Table 2.
Impact of neurotrophins on outcome measures in human TBI.
| Study | Dates of study | Number of participants and sex | Age (years) | Inclusion criteria | Treatment administered | Outcome measures |
|---|---|---|---|---|---|---|
| Exogenously administered treatment | ||||||
| Nerve growth factor for TBI | 2010-2017 | 106, all | 18-65 | Age, moderate to severe TBI | Intranasal NGF 20 μg/d for 2 weeks | GOS, mRS, BI, HAMA, HAMD |
| Cerebrolysin neural repair therapy in children with TBI and cerebral palsy | 2014-2016 | 100, all | 3 months-18 yrs | Cerebral palsy with mental retardation, severe perinatal brain insult | NGF cerebrolysin | Neurodevelopment: IQ assessment at baseline and after 3 and 6 months of therapy |
| Derivatives of omega-3 HUFA as biomarkers of TBI | 2017-2023 | 45, all | 18-55 | Age, verified TBI, ability to swallow, not pregnant, English speaking, informed consent, coenrolled in PARC-TBI protocol or TRACK-TBI, GCS 3-15 | 1, 1000 mg/day n-3 HUFA, or 2, 4,000 mg/day n-3 HUFA within 24 hours of injury for 14 days | Relationship of varying doses of n-3 HUFAs on blood levels of the following bioactive metabolites indicators of neuroinflammatory damage including BDNF, relationship of n-3 HUFA blood levels and clinical outcomes measured by the GOSE, evaluate potential adverse events |
| Simvastatin for mTBI | 2013-2017 | 6, all | ≥21 | Age, documented hazardous duty in Iraq and or Afghanistan with the U.S. armed forces. mTBI according to American Congress of Rehabilitation Medicine (ACRM) criteria. More than 6 months since last blast trauma exposure, adequate English language skills, vision, and hearing). Elevated cholesterol levels. No use of statins during the previous year and recently. No clinically significant laboratory abnormalities (electrolytes, Body Mass Index (BMI) between 18 and 36 inclusive) | Simvastatin 40 mg/day for 12 months | CSF tau concentration, CSF BDNF |
| OPTIMA-TBI pilot study | 2017-2021 | 75, all | 18-65 | Evidence of TBI or mTBI | Omega-3 polyunsaturated fatty acid, 6 g DHA+EPA for one month followed by 1.2 g DHA+EPA for two months. Capsules contain fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) | Biomarker endpoints (NFL), biomarker endpoint (inflammation), biomarker endpoint (neurogenesis serum levels of BDNF, delayed functional recovery, moderate/severe postconcussive symptoms, cognitive impairment) |
| Brain stimulation | ||||||
| rTMS to improve cognitive function in TBI | 2014-2019 | 33, all | 20-65 | Age, veteran, history of TBI, obtain motor threshold, stable environment, ability to attend appointments, not pregnant | Active rTMS; 20 sessions of rTMS | TMT part B, sustained improvement on executive function, change in QOL scale, moderators of response: PTSD score, treatment-induced change in functional connectivity, change in a mediator of response: BDNF |
| Physical activity | ||||||
| Effects of aerobic exercise on cognition, mood, and fatigue following TBI | 2007-2021 | 154, all | ≥18 | TBI within 6 months or more, basic mobility, English speaking | Behavioral exercise, 50 minutes of aerobic exercise on a treadmill 3 days a week for 8-16 weeks | HVLT-R, TMT A and B, digit span subtests of the WAIS-III, WCST, COWAT Stroop Word Color Test GF Index, BDI-II, blood draws for assessment of BDNF and VEGF levels |
| Microvascular injury and BBB dysfunction as novel biomarkers and targets for treatment in TBI | 2017-2020 | 120, all | 18-85 | Age, evidence of TBI | Change in brain volume with BBB dysfunction, change in serum biomarkers BBB dysfunction vWF, BDNF, GFAP, S100β, sTau, and sNFL, changes in GOS-E, change in RPSQ, change in PROMIS, change in posttraumatic epilepsy | |
| Aerobic exercise and cognitive training effects on postconcussive symptomology | 2018-2019 | 34, all | ≥18 | TBI, ability to exercise, persistent symptoms, access to smartphone | 30 minutes of aerobic exercise followed by a 20-minute cognitive training (CT) program | The Rivermead Post Concussion Symptoms Questionnaire, NIH Toolbox Cognition Battery-working memory, NIH toolbox Cognition Battery-attention |
| Treating persistent postconcussion symptoms with exercise | 2019-2021 | 58, all | 18-65 | mTBI, cleared for physical activity, low risk for cardiopulmonary disease, exercise intolerance (inability to exercise at preinjury intensity/duration due to acute presentation of symptoms) | Aerobic Exercise Protocol (AEP) exercise 20 minutes per day or until symptom exacerbation, 5-6 days per week | Change in symptom burden, change in sleep duration, change in daytime sleepiness, change in BDNF, change in cytokine profile, change in TL, change in fatigue. Change in anxiety, change in function related to headaches, change in depression, MRS quantification of GABA/glutathione |
| Serum/sample analysis | ||||||
| S100B in intensive care patients with and without TBI | 2007-2019 | 600, all | ≥18 | Patients of the Department of Neurosurgery, University of Erlangen Nürnberg, TBI patients, intracranial tumor patients, intensive care patients, informed consent | Blood, cerebrospinal fluid, and urine samples, in all subjects, blood (4 mL), cerebrospinal fluid (4 mL), and urine (4 mL) samples were collected daily as part of the clinical routine at 6:00 AM | GOS, Karnofsky performance status score |
| Microvascular injury and BBB dysfunction as novel biomarkers and targets for treatment in TBI | 2017-2020 | 120, all | 18-85 | Age, evidence of TBI | Change in brain volume with BBB dysfunction, change in serum biomarkers BBB dysfunction vWF, BDNF, GFAP, S100β, sTau, and sNFL, changes in GOS-E, change in RPSQ, change in PROMIS, change in posttraumatic epilepsy | |
| Epigenetic effects on TBI recovery | 2017-2023 | 300, all | 3-18 | TBI, orthopedic injury | Blood and saliva biosamples are collected at all time points and CSF when available acutely for epigenetic and proteomic analysis of BDNF | NIHTB-CB, BRIEF-2 or BRIEF-P, strengths and difficulties questionnaire, and Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) (6, 12 months' postinjury) |
mRS: modified Rankin score; BI: Barthel index; PSS-10: Perceived Stress Scale; TMS: transcranial magnetic stimulation; BDNF: brain-derived neurotrophic factor; SDF1α: stromal cell-derived factor 1α; CST: corticospinal tract; M1PMv: ventral premotor cortex; CC: corpus callosum; HIF: hypoxia-inducible factor-1; VEGF: vascular endothelial growth factor; IGF-1: insulin-like growth factor I; FA: fractional anisotropy; DDP: Duck Duck Punch; CO: peak cardiac output; VO2peak: peak exercise oxygen consumption; OUES: oxygen uptake efficiency slope; Ve-VCO2: ventilation/VCO2 ratio; ∆[O2Hb]: differences of the brain tissue oxyhemoglobin; ∆[HHb]: differences of the brain tissue deoxygenation; ∆[THb]: differences of regional blood volume; PCS: physical component score; MCS: mental component score; MMSE: minimental status examination; TAC: total antioxidant capacity; FOIS: Functional Oral Intake Scale; BBS: Berg Balance Scale; MRC: Medical Research Council; SNP: single nucleotide polymorphism; Met: a methionine; Val: valine; ARAT: Action Research Arm Test; FMA: The Fugl-Meyer Assessment-Upper Extremity Scale; FSS: Fatigue Severity Scale; TUG: Timed up and Go Test; HRV: Heart Rate Variability; GDNF: glial cell-derived neurotrophic factor; IGF2: insulin-like growth factor 2; mBI: Modified Barthel Index; CSF: cerebrospinal fluid; Lp-PLA2: lipoprotein-associated phospholipase A2; NHPT; Nine-Hole Peg Test; NIHSS: National Institutes of Health Stroke Scale; HVLT-R: Hopkins Verbal Learning Test-Revised; TMT: Trail Making Tests A and B; digit span subtests of the WAIS-III; WCST: Wisconsin card sort test; COWAT: Controlled Oral Word Association Test; GF: Stroop Word Color Test Global Fatigue Index; BDI-II: Beck Depression Inventory-II; GOS: Glascow Outcome Score; HAMA: Hamilton Anxiety Scale; HAMD: Hamilton Depression Scale; IQ: neurodevelopment: intelligence quotient; QOL: quality of life; NIHTB-CB: NIH Toolbox Cognition Battery; BRIEF-2: Behavior Rating Inventory of Executive Function, Second Edition; BRIEF-P: Behavior Rating Inventory of Executive Function, Preschool Version; Vineland-3: Vineland Adaptive Behavior Scales, Third Edition; GOSE: Glasgow Outcome Scale-Extended; BBB: blood-brain barrier dysfunction (vWF, BDNF, GFAP, S100β, sTau, and sNFL); RPSQ: Change in Rivermead Postconcussion Symptom Questionnaire; PROMIS: Change in Patient-Reported Outcomes Measurement Information System; NFL: change in posttraumatic epilepsy biomarker endpoints; TL: telomere length; ICT: Induced Constraint Therapy; MMP-9: matrix metallopeptidase 9; CD105-CXCR4: C-X-C chemokine receptor type 4-PS (phosphoserine).