Table 4.

Human clinical trial neuroproteomics.

# Of Subjects/patient demographics	Biofluid tested, proteins and clinical factors	Tests	Results/level of evidence	Data category	Institute	References
504 NCAA college athletes with concussions and control athletes (contact/non-contact sport athletes)	Blood GFAP, UCH-L1, and Tau levels recorded between 24 to 48 h after injury, and 7 days after return to play	Quanterix SIMOA multiplex assays, SCAT-3, SAC	Athletes with concussions had significant elevation in GFAP (p < 0.001), UCH-L1 (p < 0.001) and tau levels (p = 0.004). Supports the analysis of GFAP, UCH-L1, and Tau biomarkers as potential signals for concussion/ mTBI in contact sports.	Prognostic/Diagnostic Data (Concussion/mTBI)	NCAA and CARE	(278)
218 adult sTBI patients; (CSF from 138 subjects/Serum from 80 subjects)	CSF (EVD)/Serum temporal S100b profiles, recorded over 6 days post-injury. Evaluates correlations in, protein levels, age, gender, weight, & ISS.	GOS, DRS, ELISA	CSF and serum S100b levels were elevated over healthy controls across the first 6 days post-TBI (p ≤ 0.005 and p ≤ 0.031), all correlated with higher mortality and lower GCS scores. S100B levels provide significant predictions in sTBI cases.	Predictive and Prognostic Data (sTBI)	University of Pittsburgh Department of Physical Medicine and Rehabilitation	(276)
54 Geriatric Subjects (μ-age = 69–70); 23 with AACD, 16 with AD, and 15 healthy controls	CSF, Cerebral Gray Mater t-tau and p-tau181 concentrations correlated with AACD/ AD diagnosis, and MRI scans	ELISA, MRI, Voxel-based morphometry	AACD/AD subjects presented elevated t-tau and p-tau181 concentrations in respective areas of the brain. Study supports the elevated distribution of tau and p-tau in respective area of the brain for AACD and Alzheimer disease patients (p < 0.001).	Diagnostic Data (AD)	University of Heidelberg Geriatric Psychiatry and University of Frankfurt Department of Psychiatry	(280)
27 sTBI Pediatric subjects (ages 2–17 yrs.) with Glasgow Coma Scale score of ≤8	Serum/CSF GFAP levels correlated with Hypothermia treatments	GCS, GFAP quantification	CSF GFAP (15.5 +/− 6.1 ng/mL) and serum concentrations (0.6 +/− 0.2 ng/mL) were successfully utilized for predicting Pediatric Performance Category Score over CT images (p = 0.008). Elevated GFAP concentration patterns indicated prognostic data for sTBI. Control comparison of GFAP also indicated nonsignificant decreases in concentration using hypothermic interventions.	Prognostic &Treatment Intervention Data (sTBI/ pTBI)	University of Western Ontario Division of Critical Care Medicine, Department of Pediatrics	(275)
217 TBI patients (161 men/ 35 women); 196 of the patients were admitted with Level 3 acute TBI (< 24 h post-injury) while 21 patients were admitted to inpatient rehabilitation units (μ = 176.4 days post-injury).	Plasma p-tau/t-tau biomarker levels compared to CT scans and GCS scores	GSC and AUC	Total (T-tau) and P-tau levels differentiated mTBI from other forms of TBI. Illustrated that p-tau levels and the ratio of phosphorylation outperformed diagnosis from CT scans (AUC = 0.921 and 0.646, respectively). Proteomics supported p-tau as a stronger biomarker for acute TBI in comparison to t-tau or CT diagnosis.	Prognostic/Diagnostic Data (mTBI/ acute TBI)	State University of New York Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery (TRACK-TBI Pilot Study)	(279)
145 sTBI patients evaluated (< 6 h post injury). Serum samples from 86 patients and CSF samples from 59 patients	Serum/CSF UCH-L1 levels taken every 6 h.	ELISA	Supports a statistically significant increase of UCH-L1 levels overtime and respective biokinetics in CSF and serum samples for severe TBI patients in comparison to controls (p < 0.001), indicating a highly potential indicator of time dependent classification of sTBI.	Predictive data (sTBI)	University of Florida Center of Innovative Research, Banyan Biomarkers Inc., and Department of Psychiatry	(274)
28 pediatric patients	Serum S100b, NSE, IL-6, IL-8, IL-10, SICAM, L-selectin, and endothelin levels 1 Day post-injury	ELISA, GOS, ROC, Multi-ROC, and AUC,	(1) Combining biomarker levels for S100b (“screening marker”) and L-selectin/IL-6 (“varying markers”) achieved an AUC =0.98 when predicting outcome predictions. (2) Specificity and sensitivity for unfavorable outcome prediction were 96 and 100%, respectively. (3) Supports the use of multiple biomarkers (like S100b and IL-6) as potential prognostic tools for post-traumatic outcome projections.	Prognostic & predictive data (predicting unfavorable outcomes of pTBI)	University of Edinburgh Child Life and Health	(277)
217 TBI Patients 161 men; 35 women; 196 patients with acute TBI and 21 subjects with chronic TBI	Plasma AutoAb [GFAP] response levels in post-acute/chronic TBI.	Mini-Protean II Multiscreen and Immunoblot Screening	AutoAb [GFAP] levels for subjects with chronic TBI (176 days post-TBI) were significantly higher (15.08 ± 2.82; n = 21) than healthy controls and slightly higher than acute TBI patients (p < 0.001). Illustrates the significantly increased levels of autoimmune response and AutoAb [GFAP] levels in chronic TBI due to GFAP protein fragmentation.	Diagnostic Data (Acute and Chronic TBI)	University of Florida Departments of Psychiatry and Neuroscience (TRACK-TBI)	(282)
50 ABI patients (23 SAH, 15 TBI, 6 intracranial hemorrhage, 3 ischemic stroke, and 3 others) and 12 patients without ABI	Ventricular cerebrospinal fluid (vCSF), prospective study on the protein expression	DIA-SWATH mass spectrometry	The study found significant protein expression differences between patients with and without ABI. Patients with severe intracranial hypertension or death had higher GFAP expression than those without. Differences in protein expression were also found between patients with traumatic and nontraumatic ABI, with some proteins related to structural damage, complement activation, and cholesterol metabolism. However, no significant differences were found in protein expression between patients with SAH versus TBI or between those with good versus poor 3-month Glasgow Outcome Scale score.	Biomarker Discovery	Universite Libre de Bruxelles, Department of Intensive Care, Erasme Hospital	(177)
12 patients with moderate to severe TBI (initial Glasgow Coma Scale ≤12)	Urine, multivariate urinary peptidome	DIA mass spectrometry	Highly sensitive and specific models were created using top 20 discriminant peptides for DRS-and FIM-based models with area under the receiver operator curve of 0.99 and 0.95, respectively. Predictive ability was assessed using robust leave-one-out cross-validation with Q2 statistics of 0.64 (p = 0.00012) and 0.62 (p = 0.011) for DRS-and FIM-based models, respectively, both with a high predictive accuracy of 0.875. These models can help track rehabilitation progress after TBI and should be studied further for efficacy in assessing therapeutic interventions.	Biomarker Discovery, Predictive model of functional recovery during TBI rehabilitation	Virginia Commonwealth University, School of Medicine	(160)

AUC, Area Under the Curve; AACD, Aging-associated Cognitive Decline; AD, Alzheimer’s Disease; NCAA, American National Collegiate Athletic Association; CSF, Cerebrospinal Fluid; CT, Computed Tomography; DRS, Disability Rating Scale; ELISA, Enzyme-linked Immunosorbent Assay; EVD, External Ventricular Drain; GFAP, Glial Fibrillary Acidic Protein; GOS, Glasgow Outcome Score; GCS, Glasgow Coma Scale; ISS, Injury Severity Score; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-10, Interleukin-10; MRI, Magnetic Resonance Imaging; mTBI, Mild TBI; NSE, Neuron-Specific Enolase; pTBI, Pediatric TBI; p-tau, Phosphorylated Tau; ROC, Receiver Operating Characteristic; S100b, S100 Calcium-binding Protein B; sTBI, Severe TBI; SICAM, Soluble Intracellular Adhesion Molecule; SCAT-3, Sports Concussion Assessment Test-3; SAC, Standardized Assessment of Concussion; t-tau, Total Tau; UCH-L1, Ubiquitin C-terminal Hydrolase-L1; CARE, US Department of Defense Concussion Assessment, Research, and Education Consortium.