and HS-NRE normalization in the CSF and stabilized cortical grey matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and reduction in spleen volume were observed in most subjects. Significant correlations were also established between change in cognitive AEq and plasma drug exposure, plasma HS-NRE level and change in CGMV. CONCLUSION. ICV administration of tralesinidase alfa effectively normalized HS and HS-NRE as a prerequisite for clinical efficacy. Peripheral drug exposure data suggests a role for the glymphatic system in altering tralesinidase alfa efficacy. TRIAL REGISTRATION. Clinicaltrials.gov: NCT02754076.
Authors
Nicole Muschol, Anja Koehn, Katharina von Cossel, Ilyas Okur, Fatih Ezgu, Paul Harmatz, Maria Jose de Castro Lopez, Maria Luz Couce, Shuan-Pei Lin, Spyros Batzios, Maureen Cleary, Martha Solano, Igor Nestrasil, Brian D. Kaufman, Adam J. Shaywitz, Stephen M. Maricich, Bernice Kuca, Joseph Kovalchin, Eric H. Zanelli
Abstract
BACKGROUND. Studies assessing the efficacy of therapies for neovascular age-related macular degeneration (nvAMD) have demonstrated that aflibercept may have a longer treatment interval than its lesser-expensive alternative, bevacizumab. However, whether this benefit justifies the additional cost of aflibercept remains under debate. We have recently reported that a “treat-and-extend-pause/monitor” (TEP/M) approach can be used to successfully wean 31% of nvAMD patients off anti-VEGF therapy. Here we examine whether the choice of therapy influences the outcomes of this approach. METHODS. In this retrospective analysis, 122 eyes of 106 patients with nvAMD underwent 3 consecutive monthly injections with either aflibercept (n=70) or bevacizumab (n=52) followed by a treat-and-extend protocol in which the decision to extend the interval between treatments was based on visual acuity, clinical exam, and the presence or absence of fluid on optical coherence tomography (OCT). Eyes that remained stable 12 weeks from their prior treatment were given a 6-week trial of holding further treatment, followed by quarterly monitoring. Treatment was resumed for worsening vision, clinical exam, or OCT findings. RESULTS. At the end of one year, eyes receiving bevacizumab had similar vision but required more injections (8.7 ±0.3 vs. 7.2 ±0.3) compared to aflibercept. However, eyes treated with aflibercept were almost 3-times more likely to be weaned off treatment (43% vs. 15%) compared to eyes treated with bevacizumab at the end of one year. CONCLUSIONS. These observations expose a previously unappreciated advantage of aflibercept over bevacizumab and have important clinical implications for the selection of therapy for patients with nvAMD.
Authors
Xuan Cao, Jaron Castillo Sanchez, Tapan P. Patel, Zhiyong Yang, Chuanyu Guo, Danyal Malik, Anuoluwapo Sopeyin, Silvia Montaner, Akrit Sodhi
Abstract
BACKGROUND. The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanism underlying delirium, particularly in relation to the KP, remain elusive. METHODS. We undertook a multi-center observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and one-year mortality. RESULTS. In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA, OR 2.26 [1.78, 2.87], p<0.001) to be increased, as well as increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL, β 0.43, p<0.001) and was a strong predictor of one-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, p<0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons. CONCLUSION. Our data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP, and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP. FUNDING. Norwegian Health Association and the South-Eastern Norway Regional Health Authorities
Authors
Leiv Otto Watne, Christian Thomas Pollmann, Bjorn Erik Neerland, Else Quist-Paulsen, Nathalie Bodd Halaas, Ane-Victoria Idland, Bjørnar Hassel, Kristi Henjum, Anne-Brita Knapskog, Frede Frihagen, Johan Raeder, Aasmund Godø, Per Magne Ueland, Adrian McCann, Wender Figved, Geir Selbæk, Henrik Zetterberg, Evandro Fei Fang, Marius Myrstad, Lasse M. Giil
Abstract
BACKGROUND. Acute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. Disease pathophysiology remains elusive, and current dogma suggests Sweet syndrome is a “reactive” process to an unknown antigen. Corticosteroids and steroid-sparing agents remain front-line therapies, but refractory cases pose a clinical challenge. METHODS. A 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole genome sequencing, transcriptomic profiling, and cellular assays of patient’s skin and neutrophils were performed. RESULTS. We identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration towards IL-1β and neutrophil respiratory burst. Targeted treatment with an IL-1R1 antagonist in the patient resulted in a dramatic therapeutic response and enabled tapering of corticosteroids. CONCLUSIONS. Dysregulated PI3K-AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests Sweet syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogenous disease that resulted in a rational and successful clinical intervention. Future cases will benefit from efforts to identify potential mutations. The ability to directly interrogate diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for challenging patients. FUNDING Berstein Foundation, NIH, VA, Moseley Foundation, and H.T. Leung Foundation.
Authors
Shreya Bhattacharya, Sayon Basu, Emily Sheng, Christina M. Murphy, Jenny Wei, Anna E. Kersh, Caroline A. Nelson, Joshua S. Bryer, Hovik A. Ashchyan, Katherine T. Steele, Amy K. Forrestel, John T. Seykora, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
Abstract
BACKGROUND. Results of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP. METHODS. Of 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP-donors (n=113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTS. The median follow-up of patients was 396 days, the estimated 1-year survival was 78.7% in the CCP and 60.2% in the control group (p=0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared to the control group (91.5% versus 60.2%; p=0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase of neutralizing antibodies after vaccination between CCP and the control group. CONCLUSION. The trial demonstrated a trend towards better outcome in the CCP group without reaching statistical significance. A pre-defined subgroup analysis showed a significant better outcome (long-term survival; time to discharge from ICU and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared to the control group. A substantial long-term disease burden remains after severe COVID-19. TRIAL REGISTRATION. EudraCT number 2020-001310-38 FUNDING. Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802/ZMI1-2521COR802
Authors
Sixten Körper, Beate Grüner, Daniel Zickler, Thomas Wiesmann, Patrick Wuchter, Rainer Blasczyk, Kai Zacharowski, Peter Spieth, Torsten Tonn, Peter Rosenberger, Gregor Paul, Jan Pilch, Joachim Schwäble, Tamam Bakchoul, Thomas Thiele, Julian Knoerlein, Matthias M. Dollinger, Joerg Krebs, Martin Bentz, Victor M. Corman, Dzenan Kilalic, Gerlinde Schmidtke-Schrezenmeier, Philipp M. Lepper, Lucas Ernst, Hinnerk Wulf, Alexandra Ulrich, Manfred Weiss, Jan Kruse, Thomas Burkhardt, Rebecca Müller, Harald Klüter, Michael Schmidt, Bernd Jahrsdörfer, Ramin Lotfi, Markus Rojewski, Thomas Appl, Benjamin Mayer, Philipp Schnecko, Erhard Seifried, Hubert Schrezenmeier
Abstract
BACKGROUND A pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODS This prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives — 220 in a derivation cohort and 176 in a validation cohort — were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTS Prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0–6.7), male sex (aOR: 3.79, 95% CI 1.6–9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3–9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5–57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSION First-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDING Supported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the EFPIA.
Authors
Nobuharu Tamaki, Noora Ahlholm, Panu K. Luukkonen, Kimmo Porthan, Suzanne R. Sharpton, Veeral Ajmera, Yuko Kono, Shravan Dave, Aijaz Ahmed, Vinay Sundaram, Michael J. Wilkinson, Heather Patton, Hersh Gupta, Vanessa Cervantes, Christie Hernandez, Scarlett J. Lopez, Ria Loomba, Amanda Baumgartner, Lisa Richards, Perttu E.T. Arkkila, Katriina Nemes, Helena Isoniemi, Hannele Yki-Järvinen, Rohit Loomba
Abstract
Background Neuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.Methods We performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.Results Using the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.Conclusion Our analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.Funding NIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation — PCF Challenge Award).
Authors
Shuang G. Zhao, Jamie M. Sperger, Jennifer L. Schehr, Rana R. McKay, Hamid Emamekhoo, Anupama Singh, Zachery D. Schultz, Rory M. Bade, Charlotte N. Stahlfeld, Cole S. Gilsdorf, Camila I. Hernandez, Serena K. Wolfe, Richel D. Mayberry, Hannah M. Krause, Matt Bootsma, Kyle T. Helzer, Nicholas Rydzewski, Hamza Bakhtiar, Yue Shi, Grace Blitzer, Christos E. Kyriakopoulos, David Kosoff, Xiao X. Wei, John Floberg, Nan Sethakorn, Marina Sharifi, Paul M. Harari, Wei Huang, Himisha Beltran, Toni K. Choueiri, Howard I. Scher, Dana E. Rathkopf, Susan Halabi, Andrew J. Armstrong, David J. Beebe, Menggang Yu, Kaitlin E. Sundling, Mary-Ellen Taplin, Joshua M. Lang
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Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)