New neurophysiological and imaging methods for detection of microstructural changes in mild traumatic brain injury

Mild traumatic brain injury is a very common health problem. Although outcome is generally good, a significant proportion of patients have persistent symptoms or an incomplete functional recovery. The mechanisms of this are incompletely understood, but believed to include microstructural injuries that may be undetectable by presently used diagnostic tests. This thesis aims at exploring new diagnostic methods that could be utilised in examining mild traumatic brain injury. I study tested transcranial magnetic stimulation defined motor thresholds in a sample of chronic phase mild traumatic brain injury patients. Elevated motor thresholds were found compared to healthy controls, associated with altered excitability of the corticospinal tract. II study used transcranial magnetic stimulation combined with electroencephalography to probe responses of frontal brain regions. The employed method is reported to be sensitive to changes in excitability and connectivity of the brain. Differences were found between samples of fully recovered and persistently symptomatic patients with mild traumatic brain injury and healthy controls. On basis of this, transcranial magnetic stimulation and electroencephalography could be used to detect functional changes that are not paralleled by lesions on routine magnetic resonance imaging. III study compared diffusion tensor imaging based deterministic tractography and a newer method, based on constrained spherical deconvolution, automatic, deep learning based segmentation and probabilistic tractography. Participants were patients with symptomatic mild traumatic brain injury and healthy controls. The newer approach was able to find differences between the groups, while diffusion tensor method was not. This suggests the new approach may be more sensitive in detecting microstructural changes related to mild traumatic brain injury. These results show that mild traumatic brain injury can be associated with functional and structural changes in the absence of trauma-related findings on routine MRI. The methods evaluated may provide new ways to detect these changes.Uusia neurofysiologisia ja kuvantamismenetelmiä lievään aivovammaan liittyvien mikrorakenteellisten muutosten toteamisessa Lievä aivovamma on erittäin tavallinen. Toipuminen on yleensä hyvää, mutta osalle potilaista jää pitkäkestoisia oireita tai toimintakyvyn vajavuutta. Näiden syntymekanismia ei täysin ymmärretä, mutta ajatellaan sen voivan liittyä aivojen mikrorakenteellisiin muutoksiin, joiden toteamiseen nykyiset diagnostiset testit voivat olla riittämättömiä. Tämä väitöstutkimus selvittää uusia keinoja, joita voitaisiin hyödyntää lievän aivovamman arvioinnissa. I osatyössä tutkittiin transkraniaalisen magneettistimulaation avulla motorisia kynnyksiä. Tutkimusjoukkona oli lievän aivovamman saaneita, kroonisen vaiheen potilaita. Potilasjoukolla todettiin terveisiin verrokkeihin nähden korkeampia motorisia kynnyksiä, joka liittyy muutoksiin kortikospinaaliradan ärtyvyydessä. II osatyö hyödynsi transkraniaalista magneettistimulaatiota ja elektroenkefalografiaa frontaalisten aivoalueiden vasteiden tutkimisessa. Aiempien julkaisujen perusteella menetelmä on herkkä aivojen ärtyvyyden ja aivoalueiden välisten yhteyksien muutosten toteamisessa. Menetelmällä löydettiin eroja lievästä aivovammasta oireettomiksi toipuneista, pitkäkestoisesti oireilevista ja terveistä verrokeista koostuneiden osallistujajoukkojen välillä. Transkraniaalisen magneettistimulaation ja elektroenkefalografian yhdistelmällä saatetaan siten havaita toimin-nallisia muutoksia, joille ei ole vastinetta tavallisissa magneettikuvissa. III osatyössä verrattiin diffuusiotensorikuvantamista ja determinististä traktografiaa uudempaan menetelmään, joka perustui constrained spherical deconvolution -laskentaan, automaattiseen, syväoppimiseen perustuvaan segmentaatioon ja probabilistiseen traktografiaan. Tutkimusjoukkona oli lievän aivovamman saaneita, oireisia potilaita ja terveitä verrokkeja. Uudella menetelmällä löydettiin eroja ryhmien välillä, mutta vertailumenetelmällä eroja ei havaittu. Tällä perusteella uusi menetelmä vaikuttaa herkemmältä aivovammaan liittyvien mikrorakenteellisten muutosten toteamisessa. Tulokset osoittavat, että lievään aivovammaan voi liittyä toiminnallisia ja rakenteellisia muutoksia, vaikka tavanomaisen magneettikuvauksen löydös olisi normaali. Näiden muutosten toteaminen voi olla mahdollista arvioiduilla menetelmillä

Milloin kannattaa aloittaa kaikututkimuksella?

Vertaisarvioitu.• Kaikukuvaus eli ultraäänitutkimus on usein ensisijainen kuvantamis¬ menetelmä lapsia tutkittaessa. • Näkyvyys on yleensä parempi kuin aikuisia tutkittaessa, eikä diagnoosiin pääsemiseksi välttämättä tarvita muita kuvantamismenetelmiä. • Lasten ultraäänidiagnostiikassa tarvitaan tietämystä eri kehitysvaiheissa ilmenevistä tyypillisistä sairauksista ja normaalilöydöksistä.Peer reviewe

Milloin kannattaa aloittaa kaikututkimuksella?

Kaikukuvaus eli ultraäänitutkimus on usein ensisijainen kuvantamismenetelmä lapsia tutkittaessa.Näkyvyys on yleensä parempi kuin aikuisia tutkittaessa, eikä diagnoosiin pääsemiseksi välttämättä tarvita muita kuvantamismenetelmiä.Lasten ultraäänidiagnostiikassa tarvitaan tietämystä eri kehitysvaiheissa ilmenevistä tyypillisistä sairauksista ja normaalilöydöksistä.</p

Interleukin 10 and Heart Fatty Acid-Binding Protein as Early Outcome Predictors in Patients With Traumatic Brain Injury

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected &lt;24 h post trauma. The outcome was measured &gt;6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95-100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI.</p

Trajectories of interleukin 10 and heart fatty acid-binding protein levels in traumatic brain injury patients with or without extracranial injuries

BackgroundInterleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have gained interest as diagnostic biomarkers of traumatic brain injury (TBI), but factors affecting their blood levels in patients with moderate-to-severe TBI are largely unknown.ObjectiveTo investigate the trajectories of IL-10 and H-FABP between TBI patients with and without extracranial injuries (ECI); to investigate if there is a correlation between the levels of IL-10 and H-FABP with the levels of inflammation/infection markers C-reactive protein (CRP) and leukocytes; and to investigate if there is a correlation between the admission level of H-FABP with admission levels of cardiac injury markers, troponin (TnT), creatine kinase (CK), and creatine kinase MB isoenzyme mass (CK-MBm).Materials and methodsThe admission levels of IL-10, H-FABP, CRP, and leukocytes were measured within 24 h post-TBI and on days 1, 2, 3, and 7 after TBI. The admission levels of TnT, CK, and CK-MBm were measured within 24 h post-TBI.ResultsThere was a significant difference in the concentration of H-FABP between TBI patients with and without ECI on day 0 (48.2 ± 20.5 and 12.4 ± 14.7 ng/ml, p = 0.02, respectively). There was no significant difference in the levels of IL-10 between these groups at any timepoints. There was a statistically significant positive correlation between IL-10 and CRP on days 2 (R = 0.43, p &lt; 0.01) and 7 (R = 0.46, p = 0.03) after injury, and a negative correlation between H-FABP and CRP on day 0 (R = -0.45, p = 0.01). The levels of IL-10 or H-FABP did not correlate with leukocyte counts at any timepoint. The admission levels of H-FABP correlated with CK (R = 0.70, p &lt; 0.001) and CK-MBm (R = 0.61, p &lt; 0.001), but not with TnT.ConclusionInflammatory reactions during the early days after a TBI do not significantly confound the use of IL-10 and H-FABP as TBI biomarkers. Extracranial injuries and cardiac sources may influence the levels of H-FABP in patients with moderate-to-severe TBI

Cerebral Microbleeds and Structural White Matter Integrity in Patients With Traumatic Brain Injury-A Diffusion Tensor Imaging Study

Diffuse axonal injury (DAI) is a common neuropathological manifestation of traumatic brain injury (TBI), presenting as traumatic alterations in the cerebral white matter (WM) microstructure and often leading to long-term neurocognitive impairment. These WM alterations can be assessed using diffusion tensor imaging (DTI). Cerebral microbleeds (CMBs) are a common finding on head imaging in TBI and are often considered a visible sign of DAI, although they represent diffuse vascular injury. It is poorly known how they associate with long-term white matter integrity. This study included 20 patients with TBI and CMBs, 34 patients with TBI without CMBs, and 11 controls with orthopedic injuries. DTI was used to assess microstructural WM alterations. CMBs were detected using susceptibility-weighted imaging (SWI) and graded according to their location in the WM and total lesion load was counted. Patients underwent SWI within 2 months after injury. DTI and clinical outcome assessment were performed at an average of eight months after injury. Outcome was assessed using the extended Glasgow Outcome Scale (GOSe). The Glasgow Coma Scale (GCS) and length of post-traumatic amnesia (PTA) were used to assess clinical severity of the injury. We found that CMB grading and total lesion load were negatively associated with fractional anisotropy (FA) and positively associated with mean diffusivity (MD). Patients with TBI and CMBs had decreased FA and increased MD compared with patients with TBI without CMBs. CMBs were also associated with worse clinical outcome. When adjusting for the clinical severity of the injury, none of the mentioned associations were found. Thus, the difference in FA and MD is explained by patients with TBI and CMBs having more severe injuries. Our results suggest that CMBs are not associated with greater WM alterations when adjusting for the clinical severity of TBI. Thus, CMBs and WM alterations may not be strongly associated pathologies in TBI

INTERLEUKIN 10 AND HEART FATTY-ACID BINDING PROTEIN AS EARLY OUTCOME PREDICTORS IN PATIENTS WITH TRAUMATIC BRAIN INJURY

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected 6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95–100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n=22), moderate (moTBI; n=14) or mild TBI (mTBI; n=108) according to Glasgow Coma Scale. The control group (n=28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n=23), moTBI (n=7), mTBI (n=37) patients and controls (n=27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC=0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified 'TBI metabotype' in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.European Union FP7 project TBIcare (Grant ID: 270259), GE-NFL Head Health Challenge I Award (Grant ID: 7620), EVO (Finland), Maire Taponen Foundation, National Institute for Health Research, National Institute for Health Research Biomedical Research Centre Cambridge (Neuroscience Theme; Brain Injury and Repair Theme)This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ebiom.2016.07.01

Admission Levels of Total Tau and β-Amyloid Isoforms 1–40 and 1–42 in Predicting the Outcome of Mild Traumatic Brain Injury

Background: The purpose of this study was to investigate if admission levels of total tau (T-tau) and β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42) could predict clinical outcome in patients with mild traumatic brain injury (mTBI). Methods: A total of 105 patients with mTBI [Glasgow Coma Scale (GCS) ≥ 13] recruited in Turku University Hospital, Turku, Finland were included in this study. Blood samples were drawn within 24 h of admission for analysis of plasma T-tau, Aβ40, and Aβ42. Patients were divided into computed tomography (CT)-positive and CT-negative groups. The outcome was assessed 6–12 months after the injury using the Extended Glasgow Outcome Scale (GOSE). Outcomes were defined as complete (GOSE 8) or incomplete (GOSE < 8) recovery. The Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) was also used to assess mTBI-related symptoms. Predictive values of the biomarkers were analyzed independently, in panels and together with clinical parameters. Results: The admission levels of plasma T-tau, Aβ40, and Aβ42 were not significantly different between patients with complete and incomplete recovery. The levels of T-tau, Aβ40, and Aβ42 could poorly predict complete recovery, with areas under the receiver operating characteristic curve 0.56, 0.52, and 0.54, respectively. For the whole cohort, there was a significant negative correlation between the levels of T-tau and ordinal GOSE score (Spearman ρ = −0.231, p = 0.018). In a multivariate logistic regression model including age, GCS, duration of posttraumatic amnesia, Injury Severity Score (ISS), time from injury to sampling, and CT findings, none of the biomarkers could predict complete recovery independently or together with the other two biomarkers. Plasma levels of T-tau, Aβ40, and Aβ42 did not significantly differ between the outcome groups either within the CT-positive or CT-negative subgroups. Levels of Aβ40 and Aβ42 did not significantly correlate with outcome, but in the CT-positive subgroup, the levels of T-tau significantly correlated with ordinal GOSE score (Spearman ρ = −0.288, p = 0.035). The levels of T-tau, Aβ40, and Aβ42 were not correlated with the RPCSQ scores. Conclusions: The early levels of T-tau are correlated with the outcome in patients with mTBI, but none of the biomarkers either alone or in any combinations could predict complete recovery in patients with mTBI

Trajectories of interleukin 10 and heart fatty acid-binding protein levels in traumatic brain injury patients with or without extracranial injuries

Background: Interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have gained interest as diagnostic biomarkers of traumatic brain injury (TBI), but factors affecting their blood levels in patients with moderate-to-severe TBI are largely unknown. Objective: To investigate the trajectories of IL-10 and H-FABP between TBI patients with and without extracranial injuries (ECI); to investigate if there is a correlation between the levels of IL-10 and H-FABP with the levels of inflammation/infection markers C-reactive protein (CRP) and leukocytes; and to investigate if there is a correlation between the admission level of H-FABP with admission levels of cardiac injury markers, troponin (TnT), creatine kinase (CK), and creatine kinase MB isoenzyme mass (CK-MBm). Materials and methods: The admission levels of IL-10, H-FABP, CRP, and leukocytes were measured within 24 h post-TBI and on days 1, 2, 3, and 7 after TBI. The admission levels of TnT, CK, and CK-MBm were measured within 24 h post-TBI. Results: There was a significant difference in the concentration of H-FABP between TBI patients with and without ECI on day 0 (48.2 ± 20.5 and 12.4 ± 14.7 ng/ml, p = 0.02, respectively). There was no significant difference in the levels of IL-10 between these groups at any timepoints. There was a statistically significant positive correlation between IL-10 and CRP on days 2 (R = 0.43, p < 0.01) and 7 (R = 0.46, p = 0.03) after injury, and a negative correlation between H-FABP and CRP on day 0 (R = -0.45, p = 0.01). The levels of IL-10 or H-FABP did not correlate with leukocyte counts at any timepoint. The admission levels of H-FABP correlated with CK (R = 0.70, p < 0.001) and CK-MBm (R = 0.61, p < 0.001), but not with TnT. Conclusion: Inflammatory reactions during the early days after a TBI do not significantly confound the use of IL-10 and H-FABP as TBI biomarkers. Extracranial injuries and cardiac sources may influence the levels of H-FABP in patients with moderate-to-severe TBI.publishedVersionPeer reviewe