Noémi Kovács

Brain Injury Biomarkers May Improve the Predictive Power of the IMPACT Outcome Calculator

Outcome prediction following severe traumatic brain injury (sTBI) is a widely investigated field of research. A major breakthrough is represented by the IMPACT prognostic calculator based on admission data of more than 8500 patients. A growing body of scientific evidence has shown that clinically meaningful biomarkers, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and αII-spectrin breakdown product (SBDP145), could also contribute to outcome prediction. The present study was initiated to assess whether the addition of biomarkers to the IMPACT prognostic calculator could improve its predictive power. Forty-five sTBI patients (GCS score≤8) from four different sites were investigated. We utilized the core model of the IMPACT calculator (age, GCS motor score, and reaction of pupils), and measured the level of GFAP, UCH-L1, and SBDP145 in serum and cerebrospinal fluid (CSF). The forecast and actual 6-month outcomes were compared by logistic regression analysis. The results of the core model itself, as well as serum values of GFAP and CSF levels of SBDP145, showed a significant correlation with the 6-month mortality using a univariate analysis. In the core model, the Nagelkerke R(2) value was 0.214. With multivariate analysis we were able to increase this predictive power with one additional biomarker (GFAP in CSF) to R(2)=0.476, while the application of three biomarker levels (GFAP in CSF, GFAP in serum, and SBDP145 in CSF) increased the Nagelkerke R(2) to 0.700. Our preliminary results underline the importance of biomarkers in outcome prediction, and encourage further investigation to expand the predictive power of contemporary outcome calculators and prognostic models in TBI.

Glial Neuronal Ratio: A Novel Index for Differentiating Injury Type in Patients with Severe Traumatic Brain Injury

Neurobiochemical marker levels in blood after traumatic brain injury (TBI) may reflect structural changes detected by neuroimaging. This study evaluates whether correlations between neuronal (ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarkers may be used as an indicator for differing intracranial pathologies after brain trauma. In 59 patients with severe TBI (Glasgow Coma Scale [GCS] score≤8) serum samples were obtained at the time of hospital admission and analyzed for UCH-L1 and GFAP. Glial neuronal ratio (GNR) was evaluated as the ratio between GFAP and UCH-L1 concentrations. A logistic regression analysis was used to identify variables associated with type of injury. GNR had a median of 0.85 and was positively correlated with age (R=0.45, p=0.003). Twenty-nine patients presented with diffuse injury and 30 with focal mass lesions as assessed by CT scan at admission and classified according to the Marshall Classification. GNR was significantly higher in the focal mass lesion group compared with the diffuse injury group (1.77 versus 0.48, respectively; p=0.003). Receiver operating characteristic curve analysis showed that GNR discriminated between types of injury (area under the curve [AUC]=0.72; p=0.003). GNR was more accurate earlier (≤12 h after injury) than later (AUC=0.80; p=0.002). Increased GNR was independently associated with type of injury, but not age, gender, GCS score, or mechanism of injury. GNR was significantly higher in patients who died, but was not an independent predictor of death. The data from the present study indicate that GNR provides valuable information about different injury pathways, which may be of diagnostic significance. In addition, GNR may help to identify different pathophysiological mechanisms following different types of brain trauma, with implications for therapeutic interventions.

Multi-Modal Magnetic Resonance Imaging in the Acute and Sub-Acute Phase of Mild Traumatic Brain Injury: Can We See the Difference?

Advanced magnetic resonance imaging (MRI) methods were shown to be able to detect the subtle structural consequences of mild traumatic brain injury (mTBI). The objective of this study was to investigate the acute structural alterations and recovery after mTBI, using diffusion tensor imaging (DTI) to reveal axonal pathology, volumetric analysis, and susceptibility weighted imaging (SWI) to detect microhemorrhage. Fourteen patients with mTBI who had computed tomography with negative results underwent MRI within 3 days and 1 month after injury. High resolution T1-weighted imaging, DTI, and SWI, were performed at both time points. A control group of 14 matched volunteers were also examined following the same imaging protocol and time interval. Tract-Based Spatial Statistics (TBSS) were performed on DTI data to reveal group differences. T1-weighted images were fed into Freesurfer volumetric analysis. TBSS showed fractional anisotropy (FA) to be significantly (corrected p<0.05) lower, and mean diffusivity (MD) to be higher in the mTBI group in several white matter tracts (FA=40,737; MD=39,078 voxels) compared with controls at 72 hours after injury and still 1month later for FA. Longitudinal analysis revealed significant change (i.e., normalization) of FA and MD over 1 month dominantly in the left hemisphere (FA=3408; MD=7450 voxels). A significant (p<0.05) decrease in cortical volumes (mean 1%) and increase in ventricular volumes (mean 3.4%) appeared at 1 month after injury in the mTBI group. SWI did not reveal microhemorrhage in our patients. Our findings present dynamic micro- and macrostructural changes occurring in the acute to sub-acute phase in mTBI, in very mildly injured patients lacking microhemorrhage detectable by SWI. These results underscore the importance of strictly defined image acquisition time points when performing MRI studies on patients with mTBI.

Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging

Magnetic nanoparticles (NPs) MnFe2O4 and Fe3O4 were stabilised by depositing an Al(OH)3 layer via a hydrolysis process. The particles displayed excellent colloidal stability in water and a high affinity to [18F]-fluoride and bisphosphonate groups. A high radiolabeling efficiency, 97% for 18F-fluoride and 100% for 64Cu-bisphosphonate conjugate, was achieved by simply incubating NPs with radioactivity solution at room temperature for 5 min. The properties of particles were strongly dependant on the thickness and hardness of the Al(OH)3 layer which could in turn be controlled by the hydrolysis method. The application of these Al(OH)3 coated magnetic NPs in molecular imaging has been further explored. The results demonstrated that these NPs are potential candidates as dual modal probes for MR and PET. In vivo PET imaging showed a slow release of 18F from NPs, but no sign of efflux of 64Cu.

Differential regulatory role of pituitary adenylate cyclase-activating polypeptide in the serum-transfer arthritis model.

Pituitary adenylate cyclase–activating polypeptide (PACAP) expressed in capsaicin‐sensitive sensory neurons and immune cells has divergent functions in inflammatory and pain processes. This study was undertaken to investigate the involvement of PACAP in a mouse model of rheumatoid arthritis.

Synthesis, Characterization, and Application of Core–Shell Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm) Nanoparticle as Trimodal (MRI, PET/SPECT, and Optical) Imaging Agents

Multimodal nanoparticulate materials are described, offering magnetic, radionuclide, and fluorescent imaging capabilities to exploit the complementary advantages of magnetic resonance imaging (MRI), positron emission tomography/single-photon emission commuted tomography (PET/SPECT), and optical imaging. They comprise Fe3O4@NaYF4 core/shell nanoparticles (NPs) with different cation dopants in the shell or core, including Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm). These NPs are stabilized by bisphosphonate polyethylene glycol conjugates (BP-PEG), and then show a high transverse relaxivity (r2) up to 326 mM(-1) s(-1) at 3T, a high affinity to [(18)F]-fluoride or radiometal-bisphosphonate conjugates (e.g., (64)Cu and (99m)Tc), and fluorescent emissions from 500 to 800 nm under excitation at 980 nm. The biodistribution of intravenously administered particles determined by PET/MR imaging suggests that negatively charged Co0.16Fe2.84O4@NaYF4(Yb, Er)-BP-PEG (10K) NPs cleared from the blood pool more slowly than positively charged NPs Fe3O4@NaYF4(Yb, Tm)-BP-PEG (2K). Preliminary results in sentinel lymph node imaging in mice indicate the advantages of multimodal imaging.

Changes of PACAP level in cerebrospinal fluid and plasma of patients with severe traumatic brain injury

PACAP has well-known neuroprotective potential including traumatic brain injury (TBI). Its level is up-regulated following various insults of the CNS in animal models. A few studies have documented alterations of PACAP levels in human serum. The time course of post-ictal PACAP levels, for example, show correlation with migraine severity. Very little is known about the course of PACAP levels following CNS injury in humans and the presence of PACAP has not yet been detected in cerebrospinal fluid (CSF) of subjects with severe TBI (sTBI). The aim of the present study was to determine whether PACAP occurs in the CSF and plasma (Pl) of patients that suffered sTBI and to establish a time course of PACAP levels in the CSF and Pl. Thirty eight subjects with sTBI were enrolled with a Glasgow Coma Scale ≤8 on admission. Samples were taken daily, until the time of death or for maximum 10 days. Our results demonstrated that PACAP was detectable in the CSF, with higher concentrations in patients with TBI. PACAP concentrations markedly increased in both Pl and CSF in the majority of patients 24-48h after the injury stayed high thereafter. In cases of surviving patients, Pl and CSF levels displayed parallel patterns, which may imply the damage of the blood-brain barrier. However, in patients, who died within the first week, Pl levels were markedly higher than CSF levels, possibly indicating the prognostic value of high Pl PACAP levels.

Microbleeds may expand acutely after traumatic brain injury

BACKGROUND AND PURPOSE Susceptibility weighted imaging (SWI) is a very sensitive tool for the detection of microbleeds in traumatic brain injury (TBI). The number and extent of such traumatic microbleeds (TMBs) have been shown to correlate with the severity of the injury and the clinical outcome. However, the acute dynamics of TMBs have not been revealed so far. Since TBI is known to constitute dynamic pathological processes, we hypothesized that TMBs are not constant in their appearance, but may progress acutely after injury. MATERIALS AND METHODS We present here five closed moderate/severe (Glasgow coma scale≤13) TBI patients who underwent SWI very early (average=23.4 h), and once again a week (average=185.8 h) after the injury. The TMBs were mapped at both time points by a conventional radiological approach and their numbers and volumes were measured with manual tracing tools by two observers. TMB counts and extents were compared between time points. RESULTS TMBs were detected in four patients, three of them displaying an apparent TMB change. In these patients, TMB confluence and apparent growth were detected in the corpus callosum, coronal radiation or subcortical white matter, while unchanged TMBs were also present. These changes caused a decrease in the TMB count associated with an increase in the overall TMB volume over time. CONCLUSION We have found a compelling evidence that diffuse axonal injury-related microbleed development is not limited strictly to the moment of injury: the TMBs might expand in the acute phase of TBI. The timing of SWI acquisition may be relevant for optimizing the prognostic utility of this imaging biomarker.

The effects of sleep and light at night on melatonin in adolescents

OBJECTIVEThere is increasing awareness among physicians of the risks of traumatic brain injury (TBI)-induced hypopituitarism. We have assessed the prevalence and risk factors of posttraumatic hypopituitarism by analyzing the TBI database of the University of Pecs.DESIGNThis consecutive analysis of 126 TBI survivors (mean age: 42.4 years, average follow-up time: 48 months) revealed that 60.3% had severe and 39.7% moderately severe trauma based on GCS score. Subdural hemorrhage (29.3%) and diffuse injury (27%) were the most common types of injury; 17.5% of patients suffered basal skull fractures.RESULTSThe prevalence of major anterior pituitary failure was 57.1%. Occurrence of total and partial growth hormone deficiency (GHD/GHI) was 39.7%, while LH/FSH, TSH and ACTH deficiencies were less frequent, namely 23.0%, 16.7% and 10.3%, respectively. Of the 82 patients with multiple endocrine evaluations, 31.7% presented significant changes in hormonal deficiencies during the follow-up period: new hormone deficiencies developed in 16 patients, while hormonal disturbances resolved in 10 subjects. Looking for factors influencing the prevalence of pituitary dysfunction, endocrine results were analyzed in relation to age, gender, GCS scores, injury types, basal skull fracture, ventricular drain insertion and necessity of neurosurgical intervention. All hormonal disturbances were more prevalent after severe trauma (OR: 3.25, p = 0.002), while the need for surgery proved to be an independent determinant of multiple and GH deficits (OR: 3.72 (p = 0.004) and 9.33 (p = 0.001)).CONCLUSIONPost-traumatic hypopituitarism is common and may evolve or resolve over time. Victims of severe TBI and/or patients who have undergone neurosurgical intervention for head injury are the most prone to post-traumatic hypopituitarism.

A novel SPECT-based approach reveals early mechanisms of central and peripheral inflammation after cerebral ischemia.

Inflammation that develops in the brain and peripheral organs after stroke contributes profoundly to poor outcome of patients. However, mechanisms through which inflammation impacts on brain injury and overall outcome are improperly understood, in part because the earliest inflammatory events after brain injury are not revealed by current imaging tools. Here, we show that single-photon emission computed tomography (NanoSPECT/CT Plus) allows visualization of blood brain barrier (BBB) injury after experimental stroke well before changes can be detected with magnetic resonance imaging (MRI). Early 99mTc-DTPA (diethylene triamine pentaacetic acid) signal changes predict infarct development and systemic inflammation preceding experimental stroke leads to very early perfusion deficits and increased BBB injury within 2 hours after the onset of ischemia. Acute brain injury also leads to peripheral inflammation and immunosuppression, which contribute to poor outcome of stroke patients. The SPECT imaging revealed early (within 2 hours) changes in perfusion, barrier function and inflammation in the lungs and the gut after experimental stroke, with good predictive value for the development of histopathologic changes at later time points. Collectively, visualization of early inflammatory changes after stroke could open new translational research avenues to elucidate the interactions between central and peripheral inflammation and to evaluate in vivo ‘multi-system’ effects of putative anti-inflammatory treatments.