Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss

Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's ρ = -0.68, p-value = 0.01) and low CMD glucose (ρ = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI

Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

BACKGROUND: Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy. METHODS: Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls. RESULTS: Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates. CONCLUSIONS: Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration

CEREBRAL METABOLISM FOLLOWING TRAUMATIC BRAIN INJURY: A JOURNEY INTO ALTERNATIVE ENERGY SUBSTRATES

Cerebral metabolism is severely impaired in human brain after an insult such as traumatic brain injury (TBI). Immediately after the injury, a dynamic and complex pathophysiological mechanism starts in order to preserve brain integrity. Under normal condition, glucose is the primary cerebral metabolic substrate in adult brains. However, early phase of acute brain injury (ABI) processes necessitate drastic amount of energy. Hence, within hours, brain will face a shortage of glucose. To sustain brain requirements and increase the chances of recovery, alternative fuel sources appear to be mobilized such as lactate and/or ketone bodies (KBs). Due to growing evidence that brain energy dysfunction may be an important determinant of prognosis our group, led by Professor Mauro Oddo, investigated the benefits of alternative endogenous or/and exogenous energetic substrates (i.e. lactate, KBs) for ABI patients using the cerebral microdialysis (CMD) technique, which consists of patient’s bedside quantification of brain metabolites. My thesis will be a “journey” within cerebral metabolism and alternative substrates action in ABI patients. First, I sought answering the effect of intravenous infusion of hypertonic lactate (HL) solution in controlling episodes of elevated intracranial pressure (ICP) in ABI patients and its effect on cerebral metabolism compared to hypertonic saline (HS) solution. It resulted that HL is as effective as HS to control raised ICP with the advantage of avoiding hyperchloremia. Second, I explored the ketone metabolism at the acute phase in TBI patients over nutrition (fasted versus fed status). We observed that feeding was associated with a progressive significant decrease in brain and plasma total KBs, while ketogenic amino acids were increased over nutrition. Furthermore, we showed a strong correlation between brain and endogenous circulating plasma KBs. These were the first findings showing cerebral ketone metabolism may be modulated at the acute phase of TBI in humans suggesting that they may potentially act as supplemental cerebral energy substrate. Finally, in a pilot project in TBI patients, we demonstrate a strong association between acute cerebral metabolic dysfunction (reflected by CMD lactate/pyruvate ratio over 25) and long-term grey matter atrophy. -- Le métabolisme cérébral est considérablement perturbé dans le cerveau humain suite à une lésion telle qu’un traumatisme crânio-cérébral (TCC). Immédiatement après la lésion, un mécanisme physiopathologique dynamique et complexe se met en place afin de préserver les fonctionnalités du cerveau. Dans des conditions normales, le glucose est le principal substrat métabolique cérébral pour le cerveau adulte. Cependant, lors du processus de lésion cérébrale aiguë (LCA), le cerveau nécessite une quantité importante d'énergie. Par conséquent, il sera rapidement confronté à une pénurie de glucose. Pour maintenir les besoins du cerveau et augmenter les chances de récupération, des substituts alternatifs de carburant semblent être mobilisés, tels que le lactate et/ou les corps cétoniques (CCs). En raison d’indices croissants que le dysfonctionnement énergétique du cerveau peut être un déterminant important du pronostic, notre groupe, dirigé par le professeur Mauro Oddo, a étudié les avantages d'un substrat énergétique alternatif endogène ou/et exogène (lactate, CCs) pour les patients souffrant d'une LCA en utilisant la technique de microdialyse cérébrale (CMD), qui consiste à quantifier les métabolites cérébraux au chevet du patient. Ma thèse sera un "voyage" au sein du métabolisme cérébral et de l'action des substrats alternatifs chez les patients avec LCA. Tout d'abord, j'ai étudié l'effet d’une solution intraveineuse de lactate hypertonique (HL) pour contrôler les épisodes d’hypertension intracrânienne (HTIC) chez les patients avec LCA et son effet sur le métabolisme cérébral par rapport à une solution saline hypertonique (HS). Il en est ressorti que le HL est aussi efficace que le HS pour contrôler les épisodes d’HITC mais dont l’avantage supplémentaire est de limiter grandement l'hyperchlorémie. Deuxièmement, j'ai exploré le métabolisme des cétones en phase aiguë chez les patients TCC par rapport à leur statut nutritionnel (à jeun versus post- reprise nutritionnelle). Nous avons observé que l'alimentation était associée à une diminution progressive et significative des CCs totaux cérébraux et plasmatiques, alors que les acides aminés cétogènes étaient augmentés avec la nutrition. De plus, nous avons observé une forte corrélation entre les CCs cérébraux et les CCs endogènes circulants dans le plasma. Il s'agit d’une première étude montrant que le métabolisme des cétones cérébrales peut être modulé lors de la phase aiguë d'un TCC chez l'homme, ce qui suggère qu'elles peuvent potentiellement agir comme substrat énergétique cérébral supplémentaire. Enfin, dans le cadre d'un projet pilote mené auprès de patients TCC, nous démontrons une forte association entre le dysfonctionnement métabolique cérébral aigu (retranscrit par un rapport CMD lactate/pyruvate supérieur à 25) et l'atrophie de la matière grise à long-terme

Neurological Pupil Index for the Early Prediction of Outcome in Severe Acute Brain Injury Patients

In this study, we examined the early value of automated quantitative pupillary examination, using the Neurological Pupil index (NPi), to predict the long-term outcome of acute brain injured (ABI) patients. We performed a single-centre retrospective study (October 2016–March 2019) in ABI patients who underwent NPi measurement during the first 3 days following brain insult. We examined the performance of NPi—alone or in combination with other baseline demographic (age) and radiologic (CT midline shift) predictors—to prognosticate unfavourable 6-month outcome (Glasgow Outcome Scale 1–3). A total of 145 severely brain-injured subjects (65 traumatic brain injury, TBI; 80 non-TBI) were studied. At each time point tested, NPi <3 was highly predictive of unfavourable outcome, with highest specificity (100% (90–100)) at day 3 (sensitivity 24% (15–35), negative predictive value 36% (34–39)). The addition of NPi, from day 1 following ABI to age and cerebral CT scan, provided the best prognostic performance (AUROC curve 0.85 vs. 0.78 without NPi, p = 0.008; DeLong test) for 6-month neurological outcome prediction. NPi, assessed at the early post-injury phase, has a superior ability to predict unfavourable long-term neurological outcomes in severely brain-injured patients. The added prognostic value of NPi was most significant when complemented with baseline demographic and radiologic information.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Minimizing artifact-induced false-alarms for seizure detection in wearable EEG devices with gradient-boosted tree classifiers

Abstract Electroencephalography (EEG) is widely used to monitor epileptic seizures, and standard clinical practice consists of monitoring patients in dedicated epilepsy monitoring units via video surveillance and cumbersome EEG caps. Such a setting is not compatible with long-term tracking under typical living conditions, thereby motivating the development of unobtrusive wearable solutions. However, wearable EEG devices present the challenges of fewer channels, restricted computational capabilities, and lower signal-to-noise ratio. Moreover, artifacts presenting morphological similarities to seizures act as major noise sources and can be misinterpreted as seizures. This paper presents a combined seizure and artifacts detection framework targeting wearable EEG devices based on Gradient Boosted Trees. The seizure detector achieves nearly zero false alarms with average sensitivity values of $$65.27\%$$ 65.27 % for 182 seizures from the CHB-MIT dataset and $$57.26\%$$ 57.26 % for 25 seizures from the private dataset with no preliminary artifact detection or removal. The artifact detector achieves a state-of-the-art accuracy of $$93.95\%$$ 93.95 % (on the TUH-EEG Artifact Corpus dataset). Integrating artifact and seizure detection significantly reduces false alarms—up to $$96\%$$ 96 % compared to standalone seizure detection. Optimized for a Parallel Ultra-Low Power platform, these algorithms enable extended monitoring with a battery lifespan reaching 300 h. These findings highlight the benefits of integrating artifact detection in wearable epilepsy monitoring devices to limit the number of false positives

Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS

Steroid-converting enzymes in human adipose tissues and fat deposition with a focus on AKR1C enzymes.

Adipocytes express various enzymes, such as aldo-keto reductases (AKR1C), 11β-hydroxysteroid dehydrogenase (11β-HSD), aromatase, 5α-reductases, 3β-HSD, and 17β-HSDs involved in steroid hormone metabolism in adipose tissues. Increased activity of AKR1C enzymes and their expression in mature adipocytes might indicate the association of these enzymes with subcutaneous adipose tissue deposition. The inactivation of androgens by AKR1C enzymes increases adipogenesis and fat mass, particularly subcutaneous fat. AKR1C also causes reduction of estrone, a weak estrogen, to produce 17β-estradiol, a potent estrogen and, in addition, it plays a role in progesterone metabolism. Functional impairments of adipose tissue and imbalance of steroid biosynthesis could lead to metabolic disturbances. In this review, we will focus on the enzymes involved in steroid metabolism and fat tissue deposition.info:eu-repo/semantics/publishe

Mimicking the nicotinic receptor binding site by a single chain Fv selected by competitive panning from a synthetic phage library

We have developed a novel competitive method to select from a phage display library a single chain Fv which is able to mimic the alpha-bungarotoxin binding site of the muscle nicotinic receptor. The single chain Fv was selected from a large synthetic library using alpha-bungarotoxin-coated magnetic beads. Toxin-bound phages were then eluted by competition with affinity purified nicotinic receptor. Recognition of the toxin by the anti-alpha-bungarotoxin single chain Fv was very similar to that of the receptor, such as indicated by the epitope mapping of alpha-bungarotoxin through overlapping synthetic peptides. Moreover, several positively charged residues located in the toxin second loop and in the C-terminal region were found to be critical, to a similar extent, for toxin recognition by the single chain Fv and the receptor. However, although the anti-alpha-bungarotoxin single chain Fv seems to mimic the toxin binding site of the nicotinic receptor, it does not bind other nicotinic agonists or antagonists. Our results suggest that competitive selection of anti-ligand antibody phages can allow the production of receptor-mimicking molecules directly and exclusively targeted at one specific ligand. Since physiologically and pharmacologically different ligands can produce opposite effects on receptor functions, such selective ligand decoys can have important therapeutic applications