Background: Extracellular vesicles (EV) released from neurons into the blood can reflect the state of nervous tissue. Measurement of neuron derived EV (NDE) may serve as an indicator of brain injury. Methods: A sandwich immunoassay was established to measure plasma NDE using anti-neuron CD171 and anti-EV CD9 ([CD171 ⁺ CD9 ⁺ ]). Plasma samples were obtained from commercial sources, cross-country (n = 9), football (n = 22), soccer (n = 19), and rugby (n = 18) athletes over time. Plasma was also collected from patients undergoing total aortic arch replacement (TAR) with selective cerebral perfusion during cardiopulmonary bypass before and after surgery (n = 36). Results: The specificity, linearity, and reproducibility of NDE assay (measurement of [CD171 ⁺ CD9 ⁺ ]) were confirmed. By scanning electron microscopy and nanoparticle tracking, spherical vesicles ranging in size from 150 to 300 nm were confirmed. Plasma levels of NDE were widely spread over 2 to 3 logs in different individuals with a significant age-dependent decrease. However, NDE were very stable in each individual within a ± 50% change over time (cross-country, football, soccer), whereas rugby players were more variable over 4 years. In patients undergoing TAR, NDE increased rapidly in days post-surgery and were significantly ( P = .0004) higher in those developing postoperative delirium (POD) (n = 13) than non-delirium patients (n = 23). Conclusions: The blood test to determine plasma levels of NDE was established by a sandwich immunoassay using 2 antibodies against neuron (CD171) and exosomes (CD9). NDE levels varied widely in different individuals and decreased with age, indicating that NDE levels should be considered as a normalizer of NDE biomarker studies. However, NDE levels were stable over time in each individual, and increased rapidly after TAR with greater increases associated with patients developing POD. This assay may serve as a surrogate for evaluating and monitoring brain injuries.

White matter, comprising 60% of the human brain, is formed by axonal fibers supported by oligodendrocytes. It is essential for brain communication, yet damage can accumulate silently leading to severe neurological problems. Current diagnostics detect changes only after symptoms appear. To enable earlier detection damage, we developed a blood test monitoring changes in oligodendrocyte-derived extracellular vesicles (ODEs) released from the brain into circulation. After validating the assay, we have shown that ODE levels vary from different individuals. However, ODE levels remain stable under mild head impacts in soccer heading practice (n = 15) and boxing/mixed martial arts (n = 10), whereas change markedly following neurological insults such as hemorrhagic (n = 7) and ischemic stroke (n = 14), or gynecological cancer after chemotherapy (n = 11). ODE measurement can potentially provide a minimally invasive window into white matter health and support early diagnosis, personalized assessment, and new insights into human brain biology.

The first month of life represents a critical window for brain development, during which rapid and coordinated maturation of neuronal and oligodendroglial networks establishes the foundation for long-term neurodevelopmental outcomes. However, current clinical approaches based on neurological examination and neuroimaging provide only indirect and intermittently accessible measures of these dynamic processes, highlighting the need for minimally invasive biomarkers capable of longitudinal assessment. Extracellular vesicles derived from neurons and oligodendrocytes can be detected in peripheral blood using immunoassays targeting cell-specific markers. We hypothesize that paired analysis of umbilical cord blood at birth and heel-prick blood at one month may enable non-invasive monitoring of early brain development. In this framework, neuron-derived and oligodendrocyte-derived extracellular vesicles reflect gray and white matter maturation, respectively. Longitudinal changes in circulating neuron-derived and oligodendrocyte-derived extracellular vesicles may capture individualized trajectories of early brain development. This approach aims to provide continuous rather than categorical assessment of neonatal brain maturation and may support development of scalable biomarkers for early neurodevelopmental evaluation.

Background and objectives: Repetitive head impacts (RHI) are increasingly recognized as potential contributors to long-term neurological consequences. Current clinical assessments rely primarily on symptoms and acute neurological findings, limiting the ability to detect and longitudinally monitor biological responses that may occur in the absence of clinically recognized concussion. This exploratory study investigated surface-associated biomarkers on circulating oligodendrocyte-derived extracellular vesicles (ODEs) as candidate blood markers of biological responses associated with RHI exposure. Methods: Plasma ODEs were captured using an anti-myelin oligodendrocyte glycoprotein (MOG) antibody and probed for ciliary neurotrophic factor (CNTF), interleukin-1β (IL-1β), and α-synuclein (α-syn), selected to reflect neural repair, neuroinflammatory, and neurodegenerative processes, respectively. Unlike conventional EV analyses focused primarily on intravesicular cargo, this platform preserves vesicle integrity and quantifies biomolecules associated with the external surface of captured ODEs. Assays for each biomarker were analytically characterized prior to application to the athletic cohorts. Results: Longitudinal measurements were obtained from boxing and mixed martial arts fighters ( n = 18; pre-event to 5 weeks post-event), high school American football players ( n = 34; sampled monthly from July through November), and college rugby players ( n = 14; sampled 3–4 times annually from 2014 to 2017). High school cross-country runners ( n = 68) served as an athletic comparison group with substantially lower expected exposure to direct head impacts. Biomarker levels remained generally stable in the cross-country cohort, whereas subsets of combat and collision-sport athletes exhibited longitudinal changes in ODE-associated biomarkers, including individuals without clinically recognized concussion or neurological symptoms. Individual head-impact burden and relevant clinical confounders were not systematically quantified, precluding establishment of an exposure–response relationship. Conclusion: Surface-associated biomarkers on circulating ODEs demonstrated measurable longitudinal changes in subsets of athletes with expected exposure to RHI. These exploratory findings support prospective studies combining ODE-associated biomarker measurements with quantitative head-impact monitoring, clinical characterization, neuroimaging, and neurological outcomes to determine their biological and clinical significance.

Advances in cancer detection and treatment have substantially improved survival across many malignancies, increasing attention to long-term health outcomes and quality of life (QOL) (1,2). Cancer-related cognitive impairment (CRCI), often referred to colloquially as "chemobrain," may occur before, during, or after anticancer therapy and can affect multiple cognitive domains, including learning and memory, attention, processing speed, and executive function (3)(4)(5)(6). The severity, affected domains, and temporal trajectories vary considerably among individuals, indicating that CRCI is a heterogeneous rather than uniform or sequential process (3,4,6).Current CRCI assessment relies primarily on patient-reported symptoms and standardized neuropsychological testing, which provide complementary but not necessarily concordant information (4,5,7). Although essential for characterizing cognitive symptoms and performance, these approaches provide limited information about the underlying biological processes occurring within the brain. The biological basis of CRCI is multifactorial and may involve interacting inflammatory, metabolic, neurovascular, synaptic, and glial alterations resulting from cancer, host responses, individual susceptibility, and anticancer therapies (4,(8)(9)(10). These processes are difficult to assess directly and longitudinally in the living human brain, creating a need for minimally invasive approaches that can provide complementary molecular information.Circulating extracellular vesicle (EV) populations enriched for brain-associated cell markers represent one potential source of such information. Brain cells release EVs that can reach the peripheral circulation, and circulating EV populations associated with specific neural cell types are increasingly being investigated as blood-based sources of brain-related molecular information (11)(12)(13)(14). EV populations enriched using neuron-associated markers, commonly referred to as neuron-derived EVs (NDEs) (11)(12)(13), and those enriched using oligodendrocyteassociated markers, commonly referred to as oligodendrocyte-derived EVs (ODEs) (14), have been investigated as candidate sources of neuronal and oligodendroglial information, respectively. ODE measurements may provide information related to oligodendrocyte and myelin biology, whereas NDE measurements may provide complementary information regarding neuronal and synaptic processes. These approaches remain investigational, however, and require rigorous analytical and clinical validation, including evaluation of marker specificity, preanalytical variability, and potential systemic effects of cancer and its treatment on circulating EV profiles.In this Perspective, we discuss the clinical and biological complexity of CRCI and propose a conceptual framework for integrating brain-associated EV measurements with neuroimaging and cognitive assessments. Rather than proposing EVs as stand-alone diagnostic biomarkers, we consider their potential role as a complementary molecular component of longitudinal brain health monitoring in oncology.CRCI can substantially affect daily functioning, employment, medication management, independence, and QOL (2,3,7). Its clinical expression is heterogeneous, with variation in affected domains, onset, severity, and persistence across individuals (3,4,6), complicating identification of patients at increased risk and longitudinal assessment of cognitive trajectories.A major unmet need is the absence of an established framework for objective longitudinal assessment of the biological changes associated with CRCI. Unlike other treatmentrelated toxicities, such as cardiotoxicity, hepatotoxicity, nephrotoxicity, and myelosuppression, which can be monitored using established clinical, laboratory, and imaging-based measures, CRCI lacks comparable tools for routinely assessing underlying brain-related biological changes.Neuropsychological testing and patient-reported outcomes remain essential for characterizing cognitive performance and symptoms but may be constrained by time, expertise, repeated-testing effects, and limited scalability in routine oncology practice (5,7,15). Moreover, these approaches do not directly assess the molecular and cellular processes underlying CRCI. This gap highlights the need for minimally invasive molecular measures that can be obtained repeatedly across the cancer care continuum. Such measures could help define when brain-related biological changes emerge, how they relate to cognitive trajectories, and whether they persist or resolve after therapy. Ultimately, scalable biological measures integrated with cognitive assessment and other complementary approaches could facilitate investigation of individual risk, longitudinal recovery, and potential neuroprotective or rehabilitative interventions (2,7).The biological basis of CRCI is multifactorial, reflecting interacting effects of cancer, systemic host responses, individual susceptibility, and anticancer therapies rather than a single neurotoxic pathway. Proposed mechanisms include neuroinflammation, oxidative stress and mitochondrial dysfunction, blood-brain barrier and neurovascular dysfunction, impaired neurogenesis and synaptic plasticity, and oligodendrocyte and white matter injury (8)(9)(10)16) (Fig. 1). These processes may involve multiple cellular components of the brain, including neurons, oligodendrocytes, astrocytes, microglia, and cells of the neurovascular unit, and may disrupt cellular homeostasis, synaptic connectivity, myelination, and neural networks supporting memory, attention, processing speed, and executive function (8)(9)(10)16). Importantly, such alterations are not restricted to chemotherapy; cancer itself and other therapeutic modalities may contribute through overlapping biological pathways (9,10). Thus, CRCI may reflect heterogeneous and dynamic changes across multiple brain cellular compartments, providing a rationale for minimally invasive...