Reduced Cortical Thickness Correlates of Cognitive Dysfunction in Post-COVID-19 Condition: Insights from a Long-Term Follow-up.

BACKGROUND AND PURPOSE: There is a paucity of data on long-term neuroimaging findings from individuals who have developed the post-coronavirus 2019 (COVID-19) condition. Only 2 studies have investigated the correlations between cognitive assessment results and structural MR imaging in this population. This study aimed to elucidate the long-term cognitive outcomes of participants with the post-COVID-19 condition and to correlate these cognitive findings with structural MR imaging data in the post-COVID-19 condition. MATERIALS AND METHODS: A cohort of 53 participants with the post-COVID-19 condition underwent 3T brain MR imaging with T1 and FLAIR sequences obtained a median of 1.8 years after Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. A comprehensive neuropsychological battery was used to assess several cognitive domains in the same individuals. Correlations between cognitive domains and whole-brain voxel-based morphometry were performed. Different ROIs from FreeSurfer were used to perform the same correlations with other neuroimaging features. RESULTS: According to the Frascati criteria, more than one-half of the participants had deficits in the attentional (55%, n = 29) and executive (59%, n = 31) domains, while 40% (n = 21) had impairment in the memory domain. Only 1 participant (1.89%) showed problems in the visuospatial and visuoconstructive domains. We observed that reduced cortical thickness in the left parahippocampal region (t(48) = 2.28, P = .03) and the right caudal-middle-frontal region (t(48) = 2.20, P = .03) was positively correlated with the memory domain. CONCLUSIONS: Our findings suggest that cognitive impairment in individuals with the post-COVID-19 condition is associated with long-term alterations in the structure of the brain. These macrostructural changes may provide insight into the nature of cognitive symptoms.

Increased brain fractional perfusion in obesity using intravoxel incoherent motion (IVIM) MRI metrics.

OBJECTIVE: This research seeks to shed light on the associations between brain perfusion, cognitive function, and mental health in individuals with and without obesity. METHODS: In this study, we employed the noninvasive intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) technique to examine brain fractional perfusion (FP) in two groups: individuals with obesity (N = 72) and healthy controls (N = 66). Additionally, we investigated potential associations between FP, cognitive function, and depressive symptoms in the participants with and without obesity. Finally, artificial intelligence algorithms (Boruta analysis) were also used. RESULTS: Participants with obesity exhibited increased FP within dopaminergic brain circuits, particularly involving prefrontal cortex areas, anterior and posterior sections of the cingulate cortex, the right striatum, and the midbrain. Additionally, these individuals demonstrated lower working memory and higher depressive symptoms compared to the control group. Notably, higher FP in the inferior temporal and occipital cortices correlated with greater depressive symptoms, whereas increased FP in the right ventral caudate and the midbrain was associated with better working memory performance. A link between inflammatory and metabolic variables, with a particular emphasis on monocytes, and FP in obesity was also evidenced by Boruta analysis. CONCLUSIONS: Increased brain perfusion in individuals with obesity is associated with cognitive function and mental health through interaction with metabolic and inflammatory factors.

Lower serum ferritin levels are associated with worse cognitive performance in aging.

OBJECTIVES: Iron is important for neurogenesis, synaptic development, and neurotransmitter synthesis. Serum ferritin (SF) is a reliable marker for assessing iron stores. Therefore, we evaluated the cognitive function associated with SF levels. We also assessed brain iron content using R2* Magnetic Resonance Imaging (MRI) and its association with SF levels. DESIGN: Data from three cross-sectional observational studies were used. Aging Imageomics (n = 1030) was conducted on aged subjects. Health Imageomics (n = 971) and IR0NMET (n = 175) were conducted in middle-aged subjects. SETTING AND PARTICIPANTS: Participants were enrolled at Dr. Josep Trueta University Hospital facilities. The three cohorts included a total of 2176 subjects (mean age, 52 years; 48% men). MEASUREMENTS: SF levels were measured by standard laboratory methods. Total Digits Span (TDS), and Phonemic Verbal Fluency (PVF) were used to assess executive function. Language function was assessed by semantic verbal fluency (SVF), attention by the Symbol Digit Modalities Test, and memory by the Memory Binding Tests - Total Free Recall and Total Delayed Free Recall. MRI was used to assess the iron content of the brain by R2*. RESULTS: In subjects aged 65 years or older, SF levels were associated with increased TDS (ß = 0.003, p = 0.02), PVF (ß = 0.004, p = 0.01), and SVF (ß = 0.004, p = 0.002) scores. After stratification by sex, these findings were significant only in men, where SF was associated with increased TDS (ß = 0.003, p = 0.01), PVF (ß = 0.004, p = 0.03), and SVF (ß = 0.004, p = 0.009) scores. In middle-aged subjects, SF was also associated with increased SVF scores (ß = 0.005, p = 0.011). Lastly, in men, SF levels were negatively associated with R2*, a surrogate marker of brain iron content, in both the left frontal inferior opercular area (r = -0.41, p = 0.005) and the right frontal inferior opercular area (r = -0.44, p = 0.002). CONCLUSIONS: SF is significantly and positively associated with cognition. In older people with low SF levels, iron supplementation may be a promising therapy to improve cognition.

Unraveling the gut-brain connection: The association of microbiota-linked structural brain biomarkers with behavior and mental health.

AIM: The gut microbiota can influence human behavior. However, due to the massive multiple-testing problem, research into the relationship between microbiome ecosystems and the human brain faces drawbacks. This problem arises when attempting to correlate thousands of gut bacteria with thousands of brain voxels. METHODS: We performed brain magnetic resonance imaging (MRI) scans on 133 participants and applied machine-learning algorithms (Ridge regressions) combined with permutation tests. Using this approach, we were able to correlate specific gut bacterial families with brain MRI signals, circumventing the difficulties of massive multiple testing while considering sex, age, and body mass index as confounding factors. RESULTS: The relative abundance (RA) of the Selenomonadaceae, Clostridiaceae, and Veillonellaceae families in the gut was associated with altered cerebellar, visual, and frontal T2-mapping and diffusion tensor imaging measures. Conversely, decreased relative abundance of the Eubacteriaceae family was also linked to T2-mapping values in the cerebellum. Significantly, the brain regions associated with the gut microbiome were also correlated with depressive symptoms and attentional deficits. CONCLUSIONS: Our analytical strategy offers a promising approach for identifying potential brain biomarkers influenced by gut microbiota. By gathering a deeper understanding of the microbiota-brain connection, we can gain insights into the underlying mechanisms and potentially develop targeted interventions to mitigate the detrimental effects of dysbiosis on brain function and mental health.

Correlation of Cognitive Reappraisal and the Microstructural Properties of the Forceps Minor: A Deductive Exploratory Diffusion Tensor Imaging Study.

Cognitive reappraisal (CR) is a mechanism for emotion regulation, and the prefrontal cortex (PFC) plays a central role in the regulation of emotions. We tested the hypothesis of an association between CR function and microstructural properties of forceps minor (a commissural bundle within the PFC) in healthy subjects (HS). We analyzed a population of 65 young HS of a public dataset. The diffusion tensor imaging (DTI) sequence of every subject was analyzed to extract the derived shape (diameter and volume) and DTI metrics in terms of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) of the forceps minor. The CR subscale of the German version of the Emotion Regulation Questionnaire (ERQ) was used for CR assessment. The Shapiro-Wilk test was applied to test the assumption of normality in all these parameters, adopting a statistical threshold at p < 0.05. Whenever appropriate a non-parametric two-tailed partial correlation analysis was applied to test for correlations between the CR ERQ score and the derived shape and DTI metrics, including age and sex as confounders, adopting a statistical threshold at p < 0.05. The non-parametric two-tailed partial correlation analysis revealed a mildly significant correlation with FA (ρ = 0.303; p = 0.016), a weakly significant negative correlation with MD (ρ = - 0.269; p = 0.033), and a mildly significant negative correlation with RD (ρ = - 0.305; p = 0.015). These findings suggest a correlation between DTI microstructural properties of forceps minor and CR.

Impact of corpus callosum integrity on functional interhemispheric connectivity and cognition in healthy subjects.

To examine the corpus callosum's (CC) integrity in terms of fractional anisotropy (FA) and how it affects resting-state hemispheric connectivity (rs-IHC) and cognitive function in healthy individuals. Sixty-eight healthy individuals were recruited for the study. The global FA (gFA) and FA values of each CC tract (forceps minor, body, tapetum, and forceps major) were evaluated using diffusion-weighted imaging (DWI) sequences. The homotopic functional connectivity technique was used to quantify the effects of FA in the CC tracts on bilateral functional connectivity, including the confounding effect of gFA. Brain regions with higher or lower rs-IHC were identified using the threshold-free cluster enhancement family-wise error-corrected p-value of 0.05. The null hypothesis was rejected if the p-value was ≤ 0.05 for the nonparametric partial correlation technique. Several clusters of increased rs-IHC were identified in relation to the FA of individual CC tracts, each with a unique topographic distribution and extension. Only forceps minor FA values correlated with cognitive scores. The integrity of CC influences rs-IHC differently in healthy subjects. Specifically, forceps minor anisotropy impacts rs-IHC and cognition more than other CC tracts do.

Gut microbiota links to serum ferritin and cognition.

Iron is required for the replication and growth of almost all bacterial species and in the production of myelin and neurotransmitters. Increasing clinical studies evidence that the gut microbiota plays a critical role in iron metabolism and cognition. However, the understanding of the complex iron-microbiome-cognition crosstalk remains elusive. In a recent study in the Aging Imageomics cohort (n = 1,030), we identified a positive association of serum ferritin (SF) with executive function (EF) as inferred from the semantic verbal fluency (SVF,) the total digit span (TDS) and the phonemic verbal fluency tests (PVF). Here, we explored the potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. Different bacterial species belonging to the Proteobacteria phylum (Klebsiella pneumoniae, Klebsiella michiganensis, Unclassified Escherichia) were negatively associated both with SF and executive function. At the functional level, an enrichment of microbial pathways involved in phenylalanine, arginine, and proline metabolism was identified. Consistently, phenylacetylglutamine, a metabolite derived from microbial catabolism of phenylalanine, was negatively associated with SF, EF, and semantic memory. Other metabolites such as ureidobutyric acid and 19,20-DiHDPA, a DHA-derived oxylipin, were also consistently and negatively associated with SF, EF, and semantic memory, while plasma eicosapentaenoic acid was positively associated. The associations of SF with cognition could be mediated by the gut microbiome through microbial-derived metabolites.

Cognitive improvement following endovascular embolization in patients with intracranial dural arteriovenous fistula: The Neuropsychology in dural ArterIal Fistula (NAIF) Study.

BACKGROUND: Cognitive improvement after endovascular embolization of an intracranial dural arteriovenous fistula (dAVF) remains unexplored. We aim to investigate cognitive changes following endovascular embolization of dAVFs. METHODS: Neuropsychology in dural ArterIal Fistula (NAIF) was a prospective multicentric study including patients with an angiographic diagnosis of dAVF who underwent endovascular embolization over the course of 4 years. A complete neuropsychological evaluation comprising five cognitive domains (attention and executive functions, memory, language, praxis, gnosis) was performed at baseline and 3 months follow-up. Mean Z scores for cognitive tests were compared pre- and post-treatment using paired sample t-tests, where higher Z scores indicate better cognition. Effect sizes were computed as Cohen's d. RESULTS: A total of 32 patients (mean age 61.1±15.4 years, 10 (31.3%) females) were included. Patients exhibited improved performance in attention and executive functions: executive functions-attention (+0.282, P=0.009, d=0.29), executive functions-fluencies (+0.283, P=0.029, d=0.4), and executive functions-processing speed (+0.471, P=0.039, d=0.41). There was an increase in memory: verbal learning and verbal delayed recall scores (+0.513, P<0.001, d=0.55, and +0.385, P=0.001, d=0.41, respectively), while verbal recognition parameters (+0.839, P=0.086, d=0.37) and visual memory (delayed recall) (+0.430, P=0.060, d=0.35) displayed trends toward improved performance. Regarding language, there was significant overall improvement (+0.300, P=0.014, d=0.24), but neither praxis nor gnosis changed significantly. These cognitive outcomes were independent of the severity (measured as Cognard classification), and no patient experienced cognitive worsening. CONCLUSION: This study suggests that endovascular embolization confers cognitive benefits on dAVF patients undergoing endovascular embolization and may be beneficial even for patients with a low risk of hemorrhage.

Impact of Balloon Guide Catheters in Elderly Patients Treated with Mechanical Thrombectomy: Insights from the ROSSETTI Registry.

BACKGROUND AND PURPOSE: Several nonrandomized studies have demonstrated the effectiveness of balloon guide catheters in treating patients with anterior circulation large-vessel occlusion. However, their impact on the elderly populations has been underreported. We aimed to analyze the effect of balloon guide catheters in a cohort of elderly patients (80 years of age or older) with anterior circulation large-vessel occlusion. MATERIALS AND METHODS: Consecutive patients from June 2019 to June 2022 were collected from the ROSSETTI Registry. Demographic and clinical data, angiographic endovascular technique, and clinical outcome were compared between balloon guide catheter and non-balloon guide catheter groups. We studied the association between balloon guide catheters and the rate of complete recanalization after a single first-pass effect modified TICI 2c-3, as well as their association with functional independence at 3 months. RESULTS: A total of 808 patients were included during this period, 465 (57.5%) of whom were treated with balloon guide catheters. Patients treated with balloon guide catheters were older, had more neurologic severity at admission and lower baseline ASPECTS, and were less likely to receive IV fibrinolytics. No differences were observed in terms of the modified first-pass effect between groups (45.8 versus 39.9%, P = .096). In the multivariable regression analysis, balloon guide catheter use was not independently associated with a modified first-pass effect or the final modified TICI 2c-3, or with functional independence at 3 months. CONCLUSIONS: In our study, balloon guide catheter use during endovascular treatment of anterior circulation large-vessel occlusion in elderly patients did not predict the first-pass effect, near-complete final recanalization, or functional independence at 3 months. Further studies, including randomized clinical trials, are needed to confirm these results.

The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.

Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.

Aortic valve Replacement compared to Transcatheter Implant and its relationship with COgnitive Impairment (ARTICO) evaluated with neuropsychological and advanced neuroimaging: a longitudinal cohort study.

BACKGROUND: Aortic stenosis is the most common valvulopathy in Western countries. The treatment of choice had been surgery aortic valve replacement (SAVR), but the improvement in endovascular approaches as transcatheter aortic valve implantation (TAVI), initially reserved for patients with very high surgical risk, has been extended to high and intermediate, and recently also to low-risk patients. Stroke and vascular cognitive impairment are the most important complications. It is not entirely clear which technique is best to avoid these complications as well as their impact. Our goal is to evaluate changes in cognitive performance in the early (1-month) and late (1-year) postoperative period in patients undergoing SAVR or TAVI, by extensive neuropsychological study (NRP) and advanced Magnetic Resonance Imaging (MRI). Specifically, to compare early and late cognitive changes after the intervention between both groups, the occurrence of stroke during follow-up and to compare the appearance of silent vascular lesions and changes in brain activity and functional connectivity with functional MRI during follow-up between both groups. METHODS/DESIGN: Prospective longitudinal cohort study. A non-selected representative sample of 80 subjects, 40 SAVR and 40 TAVI to obtain a final sample of 36 eligible subjects in each group, ranging from 70 to 85 years old, with indication for aortic replacement and intermediate or high surgical risk will be studied. At baseline, within one month before the treatment, all individuals will undergo an extensive NRP and advanced MRI study. These studies will also be performed 1-month and 1-year after treatment, to assess the appearance of new vascular lesions, as well as changes in cognitive performance with respect to baseline. DISCUSSION: This study aims to evaluate changes in cognitive performance as well as both clinical and silent vascular events occurring in the early (1-month) and late (1-year) periods after SAVR and TAVI. We will also analyze the correlation between neuropsychological and neuroimaging approaches in order to evaluate cognition. Therefore, it may provide high-quality data of cognitive changes and vascular events for both techniques, and be useful to tailor interventions to individual characteristics and ultimately aiding in decision-making. TRIAL REGISTRATION: This study is register in Clinicaltrials.gov (NCT05235529) on 11th February 2022.

Adipose tissue coregulates cognitive function.

Obesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)-brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle-associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.

Magnetic resonance imaging as a predictor of therapeutic response to pasireotide in acromegaly.

OBJECTIVE: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. RESULTS: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. CONCLUSIONS: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

Texture Analysis of the Apparent Diffusion Coefficient Focused on Contrast-Enhancing Lesions in Predicting Survival for Bevacizumab-Treated Patients with Recurrent Glioblastoma.

PURPOSE: Glioblastoma often recurs after treatment. Bevacizumab increases progression-free survival in some patients with recurrent glioblastoma. Identifying pretreatment predictors of survival can help clinical decision making. Magnetic resonance texture analysis (MRTA) quantifies macroscopic tissue heterogeneity indirectly linked to microscopic tissue properties. We investigated the usefulness of MRTA in predicting survival in patients with recurrent glioblastoma treated with bevacizumab. METHODS: We evaluated retrospective longitudinal data from 33 patients (20 men; mean age 56 ± 13 years) who received bevacizumab on the first recurrence of glioblastoma. Volumes of contrast-enhancing lesions segmented on postcontrast T1-weighted sequences were co-registered on apparent diffusion coefficient maps to extract 107 radiomic features. To assess the performance of textural parameters in predicting progression-free survival and overall survival, we used receiver operating characteristic curves, univariate and multivariate regression analysis, and Kaplan-Meier plots. RESULTS: Longer progression-free survival (>6 months) and overall survival (>1 year) were associated with lower values of major axis length (MAL), a lower maximum 2D diameter row (m2Ddr), and higher skewness values. Longer progression-free survival was also associated with higher kurtosis, and longer overall survival with higher elongation values. The model combining MAL, m2Ddr, and skewness best predicted progression-free survival at 6 months (AUC 0.886, 100% sensitivity, 77.8% specificity, 50% PPV, 100% NPV), and the model combining m2Ddr, elongation, and skewness best predicted overall survival (AUC 0.895, 83.3% sensitivity, 85.2% specificity, 55.6% PPV, 95.8% NPV). CONCLUSIONS: Our preliminary analyses suggest that in patients with recurrent glioblastoma pretreatment, MRTA helps to predict survival after bevacizumab treatment.

Consumption of ultra-processed foods is associated with depression, mesocorticolimbic volume, and inflammation.

BACKGROUND: The consumption of ultra-processed foods and drinks (UPF) has been associated with depression and inflammation and preclinical studies showed that some UPF components disrupt the amygdala-hippocampal complex. We combine diet, clinical and brain imaging data to investigate the relationship between the UPF consumption, depressive symptoms, and brain volumes in humans, considering interactions with obesity, and the mediation effect of inflammation biomarkers. METHODS: One-hundred fifty-two adults underwent diet, depressive symptoms, anatomic magnetic resonance imaging assessments and laboratory tests. Relationships between the % of UPF consumption (in grams) of the total diet, depressive symptoms, and gray matter brain volumes were explored using several adjusted regression models, and in interaction with the presence of obesity. Whether inflammatory biomarkers (i.e., white blood cell count, lipopolysaccharide-binding protein, c-reactive protein) mediate the previous associations was investigated using R mediation package. RESULTS: High UPF consumption was associated with higher depressive symptoms in all participants (ß = 0.178, CI = 0.008-0.261) and in those with obesity (ß = 0.214, CI = -0.004-0.333). Higher consumption was also associated with lower volumes in the posterior cingulate cortex and the left amygdala, which in the participants with obesity also encompassed the left ventral putamen and the dorsal frontal cortex. White blood count levels mediated the association between UPF consumption and depressive symptoms (p = 0.022). LIMITATIONS: The present study precludes any causal conclusions. CONCLUSIONS: UPF consumption is associated with depressive symptoms and lower volumes within the mesocorticolimbic brain network implicated in reward processes and conflict monitoring. Associations were partially dependent on obesity and white blood cell count.

Plasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome.

Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of "omic" techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30-100 years old; 2: n = 68, 70% females, 19-107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial ß-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.

Intensive Rehabilitation Program in Older Adults with Stroke: Therapy Content and Feasibility-Preliminary Results from the BRAIN-CONNECTS Study.

The main objective was to assess the feasibility of an intensive rehabilitation program (IRP) for stroke patients; and secondly, to detect eventual age-related differences in content, duration, tolerability, and safety in a prospective observational cohort of patients diagnosed with subacute stroke, admitted to inpatient rehabilitation (BRAIN-CONNECTS project). Activities during physical, occupational and speech therapy, and time dedicated to each one were recorded. Forty-five subjects (63.0 years, 77.8% men) were included. The mean time of therapy was 173.8 (SD 31.5) minutes per day. The only age-related differences when comparing patients ≥65 and <65 years were a shorter time allocated for occupational therapy (-7.5 min (95% CI -12.5 to -2.6), p = 0.004) and a greater need of speech therapy (90% vs. 44%) in the older adults. Gait training, movement patterns of upper limbs, and lingual praxis were the most commonly performed activities. Regarding tolerability and safety, there were no losses to follow-up, and the attendance ratio was above 95%. No adverse events occurred during any session in all patients. Conclusion: IRP is a feasible intervention in patients with subacute stroke, regardless of age, and there are no relevant differences on content or duration of therapy.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

The Longitudinal Changes in Subcutaneous Abdominal Tissue and Visceral Adipose Tissue Volumetries Are Associated with Iron Status.

Excess iron is known to trigger adipose tissue dysfunction and insulin resistance. Circulating markers of iron status have been associated with obesity and adipose tissue in cross-sectional studies. We aimed to evaluate whether iron status is linked to changes in abdominal adipose tissue longitudinally. Subcutaneous abdominal tissue (SAT) and visceral adipose tissue (VAT) and its quotient (pSAT) were assessed using magnetic resonance imaging (MRI), at baseline and after one year of follow-up, in 131 (79 in follow-up) apparently healthy subjects, with and without obesity. Insulin sensitivity (euglycemic- hyperinsulinemic clamp) and markers of iron status were also evaluated. Baseline serum hepcidin (p = 0.005 and p = 0.002) and ferritin (p = 0.02 and p = 0.01)) were associated with an increase in VAT and SAT over one year in all subjects, while serum transferrin (p = 0.01 and p = 0.03) and total iron-binding capacity (p = 0.02 and p = 0.04) were negatively associated. These associations were mainly observed in women and in subjects without obesity, and were independent of insulin sensitivity. After controlling for age and sex, serum hepcidin was significantly associated with changes in subcutaneous abdominal tissue index (iSAT) (ß = 0.406, p = 0.007) and visceral adipose tissue index (iVAT) (ß = 0.306, p = 0.04), while changes in insulin sensitivity (ß = 0.287, p = 0.03) and fasting triglycerides (ß = -0.285, p = 0.03) were associated with changes in pSAT. These data indicated that serum hepcidin are associated with longitudinal changes in SAT and VAT, independently of insulin sensitivity. This would be the first prospective study evaluating the redistribution of fat according to iron status and chronic inflammation.

Establishment of a reproducible and minimally invasive ischemic stroke model in swine.

The need for advances in the management/treatment options for ischemic stroke patients requires that upcoming preclinical research uses animals with more human-like brain characteristics. The porcine brain is considered appropriate, although the presence of the rete mirabile (RM) prevents direct catheterization of the intracranial arteries to produce focal cerebral ischemia. To develop a reproducible minimally invasive porcine stroke model, a guide catheter and guide wire were introduced through the femoral artery until reaching the left RM. Using the pressure cooker technique, Squid-12 embolization material was deposited to fill, overflow, and occlude the left RM, the left internal carotid artery, and left circle of Willis wing up to the origins of the middle cerebral arteries (MCAs), mimicking the occlusion produced in the filament model in rodents. Longitudinal multimodal cerebral MRI was conducted to assess the brain damage and cerebral blood supply. The technique we describe here occluded up to the origins of the MCAs in 7 of 8 swine, inducing early damage 90 minutes after occlusion that later evolved to a large cerebral infarction and producing no mortality during the intervention. This minimally invasive ischemic stroke model in swine produced reproducible infarcts and shows translational features common to human stroke.