Microbiota alterations in proline metabolism impact depression

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not ad- dressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of pro-line and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment

Estudio de la rigidez arterial en arteria carótida y depósito tisular de hierro mediante resonancia magnética: relación con los factores de riesgo asociados al síndrome metabólico

The aim is to demonstrate the utility of magnetic resonance (MR) for identifying subclinical changes associated with the metabolic syndrome (MS) that contribute to increased cardiometabolic risk. The effect of MS on arterial stiffness and tissue iron load were evaluated using MR in subjects with the MS and control subjects. Arterial stiffness was higher in subjects with MS than in those without. The components contributing independently to an increased pulse wave velocity were hypertension and hypertriglyceridemia. Increased iron concentration was significantly detected at the liver and brain in obese subjects. Obesity-associated brain iron overload was correlated with worse cognitive performance. Obesity and insulin resistance were found as the main factors that contribute to tissue iron deposition. In conclusion, this thesis demonstrates the utility of MR to evaluate subclinical risk changes associated with the MS in subjects without diabetes or ischemic diseaseL'objectiu general consisteix en posar de manifest la utilitat de la ressonància magnètica (RM) per identificar canvis subclínics associats a la síndrome metabòlica (SM)i que contribueixen a l'increment del risc cardiometabòlic. Es va avaluar l'efecte de la SM sobre la rigidesa arterial i el dipósit de ferro tisular mitjançant RM en individus amb SM i controls. Es va observar un augment de la rigidesa arterial associada a la SM, essent l’hipertensió i hipertrigliceridèmia els principals components desencadenants. També es va observar un augment del dipòsit de ferro hepàtic i cerebral associat a l’obesitat. La sobrecàrrega de ferro cerebral es va correlacionar amb pitjors puntuacions del rendiment cognitiu. Els principals factors precursors de dipòsit de ferro van ser la insulino-resistencia i l'obesitat. En conclusió, es posa de manifest l’utilitat de la RM per avaluar canvis subclínics associats a la SM en individus sense antecedents de diabetis o malaltia vascular isquèmic

Estudio piloto de la relación entre el aumento de la velocidad de onda del pulso en arteria carótida común medida por resonancia magnética y los factores de riesgo vasculares clásicos en sujetos con sospecha de lesión cerebrovascular isquémica

Arterial stiffness assessed by carotid-femoral pulse wave velocity (cfPWV) measurement is now well accepted as an independent predictor of vascular mortality and morbidity. However, the value of cfPWV has been considered to be limited for risk classification in patients with several vascular risk factors. Magnetic resonance (MR) allows measurement of PWV between two points, though to date mainly used to study the aorta. To assess the common carotid artery pulse wave velocity by magnetic resonance, determine their association with classical vascular risk factors and ischemic brain injury burden in patients with suspected ischemic cerebrovascular diseaseLa RA medida mediante cfVOP está establecida como predictor independiente de mortalidad y morbilidad vascular. Sin embargo, se ha considerado la cfVOP pueda tener un valor limitado para la clasificación y estratificación del RCV en pacientes con varios FRV. La RM permite la medición de la VOP, aunque hasta la fecha, principalmente, ha sido utilizada para medirla en arteria aorta.En este estudio se pretende analizar la VOP de la ACC mediante RM, determinar su asociación con los principales FRV clásicos y la carga isquémica cerebral en pacientes con sospecha de lesión cerebrovascular isquémic

Hypothalamic damage is associated with inflammatory markers and worse cognitive performance in obese subjects

Context: Growing evidence implicates hypothalamic inflammation in the pathogenesis of dietinduced obesity and cognitive dysfunction in rodent models. Few studies have addressed the association between obesity and hypothalamic damage in humans and its relevance. Objective: To determine markers of obesity-associated hypothalamic damage on diffusion tensor imaging (DTI) and to determine whether DTI-metrics are associated with performance on cognitive testing. Design and Participants: This cross-sectional study analyzed DTI-metrics (primary (λ1), secondary (λ2), and tertiary (λ3) eigenvalues; fractional anisotropy (FA); and mean diffusivity (MD)) in the hypothalamus of 24 consecutive middle-aged obese subjects (13 women; 49.8 ± 8.1 years; body mass index [BMI] 43.9 ± 0.92 Kg/m2) and 20 healthy volunteers (10 women; 48.8 ± 9.5 years; BMI 24.3 ± 0.79 Kg/m2). Outcome: measures: Hypothalamic damage assessed by DTI-metrics and cognitive performance evaluated by neuropsychological test-battery. Results: λ1 values in the hypothalamus were significantly lower in obese subjects (P<0.0001). The sensitivity, specificity, and positive and negative predictive values for obesity-associated hypothalamic damage by λ1<1.072 were 75%, 87.5%, 83.3%, and 80.7%, respectively. Patients with hypothalamic λ1<1.072 had higher values of BMI, fat mass, inflammatory markers, carotid-intima media thickness, and hepatic steatosis and lower scores on cognitive tests. Combined BMI and alanine aminotransferase had the strongest association with hypothalamic damage reflected by λ1<1.072 (AUC=0.89). Conclusions: DTI detects obesity-associated hypothalamic damage associated with inflammatory markers and worse cognitive performance. This study highlights the potential utility of λ1 as a surrogate marker of obesity-associated hypothalamic damag

Acute damage to the posterior limb of the internal capsule on diffusion tensor tractography as an early imaging predictor of motor outcome after stroke

BACKGROUND AND PURPOSE: Early prediction of motor outcome is of interest in stroke management. We aimed to determine whether lesion location at DTT is predictive of motor outcome after acute stroke and whether this information improves the predictive accuracy of the clinical scores. MATERIALS AND METHODS: We evaluated 60 consecutive patients within 12 hours of middle cerebral artery stroke onset. We used DTT to evaluate CST involvement in the motor cortex and premotor cortex, centrum semiovale, corona radiata, and PLIC and in combinations of these regions at admission, at day 3, and at day 30. Severity of limb weakness was assessed by using the motor subindex scores of the National Institutes of Health Stroke Scale (5a, 5b, 6a, 6b). We calculated volumes of infarct and fractional anisotropy values in the CST of the pons. RESULTS: Acute damage to the PLIC was the best predictor associated with poor motor outcome, axonal damage, and clinical severity at admission (P < .001). There was no significant correlation between acute infarct volume and motor outcome at day 90 (P = .176, r = 0.485). The sensitivity, specificity, and positive and negative predictive values of acute CST involvement at the level of the PLIC for motor outcome at day 90 were 73.7%, 100%, 100%, and 89.1%, respectively. In the acute stage, DTT predicted motor outcome at day 90 better than the clinical scores (R2 = 75.50, F = 80.09, P < .001). CONCLUSIONS: In the acute setting, DTT is promising for stroke mapping to predict motor outcome. Acute CST damage at the level of the PLIC is a significant predictor of unfavorable motor outcom

Intravoxel Incoherent Motion Metrics as Potential Biomarkers for Survival in Glioblastoma

Intravoxel incoherent motion (IVIM) is an MRI technique with potential applications in measuring brain tumor perfusion, but its clinical impact remains to be determined. We assessed the usefulness of IVIM-metrics in predicting survival in newly diagnosed glioblastoma. Methods Fifteen patients with glioblastoma underwent MRI including spin-echo echo-planar DWI using 13 b-values ranging from 0 to 1000 s/mm2. Parametric maps for diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were generated for contrast-enhancing regions (CER) and non-enhancing regions (NCER). Regions of interest were manually drawn in regions of maximum f and on the corresponding dynamic susceptibility contrast images. Prognostic factors were evaluated by Kaplan-Meier survival and Cox proportional hazards analyses. Results We found that fCER and D*CER correlated with rCBFCER. The best cutoffs for 6-month survival were fCER>9.86% and D*CER>21.712 x10−3mm2/s (100% sensitivity, 71.4% specificity, 100% and 80% positive predictive values, and 80% and 100% negative predictive values; AUC:0.893 and 0.857, respectively). Treatment yielded the highest hazard ratio (5.484; 95% CI: 1.162–25.88; AUC: 0.723; P = 0.031); fCER combined with treatment predicted survival with 100% accuracy. Conclusions The IVIM-metrics fCER and D*CER are promising biomarkers of 6-month survival in newly diagnosed glioblastom

Quantification of thrombus Hounsfield units on noncontrast CT predicts stroke subtype and early recanalization after intravenous recombinant tissue plasminogen activator

BACKGROUND AND PURPOSE: Little is known about the factors that determine recanalization after intravenous thrombolysis. We assessed the value of thrombus Hounsfield unit quantification as a predictive marker of stroke subtype and MCA recanalization after intravenous rtPA treatment. MATERIALS AND METHODS: NCCT scans and CTA were performed on patients with MCA acute stroke within 4.5 hours of symptom onset. Demographics, stroke severity, vessel hyperattenuation, occlusion site, thrombus length, and time to thrombolysis were recorded. Stroke origin was categorized as LAA, cardioembolic, or indeterminate according to TOAST criteria. Two blinded neuroradiologists calculated the Hounsfield unit values for the thrombus and contralateral MCA segment. We used ROC curves to determine the rHU cutoff point to discriminate patients with successful recanalization from those without. We assessed the accuracy (sensitivity, specificity, and positive and negative predictive values) of rHU in the prediction of recanalization. RESULTS: Of 87 consecutive patients, 45 received intravenous rtPA and only 15 (33.3%) patients had acute recanalization. rHU values and stroke mechanism were the highest predictive factors of recanalization. The Matthews correlation coefficient was highest for rHU (0.901). The sensitivity, specificity, and positive and negative predictive values for lack of recanalization after intravenous rtPA for rHU ≤ 1.382 were 100%, 86.67%, 93.75%, and 100%, respectively. LAA thrombi had lower rHU than cardioembolic and indeterminate stroke thrombi (P = .004). CONCLUSIONS: The Hounsfield unit thrombus measurement ratio can predict recanalization with intravenous rtPA and may have clinical utility for endovascular treatment decision making

Wallerian degeneration in the corticospinal tract evaluated by diffusion tensor imaging correlates with motor deficit 30 days after middle cerebral artery ischemic stroke

BACKGROUND AND PURPOSE: The quantification and clinical significance of WD in CSTs following supratentorial stroke are not well understood. We evaluated the anisotropy by using DTI and signalintensity changes on conventional MR imaging in the CST to determine whether these findings are correlated with limb motor deficit in patients with MCA ischemic stroke. MATERIALS AND METHODS: We studied 60 patients within 12 hours of stroke onset. At admission, day 3, and day 30 of evolution, patients underwent multimodal MR imaging, including DTI sequences. We assessed the severity of limb weakness by using the motor subindex scores (5a, 5b, 6a, 6b) of the m-NIHSS and established 3 groups: I (m-NIHSS scores of 0), II (m-NIHSS, 1-4), and III (m-NIHSS, 5-8). FA values and rFAs were measured on the affected and the unaffected CSTs in the pons. RESULTS: FA values for the CST were significantly lower on the affected side compared with the unaffected side only at day 30 (P < .001), and the rFA was significantly correlated with the motor deficit at day 30 (P < .001; r=-0.793). The sensitivity, specificity, and positive and negative predictive values for motor deficit by rFA < 0.925 were 95.2%, 94.9%, 90.9%, and 97.4%, respectively. CONCLUSIONS: WD in the CST revealed by DTI correlates with motor deficit 30 days after MCA ischemic stroke. This study highlights the utility of imaging follow-up at 30 days and the potential of DTI as a surrogate marker in clinical trial

Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways

Background: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. Methods: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. Results: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. Conclusion: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.This work was partially supported by research grants FIS (PI15/01934 and PI18/01022) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R and #AEI-SAF2017-84060-R-FEDER from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain; and also by Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2015), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), the Catalan Goverment (Agency for Management of University and Research Grants [2017SGR696] and Department of Health [STL002/16/00250]; the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT); and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). MA-R is funded by a predoctoral Río Hortega contract from the Instituto de Salud Carlos III (ISCIII, CM19/00190), co-funded by the European Social Fund “Investing in your future”. OC-R is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP20/00165), co-funded by the Europeran Social Fund "Investing in your future". JM-P is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund “Investing in your future”. JS is funded by a predoctoral PERIS contract (SLT002/16/00250) from the Catalan Government. MJ is a professor under the “Serra Hunter” programme (Generalitat de Catalunya)