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Song, Weichen, Weidi Wang, Zhe Liu, Wenxiang Cai, Shunying Yu, Min Zhao, and Guan Ning Lin. "A Comprehensive Evaluation of Cross-Omics Blood-Based Biomarkers for Neuropsychiatric Disorders." Journal of Personalized Medicine 11, no. 12 (November 24, 2021): 1247. http://dx.doi.org/10.3390/jpm11121247.
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The identification of peripheral multi-omics biomarkers of brain disorders has long been hindered by insufficient sample size and confounder influence. This study aimed to compare biomarker potential for different molecules and diseases. We leveraged summary statistics of five blood quantitative trait loci studies (N = 1980 to 22,609) and genome-wide association studies (N = 9725 to 500,199) from 14 different brain disorders, such as Schizophrenia (SCZ) and Alzheimer’s Disease (AD). We applied summary-based and two-sample Mendelian Randomization to estimate the associations between blood molecules and brain disorders. We identified 524 RNA, 807 methylation sites, 29 proteins, seven cytokines, and 22 metabolites having a significant association with at least one of 14 brain disorders. Simulation analyses indicated that a cross-omics combination of biomarkers had better performance for most disorders, and different disorders could associate with different omics. We identified an 11-methylation-site model for SCZ diagnosis (Area Under Curve, AUC = 0.74) by analyzing selected candidate markers in published datasets (total N = 6098). Moreover, we constructed an 18-methylation-sites model that could predict the prognosis of elders with mild cognitive impairment (hazard ratio = 2.32). We provided an association landscape between blood cross-omic biomarkers and 14 brain disorders as well as a suggestion guide for future clinical discovery and application.
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Marrugo-Ramírez, Jose, Montserrat Rodríguez-Núñez, M. Pilar Marco, Mónica Mir, and Josep Samitier. "Kynurenic Acid Electrochemical Immunosensor: Blood-Based Diagnosis of Alzheimer’s Disease." Biosensors 11, no. 1 (January 12, 2021): 20. http://dx.doi.org/10.3390/bios11010020.
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Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by a functional deterioration of the brain. Currently, there are selected biomarkers for its diagnosis in cerebrospinal fluid. However, its extraction has several disadvantages for the patient. Therefore, there is an urgent need for a detection method using sensitive and selective blood-based biomarkers. Kynurenic acid (KYNA) is a potential biomarker candidate for this purpose. The alteration of the KYNA levels in blood has been related with inflammatory processes in the brain, produced as a protective function when neurons are damaged. This paper describes a novel electrochemical immunosensor for KYNA detection, based on successive functionalization multi-electrode array. The resultant sensor was characterized by cyclic voltammetry (CV), chronoamperometry (CA), and electrochemical impedance spectroscopy (EIS). The proposed biosensor detects KYNA within a linear calibration range from 10 pM to 100 nM using CA and EIS, obtaining a limit of detection (LOD) of 16.9 pM and 37.6 pM in buffer, respectively, being the lowest reported LOD for this biomarker. Moreover, to assess our device closer to the real application, the developed immunosensor was also tested under human serum matrix, obtaining an LOD of 391.71 pM for CA and 278.8 pM for EIS with diluted serum.
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Long, Jintao, Genhua Pan, Emmanuel Ifeachor, Robert Belshaw, and Xinzhong Li. "Discovery of Novel Biomarkers for Alzheimer’s Disease from Blood." Disease Markers 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/4250480.
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Blood-based biomarkers for Alzheimer’s disease would be very valuable because blood is a more accessible biofluid and is suitable for repeated sampling. However, currently there are no robust and reliable blood-based biomarkers for practical diagnosis. In this study we used a knowledge-based protein feature pool and two novel support vector machine embedded feature selection methods to find panels consisting of two and three biomarkers. We validated these biomarker sets using another serum cohort and an RNA profile cohort from the brain. Our panels included the proteins ECH1, NHLRC2, HOXB7, FN1, ERBB2, and SLC6A13 and demonstrated promising sensitivity (>87%), specificity (>91%), and accuracy (>89%).
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Schnakers, Caroline, Emily Rosario, Kathleen Weaver, and Vanessa Morales. "Blood-based Biomarkers of Late Recovery in Traumatic Brain Injury." Archives of Physical Medicine and Rehabilitation 99, no. 11 (November 2018): e130. http://dx.doi.org/10.1016/j.apmr.2018.08.009.
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Rosario, Emily R., Vanessa Morales, Caroline Schnakers, and Kathleen Weaver. "Blood-Based Biomarkers of Late Recovery in Traumatic Brain Injury." Archives of Physical Medicine and Rehabilitation 99, no. 10 (October 2018): e3. http://dx.doi.org/10.1016/j.apmr.2018.07.008.
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Kong, Qianqian, Xinxin Xie, Ziyue Wang, Yi Zhang, Xirui Zhou, Lingshan Wu, Zhiyuan Yu, Hao Huang, and Xiang Luo. "Correlations of Plasma Biomarkers and Imaging Characteristics of Cerebral Small Vessel Disease." Brain Sciences 14, no. 3 (March 12, 2024): 269. http://dx.doi.org/10.3390/brainsci14030269.
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Cerebral small vessel disease (CSVD), which is a group of pathological processes affecting cerebral microvessels, leads to functional loss in the elderly population and mostly presents as cognitive impairment and gait decline. CSVD is diagnosed based on brain imaging biomarkers, but blood biomarkers are of great significance for the early diagnosis and progression prediction of CSVD and have become a research focus because of their noninvasiveness and easy accessibility. Notably, many blood biomarkers have been reported to be associated with CSVD in a relatively large population, particularly serum neurofilament light chain (NfL), which has been regarded as a promising biomarker to track the variation trend in WMH and to predict the further status of white matter hyperintensities (WMH) and lacunar infarcts. And neuro-glio-vascular unit structure and blood–brain barrier function have been proposed as underlying mechanisms of CSVD. The article starts from the neuroimaging markers of CSVD, including recent small subcortical infarcts (RSSI), white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMB), enlarged perivascular spaces (EPVS), cerebral atrophy, and the combined small vessel disease score, and attempts to systematically review and summarize the research progress regarding the blood biomarkers of CSVD that form the changes in the neuro-glio-vascular unit structure and blood–brain barrier function.
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Halicki, Michal J., Karen Hind, and Paul L. Chazot. "Blood-Based Biomarkers in the Diagnosis of Chronic Traumatic Encephalopathy: Research to Date and Future Directions." International Journal of Molecular Sciences 24, no. 16 (August 8, 2023): 12556. http://dx.doi.org/10.3390/ijms241612556.
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Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease consistently associated with repetitive traumatic brain injuries (TBIs), which makes multiple professions, such as contact sports athletes and the military, especially susceptible to its onset. There are currently no approved biomarkers to diagnose CTE, thus it can only be confirmed through a post-mortem brain autopsy. Several imaging and cerebrospinal fluid biomarkers have shown promise in the diagnosis. However, blood-based biomarkers can be more easily obtained and quantified, increasing their clinical feasibility and potential for prophylactic use. This article aimed to comprehensively review the studies into potential blood-based biomarkers of CTE, discussing common themes and limitations, as well as suggesting future research directions. While the interest in blood-based biomarkers of CTE has recently increased, the research is still in its early stages. The main issue for many proposed biomarkers is their lack of selectivity for CTE. However, several molecules, such as different phosphorylated tau isoforms, were able to discern CTE from different neurodegenerative diseases. Further, the results from studies on exosomal biomarkers suggest that exosomes are a promising source of biomarkers, reflective of the internal environment of the brain. Nonetheless, more longitudinal studies combining imaging, neurobehavioral, and biochemical approaches are warranted to establish robust biomarkers for CTE.
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Rauchman, Steven H., Aaron Pinkhasov, Shelly Gulkarov, Dimitris G. Placantonakis, Joshua De Leon, and Allison B. Reiss. "Maximizing the Clinical Value of Blood-Based Biomarkers for Mild Traumatic Brain Injury." Diagnostics 13, no. 21 (October 28, 2023): 3330. http://dx.doi.org/10.3390/diagnostics13213330.
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Mild traumatic brain injury (TBI) and concussion can have serious consequences that develop over time with unpredictable levels of recovery. Millions of concussions occur yearly, and a substantial number result in lingering symptoms, loss of productivity, and lower quality of life. The diagnosis may not be made for multiple reasons, including due to patient hesitancy to undergo neuroimaging and inability of imaging to detect minimal damage. Biomarkers could fill this gap, but the time needed to send blood to a laboratory for analysis made this impractical until point-of-care measurement became available. A handheld blood test is now on the market for diagnosis of concussion based on the specific blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl terminal hydrolase L1 (UCH-L1). This paper discusses rapid blood biomarker assessment for mild TBI and its implications in improving prediction of TBI course, avoiding repeated head trauma, and its potential role in assessing new therapeutic options. Although we focus on the Abbott i-STAT TBI plasma test because it is the first to be FDA-cleared, our discussion applies to any comparable test systems that may become available in the future. The difficulties in changing emergency department protocols to include new technology are addressed.
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Shearon, Jennifer, Baylie Rushing, Madeleine Love, and Denise Head. "BLOOD-BASED CARDIAC BIOMARKERS AND PHYSICAL ACTIVITY: PRELIMINARY RESULTS." Innovation in Aging 8, Supplement_1 (December 2024): 1081–82. https://doi.org/10.1093/geroni/igae098.3475.
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Abstract Mixed findings regarding effects of physical activity on the brain in later adulthood motivate further research into mechanisms and moderators of potential effects. Cardiovascular health could be part of a mechanistic pathway and/or a moderator of physical activity effects. While there are myriad indicators of cardiovascular health, blood-based cardiac markers may prove particularly sensitive. One goal of this study was to investigate associations of two blood-based markers of cardiovascular health with physical activity/cardiorespiratory fitness. The second aim was to examine the moderating effect of cardiac biomarkers in associations of physical activity/fitness with neurotrophins, considered molecular mechanisms of physical activity effects, as well as with hippocampal volumes. Cognitively normal participants in the Knight ADRC Adult Children Study (n=56, ages 43-85) completed a blood draw for assessment of cardiac biomarkers (high sensitivity cardiac troponin T, N-terminal probrain natriuretic peptide) and neurotrophins (brain-derived neurotrophic factor, insulin-like growth factor, vascular endothelial growth factor). Composites were created for cardiac biomarkers and for neurotrophins. Participants completed a submaximal exercise test to estimate cardiorespiratory fitness and wore an actigraphy watch for seven days, from which a physical activity composite score was created. Hippocampal volumes were from the most recent MRI scan. Higher physical activity was associated with lower levels of cardiac biomarkers (p=0.03). There was no moderating effect of cardiac biomarkers on associations between physical activity and neurotrophin levels (p=0.74) or physical activity and hippocampal volumes (p=0.24). Blood-based cardiac biomarkers may be useful for considering mechanistic associations between physical activity and cardiovascular health in larger samples.
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Reddy, Doodipala Samba, and Hasara Nethma Abeygunaratne. "Experimental and Clinical Biomarkers for Progressive Evaluation of Neuropathology and Therapeutic Interventions for Acute and Chronic Neurological Disorders." International Journal of Molecular Sciences 23, no. 19 (October 3, 2022): 11734. http://dx.doi.org/10.3390/ijms231911734.
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This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.
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Agoston, Denes V., and Adel Helmy. "Fluid-Based Protein Biomarkers in Traumatic Brain Injury: The View from the Bedside." International Journal of Molecular Sciences 24, no. 22 (November 13, 2023): 16267. http://dx.doi.org/10.3390/ijms242216267.
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There has been an explosion of research into biofluid (blood, cerebrospinal fluid, CSF)-based protein biomarkers in traumatic brain injury (TBI) over the past decade. The availability of very large datasets, such as CENTRE-TBI and TRACK-TBI, allows for correlation of blood- and CSF-based molecular (protein), radiological (structural) and clinical (physiological) marker data to adverse clinical outcomes. The quality of a given biomarker has often been framed in relation to the predictive power on the outcome quantified from the area under the Receiver Operating Characteristic (ROC) curve. However, this does not in itself provide clinical utility but reflects a statistical association in any given population between one or more variables and clinical outcome. It is not currently established how to incorporate and integrate biofluid-based biomarker data into patient management because there is no standardized role for such data in clinical decision making. We review the current status of biomarker research and discuss how we can integrate existing markers into current clinical practice and what additional biomarkers do we need to improve diagnoses and to guide therapy and to assess treatment efficacy. Furthermore, we argue for employing machine learning (ML) capabilities to integrate the protein biomarker data with other established, routinely used clinical diagnostic tools, to provide the clinician with actionable information to guide medical intervention.
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Palta, Priya, James Pike, Yifei Lu, Jinyu Chen, Keenan Walker, Kevin Sullivan, and Thomas Mosley. "DESIGN, MEASURES, AND CORRELATES OF CHANGES IN AD BLOOD BIOMARKERS AND ASSOCIATIONS WITH NEUROIMAGING OUTCOMES." Innovation in Aging 8, Supplement_1 (December 2024): 1. https://doi.org/10.1093/geroni/igae098.0002.
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Abstract Few studies have examined changes in blood-based biomarkers of AD pathology and neurodegeneration particularly during the mid- to late-life transition period and associations with brain pathology. Among 1525 (59.9% women, 25.8% Black) ARIC participants, we measured blood-based biomarkers of Aβ42, Aβ40, p-Tau181, NfL, and GFAP using stored specimens from midlife (1993-1995, mean age 58.3 years) and late-life (2011-2013, mean age 76.0 years followed to 2016-2019, mean age 80.7 years). Using linear mixed effects models, we examined whether known dementia-related risk factors in midlife (i.e., hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) are associated with 20-year biomarker changes. We also examined the associations of midlife, late-life, and mid- to late-life changes in blood biomarkers with measures of whole brain cortical thickness, brain volume, and white matter hyperintensity volume (WMH) from a 3T brain MRI scan in multivariable linear regression models. All models were adjusted for age, sex, race-center, education, APOE, eGFR, body mass index, cardiovascular risk factors, and intracranial volume for volumetric analyses. Decreasing Aβ42/Aβ40 and increasing p-Tau181, NfL, and GFAP were observed from midlife to late-life. Midlife hypertension and diabetes were associated with a steeper rise in NfL and GFAP. Lower late-life levels of Aβ42/Aβ40 and higher late-life levels of p-Tau181, p-Tau181/Aβ42, NfL, and GFAP were associated with smaller cortical thickness and total brain volume, and larger WMH volume. Blood biomarkers of AD neuropathology, neuronal injury, and astrogliosis rise with age and are associated with known dementia risk factors and markers of neurodegeneration and cerebrovascular disease.
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González-Quevedo, A., S. González-García, O. Fernández Concepción, M. Peña-Sánchez, L. Quevedo-Sotolongo, R. Santiesteban-Freixas, M. C. Menéndez-Saínz, R. A. Fernández-Carriera, I. Fernández-Almirall, and Z. M. Hernández-Díaz. "Blood based biomarkers to identify subclinical brain damage in essential hypertension." Journal of the Neurological Sciences 357 (October 2015): e105. http://dx.doi.org/10.1016/j.jns.2015.08.341.
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Rosario, Emily, Vanessa Morales, Caroline Schnakers, and Kat Weaver. "Characterizing Longitudinal Changes in Blood-based Biomarkers Following Traumatic Brain Injury." Archives of Physical Medicine and Rehabilitation 98, no. 10 (October 2017): e42. http://dx.doi.org/10.1016/j.apmr.2017.08.129.
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Varesi, Angelica, Adelaide Carrara, Vitor Gomes Pires, Valentina Floris, Elisa Pierella, Gabriele Savioli, Sakshi Prasad, et al. "Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview." Cells 11, no. 8 (April 17, 2022): 1367. http://dx.doi.org/10.3390/cells11081367.
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Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1–42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.
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Fundaun, Joel, Melissa Kolski, Miguel Molina-Álvarez, Georgios Baskozos, and Annina B. Schmid. "Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies." JAMA Network Open 5, no. 12 (December 27, 2022): e2248593. http://dx.doi.org/10.1001/jamanetworkopen.2022.48593.
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ImportancePeripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system.ObjectiveTo assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants.Data SourcesOvid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021.Study SelectionObservational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second.Data Extraction and SynthesisData were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included.Main Outcomes and MeasuresThe outcome of interest was concentration of biomarkers.ResultsThis review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P < .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, −3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, −0.52 [95% CI, −2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, −0.00 [95% CI, −1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants.Conclusions and RelevanceThe findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.
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Angiulli, Federica, Elisa Conti, Chiara Paola Zoia, Fulvio Da Re, Ildebrando Appollonio, Carlo Ferrarese, and Lucio Tremolizzo. "Blood-Based Biomarkers of Neuroinflammation in Alzheimer’s Disease: A Central Role for Periphery?" Diagnostics 11, no. 9 (August 24, 2021): 1525. http://dx.doi.org/10.3390/diagnostics11091525.
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Neuroinflammation represents a central feature in the development of Alzheimer’s disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system—by virtue of a dysfunctional blood–brain barrier (BBB)—is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.
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Palta, Priya, Kevin Sullivan, and Natascha Merten. "AD BLOOD BIOMARKERS IN DIVERSE COMMUNITY SETTINGS: A LONGITUDINAL PERSPECTIVE FROM THE ARIC STUDY." Innovation in Aging 8, Supplement_1 (December 2024): 1. https://doi.org/10.1093/geroni/igae098.0001.
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Abstract Alzheimer’s disease and related dementias (ADRD) feature a prolonged preclinical stage spanning decades, with the transition from mid- to late-life marking the critical period for onset and accumulation of pathological brain changes that may lead to physical and cognitive disability. Identifying individuals at risk for cognitive and physical decline during preclinical stages when interventions or disease modifying treatments are more likely to be effective is needed. Blood biomarkers of ADRD pathology and neurodegeneration are promising cost-effective and non-invasive options to fill this gap. To date, however, there are limited data on temporal changes in blood biomarkers and their associations with cognitive, mobility, and neuroimaging outcomes in diverse community-based cohorts. This symposium will feature 23 years of data from the well-established community-based Atherosclerosis Risk in Communities (ARIC) Study cohort which assayed blood biomarkers of amyloid-β (Aβ)42/40, phosphorylated tau at threonine 181 (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) using Quanterix Simoa assays on stored specimens at up to 3 timepoints in midlife and late-life in ~1,800 participants. This session will present findings on temporal blood biomarker changes from mid- to late-life and associated risk and protective factors of biomarker changes; mid- to late-life changes in blood biomarkers and associations with late-life neuroimaging measures of neurodegeneration, cerebrovascular disease, and amyloid deposition; and the associations of late-life blood biomarkers with prevalent and incident mobility and cognitive impairment.
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Pike, James, Yifei Lu, Jinyu Chen, Keenan Walker, Kevin Sullivan, Michael Griswold, Thomas Mosley, and Priya Palta. "CHANGE IN ALZHEIMER’S DISEASE BLOOD-BASED BIOMARKERS AND ASSOCIATIONS WITH BRAIN AMYLOID DEPOSITION." Innovation in Aging 8, Supplement_1 (December 2024): 2. https://doi.org/10.1093/geroni/igae098.0004.
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Abstract Blood-based biomarkers show promise as a noninvasive, inexpensive method for measuring Alzheimer’s disease pathology throughout the lifecourse. However, the prospective associations and discriminatory accuracy of these biomarkers at different stages of the lifecourse and among diverse, community-dwelling populations requires further investigation. Between 2014 and 2015, 329 dementia-free participants from the Atherosclerosis Risk in Communities Study underwent brain MRI and PET scans. Amyloid positivity was defined as a standardized uptake value ratio greater than 1.2. Stored plasma samples collected in midlife (1993-95, mean age 58.5 years) and late-life (2011-13, mean age 76.2 years) from a subsample of 259 participants were assayed in 2022. The assay quantified amyloid-β (Aβ)42/40, phosphorylated tau (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Logistic regression models estimated the association between plasma biomarkers from midlife and late-life and amyloid positivity in late-life. Receiver operating characteristic curves documented the discriminatory accuracy of the biomarkers. Assays from midlife were not associated with amyloid positivity in late-life. However, late-life measurements of Aβ42/40, p-Tau181, and GFAP and change per decade from midlife to late-life in p-Tau181 and GFAP were associated with greater odds of amyloid positivity. The greatest discriminatory accuracy was achieved by using all assays measured in midlife and late-life (AUC = 0.754), although the accuracy when using only late-life measures was comparable (AUC = 0.737). Additional longitudinal research is needed to determine whether changes in plasma biomarkers measured before an individual is amyloid positive can identify older adults at risk of developing Alzheimer’s disease.
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Liu, Xingyun, Yibiao Liu, and Qiong Liu. "Fluorescent Sensing Platforms for Detecting and Imaging the Biomarkers of Alzheimer’s Disease." Biosensors 13, no. 5 (April 30, 2023): 515. http://dx.doi.org/10.3390/bios13050515.
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Alzheimer’s disease (AD) is an irreversible neurodegenerative disease with clinical symptoms of memory loss and cognitive impairment. Currently, no effective drug or therapeutic method is available for curing this disease. The major strategy used is to identify and block AD at its initial stage. Thus, early diagnosis is very important for intervention of the disease and assessment of drug efficacy. The gold standards of clinical diagnosis include the measurement of AD biomarkers in cerebrospinal fluid and positron emission tomography imaging of the brain for amyloid-β (Aβ) deposits. However, these methods are difficult to apply to the general screening of a large aging population because of their high cost, radioactivity and inaccessibility. Comparatively, blood sample detection is less invasive and more accessible for the diagnosis of AD. Hence, a variety of assays based on fluorescence analysis, surface-enhanced Raman scattering, electrochemistry, etc., were developed for the detection of AD biomarkers in blood. These methods play significant roles in recognizing asymptomatic AD and predicting the course of the disease. In a clinical setting, the combination of blood biomarker detection with brain imaging may enhance the accuracy of early diagnosis. Fluorescence-sensing techniques can be used not only to detect the levels of biomarkers in blood but also to image biomarkers in the brain in real time due to their low toxicity, high sensitivity and good biocompatibility. In this review, we summarize the newly developed fluorescent sensing platforms and their application in detecting and imaging biomarkers of AD, such as Aβ and tau in the last five years, and discuss their prospects for clinical applications.
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Friis, Therese, Anna-Karin Wikström, Jesenia Acurio, José León, Henrik Zetterberg, Kaj Blennow, Maria Nelander, et al. "Cerebral Biomarkers and Blood-Brain Barrier Integrity in Preeclampsia." Cells 11, no. 5 (February 24, 2022): 789. http://dx.doi.org/10.3390/cells11050789.
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Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and non-pregnant women (n = 16) was analyzed for concentrations of the cerebral biomarkers neurofilament light (NfL), tau, neuron-specific enolase (NSE) and S100B. Then, an in vitro blood–brain barrier (BBB) model, based on the human cerebral microvascular endothelial cell line (hCMEC/D3), was employed to assess the effect of plasma from the three study groups. Transendothelial electrical resistance (TEER) was used as an estimation of BBB integrity. NfL and tau are proteins expressed in axons, NSE in neurons and S100B in glial cells and are used as biomarkers for neurological injury in other diseases such as dementia, traumatic brain injury and hypoxic brain injury. Plasma concentrations of NfL, tau, NSE and S100B were all higher in women with preeclampsia compared with women with normal pregnancies (8.85 vs. 5.25 ng/L, p < 0.001; 2.90 vs. 2.40 ng/L, p < 0.05; 3.50 vs. 2.37 µg/L, p < 0.001 and 0.08 vs. 0.05 µg/L, p < 0.01, respectively). Plasma concentrations of NfL were also higher in women with preeclampsia compared with non-pregnant women (p < 0.001). Higher plasma concentrations of the cerebral biomarker NfL were associated with decreased TEER (p = 0.002) in an in vitro model of the BBB, a finding which indicates that NfL could be a promising biomarker for BBB alterations in preeclampsia.
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Gheorghe, Sorin Sebastian, Ruxandra Maria Ilie-Mihai, Raluca-Ioana Stefan-van Staden, and Alexandru Bratei. "Validation of a Screening Method Based on a Needle Stochastic Sensor for the Determination of Interleukins 1β, 6, and 12 in Biological Samples." Proceedings 55, no. 1 (October 10, 2020): 14. http://dx.doi.org/10.3390/proceedings2020055014.
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Interleukins proved to be valuable biomarkers for different diseases. Interleukins 1β, 6, and 12 can be used as biomarkers for brain cancer diagnosis, and therefore this paper proposed a needle stochastic sensor based on protoporphyrin IX immobilized in nano-diamond paste for fast screening of biological samples, such as whole blood, urine and brain tumoral tissue, for these interleukins. The results obtained using this needle stochastic sensor proved that the interleukins 1β, 6, and 12 can be reliably determined from whole blood, urine and brain tumoral tissue, with recoveries higher than 96.00% and with relative standard deviations lower than 1.00%. The validation of the method was performed using whole blood and tissue samples collected from the patients confirmed with brain tumor.
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Williams, Stephanie M., Carrie Peltz, Kristine Yaffe, Philip Schulz, and Michael R. Sierks. "CNS disease-related protein variants as blood-based biomarkers in traumatic brain injury." Neurology 91, no. 15 (October 8, 2018): 702–9. http://dx.doi.org/10.1212/wnl.0000000000006322.
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ObjectiveTo utilize a panel of 11 single chain variable fragments (scFvs) that selectively bind disease-related variants of TAR DNA-binding protein (TDP)-43, β-amyloid, tau, and α-synuclein to assess damage following traumatic brain injury (TBI), and determine if the presence of protein variants could account for the increased risk of various neurodegenerative diseases following TBI.MethodsWe utilized the panel of 11 scFvs in a sensitive ELISA format to analyze sera from 43 older veterans, 25 who had experienced at least 1 TBI incident during their lifetime (∼29.4 years after TBI), and 18 controls who did not incur TBI, in a cross-sectional study.ResultsEach of the 11 scFvs individually could significantly distinguish between TBI and control samples, though they did not detect each TBI sample. Comparing the levels of all 11 variants, all 25 TBI cases displayed higher reactivity compared to the controls and receiver operating characteristic analysis revealed 100% sensitivity and specificity. Higher total protein variants levels correlated with TBI severity and with loss of consciousness. Oligomeric tau levels distinguished between single and multiple TBI incidents. While all TBI cases were readily selected with the panel, the binding pattern varied from patient to patient, suggesting subgroups that are at increased risk for different neurodegenerative diseases.ConclusionThe panel of protein variants-specific scFvs can be used to identify blood-based biomarkers indicative of TBI even 20 years or more after the initial TBI. Being able to identify subgroups of biomarker profiles allows for the possibility of individually targeted treatments.
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Bartlett, Maggie, Heather Poeck-Goux, Linwood Johnson Johnson, Kevin Scully, Amy Vittor, Ronald Hayes, Jean-Paul Carrera, and Darci R. Smith. "Biomarkers of Neurological Injury for Emerging Viral Threats and Post Viral Disease." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 235.23. http://dx.doi.org/10.4049/jimmunol.210.supp.235.23.
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Abstract Neurotropic viral infection and the ensuant immune response are a significant cause of morbidity and mortality worldwide, which can range in severity from mild to permanent central nervous system (CNS) damage and death. Encephalitic alphaviruses include Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV; Alphavirus; Togaviridae). Injury to the CNS is an important determinant of poor outcome and tools to predict this outcome are lacking. Neurons are the primary target cells of encephalitic alphaviruses where cytopathology plays a major role in CNS dysfunction. Proteins are released following cell death, such as ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) are neuromarkers of CNS tissue injury which could serve as biomarkers to assess injury severity, monitor disease progression, direct treatment, and as reliable endpoints to help develop novel medical countermeasures. Recent advances in the use of blood-based biomarkers for diagnosis of traumatic brain injury (TBI) which have FDA approved assays have provided a scientific foundation for expanding the biomarker technology to brain damage caused by other CNS pathologies like viral encephalitis. Here we evaluated the ability to detect these biomarkers for encephalitic alphaviruses, encephalitis of unknown origin, and hospitalized patients with severe coronavirus disease (COVID-19). Higher levels of specific biomarkers were detected in patients diagnosed with alphavirus or unknown encephalitis which may be useful in prognosis and treatment guidance of post viral disease. Collectively, our results suggest that these blood-based biomarkers may be a good indicator for brain injury resulting from viral infection.
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Makranz, Chen, Asael Lubotzky, Hai Zemmour, Ruth Shemer, Benjamin Glaser, Jonathan Cohen, Myriam Maoz, et al. "Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study." PLOS ONE 18, no. 11 (November 28, 2023): e0285646. http://dx.doi.org/10.1371/journal.pone.0285646.
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Background Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. Methods Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. Results During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. Conclusions Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.
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O’Connell, Grant C., Megan L. Alder, Christine G. Smothers, and Julia H. C. Chang. "Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage." Proceedings of the National Academy of Sciences 117, no. 34 (August 6, 2020): 20764–75. http://dx.doi.org/10.1073/pnas.2007719117.
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The identification of precision blood biomarkers which can accurately indicate damage to brain tissue could yield molecular diagnostics with the potential to improve how we detect and treat neurological pathologies. However, a majority of candidate blood biomarkers for neurological damage that are studied today are proteins which were arbitrarily proposed several decades before the advent of high-throughput omic techniques, and it is unclear whether they represent the best possible targets relative to the remainder of the human proteome. Here, we leveraged mRNA expression data generated from nearly 12,000 human specimens to algorithmically evaluate over 17,000 protein-coding genes in terms of their potential to produce blood biomarkers for neurological damage based on their expression profiles both across the body and within the brain. The circulating levels of proteins associated with the top-ranked genes were then measured in blood sampled from a diverse cohort of patients diagnosed with a variety of acute and chronic neurological disorders, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, Alzheimer’s disease, and multiple sclerosis, and evaluated for their diagnostic performance. Our analysis identifies several previously unexplored candidate blood biomarkers of neurological damage with possible clinical utility, many of which whose presence in blood is likely linked to specific cell-level pathologic processes. Furthermore, our findings also suggest that many frequently cited previously proposed blood biomarkers exhibit expression profiles which could limit their diagnostic efficacy.
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Georgountzos, Georgios, Ioannis Gkalonakis, Lykourgos Anastasopoulos, George Stranjalis, and Theodosis Κalamatianos. "Biofluid Biomarkers in the Prognosis of Chronic Subdural Hematoma: A Systematic Scoping Review." Diagnostics 13, no. 14 (July 22, 2023): 2449. http://dx.doi.org/10.3390/diagnostics13142449.
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The present systematic scoping review aimed at mapping and analyzing the available literature on biological fluid (biofluid) biomarkers showing promise in the prediction of chronic subdural hematoma (cSDH) recurrence and the prognosis of neurological/functional patient outcome. Twenty-three studies published between 2003 and 2023 investigating a diverse range of biomarkers in hematoma fluid and/or the circulation in 3749 patients were included. Immune cell populations and inflammatory/anti-inflammatory cytokines comprised the most studied category of biomarkers displaying significant findings. A notable time trend in biomarker studies was a recent shift in research focus towards the analysis of circulating biomarkers. Several biomarkers were indicated as independent predictors of cSDH recurrence and/or functional/neurological outcome, including circulating fibrinogen degradation products (FDP), brain natriuretic peptide (BNP-1) and high-density lipoprotein (HDL), as well as blood urea nitrogen (BUN) and the ratios of blood neutrophil to lymphocyte (NLR) or red blood cell distribution width to platelet count (RPR). While studies on cSDH prognostic biomarkers have gained, in recent years, momentum, additional multicenter prospective studies are warranted to confirm and extend their findings. The identification of prognostic biofluid biomarkers in cSDH is an active field of research that may provide future tools, guiding clinical decisions and allowing for the design of treatments based on risk stratification.
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Malhotra, Sunny, Carme Costa, Herena Eixarch, Christian W. Keller, Lukas Amman, Helios Martínez-Banaclocha, Luciana Midaglia, et al. "NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients." Brain 143, no. 5 (April 13, 2020): 1414–30. http://dx.doi.org/10.1093/brain/awaa084.
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Abstract Primary progressive multiple sclerosis is a poorly understood disease entity with no specific prognostic biomarkers and scarce therapeutic options. We aimed to identify disease activity biomarkers in multiple sclerosis by performing an RNA sequencing approach in peripheral blood mononuclear cells from a discovery cohort of 44 untreated patients with multiple sclerosis belonging to different clinical forms and activity phases of the disease, and 12 healthy control subjects. A validation cohort of 58 patients with multiple sclerosis and 26 healthy control subjects was included in the study to replicate the RNA sequencing findings. The RNA sequencing revealed an interleukin 1 beta (IL1B) signature in patients with primary progressive multiple sclerosis. Subsequent immunophenotyping pointed to blood monocytes as responsible for the IL1B signature observed in this group of patients. Functional experiments at baseline measuring apoptosis-associated speck-like protein containing a CARD (ASC) speck formation showed that the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome was overactive in monocytes from patients with primary progressive multiple sclerosis, and canonical NLRP3 inflammasome activation with a combination of ATP plus lipopolysaccharide was associated with increased IL1B production in this group of patients. Primary progressive multiple sclerosis patients with high IL1B gene expression levels in peripheral blood mononuclear cells progressed significantly faster compared to patients with low IL1B levels based on the time to reach an EDSS of 6.0 and the Multiple Sclerosis Severity Score. In agreement with peripheral blood findings, both NLRP3 and IL1B expression in brain tissue from patients with primary progressive multiple sclerosis was mainly restricted to cells of myeloid lineage. Treatment of mice with a specific NLRP3 inflammasome inhibitor attenuated established experimental autoimmune encephalomyelitis disease severity and improved CNS histopathology. NLRP3 inflammasome-specific inhibition was also effective in reducing axonal damage in a model of lipopolysaccharide-neuroinflammation using organotypic cerebellar cultures. Altogether, these results point to a role of IL1B and the NLRP3 inflammasome as prognostic biomarker and potential therapeutic target, respectively, in patients with primary progressive multiple sclerosis.
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Bakker, Akke, Anna E. Ixkes, Hema Venugopal, Mario G. Ries, Nathalie S. M. Lak, Filip Y. F. L. de Vos, Dannis G. van Vuurden, and Tom J. Snijders. "Focused Ultrasound-Enhanced Liquid Biopsy: A Promising Diagnostic Tool for Brain Tumor Patients." Cancers 16, no. 8 (April 19, 2024): 1576. http://dx.doi.org/10.3390/cancers16081576.
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The performance of minimally invasive molecular diagnostic tools in brain tumors, such as liquid biopsy, has so far been limited by the blood–brain barrier (BBB). The BBB hinders the release of brain tumor biomarkers into the bloodstream. The use of focused ultrasound in conjunction with microbubbles has been shown to temporarily open the BBB (FUS-BBBO). This may enhance blood-based tumor biomarker levels. This systematic review provides an overview of the data regarding FUS-BBBO-enhanced liquid biopsy for primary brain tumors. A systematic search was conducted in PubMed and Embase databases with key terms “brain tumors”, “liquid biopsy”, “FUS” and their synonyms, in accordance with PRISMA statement guidelines. Five preclinical and two clinical studies were included. Preclinical studies utilized mouse, rat and porcine glioma models. Biomarker levels were found to be higher in sonicated groups compared to control groups. Both stable and inertial microbubble cavitation increased biomarker levels, whereas only inertial cavitation induced microhemorrhages. In clinical studies involving 14 patients with high-grade brain tumors, biomarker levels were increased after FUS-BBBO with stable cavitation. In conclusion, FUS-BBBO-enhanced liquid biopsy using stable cavitation shows diagnostic potential for primary brain tumors. Further research is imperative before integrating FUS-BBBO for liquid biopsy enhancement into clinical practice.
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Bolton, Corey J., Omair A. Khan, Dandan Liu, Timothy J. Hohman, Katherine A. Gifford, Kaj Blennow, Henrik Zetterberg, and Angela L. Jefferson. "14 Performance of Novel Blood Based Biomarkers of Alzheimer's Disease is Dependent on Renal Functioning." Journal of the International Neuropsychological Society 29, s1 (November 2023): 225–26. http://dx.doi.org/10.1017/s1355617723003338.
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Objective:Novel blood-based biomarkers for Alzheimer's disease (AD) could transform AD diagnosis in the community; however, their interpretation in individuals with medical comorbidities is not well understood. Specifically, kidney function has been shown to influence plasma levels of various brain proteins. This study sought to evaluate the effect of one common marker of kidney function (estimated glomerular filtration rate (eGFR)) on the association between various blood-based biomarkers of AD/neurodegeneration (glial fibrillary acidic protein (GFAP), neurofilament light (NfL), amyloid-b42 (Ab42), total tau) and established CSF biomarkers of AD (Ab42/40 ratio, tau, phosphorylated-tau (p-tau)), neuroimaging markers of AD (AD-signature region cortical thickness), and episodic memory performance.Participants and Methods:Vanderbilt Memory and Aging Project participants (n=329, 73±7 years, 40% mild cognitive impairment, 41% female) completed fasting venous blood draw, fasting lumbar puncture, 3T brain MRI, and neuropsychological assessment at study entry and at 18-month, 3-year, and 5-year follow-up visits. Plasma GFAP, Ab42, total tau, and NfL were quantified on the Quanterix single molecule array platform. CSF biomarkers for Ab were quantified using Meso Scale Discovery immunoassays and tau and p-tau were quantified using INNOTEST immunoassays. AD-signature region atrophy was calculated by summing bilateral cortical thickness measurements captured on T1-weighted brain MRI from regions shown to distinguish individuals with AD from normal cognition. Episodic memory functioning was measured using a previously developed composite score. Linear mixed-effects regression models related predictors to each outcome adjusting for age, sex, education, race/ethnicity, apolipoprotein E-e4 status, and cognitive status. Models were repeated with a blood-based biomarker x eGFR x time interaction term with follow-up models stratified by chronic kidney disease (CKD) staging (stage 1/no CKD: eGFR>90 mL/min/1.73m2, stage 2: eGFR=60-89 mL/min/1.73m2; stage 3: eGFR=44-59mL/min/1.73m2 (no participants with higher than stage 3)).Results:Cross-sectionally, GFAP was associated with all outcomes (p-values<0.005) and NfL was associated with memory and AD-signature region cortical thickness (p-values<0.05). In predictor x eGFR interaction models, GFAP and NfL interacted with eGFR on AD-signature cortical thickness, (p-values<0.004) and Ab42 interacted with eGFR on tau, p-tau, and memory (p-values<0.03). Tau did not interact with eGFR. Stratified models across predictors showed that associations were stronger in individuals with better renal functioning and no significant associations were found in individuals with stage 3 CKD. Longitudinally, higher GFAP and NfL were associated with memory decline (p-values<0.001). In predictor x eGFR x time interaction models, GFAP and NfL interacted with eGFR on p-tau (p-values<0.04). Other models were nonsignificant. Stratified models showed that associations were significant only in individuals with no CKD/stage 1 CKD and were not significant in participants with stage 2 or 3 CKD.Conclusions:In this community-based sample of older adults free of dementia, plasma biomarkers of AD/neurodegeneration were associated with AD-related clinical outcomes both cross-sectionally and longitudinally; however, these associations were modified by renal functioning with no associations in individuals with stage 3 CKD. These results highlight the value of blood-based biomarkers in individuals with healthy renal functioning and suggest caution in interpreting these biomarkers in individuals with mild to moderate CKD.
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Visser, Koen, Milou Koggel, Jurre Blaauw, Harm Jan van der Horn, Bram Jacobs, and Joukje van der Naalt. "Blood-based biomarkers of inflammation in mild traumatic brain injury: A systematic review." Neuroscience & Biobehavioral Reviews 132 (January 2022): 154–68. http://dx.doi.org/10.1016/j.neubiorev.2021.11.036.
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Harpaz, Dorin, Raymond C. S. Seet, Robert S. Marks, and Alfred I. Y. Tok. "Blood-Based Biomarkers Are Associated with Different Ischemic Stroke Mechanisms and Enable Rapid Classification between Cardioembolic and Atherosclerosis Etiologies." Diagnostics 10, no. 10 (October 9, 2020): 804. http://dx.doi.org/10.3390/diagnostics10100804.
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Stroke is a top leading cause of death, which occurs due to interference in the blood flow of the brain. Ischemic stroke (blockage) accounts for most cases (87%) and is further subtyped into cardioembolic, atherosclerosis, lacunar, other causes, and cryptogenic strokes. The main value of subtyping ischemic stroke patients is for a better therapeutic decision-making process. The current classification methods are complex and time-consuming (hours to days). Specific blood-based biomarker measurements have promising potential to improve ischemic stroke mechanism classification. Over the past decades, the hypothesis that different blood-based biomarkers are associated with different ischemic stroke mechanisms is increasingly investigated. This review presents the recent studies that investigated blood-based biomarker characteristics differentiation between ischemic stroke mechanisms. Different blood-based biomarkers are specifically discussed (b-type natriuretic peptide, d-dimer, c-reactive protein, tumor necrosis factor-α, interleukin-6, interleukin-1β, neutrophil–lymphocyte ratio, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein and apolipoprotein A), as well as the different cut-off values that may be useful in specific classifications for cardioembolic and atherosclerosis etiologies. Lastly, the structure of a point-of-care biosensor device is presented, as a measuring tool on-site. The information presented in this review will hopefully contribute to the major efforts to improve the care for stroke patients.
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Yu, Qing-Shan, Wan-Qing Feng, Lan-Lan Shi, Rui-Ze Niu, and Jia Liu. "Integrated Analysis of Cortex Single-Cell Transcriptome and Serum Proteome Reveals the Novel Biomarkers in Alzheimer’s Disease." Brain Sciences 12, no. 8 (August 1, 2022): 1022. http://dx.doi.org/10.3390/brainsci12081022.
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Blood-based proteomic analysis is a routine practice for detecting the biomarkers of human disease. The results obtained from blood alone cannot fully reflect the alterations of nerve cells, including neurons and glia cells, in Alzheimer’s disease (AD) brains. Therefore, the present study aimed to investigate novel potential AD biomarker candidates, through an integrated multi-omics approach in AD. We propose a comprehensive strategy to identify high-confidence candidate biomarkers by integrating multi-omics data from AD, including single-nuclei RNA sequencing (snRNA-seq) datasets of the prefrontal and entorhinal cortices, as wells as serum proteomic datasets. We first quantified a total of 124,658 nuclei, 8 cell types, and 3701 differentially expressed genes (DEGs) from snRNA-seq dataset of 30 human cortices, as well as 1291 differentially expressed proteins (DEPs) from serum proteomic dataset of 11 individuals. Then, ten DEGs/DEPs (NEBL, CHSY3, STMN2, MARCKS, VIM, FGD4, EPB41L2, PLEKHG1, PTPRZ1, and PPP1R14A) were identified by integration analysis of snRNA-seq and proteomics data. Finally, four novel candidate biomarkers (NEBL, EPB41L2, FGD4, and MARCKS) for AD further stood out, according to bioinformatics analysis, and they were verified by enzyme-linked immunosorbent assay (ELISA) verification. These candidate biomarkers are related to the regulation process of the actin cytoskeleton, which is involved in the regulation of synaptic loss in the AD brain tissue. Collectively, this study identified novel cell type-related biomarkers for AD by integrating multi-omics datasets from brains and serum. Our findings provided new targets for the clinical treatment and prognosis of AD.
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Kos, Mark Z., Sobha Puppala, Dianne Cruz, Jennifer L. Neary, Ashish Kumar, Emma Dalan, Cun Li, Peter Nathanielsz, and Melanie A. Carless. "Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression." Frontiers in Molecular Neuroscience 15 (March 22, 2022). http://dx.doi.org/10.3389/fnmol.2022.817290.
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The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P < 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman’s rank correlations between PBMCs and the brain regions are all highly significant (rs = 0.47–0.57; P < 2.2 × 10–16), although pairwise correlations among the brain regions are markedly stronger (rs = 0.86–0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (>70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes.
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Lisi, Ilaria, Federico Moro, Edoardo Mazzone, Niklas Marklund, Francesca Pischiutta, Firas Kobeissy, Xiang Mao, et al. "Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury." Brain, November 9, 2024. http://dx.doi.org/10.1093/brain/awae350.
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Abstract Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, t-Tau, or p-Tau, published in PubMed/EMBASE up to April 10th, 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g., ICP monitoring), thus we focused on blood biomarkers’ temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Out of the 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19, and p-Tau in seven. Data in rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham) with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP’s rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers’ trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.
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Ramanan, Vijay K., Robel K. Gebre, Jonathan Graff-Radford, Ekaterina Hofrenning, Alicia Algeciras-Schimnich, Daniel J. Figdore, Val J. Lowe, et al. "Genetic risk scores enhance the diagnostic value of plasma biomarkers of brain amyloidosis." Brain, June 5, 2023. http://dx.doi.org/10.1093/brain/awad196.
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Abstract Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrollment, and treatment monitoring in Alzheimer’s disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer’s disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analyzing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, Aβ42/40, GFAP, or NfL. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% vs. 68%; p = 0.001). A machine learning approach incorporating plasma biomarkers, demographics, and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set), and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity which could noninvasively enhance the interpretation of blood-based AD biomarker profiles in the population.
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Erickson, Kirk I. "Aerobic exercise and Alzheimer’s disease blood‐based biomarkers." Alzheimer's & Dementia 20, S7 (December 2024). https://doi.org/10.1002/alz.088040.
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AbstractA greater amount of physical activity is associated with a reduced risk of developing dementia, including Alzheimer’s disease. Engaging in physical activity affects several pathways that are associated with memory impairments including hippocampal integrity, resting state networks, and metabolic function. Further, exercise interventions are effective at improving various measures of brain health in late adulthood that overlap with the cognitive functions that these brain regions support. Yet, there remains a poor understanding of the mechanisms that link physical activity and exercise behaviors to improvements in brain health outcomes and reduced risk of developing dementia. There is also significant heterogeneity in this literature that could likely be explained by factors that moderate the impact of exercise on brain health. In this presentation we will discuss recent research on exercise and brain health in late adulthood and will discuss the evidence for several levels of mechanisms and moderators of these effects including examining the impact of exercise interventions on Alzheimer’s disease blood‐based biomarkers. Preliminary results will be described from a multi‐site, 12‐month, 3x per week supervised, moderate‐intensity, Phase III randomized clinical trial of aerobic exercise in 648 cognitively normal adults between 65‐80 years of age. Blood samples were taken before and after the completion of the intervention as well as a comprehensive cognitive battery and PET amyloid. The results from this aerobic exercise intervention will be discussed including the impact of the intervention on cognitive performance and the role that changes in Alzheimer’s disease blood‐based biomarkers play in relation to functional outcomes. Overall, physical activity and exercise behaviors are important modifiable lifestyles that carry significant consequences for learning, memory, and Alzheimer’s disease risk in late adulthood.
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Mohs, Richard C., Douglas Beauregard, John Dwyer, Jennifer Gaudioso, Jason Bork, Tamiko MaGee‐Rodgers, Mickeal N. Key, Diana R. Kerwin, Lynn Hughes, and Cyndy B. Cordell. "The Bio‐Hermes Study: Biomarker database developed to investigate blood‐based and digital biomarkers in community‐based, diverse populations clinically screened for Alzheimer's disease." Alzheimer's & Dementia, February 28, 2024. http://dx.doi.org/10.1002/alz.13722.
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AbstractINTRODUCTIONAlzheimer's disease (AD) trial participants are often screened for eligibility by brain amyloid positron emission tomography/cerebrospinal fluid (PET/CSF), which is inefficient as many are not amyloid positive. Use of blood‐based biomarkers may reduce screen failures.METHODSWe recruited 755 non‐Hispanic White, 115 Hispanic, 112 non‐Hispanic Black, and 19 other minority participants across groups of cognitively normal (n = 417), mild cognitive impairment (n = 312), or mild AD (n = 272) participants. Plasma amyloid beta (Aβ)40, Aβ42, Aβ42/Aβ40, total tau, phosphorylated tau (p‐tau)181, and p‐tau217 were measured; amyloid PET/CSF (n = 956) determined amyloid positivity. Clinical, blood biomarker, and ethnicity/race differences associated with amyloid status were evaluated.RESULTSGreater impairment, older age, and carrying an apolipoprotein E (apoE) ε4 allele were associated with greater amyloid burden. Areas under the receiver operating characteristic curve for amyloid status of plasma Aβ42/Aβ40, p‐tau181, and p‐tau217 with amyloid positivity were ≥ 0.7117 for all ethnoracial groups (p‐tau217, ≥0.8128). Age and apoE ε4 adjustments and imputation of biomarker values outside limit of quantitation provided small improvement in predictive power.DISCUSSIONBlood‐based biomarkers are highly associated with amyloid PET/CSF results in diverse populations enrolled at clinical trial sites.Highlights Amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p‐tau)181, and p‐tau 217 blood‐based biomarkers predicted brain amyloid positivity. P‐tau 217 was the strongest predictor of brain amyloid positivity. Biomarkers from diverse ethnic, racial, and clinical cohorts predicted brain amyloid positivity. Community‐based populations have similar Alzheimer's disease (AD) biomarker levels as other populations. A prescreen process with blood‐based assays may reduce the number of AD trial screen failures.
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van der Ende, Emma L., Esther E. Bron, Jackie M. Poos, Lize C. Jiskoot, Jessica L. Panman, Janne M. Papma, Lieke H. Meeter, et al. "A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia." Brain, October 11, 2021. http://dx.doi.org/10.1093/brain/awab382.
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Abstract Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection (‘converters’). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80–0.89) and 0.90 (0.86–0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75–0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model’s ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.
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Gonzalez-Ortiz, Fernando, Bjørn-Eivind Kirsebom, José Contador, Jordan E. Tanley, Per Selnes, Berglind Gísladóttir, Lene Pålhaugen, et al. "Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease." Nature Communications 15, no. 1 (April 4, 2024). http://dx.doi.org/10.1038/s41467-024-47286-5.
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AbstractStaging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
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Oosthoek, Marlies, Lisa Vermunt, Arno de Wilde, Bram Bongers, Daniel Antwi-Berko, Philip Scheltens, Pieter van Bokhoven, Everard G. B. Vijverberg, and Charlotte E. Teunissen. "Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer’s disease: a systematic review." Alzheimer's Research & Therapy 16, no. 1 (April 27, 2024). http://dx.doi.org/10.1186/s13195-024-01456-1.
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Abstract Background Clinical trials in Alzheimer’s disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development. Methods We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01–01-2017 and 01–01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type. Results We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aβ (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers. Conclusions As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets.
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Nguyen, Andrew M., Vishal Saini, and H. E. Hinson. "Blood-Based Biomarkers for Neuroprognostication in Acute Brain Injury." Seminars in Neurology, September 26, 2023. http://dx.doi.org/10.1055/s-0043-1775764.
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AbstractAcute brain injury causes loss of functionality in patients that often is devastating. Predicting the degree of functional loss and overall prognosis requires a multifaceted approach to help patients, and more so their families, make important decisions regarding plans and goals of care. A variety of blood-based markers have been studied as one aspect of this determination. In this review, we discuss CNS-derived and systemic markers that have been studied for neuroprognostication purposes. We discuss the foundation of each protein, the conditions in which it has been studied, and how the literature has used these markers for interpretation. We also discuss challenges to using each marker in each section as well.
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Beauregard, Douglas W., Jennifer Gaudioso, Richard Mohs, Sarah Hollingshead, John Dwyer, Jason Bork, and Diana R. Kerwin. "Bio‐Hermes study topline results: Aß 40/42 and p‐tau181/217/231 blood‐based biomarkers compared to amyloid PET and CSF in a diverse, community‐based population." Alzheimer's & Dementia 19, S24 (December 2023). http://dx.doi.org/10.1002/alz.083156.
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AbstractBackgroundResearch of blood‐based biomarkers to indirectly assess amyloid presence in the brain has mainly been conducted in special populations (e.g., those enrolled in autopsy programs or single site populations selected for genetic vulnerability). To more accurately reflect clinical trial populations and to increase diversity, the Bio‐Hermes study used 17 sites and monitored recruitment to achieve ≥19% underrepresented minorities (URM) in each of the 3 clinical trial cohorts of Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Mild AD. In addition to blood‐based biomarkers and the presence of amyloid plaques identified through brain amyloid PET and CSF, numerous digital tests and genetic assays were performed resulting in a robust Bio‐Hermes database.MethodWithin 18 months, 17 sites enrolled 1,001 participants (60‐85 y/o) in clinically defined cohorts of: CN (N = 417), MCI (N = 312), and Mild AD (N = 272). Traditional and digital cognitive testing, amyloid PET imaging, biospecimen collection, and speech analytics were performed. A subset of participants received a retinal exam. Blood biomarkers included Aß 42/40, p‐Tau181/217/231, NfL, GFAP, full genome sequencing, including APOE status, and proteomics. Digital biomarkers included memory recall, executive functions, and drawing‐based and speech elicitation tasks. Blood biomarkers’ relationship to amyloid PET was measured using Spearman’s rank correlation. A ROC curve analysis assessed the sensitivity and specificity of each biomarker and combination of biomarkers compared with amyloid positivity from PET and CSF.ResultBrain amyloid positivity results were 21%, 34%, and 61% for the CN, MCI, and Mild AD cohorts, respectively. Initial data analysis by Global Alzheimer’s Platform Foundation® (GAP) compared results of blood Aß 42/40, t‐tau, and p‐tau181/217/231 tests with brain amyloid positivity. ROC analysis showed more favorable AUC for Aß 40/42 and p‐tau181 (0.8268), Aß 40/42 and t‐tau (0.7922), and Aß 40/42 (0.7918). For Black/African Americans, brain amyloid positivity was 24%, 23%, and 38% for the CN, MCI, and Mild AD cohorts, respectively, and for Hispanic/Latinos results were 4%, 37%, and 53%, respectively. Additional correlation and URM data will be available July 2023.ConclusionInitial topline results show blood‐based AD biomarkers are associated with brain amyloid positivity warranting further analysis of the Bio‐Hermes community‐derived database of blood‐based and digital biomarkers.
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Azizi, Sima, Daniel B. Hier, Blaine Allen, Tayo Obafemi-Ajayi, Gayla R. Olbricht, Matthew S. Thimgan, and Donald C. Wunsch. "A Kinetic Model for Blood Biomarker Levels After Mild Traumatic Brain Injury." Frontiers in Neurology 12 (July 6, 2021). http://dx.doi.org/10.3389/fneur.2021.668606.
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Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI.
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Dan, Yuet Ruh, and Keng-Hwee Chiam. "Discovery of plasma biomarkers related to blood-brain barrier dysregulation in Alzheimer’s disease." Frontiers in Bioinformatics 4 (October 4, 2024). http://dx.doi.org/10.3389/fbinf.2024.1463001.
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IntroductionBlood-based biomarkers are quantitative, non-invasive diagnostic tools. This study aimed to identify candidate biomarkers for Alzheimer’s disease (AD) using publicly available omics datasets, using the hypothesis that with blood-brain barrier dysfunction in AD, brain-synthesized proteins can leak into plasma for detection.MethodsDifferential abundance results of plasma and brain proteomic datasets were integrated to obtain a list of potential biomarkers. Biological validity was investigated with intercellular communication and gene regulatory analyses on brain single-cell transcriptomics data.ResultsFive proteins (APOD, B2M, CFH, CLU, and C3) fit biomarker criteria. 4 corresponding transcripts (APOD, B2M, CLU, and C3) were overexpressed in AD astrocytes, mediated by AD-related dysregulations in transcription factors regulating neuroinflammation. Additionally, CLU specifically induced downstream expression of neuronal death genes.DiscussionIn conclusion, a 5-protein panel is shown to effectively identify AD patients, with evidence of disease specificity and biological validity. Future research should investigate the mechanism of protein leakage through the blood-brain barrier.
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Posti, Jussi P., and Olli Tenovuo. "Blood‐based biomarkers and traumatic brain injury—A clinical perspective." Acta Neurologica Scandinavica, April 5, 2022. http://dx.doi.org/10.1111/ane.13620.
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Beauregard, Douglas W., Richard Mohs, John Dwyer, Sarah Hollingshead, Katy Smith, Jason Bork, and Diana R. Kerwin. "Bio‐Hermes: A study to assess the relationship of blood and digital biomarkers with Aβ PET scans in older persons with normal cognition, MCI or mild AD." Alzheimer's & Dementia 19, S14 (December 2023). http://dx.doi.org/10.1002/alz.076541.
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AbstractBackgroundRecently developed blood and digital biomarkers may enable the identification of persons with amyloid deposits in the brain. While these biomarkers are promising, most haven’t been evaluated in populations like those screened for clinical treatment trials or in populations with racial and ethnic diversity similar to the US population. The Global Alzheimer’s Platform Foundation® (GAP) completed its biomarker study (Bio‐Hermes) comparing results of blood and digital biomarker tests with brain amyloid PET scans and traditional cognitive tests. The trial enrolled 1,002 participants in three cohorts: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Mild AD.MethodWithin 18 months, 17 sites enrolled 1,002 participants (60‐85 y/o) in clinically defined cohorts of: CN (N = 417), MCI (N = 312), and Mild AD (N = 273). Traditional and digital cognitive testing, amyloid PET imaging, biospecimen collection, and speech analytics were performed. A subset of participants received a retinal exam. Blood biomarkers included, Aß 42/40, p‐Tau181/217/231, NfL, GFAP, full genome sequencing, including APOE status, and proteomics. Digital biomarkers included memory recall, executive functions, and drawing‐based and speech elicitation tasks. Blood biomarkers’ relationship to amyloid PET was measured using Spearman’s rank correlation. A ROC curve analysis will assess the sensitivity and specificity of each biomarker and combination of biomarkers compared with amyloid positivity from PET.ResultStatistical models to be competed in April 2023 for presentation.24% of participants were from underrepresented populations (URP) either African American, Hispanic or other. The CN cohort was 61% female, with 21% amyloid PET Positive; the MCI cohort was 54% female with 34% amyloid PET Positive; the Mild AD cohort was 51% female with 62% amyloid PET Positive. Penalized multiple regression will be used to predict amyloid level (continuous) and amyloid positivity status. Candidate predictors include cohorts, blood‐based biomarkers, cognitive assessments (rating scales and digital), retinal measurements, and speech recognition digital biomarkers.ConclusionBio‐Hermes generated a unique, well‐characterized, diverse sample set that determined the utility of several promising biomarkers. Validation of these biomarkers will expedite AD clinical trial enrollment by quickly identifying appropriate participants while reducing the variability and burden of screen failures from high‐cost brain scan procedures.
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Jiang, Yuanbing, Hyebin Uhm, Fanny C. Ip, Li Ouyang, Ronnie M. N. Lo, Elaine Y. L. Cheng, Xiaoyun Cao, et al. "A blood‐based multi‐pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups." Alzheimer's & Dementia, January 6, 2024. http://dx.doi.org/10.1002/alz.13676.
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AbstractINTRODUCTIONExisting blood‐based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood‐based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited.METHODSWe developed a blood‐based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD‐related endophenotypes in three independent cohorts from Chinese or European‐descent populations.RESULTSThe 21‐protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic‐specific dysregulations of biological processes upon AD progression.DISCUSSIONThis study demonstrated the utility of a blood‐based, multi‐pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine.HIGHLIGHTS The authors developed a blood‐based biomarker assay for Alzheimer's disease. The 21‐protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21‐protein assay can simultaneously assess activities of five biological processes. Ethnic‐specific dysregulations of biological processes in AD were revealed.
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Janigro, Damir, Damian M. Bailey, Sylvain Lehmann, Jerome Badaut, Robin O'Flynn, Christophe Hirtz, and Nicola Marchi. "Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts." Frontiers in Neurology 11 (February 4, 2021). http://dx.doi.org/10.3389/fneur.2020.577312.
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Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.
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Gardner, Raquel C., Ava M. Puccio, Frederick K. Korley, Kevin K. W. Wang, Ramon Diaz-Arrastia, David O. Okonkwo, Ross C. Puffer, et al. "Effects of age and time since injury on traumatic brain injury blood biomarkers: a TRACK-TBI study." Brain Communications, December 1, 2022. http://dx.doi.org/10.1093/braincomms/fcac316.
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Abstract Older adults have the highest incidence of traumatic brain injury globally. Accurate blood-based biomarkers are needed to assist with diagnosis of patients across the spectrum of age and time post-injury. Several reports have suggested lower accuracy for blood-based biomarkers in older adults, and there is a paucity of data beyond day-1 post-injury. Our aims were to investigate age-related differences in diagnostic accuracy and 2-week evolution of 4 leading candidate blood-based traumatic brain injury biomarkers – plasma glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, S100 calcium binding protein B, and neuron specific enolase – among participants in the 18-site prospective cohort study Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI). Day-1 biomarker data were available for 2602 participants including 2151 patients with traumatic brain injury, 242 orthopedic trauma controls, and 209 healthy controls. Participants were stratified into 3 age categories (young: 17-39 years, middle-aged: 40-64 years, older: 65-90 years). We investigated age-stratified biomarker levels and biomarker discriminative abilities across 3 diagnostic groups: head CT-positive/negative; traumatic brain injury/orthopedic controls; traumatic brain injury/healthy controls. The difference in day-1 glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neuron specific enolase levels across most diagnostic groups was significantly smaller for older versus younger adults, resulting in a narrower range within which a traumatic brain injury diagnosis may be discriminated in older adults. Despite this, day-1 glial fibrillary acidic protein had good to excellent performance across all age-categories for discriminating all 3 diagnostic groups (area under the curve 0.84-0.96; lower limit of 95% confidence intervals all >0.78). Day-1 S100 calcium binding protein B and ubiquitin carboxy-terminal hydrolase L1 showed good discrimination of CT-positive vs. negative only among adults under age 40 years within 6 hours of injury. Longitudinal blood-based biomarker data were available for 522 hospitalized patients with traumatic brain injury and 24 hospitalized orthopedic controls. Glial fibrillary acidic protein levels maintained good to excellent discrimination across diagnostic groups until day 3 post-injury irrespective of age, until day 5 post-injury among middle-aged or younger patients, and until week 2 post-injury among young patients only. In conclusion, the blood-based glial fibrillary acidic protein assay tested here has good to excellent performance across all age-categories for discriminating key traumatic brain injury diagnostic groups to at least 3 days post-injury in this trauma center cohort. The addition of a blood-based diagnostic to the evaluation of traumatic brain injury, including geriatric traumatic brain injury, has potential to streamline diagnosis.