Exosomal neurofilament light

Abstract

ObjectiveTo measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms.MethodsExosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)–α, interleukin (IL)–6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1–2 mTBIs, and repetitive (3 or more) mTBIs.ResultsElevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF.ConclusionRepetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.

Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

“…The finding of chronic elevations of EV GFAP and NfL at 1 year postinjury in patients with moderate or severe TBIs expands on our previous work in which EV and plasma NfL levels were elevated many years after injury in military personnel with repetitive mTBI 9 . Our finding that EV GFAP and NfL continue to have diagnostic and prognostic utility when sampled at 1 year postinjury constitute increasing evidence that GFAP and NfL are valuable chronic biomarkers of TBI.…”

“…Our lab has recently investigated the utility of EV biomarkers in a sample of military personnel and Veterans with remote mTBI. Our findings suggest that repetitive, remote mTBIs are associated with elevations of EV NfL, especially among individuals with chronic neurobehavioral or psychological symptoms 9 . However, the utility of EV NfL in civilian patients with a history of single TBI and in comparison with EV GFAP has not been previously investigated.…”

“…Elevated GFAP is considered an indicator of astrocytic cell impairment following TBI 16 , 17 , and elevated NfL is suggestive of neuroaxonal damage 18 – 20 . Levels of NfL in exosomes and other EVs following TBI have been evaluated in few studies, with variable results 9 , 21 – 23 . A recent study has shown an association between GFAP levels in EVs, but not free-circulating GFAP, and presence of diffuse injury as compared to other lesion types 23 .…”

The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)

“…An important area of brain injury and disease research is the search for blood biomarkers that reflect brain processes, to predict disease course and used as readouts to assess utility of interventions to improve outcome for patients. Recently, a range of proteins, including neurofilament light (NfL) polypeptide released from damaged axons, have been proposed as viable biomarkers of mild TBI ( 60 , 124 , 125 ). The brain's immune response to mild TBI is also evident in the blood, as elevated c-reactive protein (CRP) levels at admission are independently associated with the increased risk of persistent psychological problems and cognitive impairment ( 29 ).…”

Assessment of Long-Term Effects of Sports-Related Concussions: Biological Mechanisms and Exosomal Biomarkers

“…This correlation was not present when measuring total Tau in plasma, although this measure was positively associated with cumulative head impact index ( Alosco et al, 2018 ). Guedes et al (2020) measured plasma and exosomal levels of NF-light in veterans with history of mTBIs and found that those experiencing chronic PCS and post-traumatic stress disorder (PTSD) exhibited the highest NF-light levels both in plasma and exosomes.…”