Cerebral Disease Research Articles

Neuroprotection on ischemic brain injury by Mg2+/H2 released from endovascular Mg implant

Most acute ischemic stroke patients with large vessel occlusion require stent implantation for complete recanalization. Yet, due to ischemia-reperfusion injury, over half of these patients still experience poor prognoses. Thus, neuroprotective treatment is imperative to alleviate the ischemic brain injury, and a proof-of-concept study was conducted on “biodegradable neuroprotective stent”. This concept is premised on the hypothesis that locally released Mg2+/H2 from Mg metal within the bloodstream could offer synergistic neuroprotection against reperfusion injury in distant cerebral ischemic tissues. Initially, the study evaluated pure Mg's neuroactive potential using oxygen-glucose deprivation/reoxygenation (OGD/R) injured neuron cells. Subsequently, a pure Mg wire was implanted into the common carotid artery of the transient middle cerebral artery occlusion (MCAO) rat model to simulate human brain ischemia/reperfusion injury. In vitro analyses revealed that pure Mg extract aided mouse hippocampal neuronal cell (HT-22) in defending against OGD/R injury. Additionally, the protective effects of the Mg wire on behavioral abnormalities, neural injury, blood-brain barrier disruption, and cerebral blood flow reduction in MCAO rats were verified. Conclusively, Mg-based biodegradable neuroprotective implants could serve as an effective local Mg2+/H2 delivery system for treating distant cerebral ischemic diseases.

RNF213 Mutation Associated with the Progression from Middle Cerebral Artery Steno-Occlusive Disease to Moyamoya Disease.

Middle cerebral artery steno-occlusive disease (MCAD) has been recognized as a different clinical entity from moyamoya disease (MMD). Although MCAD can progress to MMD, the extent to which patients actually progress and the risk factors for this progression have not been fully elucidated. We retrospectively reviewed patients with MCAD who underwent RNF213 genotyping. Demographic features, RNF213 p.R4810K mutation, medical history, and longitudinal changes in angiography were analyzed. Sixty patients with 81 affected hemispheres were enrolled. During the follow-up period, 17 patients developed MMD, and the RNF213 p.R4810K mutation was the only factor significantly associated with progression to MMD (odds ratio, 16.1; 95% CI, 2.13-731; P = 0.001). The log-rank test demonstrated that patients with the mutation had a higher risk of progression to MMD (P = 0.007), stenosis progression (P = 0.010), and symptomatic cerebral infarction or hemorrhage (P = 0.026). In Cox regression analysis the p.R4810K mutation remained a significant factor after adjusting for age group (childhood or adult onset) at diagnosis (hazard ratio, 8.42; 95% CI, 1.10-64.4). Hemisphere-based analysis also showed that the mutation was associated with a higher risk of progression to the MMD hemisphere (P = 0.002), stenosis progression (P = 0.005), and cerebral infarction or hemorrhage (P = 0.012). The RNF213 p.R4810K mutation was identified as a risk factor for progression from MCAD to MMD. Genotyping for this mutation may contribute to risk stratification in MCAD.

The use of reduced DOAC doses in atrial fibrillation patients does not always lead to good anticoagulation levels and avoid adverse events

BackgroundThe MAS study (Blood Advances 2024) showed that a high proportion of Italian AF patients treated with direct oral anticoagulants (DOACs) receive reduced doses. This sub-analysis of MAS data aimed to analyze the effects of reduced (appropriate or not)- or standard-dose use on DOAC activity assessed at baseline and the occurrence of thrombotic or bleeding complications during follow-up. MethodsThe MAS study design, the methods for DOAC measurement, the results, and the adverse events during follow-up, are described in detail elsewhere. ResultsSeven hundred AF patients (42 % of the total 1657) received a reduced dose (considered inappropriate in 140 [20 %]). They were older, more frequently women, with lower body mass index (BMI), hemoglobin levels, and creatinine clearance. They more often had cerebral or cardiovascular diseases, were taking more medications, with higher scores for thrombotic or bleeding risk. Despite the use of low doses, 133 (19.0 %) patients had high standardized C-trough DOAC levels and experienced a high proportion of bleeding events (8.3 % per year). Conversely, some patients (4.7 %) had very low levels, resulting in a high incidence of thrombotic events (6.7 % per year). No difference was detected if the reduced dose was appropriate or not. ConclusionThe unpredictable, highly variable inter-individual anticoagulant effect of DOACs may lead to either too low or too high anticoagulant levels, increasing the risk of thrombotic or bleeding events. This is particularly relevant for patients with high-risk conditions, such as those chosen for reduced-dose treatment. Further studies are needed to investigate this important clinical issue.

Study on the mechanism of ischemic stroke treatment based on network pharmacology and Raman spectroscopy in the larval zebrafish model, Calculus Bovis as a case

Calculus Bovis (C. bovis) is a precious traditional Chinese medicine of animal origin, and it is one of the traditional medicines for treating cerebral inflammatory diseases such as stroke. However, the pharmacological action of C. bovis on ischemic stroke (IS) and its mechanism are still unclear. The purpose of this study was to investigate the potential mechanism to treat IS. Chemical constituents of different varieties of C. bovis were analyzed and confirmed by HPLC-MS/MS technique. We constructed a component and corresponding target network and drug-disease target protein–protein interaction (PPI) network. GO and KEGG enrichment analysis were performed. The molecular docking of the main compound with the target protein. Subsequently, the potential mechanism of therapy for IS was verified in vivo by zebrafish model. We introduced Raman spectroscopy to detect changes in the biochemical composition of zebrafish. 13 active chemical constituents and 129 potential targets were selected. 122 KEGG signaling pathways were obtained. The binding energy of the main compounds is less than −4.5. The results of animal experiments showed that C. bovis could significantly improve Ponatinib-induced IS, decrease the aggregation degree of brain macrophages, reduce the number of macrophage migrations, and significantly increase the expression level of NR3C1. Raman information indicated that the biochemical composition in the brain of the Ponatinib-induced group shifted to the control group. The mechanism may be related to anti-inflammatory process and regulation of lipid metabolism. This study demonstrates that Raman spectroscopy has great potential as a drug evaluation tool in living larval zebrafish.

Biomimetic nanocomplexes orchestrate post-stroke cerebral microenvironment via microglia-targeted siRNA delivery

Modulating the inflammatory cerebral microenvironment via RNA interference holds great potentials for managing post-stroke ischemia-reperfusion (IR) injury. Herein, biomimetic nanocomplexes (NCs) cloaked with platelet-microglia hybrid membrane (HM) are developed to mediate microglia-targeted sphingosine kinase 1 siRNA (siSPHK-1) delivery against cerebral IR injury. The NCs consist of a cationic nano-core assembled from ROS-degradable, branched poly(β-amino ester) (BS) and siSPHK-1, and an outer shell of HM. After intravenous administration, the NCs accumulate at the lesion site due to platelet membrane (PM)-assisted microthrombus targeting, penetrate blood-brain barrier due to CD29-assisted transendothelial migration, and enter microglia via CD51/61-assisted homotypic targeting and CD29-assisted, receptor-mediated endocytosis. The over-produced ROS inside inflamed microglia triggers BS degradation and siSPHK-1 release, thereby provoking SPHK-1 silencing to remodel the inflammatory microenvironment, protect the neurovascular unit, and recover the cognitive/memory ability of IR-injured mice. This study reports a bio-inspired strategy to overcome the multiple physiological barriers against cerebral siRNA delivery, and renders promising implications for gene therapy against cerebral diseases.

Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion

A nine-year boy with adrenoleukodystrophy due to an ABCD1 whole gene deletion was diagnosed with the active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hemopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel, elivaldogene autotemcel) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient’s MRI showed gadolinium resolution; whole blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant showing reactivity to peroxisomes, suggesting an immune response, however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient’s whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

Cerebrovascular Involvement in Transthyretin Amyloid Cardiomyopathy.

Background: Intracardiac thrombosis is common in transthyretin amyloid cardiomyopathy (ATTR-CM), and patients are at risk for thromboembolic events. However, silent cerebral infarcts and the extent of cerebral small vessel disease in patients with cardiac amyloidosis are unknown. Methods: Thirty-two consecutively selected ATTR-CM patients were prospectively studied by cerebral magnetic resonance imaging (cMRI) and compared with 43 CHA2DS2-VASc-matched controls (Co). Structural clinical standard cMRI sequences and features of cerebral vessel involvement were included and quantified by two board certified neuroradiologists in consensus blinded to clinical status. Group differences were estimated using generalized (logistic) linear regression models adjusting for vascular risk factors based on the CHA2DS2-VASc score. Results: The median CHA2DS2-VASc score was 4 for ATTR-CM and Co (p = 0.905). There were no differences between groups in the frequency of current or former smokers (p = 0.755), body-mass-index > 30 (p = 0.106), and hyperlipidemia (p = 0.869). The number of territorial infarcts (4 vs. 0, p = 0.018) was higher in ATTR-CM compared to Co, as was the mean number of cerebral microbleeds (1.4 vs. 0.3, p ≤ 0.001) and the number of Virchow-Robin spaces (43.8 vs. 20.6, p ≤ 0.001). Lacunar lesion presence was higher in ATTR-CM (6 vs. 2, p = 0.054). CHA2DS2-VASc score, atrial fibrillation, anticoagulation, and the interaction term of CHA2DS2-VASc score and atrial fibrillation did not affect the probability of a territorial ischemic lesion or lacunar lesion in logistic regression modeling. Conclusions: In patients with ATTR-CM free from clinically apparent neurological symptoms, cMRI revealed unreported significant small cerebral vessel disease and territorial ischemia. Our findings may support low thresholds for anticoagulation and cMRI in patients with ATTR-CM.

Small vessel disease burden predicts incident stroke and all-cause death, but not acute coronary event.

Total small vessel disease (SVD) score is used to measure the burden of SVD by incorporating four established neuroimaging markers; white matter hyperintensity, lacune, cerebral microbleed, and enlarged perivascular space, ranging from 0 to 4. Whether total SVD scores predict all vascular outcomes remains unclear. This study aimed to clarify the predictive value of the total SVD score for incident stroke, mortality, and acute coronary syndrome in independent outpatients with vascular risk factors. We derived data from The Tokyo Women's Medical University Cerebrovascular Disease registry, a prospective observational registry in which 1011 patients with evidence of cerebral vessel disease on magnetic resonance imaging were enrolled. They were followed up until March 2023. The primary outcomes were stroke, all-cause death, and acute coronary syndrome (ACS). After excluding those with a modified Rankin scale score >1, Mini-mental State Examination score <24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, stroke, ACS, and all-cause death occurred in 52, 24, and 45 patients, respectively. In multivariate analysis, the total SVD score was independently associated with stroke, and all-cause death but not with acute coronary syndrome. Both cutoff values of the total SVD score for stroke, and all-cause death were 1. In conclusion, the total SVD score could predict stroke and mortality but not acute coronary syndrome. Our results suggest intensive management of patients with a total SVD score ≥1 to prevent stroke and all-cause death. Patients with higher total SVD scores were significantly more likely to have a stroke (A; P = 0.012) than those with lower total SVD scores. However, no association was observed between total SVD scores and acute coronary syndrome (B, P = 0.604). For incident stroke, total SVD scores of 1 and 2 were the cutoff levels.

Peptide Functionalization of Emulsion-Based Nanocarrier to Improve Uptake across Blood-Brain Barrier.

New strategies for enhancing drug delivery to the blood-brain barrier (BBB) represent a major challenge in treating cerebral diseases. Nanoemulsion-based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel-loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, a model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a 41.5% higher uptake of CRT functionalized nano-emulsion than the negative control, demonstrating the ability of this novel tool to be accumulated in brain endothelium tissue. Based upon these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.

Back to Bernoulli: a simple formula for trans-stenotic pressure gradients and retrospective estimation of flow rates in cerebral venous disease

BackgroundVenous sinus stenosis can be associated with cerebrovascular disorders. Understanding the role of blood flow disturbances in these disorders is often hampered by the lack of patient-specific flow rates. Our...

Apelin Receptor Homodimerisation Inhibits Hippocampal Neuronal Autophagy via G Protein-Dependent Signalling in Vascular Dementia.

Vascular dementia (VD), a progressive vascular cognitive impairment, is characterised by the presence of cerebral hypoperfusion, increased blood-brain barrier permeability, and white matter lesions. Although current treatment strategies primarily focus on risk factors such as hypertension, diabetes, and heart disease, efficient and targeted therapies are lacking and the underlying mechanisms of VD remain unclear. We previously discovered that Apelin receptors (APJ), which are G protein-coupled receptors (GPCRs), can homodimerize and generate signals that are distinct from those of APJ monomers in VD rats. Apelin-13 reduces the level of APJ homodimers and leads to the proliferation of endogenous neural stem cells in the hippocampal dentate gyrus area, suggesting that it has a neuroprotective role. In this study, we established a rat and cellular oxygen-glucose deprivation/reoxygenation VD model to investigate the impact of APJ homodimerisation on autophagy. We found that APJ homodimers protect against VD by inhibiting autophagy through the Gαq and PI3K/Akt/mTOR pathways upon Gαi signalling, both in vivo and in vitro. This discovery provides a promising therapeutic target for chronic cerebral ischaemia-reperfusion diseases and an experimental foundation for the development of drugs that target APJ homodimers.

CT histogram analysis to distinguish between acute intracerebral hemorrhage and cavernous hemangioma

Acute intracerebral hemorrhage (AICH) and cerebral cavernous hemangioma (CCM) are two common cerebral hemorrhage diseases with partially overlapping CT findings and clinical symptoms, making it hard to distinguish between them. The current study used histogram analysis based on CT images to differentiate between CCM and AICH and test its diagnosis performance. This retrospective study included 158 patients with CCM and 137 patients with AICH. The histograms of brain CT plain scan images of both groups were extracted using Python code and included 18 histogram parameters of the lesions. The most effective parameters were selected by univariate logistic regression analysis and Spearman correlation analysis and included in the final multivariate logistic regression model. The sample was randomly divided into the training set and the validation set by 7:3. The ROC curve was constructed to evaluate the discriminant efficiency of the final logistic regression model in distinguishing between AICH and CCM. The univariate analysis identified seven significant histogram parameters with the following final logistic regression model: F=3.731+2.6411×10-9×Energy-1.192×Kurtosis-0.003×Minimum-1.449×Skewness + 2.5002×10-10×Total Energy-1.103×Uniformity+0.009×Variance. The model showed good diagnostic performance in distinguishing between AICH and CCM, with an AUC of 0.876, sensitivity of 70.8%, and specificity of 91.9% in the training set, and an AUC of 0.870, sensitivity of 82.9%, and specificity of 85.1% in the validation set. The histogram analysis of brain CT images can be used as an auxiliary method to distinguish between AICH and CCM effectively.

COVID-19-associated rhino-orbito-cerebral mucormycosis: a single center prospective study of 264 patients

ABSTRACT Purpose Outbreaks of mucormycosis were reported worldwide throughout the COVID-19 pandemic. We report clinical outcomes of a treatment protocol for COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM). Methods Patients with biopsy-proven mucormycosis and COVID-19 were included. All received intravenous amphotericin B deoxycholate 1 mg/kg and surgical endoscopic sinus debridement (FESS). Those with rhino-orbital or cerebral disease limited to the cavernous sinus were eligible for transcutaneous retrobulbar amphotericin B (TRAMB). Patients were followed with weekly imaging, endoscopic examinations, and serial debridement as necessary. Patients were discharged on oral posaconazole for 6 months. Results In total, 264 patients were followed for a mean of 2.5 months. On presentation, 163 patients (174 eyes) had eye involvement. Of these, 141 eyes (81.0%) had light perception or worse vision. By the last follow-up, 163 patients (176 eyes) were affected, and of these, 96 eyes (54.5%) had no light perception. Twenty-one patients (8%) died and 3 orbits (0.5%) were exenterated. There was no change in mortality (p = 0.38) or exenteration (p = 0.38) in the 55 patients who received TRAMB compared to patients with rhino-orbital or cerebral disease limited to the cavernous sinus who did not. Asymptomatic COVID-19 was associated with higher mortality than symptomatic COVID-19 (p = 0.025). Uncontrolled diabetes was a risk factor for death (p = 0.022). New diabetes was associated with increased mortality versus pre-existing diabetes (p = 0.005). Conclusion A multidisciplinary approach is crucial to manage COVID-19-ROCM. In our cohort, TRAMB therapy did not increase mortality or exenteration rates. While poor vision on presentation was profound, some vision recovery was noted with treatment. COVID-19 immune dysregulation may predispose patients to ROCM, particularly those with asymptomatic disease.

Single-centre real-life observational study on mortality and outcomes: decompressive craniectomy and brain death in traumatic brain injury, haemorrhage, and other cerebral diseases

BackgroundDecompressive hemicraniectomy (DHC) is used after severe brain damages with elevated, refractory intracranial pressure (ICP). In a non age-restricted population, mortality rates and long-term outcomes following DHC are still unclear. This study’s objectives were to examine both, as well as to identify predictors of unfavourable outcomes.MethodsWe undertook a retrospective observational analysis of patients aged 18 years and older who underwent DHC at the University Hospital of Bonn between 2018 and 2020, due to traumatic brain injury (TBI), haemorrhage, tumours or infections. Patient outcomes were assessed by conducting telephone interviews, utilising questionnaires for modified Rankin Scale (mRS) and extended Glasgow Outcome scale (GOSE). We evaluated the health-related quality of life using the EuroQol (EQ-5D-5L) scale.ResultsA total of 144 patients with a median age of 58.5 years (range: 18 to 85 years) were evaluated. The mortality rate was 67%, with patients passing away at a median of 6.0 days (IQR [1.9–37.6]) after DHC. Favourable outcomes, as assessed by the mRS and GOSE were observed in 10.4% and 6.3% of patients, respectively. Cox regression analysis revealed a 2.0% increase in the mortality risk for every year of age (HR = 1.017; 95% CI [1.01–1.03]; p = 0.004). Uni- and bilateral fixed pupils were associated with a 1.72 (95% CI [1.03–2.87]; p = 0.037) and 3.97 (95% CI [2.44–6.46]; p < 0.001) times higher mortality risk, respectively. ROC-analysis demonstrated that age and pupillary reactivity predicted 6-month mortality with an AUC of 0.77 (95% CI [0.69–0.84]). The only parameter significantly associated with a better quality of life was younger age.ConclusionsFollowing DHC, mortality remains substantial, and favourable outcomes occur rarely. Particularly in elderly patients and in the presence of clinical signs of herniation, mortality rates are notably elevated. Hence, the indication for DHC should be set critically.

Small-Vessel Disease and Intracranial Large Artery Disease in Brain MRI Predict Dementia and Acute Coronary Syndrome, Respectively: A Prospective, Observational Study in the Population at High Vascular Risk.

We aimed to clarify the predictive value of cerebral small-vessel disease and intracranial large artery disease (LAD) observed in magnetic resonance imaging of the brain and magnetic resonance angiography on future vascular events and cognitive impairment. Data were derived from a Japanese cohort with evidence of cerebral vessel disease on magnetic resonance imaging. This study included 862 participants who underwent magnetic resonance angiography after excluding patients with a modified Rankin Scale score >1 and Mini-Mental State Examination score <24. We evaluated small-vessel disease such as white matter hyperintensities and lacunes in magnetic resonance imaging and LAD with magnetic resonance angiography. Outcomes were incident stroke, dementia, acute coronary syndrome,and all-cause death. Over a median follow-up period of 4.5 years, 54 incident stroke, 39 cases of dementia, and 27 cases of acute coronary syndrome were documented. Both small-vessel disease (white matter hyperintensities and lacunes) and LAD were associated with stroke; however, only white matter hyperintensities were related to dementia. In contrast, only LAD was associated with acute coronary syndrome. Among the 357 patients with no prior history of stroke, coronary or peripheral artery disease, or atrial fibrillation, white matter hyperintensities emerged as the sole predictor of future stroke and dementia, while LAD was the sole predictor of acute coronary syndrome. Among cerebral vessels, small-vessel disease could underlie the cognitive impairment while LAD was associated with coronary artery disease as atherosclerotic vessel disease.

Comparative clinical study of attenuation of hemodynamic response to laryngoscopy and endotracheal intubation using clinical assessment guidance versus neuromuscular block monitoring guidance

Background: The hemodynamic response to the stress of laryngoscopy and endotracheal intubation does not present a problem for most patients, except in cardiovascular or cerebral disease. Various anesthetic techniques and drugs are available to control the hemodynamic response to laryngoscopy and intubation. However administration of an additional drug may adversely affect hemodynamics of the patient or unnecessarily increase the depth of anesthesia. Hence a non pharmacological measure to reduce response is preferred. The purpose of this study was to compare the hemodynamic response during laryngoscopy and intubation when choice of the moment of intubation is directed by either clinical assessment and neuromuscular monitoring with train of four. Methods: A total of 60 patients were randomised into two groups. In Group M endotracheal intubation was done after train of four count became zero in adductor pollicis muscle. In Group C timing of intubation was determined clinically by assessment of jaw muscle relaxation. Changes in heart rate (HR), systolic BP (SBP), diasolic BP (DBP), mean arterial pressure (MAP), time between the administration of neuromuscular blocking agent and endotracheal intubation was recorded. Results were analysed by the analysis of variance and chi square test. Results: Heart rate, SBP, DBP and mean arterial pressure were significantly higher in Group C as compared to Group M after laryngoscopy and endotracheal intubation (P&lt;0.05). The mean time required for onset of intubation was significantly shorter in Group C compared to Group M. Conclusion: The objective assessment of neuromuscular relaxation prior to endotracheal intubation provides better attenuation of hemodynamic responses. Keywords: hemodynamic response; laryngoscopy; endotracheal intubation; neuromuscular block

Recent advances of MRI in diagnosis of cerebral atherosclerotic disease

Recent advances of MRI in diagnosis of cerebral atherosclerotic disease

Type-I-interferon-responsive microglia: participates in cerebral development and disease.

Type-I-interferon-responsive microglia: participates in cerebral development and disease.

The Human Developing Cerebral Cortex Is Characterized by an Elevated De Novo Expression of Long Noncoding RNAs in Excitatory Neurons.

The outstanding human cognitive capacities are computed in the cerebral cortex, a mammalian-specific brain region and the place of massive biological innovation. Long noncoding RNAs have emerged as gene regulatory elements with higher evolutionary turnover than mRNAs. The many long noncoding RNAs identified in neural tissues make them candidates for molecular sources of cerebral cortex evolution and disease. Here, we characterized the genomic and cellular shifts that occurred during the evolution of the long noncoding RNA repertoire expressed in the developing cerebral cortex and explored putative roles for these long noncoding RNAs in the evolution of the human brain. Using transcriptomics and comparative genomics, we comprehensively annotated the cortical transcriptomes of humans, rhesus macaques, mice, and chickens and classified human cortical long noncoding RNAs into evolutionary groups as a function of their predicted minimal ages. Long noncoding RNA evolutionary groups showed differences in expression levels, splicing efficiencies, transposable element contents, genomic distributions, and transcription factor binding to their promoters. Furthermore, older long noncoding RNAs showed preferential expression in germinative zones, outer radial glial cells, and cortical inhibitory (GABAergic) neurons. In comparison, younger long noncoding RNAs showed preferential expression in cortical excitatory (glutamatergic) neurons, were enriched in primate and human-specific gene co-expression modules, and were dysregulated in neurodevelopmental disorders. These results suggest different evolutionary routes for older and younger cortical long noncoding RNAs, highlighting old long noncoding RNAs as a possible source of molecular evolution of conserved developmental programs; conversely, we propose that the de novo expression of primate- and human-specific young long noncoding RNAs is a putative source of molecular evolution and dysfunction of cortical excitatory neurons, warranting further investigation.

Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study

Sex differences in cardiovascular disease (CVD) are well-established, but whether chronic kidney disease (CKD) modifies these risk differences, and whether they differ between atheromatous (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study. Prospective cohort study. Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France. Sex. Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic stroke, and arrhythmias). Multivariable cause-specific Cox proportional hazards models. 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m2) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m2. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied. Cardiovascular biomarkers and sex hormones were not assessed. This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.