Table 1.
Impact of neurotrophins on outcome measures in human stroke.
| Stroke and neurotrophins | ||||||
|---|---|---|---|---|---|---|
| Study | Dates of study | Number of participants and sex | Age (years) | Inclusion criteria | Treatment administered | Outcome measures |
| Exogenous administered treatment | ||||||
| The neurotrophic effects of lithium carbonate following stroke: a feasibility study | 2010-2017 | 12, all | ≥40 | Age, English speaking, stroke within 12 months | Lithium carbonate, 0.4-0.8 mmol/L for 2 months | Increase in total brain gray matter volumes, cognitive tasks of the neurological disorders and stroke, serum BDNF levels, serum lithium and creatinine levels |
| Kinetics of plasma and serum levels of BDNF in patients with ischemic stroke | 2011-2012 | 50, all | ≥18 | Age, recent ischemic stroke, informed consent, cerebral imaging | Intravenous fibrinolysis using rt-PA to increase circulating BDNF | Measurement of plasma levels of BDNF Measurement of serum levels of BDNF |
| The STem Cell Application Researches and Trials In NeuroloGy-2 (STARTING-2) Study | 2012-2017 | 60, all | 30-75 | Stroke within 90 days, radiological legions, neurological deficits, informed consent | Mesenchymal stem cell intravenous transplantation | Categorical shift in mRS, cognitive battery, exploration of biomarkers SDF-1α (chemokine) S100β (protection and regeneration), HIF-1 (preconditioning), circulating MSCs and MSC-derived microparticles CD105-CXCR4-PS BDNF levels and its polymorphism, and VEGF levels |
| Effects of intranasal NGF for acute ischemic stroke | 2016-2020 | 106, all | ≥18 | Age, acute ischemic stroke, informed consent | Intranasal NGF 20 μg/d for 2 weeks | Neurological function (low mRS score) |
| Study the result of ayurvedic SUVED & Reimmugen (colostrum) treatment on vascular disease, CAD, CVA, DVT | 2016-2017 | 96, all | 18-70 | Diagnosis of vascular disease leading to IHD, CAD, CVA, DVT, PAD at any stage | SUVED ayurvedic formulation in Ghana (concentrated) in capsules; 500 mg each, Reimmugen, whole cow colostrum in powder put in capsules; 300 mg each | Changes in IMT as an indicator of atherosclerosis reversal, assessing the development/risk of ischemic events in other circulations |
| Brain correlates of multimodal rehabilitation in chronic poststroke aphasia | 2019-2020 | 20, all | ≥18 | Age, diagnosis of poststroke aphasia | 5 mg and 10 mg donepezil tablet, intensive language action therapy, transcranial direct current stimulation | Western Aphasia Battery Assessment, Stroke and Aphasia Quality of Life Scale 39, Communication Activity Log, Stroke Aphasia Depression Questionnaire |
| Evaluation of Memantine Versus Placebo on Ischemic Stroke Outcome (EMISO) | 2015-2017 | 47, all | ≥18 | age, confirmation of ischemic stroke in MCA territory by imaging, presentation at first 24 hrs of disease onset | 20 mg/d (2 tab 5 mg) memantine for 7 days and then 10 mg/d (1 tab 5 mg) memantine for 21 days or placebo tablet for 21 days | Changes in neurological deficit by National Institute of Health Scale Score (NIHSS), assessed disability by modified Rankin scale (mRS) |
| Memantine for enhanced stroke recovery | 2014-2022 | 20, all | ≥18 | Age, diagnosis of ischemic stroke, arm weakness, ability to swallow pills, supratentorial location of stroke, living independently prior to stroke, able to voluntarily move affected UE | Memantine or placebo treatment given increasing by 7 mg (1 capsule) per week until a goal dose of 28 mg daily (goal dose) for 90 days | Motor Activity Log, ten-meter walk test, Stroke Impact Scale (SIS), Cancellation Tests, Grip Strength Test, Montreal Cognitive Assessment |
| Brain stimulation | ||||||
| Use of deep transcranial magnetic stimulation after stroke | 2010-2014 | 15, all | 18-85 | Age, acute ischemic stroke, neurological deficits after stroke, informed consent, NIHSS ≤ 18 | Deep TMS (transcranial magnetic stimulation 10 Hz) 7; 15-minute sessions of TMS to increase secretion of BDNF | mRS < 2 and BI > 95 obtained at 3 months after stroke onset, safety, neurological outcome assessed by NIHSS at discharge < 5 or showing improvement of at least 8 points from the initial stroke score or improvement of at least 2 points on item 6 of the NIHSS (motor score leg), good neurological outcome as assessed by NIHSS at 3 months < 5 or showing improvement of at least 8 points from the initial stroke score or improvement of at least 2 points on item 6 of the NIHSS (motor score leg) |
| IMPULSE—stimulation of brain plasticity to improve upper limb recovery after stroke | 2020-2023 | 90, all | 18-80 | Age, 8 weeks-12 months after ischemic stroke, low mRS score, Action Research Arm Test (ARAT) score 13-50, both inclusive, Shoulder Abduction Finger Extension (SAFE) score ≥ 5, informed consent | Cerebrolysin 30 mL once daily (+70 mL 0.9% saline), noninvasive brain stimulation 2 mA/35 cm² for 2 × 20 minutes, once daily |
ARAT, NHPT, hand grip dynamometry, NIHSS |
| Cortical priming to optimize gait rehabilitation in stroke: a renewal | 2020-2025 | 100, all | 18-80 | Age, stroke within 3 months, residual hemiparetic gait deficits, ability to walk without ankle orthotic, walking speed lesser than 1.4 m/s, lower limb Fugl-Meyer motor score between 20 and 30, at least 5 deg of ankle dorsiflexion necessary to perform the ankle-tracking task | Transcranial direct current stimulation (tDCS) 1 mA tDCS, ankle motor training, high-intensity interval speed-based treadmill training (HIISTT) |
Walking speed with 10-meter walk test, BDNF, salivary samples for BDNF, corticomotor excitability using TMS, cognitive battery |
| Physical activity | ||||||
| Effects of upper limb motor and robotic training over neuroplasticity and function capacity | 2012-2017 | 51, all | ≥18 | Stroke within 6-36 months, clinically unstable, informed consent, low upper limb Brunnstrom scale score, minimal wrist extension | ICT two times a week for ten weeks, robotic occupational therapy three times a week for twelve weeks | Change on motor function, neuroplasticity as assessed by BDNF, psychological evaluation assessed by PSS-10, corticospinal excitability as assessed by TMS, neurologic evaluation as assessed by electroencephalography |
| Effects of combined resistance and aerobic training vs. aerobic training on cognition and mobility following stroke | 2013-2016 | 72, all | Child adult, older adult | Stroke, ability to walk, no pain limitation, living in community for 3 months poststroke, motor impairment, informed consent | Combined resistance and aerobic training For the group randomized to AT+RT, patients will gradually be progressed from 1 to 2 sets and then from 10 to 15 repetitions and then increase resistance |
Cognitive function, body composition, biochemical changes (blood samples BDNF, IGF-I, homocysteine, and C-reactive protein), functional mobility |
| The safety and tolerability of an aerobic and resistance exercise program with cognitive training poststroke | 2014-2019 | 132, all | ≥18 | Ischemic or hemorrhagic stroke, high mRS score, recently discharged from the hospital, less than ideal physical activity, able to walk ≥10 meters with or without assistance | ARET: combined aerobic and resistance exercise training; CTI: cognitive training intervention | Number of participants with treatment-emergent serious adverse events, adherence to a 12-week combined exercise and cognitive training protocol versus a sham group, change in cognitive performance on cognitive neuropsychological battery done at pre-, post- and 6-month follow-up visits, change in health-related quality of life–depression, change in health-related quality of life-daily activities, change in blood plasma concentration of BDNF |
| Aerobic trainings on stroke patients | 2016-2018 | 23, all | 20-80 | Stroke, MMSE ≥ 24, no acute coronary syndrome | Aerobic exercise training | Peak CO, exercise VO2peak, OUES, VCO2 ratio Ve-VCO2, differences of the brain ∆[O2Hb], differences of the brain ∆[HHb], differences of regional blood volume ∆[THb], PCS, MCS, MMSE, BDNF levels, percentage of cell bearing neurites, neuron images |
| Serum BDNF role as a biomarker for stroke rehabilitation | 2017-2019 | 150, female | ≥19 | Unilateral stroke, rehabilitation within 1 month of stroke onset, motor impairment | Conventional inpatient rehabilitation Comprehensive inpatient rehabilitation for 2 weeks |
Serum BDNF levels, serum proBDNF, MMP-9 |
| Effects of combined cognitive training with aerobic exercise in stroke patients with MCI | 2018-2021 | 75, all | 20-90 | Ischemic or hemorrhagic stroke, age, low cognitive assessment score, cognitive impairment, ability to follow instructions, ability to exercise, ability to walk | Aerobic exercise training, computerized cognitive training | Cognitive battery, BDNF val66met genotype saliva samples, serum BDNF level, TAC, glucose indicator, plasma lipid level |
| Chiropractic care plus physiotherapy compared to physiotherapy alone in chronic stroke patients | 2019-2019 | 100, all | Child, adult, older adult | Stroke within 12 weeks of trial, neurological deficits, upper/lower limb weakness, Fugl-Meyer Assessment (FMA) motor score of less than 80 at the time of enrollment | Chiropractic care | FMA, stroke-specific quality of life scale, mRS, TUG, HRV, daily movement, blood marker BDNF, blood marker GDNF, blood marker IGF2, transcranial magnetic stimulation |
| Biologic mechanisms of early exercise after intracerebral hemorrhage | 2019-2021 | 40, all | ≥18 | Supratentorial intracerebral hemorrhage with or without intraventricular hemorrhage, premorbid mRS score 0-2, informed consent | Supine cycle ergometry of the lower extremities | Change in interleukin-1beta level in blood, change in interleukin-6 level in blood, change in tumor necrosis factor-alpha level in blood, change in C-reactive protein level in blood, change in BDNF level in blood, change in interleukin-1beta level in CSF, change in interleukin-6 level in CSF |
| Group Lifestyle Balance™ for individuals with stroke (GLB-CVA) | 2019-2021 | 65, all | 18-65 | Age, BMI ≥ 25, stroke within 12 months, physician approval | GLB weight loss intervention, Group Lifestyle Balance | Change in weight, biomarker analysis (isrin, angiogenic factors VEGF, total homocysteine, Lp-PLA2, ICF-1, BDNF, and tau proteins, physical activity, blood pressure, cholesterol) |
| Muscle trajectories in acute stroke patients | 2019-2024 | 200, all | ≥18 | Age, hospitalized at neurology ward of UZ Brussel, stroke, informed consent | Follow-up assessments | Functional ambulation categories, 6-minute walking test, circulating biomarkers, blood sampling circulating biomarkers: brain-derived neurotrophic factor (BDNF), inflammation-related biomarkers |
| Rehabilomics study in stroke patients after robotic rehabilitation | 2020-2021 | 100, all | 55-85 | Stroke within 2-24 weeks, age, ability to perform rehabilitation treatment, language abilities | Robotic-assisted intervention (30 sessions, 5 times a week) | Presence/absence of rs6265 in the BDNF, presence/absence of 5-HTTLPR in the SLC6A4, change in promoter methylation levels of BDNF gene, change in promoter methylation levels of SLC6A4 gene, cognitive battery |
| Exercise-primed upper extremity motor practice in chronic stroke | 2021-2022 | 10, all | 21-90 | Unilateral stroke within 6 months, impaired shoulder flexion, arm movement impairment, passive range of motion, age, ability to exercise, ability to communicate | Aerobic exercise+DDP, 15 minutes of aerobic exercise on a recumbent stationary cycle, 200 repetitions on an upper extremity rehabilitation game called DDP | Change in upper extremity impairment as assessed by the FMA extremity, change in upper extremity as assessed by the Wolf Motor Function Test, change in physical function and health-related quality of life as assessed by Stroke Impact Scale, change in neuroplastic potential as assessed by paired associative stimulation, assessment of BDNF |
| Aerobic exercise training in acute ischemic stroke | 2021-2022 | 30, all | ≥18 | Age, stroke, medically stable, English speaking, ability to move lower limbs | Aerobic exercise training 5-day, power-assisted, low to moderate intensity, aerobic exercise training programme. Exercise duration to progress from 10 minutes on day 1 to 30 minutes on day 5 | Safety of aerobic exercise training, acceptability of aerobic exercise training, rectus femoris cross-sectional area, rectus femoris muscle thickness, vastus lateralis muscle thickness, vastus lateralis angle of pennation, cognitive function, anxiety, depression, aerobic exercise-induced changes in mature BDNF serum and plasma |
| Serum and plasma analysis of BDNF | ||||||
| Neuroactive steroids in acute ischemic stroke | 2016-2016 | 80, all | 60-90 | age, acute ischemic stroke, 9 ≥ score on Glasgow coma scale, females in menopause, patients without prior cognitive impairment, informed consent, no prior cognitive impairment | Observed changes in plasma BDNF and nitrites | Neurological deficit, cognition, emotional state, functional dependency of daily life activities, cortisol, quantification of nitrite concentration, BDNF quantification in plasma |
| Functional prognosis in patients with ischemic stroke according to the therapeutic strategy used | 2016-2020 | 300, all | ≥18 | Ischemic stroke, age, informed consent | A blood sample taken at different times to study the value of growth differentiation factors (GDF) 8, 11, and 15 and brain-derived neurotrophic factor as prognostic biomarkers | Rate of handicap, serum levels of biomarkers of stress |
| Effects of repetitive hyperbaric oxygen therapy in patients with acute ischemic stroke | 2018-2020 | 60, all | 18-80 | Acute ischemic stroke, Glasgow coma scale more than 10 | Hyperbaric oxygen, 10 sessions of HBOT at 2.0 atmosphere absolute (ATA) for one hour in a hyperbaric chamber pressured with compressed air to upregulate expression of glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) | Change in National Institutes of Health stroke score before and after treatment with hyperbaric oxygen therapy, hospital mortality, hospital length of stay |
| Effect of lifestyle changes on BDNF level after stroke | 2018-2019 | 12, all | 30-90 | History of stroke, ability to move at least 10 feet with little assistance, ability to travel to intervention site | Assessing BDNF levels at different time points throughout study | BDNF level–final, BDNF level-postexercise, BDNF genotype, cardiovascular fitness-VO2 max, cardiovascular fitness–METs, 6-minute walk test |
| Role of genetic polymorphism in neuroplasticity involved in dysphagia recovery | 2018-2019 | 220, all | Child, adult, older adult | Lesions from stroke and TBI, patients hospitalized for 30 days and were followed up at 3 months after lesion, informed consent, patients able to swallow | Blood serum analysis | Change in FOIS, change in BBS, change in MRC grade disability level, cognitive battery, blood serum analysis |
| White matter integrity according to BDNF genotype after stroke | 2018-2019 | 58, all | 18-80 | Diagnosed with first-ever hemispheric ischemic infarction with damage to the supratentorial area confirmed by brain MRI within 2 weeks after stroke onset | BDNF serum analysis | Changes in FA in CST, the intrahemispheric corticocortical tract from the M1PMv and CC from 2 weeks to 3 months after stroke according to BDNF genotype. BDNF genotype SNP: Met substitution for Val at codon 66 (Val66Met; rs6265) |
| Moderate intensity aerobic training in subacute and chronic stroke patients-the influence on BDNF and upper-limb rehabilitation. A protocol for a randomized control trial and health economic evaluation | 2019-2020 | 30, all | ≥18 | Stroke within the last 3 months or more, ability to move shoulders | Assessing BDNF levels at different time points throughout study | BDNF serum levels, ARAT, the FMA, 10-meter walking test, trunk sway in standing with eyes closed, cognitive battery, the FSS, stroke impact scale |
| Muscle trajectories in acute stroke patients | 2019-2024 | 200, all | ≥18 | Age, hospitalized at neurology ward of UZ Brussel, stroke, informed consent | Follow-up assessments | Functional ambulation categories, 6-minute walking test, circulating biomarkers, blood sampling circulating biomarkers: brain-derived neurotrophic factor (BDNF), inflammation-related biomarkers |