Browsing by Author "Zetterberg, Henrik"

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    The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans
    (Elsevier, 2015-07) Kang, Ju-Hee; Korecka, Magdalena; Figurski, Michal J.; Toledo, Jon B.; Blennow, Kaj; Zetterberg, Henrik; Waligorska, Teresa; Brylska, Magdalena; Fields, Leona; Shah, Nirali; Soares, Holly; Dean, Robert A.; Vanderstichele, Hugo; Petersen, Ronald C.; Aisen, Paul S.; Saykin, Andrew J.; Weiner, Michael W.; Trojanowski, John Q.; Shaw, Leslie M.; Alzheimer's Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. METHODS: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1-42, t-tau, and p-tau181 data. RESULTS: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. DISCUSSION: Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.
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    Association between plasma tau and postoperative delirium incidence and severity: a prospective observational study
    (Elsevier, 2021) Ballweg, Tyler; White, Marissa; Parker, Margaret; Casey, Cameron; Bo, Amber; Farahbakhsh, Zahra; Kayser, Austin; Blair, Alexander; Lindroth, Heidi; Pearce, Robert A.; Blennow, Kaj; Zetterberg, Henrik; Lennertz, Richard; Sanders, Robert D.; Medicine, School of Medicine
    Background: Postoperative delirium is associated with increases in the neuronal injury biomarker, neurofilament light (NfL). Here we tested whether two other biomarkers, glial fibrillary acidic protein (GFAP) and tau, are associated with postoperative delirium. Methods: A total of 114 surgical patients were recruited into two prospective biomarker cohort studies with assessment of delirium severity and incidence. Plasma samples were sent for biomarker analysis including tau, NfL, and GFAP, and a panel of 10 cytokines. We determined a priori to adjust for interleukin-8 (IL-8), a marker of inflammation, when assessing associations between biomarkers and delirium incidence and severity. Results: GFAP concentrations showed no relationship to delirium. The change in tau from preoperative concentrations to postoperative Day 1 was greater in patients with postoperative delirium (P<0.001) and correlated with delirium severity (ρ=0.39, P<0.001). The change in tau correlated with increases in IL-8 (P<0.001) and IL-10 (P=0.0029). Linear regression showed that the relevant clinical predictors of tau changes were age (P=0.037), prior stroke/transient ischaemic attack (P=0.001), and surgical blood loss (P<0.001). After adjusting for age, sex, preoperative cognition, and change in IL-8, tau remained significantly associated with delirium severity (P=0.026). Using linear mixed effect models, only tau (not NfL or IL-8) predicted recovery from delirium (P<0.001). Conclusions: The change in plasma tau was associated with delirium incidence and severity, and resolved over time in parallel with delirium features. The impact of this putative perioperative neuronal injury biomarker on long-term cognition merits further investigation.
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    Biomarkers for dementia in Latin American countries: Gaps and opportunities
    (Wiley, 2023) Parra, Mario A.; Orellana, Paulina; Leon, Tomas; Victoria, Cabello G.; Henriquez, Fernando; Gomez, Rodrigo; Avalos, Constanza; Damian, Andres; Slachevsky, Andrea; Ibañez, Agustin; Zetterberg, Henrik; Tijms, Betty M.; Yokoyama, Jennifer S.; Piña-Escudero, Stefanie D.; Cochran, J. Nicholas; Matallana, Diana L.; Acosta, Daisy; Allegri, Ricardo; Arias-Suárez, Bianca P.; Barra, Bernardo; Behrens, Maria Isabel; Brucki, Sonia M. D.; Busatto, Geraldo; Caramelli, Paulo; Castro-Suarez, Sheila; Contreras, Valeria; Custodio, Nilton; Dansilio, Sergio; De la Cruz-Puebla, Myriam; de Souza, Leonardo Cruz; Diaz, Monica M.; Duque, Lissette; Farías, Gonzalo A.; Ferreira, Sergio T.; Guimet, Nahuel Magrath; Kmaid, Ana; Lira, David; Lopera, Francisco; Mar Meza, Beatriz; Miotto, Eliane C.; Nitrini, Ricardo; Nuñez, Alberto; O'Neill, Santiago; Ochoa, John; Pintado-Caipa, Maritza; Resende, Elisa de Paula França; Risacher, Shannon; Rojas, Luz Angela; Sabaj, Valentina; Schilling, Lucas; Sellek, Allis F.; Sosa, Ana; Takada, Leonel T.; Teixeira, Antonio L.; Unaucho-Pilalumbo, Martha; Duran-Aniotz, Claudia; Radiology and Imaging Sciences, School of Medicine
    Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.
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    Blood biomarkers for Alzheimer’s disease in clinical practice and trials
    (Springer Nature, 2023) Hansson, Oskar; Blennow, Kaj; Zetterberg, Henrik; Dage, Jeffrey; Neurology, School of Medicine
    Blood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice. This is very timely, considering the recent development of anti-amyloid-β (Aβ) immunotherapies. Several assays for measuring phosphorylated tau (p-tau) in plasma exhibit high diagnostic accuracy in distinguishing AD from all other neurodegenerative diseases in patients with cognitive impairment. Prognostic models based on plasma p-tau levels can also predict future development of AD dementia in patients with mild cognitive complaints. The use of such high-performing plasma p-tau assays in the clinical practice of specialist memory clinics would reduce the need for more costly investigations involving cerebrospinal fluid samples or positron emission tomography. Indeed, blood-based biomarkers already facilitate identification of individuals with pre-symptomatic AD in the context of clinical trials. Longitudinal measurements of such biomarkers will also improve the detection of relevant disease-modifying effects of new drugs or lifestyle interventions.
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    Blood-based biomarkers for Alzheimer's disease and related dementias: Keys to success and things to consider
    (Elsevier, 2019-11-14) Zetterberg, Henrik; Apostolova, Liana G.; Snyder, Peter J.; Radiology and Imaging Sciences, School of Medicine
    During the last two decades, considerable progress has been made in the field of fluid and imaging biomarkers for neurodegenerative dementias. As a result, the most recent research and clinical guidelines (the National Institute on Aging and Alzheimer's Association, International Working Group 2, National Institute for Health and Care Excellence) incorporate cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers in the diagnostic criteria of dementia and mild cognitive impairment due to Alzheimer's disease (AD) [[1], [2], [3]]. However, as both CSF and amyloid PET examinations require expert knowledge and are of limited availability outside specialized memory clinics, there is no doubt that blood tests would be much easier to implement in clinical medicine and as screening tools when recruiting patients for clinical trials.
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    Characterization of pre-analytical sample handling effects on a panel of Alzheimer's disease–related blood-based biomarkers: Results from the Standardization of Alzheimer's Blood Biomarkers (SABB) working group
    (Wiley, 2022) Verberk, Inge M. W.; Misdorp, Els O.; Koelewijn, Jannet; Ball, Andrew J.; Blennow, Kaj; Dage, Jeffrey L.; Fandos, Noelia; Hansson, Oskar; Hirtz, Christophe; Janelidze, Shorena; Kang, Sungmin; Kirmess, Kristopher; Kindermans, Jana; Lee, Ryan; Meyer, Matthew R.; Shan, Dandan; Shaw, Leslie M.; Waligorska, Teresa; West, Tim; Zetterberg, Henrik; Edelmayer, Rebecca M.; Teunissen, Charlotte E.; Neurology, School of Medicine
    Introduction: Pre-analytical sample handling might affect the results of Alzheimer's disease blood-based biomarkers. We empirically tested variations of common blood collection and handling procedures. Methods: We created sample sets that address the effect of blood collection tube type, and of ethylene diamine tetraacetic acid plasma delayed centrifugation, centrifugation temperature, aliquot volume, delayed storage, and freeze–thawing. We measured amyloid beta (Aβ)42 and 40 peptides with six assays, and Aβ oligomerization-tendency (OAβ), amyloid precursor protein (APP)699-711, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), total tau (t-tau), and phosphorylated tau181. Results: Collection tube type resulted in different values of all assessed markers. Delayed plasma centrifugation and storage affected Aβ and t-tau; t-tau was additionally affected by centrifugation temperature. The other markers were resistant to handling variations. Discussion: We constructed a standardized operating procedure for plasma handling, to facilitate introduction of blood-based biomarkers into the research and clinical settings.
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    Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231
    (BMC, 2021-12-04) Bayoumy, Sherif; Verberk, Inge M.W.; den Dulk, Ben; Hussainali, Zulaiga; Zwan, Marissa; van der Flier, Wiesje M.; Ashton, Nicholas J.; Zetterberg, Henrik; Blennow, Kaj; Vanbrabant, Jeroen; Stoops, Erik; Vanmechelen, Eugeen; Dage, Jeffrey L.; Teunissen, Charlotte E.; Neurology, School of Medicine
    Introduction: Studies using different assays and technologies showed highly promising diagnostic value of plasma phosphorylated (P-)tau levels for Alzheimer's disease (AD). We aimed to compare six P-tau Simoa assays, including three P-tau181 (Eli Lilly, ADx, Quanterix), one P-tau217 (Eli Lilly), and two P-tau231 (ADx, Gothenburg). Methods: We studied the analytical (sensitivity, precision, parallelism, dilution linearity, and recovery) and clinical (40 AD dementia patients, age 66±8years, 50%F; 40 age- and sex-matched controls) performance of the assays. Results: All assays showed robust analytical performance, and particularly P-tau217 Eli Lilly; P-tau231 Gothenburg and all P-tau181 assays showed robust clinical performance to differentiate AD from controls, with AUCs 0.936-0.995 (P-tau231 ADx: AUC = 0.719). Results obtained with all P-tau181 assays, P-tau217 Eli Lilly assay, and P-tau231 Gothenburg assay strongly correlated (Spearman's rho > 0.86), while correlations with P-tau231 ADx results were moderate (rho < 0.65). Discussion: P-tau isoforms can be measured robustly by several novel high-sensitive Simoa assays.
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    Cognitive and Neuronal Link With Inflammation: A Longitudinal Study in People With and Without HIV Infection
    (Wolters Kluwer, 2020-12) Anderson, Albert M.; Jang, Jeong Hoon; Easley, Kirk A.; Fuchs, Dietmar; Gisslen, Magnus; Zetterberg, Henrik; Blennow, Kaj; Ellis, Ronald J.; Franklin, Donald; Heaton, Robert K.; Grant, Igor; Letendre, Scott L.; Biostatistics, School of Public Health
    Background: Across many settings, lack of virologic control remains common in people with HIV (PWH) because of late presentation and lack of retention in care. This contributes to neuronal damage and neurocognitive impairment, which remains prevalent. More evidence is needed to understand these outcomes in both PWH and people without HIV (PWOH). Methods: We recruited PWH initiating antiretroviral therapy and PWOH at 2 sites in the United States. One hundred eight adults were enrolled (56 PWOH and 52 PWH), most of whom had a second assessment at least 24 weeks later (193 total assessments). Tumor necrosis factor alpha, monocyte chemotactic protein-1 (MCP-1), neopterin, soluble CD14, and neurofilament light chain protein (NFL) were measured in plasma and cerebrospinal fluid (CSF). Using multivariate models including Bayesian model averaging, we analyzed factors associated with global neuropsychological performance (NPT-9) and CSF NFL at baseline and over time. Results: At baseline, higher CSF MCP-1 and plasma sCD14 were associated with worse NPT-9 in PWH, while CSF HIV RNA decrease was the only marker associated with improved NPT-9 over time. Among PWH, higher CSF neopterin was most closely associated with higher NFL. Among PWOH, higher CSF MCP-1 was most closely associated with higher NFL. After antiretroviral therapy initiation, decrease in CSF MCP-1 was most closely associated with NFL decrease. Conclusion: Monocyte-associated CSF biomarkers are highly associated with neuronal damage in both PWH and PWOH. More research is needed to evaluate whether therapies targeting monocyte-associated inflammation may ameliorate HIV-associated neurobehavioral diseases.
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    Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes
    (American Medical Association, 2021) Mielke, Michelle M.; Frank, Ryan D.; Dage, Jeffrey L.; Jeromin, Andreas; Ashton, Nicholas J.; Blennow, Kaj; Karikari, Thomas K.; Vanmechelen, Eugene; Zetterberg, Henrik; Algeciras-Schimnich, Alicia; Knopman, David S.; Lowe, Val; Bu, Guojun; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Petersen, Ronald C.; Neurology, School of Medicine
    Importance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed. Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. Design, setting, and participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. Main outcomes and measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. Conclusions and relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.
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    Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression
    (Public Library of Science, 2021-05-13) Gisslen, Magnus; Keating, Sheila M.; Spudich, Serena; Arechiga, Victor; Stephenson, Sophie; Zetterberg, Henrik; Di Germanio, Clara; Blennow, Kaj; Fuchs, Dietmar; Hagberg, Lars; Norris, Philip J.; Peterson, Julia; Shacklett, Barbara L.; Yiannoutsos, Constantin T.; Price, Richard W.; Biostatistics, School of Public Health
    Objective: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. Methods: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. Findings: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.