Peripheral Blood Gene Expression Profiling Reveals Molecular Pathways Associated with Cervical Artery Dissection.

Cervical artery dissection (CeAD) is the primary cause of ischemic stroke in young adults. Monogenic heritable connective tissue diseases account for fewer than 5% of cases of CeAD. The remaining sporadic cases have known risk factors. The clinical, radiological, and histological characteristics of systemic vasculopathy and undifferentiated connective tissue dysplasia are present in up to 70% of individuals with sporadic CeAD. Genome-wide association studies identified CeAD-associated genetic variants in the non-coding genomic regions that may impact the gene transcription and RNA processing. However, global gene expression profile analysis has not yet been carried out for CeAD patients. We conducted bulk RNA sequencing and differential gene expression analysis to investigate the expression profile of protein-coding genes in the peripheral blood of 19 CeAD patients and 18 healthy volunteers. This was followed by functional annotation, heatmap clustering, reports on gene-disease associations and protein-protein interactions, as well as gene set enrichment analysis. We found potential correlations between CeAD and the dysregulation of genes linked to nucleolar stress, senescence-associated secretory phenotype, mitochondrial malfunction, and epithelial-mesenchymal plasticity.

Age-related changes of interoceptive brain networks: Implications for interoception and alexithymia.

Aging is known to be associated with a decline in interoceptive abilities and changes in emotional processing, including alexithymia. As the brain areas supporting interoceptive awareness participate in the perception of emotion, we suggested that interoceptive decline and alexithymia in older adults may share common neural ground. To test this hypothesis, we administered functional magnetic resonance imaging-based heartbeat detection task to 62 adults of diverse ages (range 18-73) and evaluated a larger sample of older and younger adults using questionnaires characterizing interoceptive sensibility, alexithymia, and depressive attitudes. We found that increasing age was linked to decreased activation during the interoceptive task, including the right insular-opercular and supplementary motor areas (SMAs). Age also affected task-based functional connectivity, with two major effects being a decrease in the connectivity of the SMA-insular network and an increase in the connectivity of the prefrontal-lateral occipital network. Path analysis performed for interoceptive accuracy as the endogenous variable revealed that the impact of age was mediated by the functional activation of the insular cortex and SMA and by the connectivity between these areas. Another path analysis using alexithymia as the endogenous variable while controlling for depressive attitudes showed that the effect of age was mediated by interoceptive decline. The study supports the role of central mechanisms in age-related interoceptive decline and shows its implications for alexithymia. Since alexithymia represents a risk factor for mental and cardiovascular diseases, the study findings may open an important direction toward maintaining older adults' well-being. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

L-Arginine-eNOS-NO Functional System in Brain Damage and Cognitive Impairments in Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) is a significant cause of cognitive impairment (CI), disability, and mortality. The insufficient effectiveness of antihypertensive therapy in curbing the disease justifies the search for potential targets for modifying therapy and indicators supporting its use. Using a laser-assisted optical rotational cell analyzer (LORRCA, Mechatronics, The Netherlands), the rheological properties and deformability of erythrocytes before and after incubation with 10 µmol/L of L-arginine, the nitric oxide (NO) donor, blood-brain barrier (BBB) permeability assessed by dynamic contrast-enhanced MRI, clinical, and MRI signs were studied in 73 patients with CSVD (48 women, mean age 60.1 ± 6.5 years). The control group consisted of 19 volunteers (14 women (73.7%), mean age 56.9 ± 6.4 years). The erythrocyte disaggregation rate (y-dis) after incubation with L-arginine showed better performance than other rheological characteristics in differentiating patients with reduced NO bioavailability/NO deficiency by its threshold values. Patients with y-dis > 113 s-1 had more severe CI, arterial hypertension, white matter lesions, and increased BBB permeability in grey matter and normal-appearing white matter (NAWM). A test to assess changes in the erythrocyte disaggregation rate after incubation with L-arginine can be used to identify patients with impaired NO bioavailability. L-arginine may be part of a therapeutic strategy for CSVD with CI.

Enhancing Brain Connectivity With Infra-Low Frequency Neurofeedback During Aging: A Pilot Study.

Aging is associated with decreased functional connectivity in the main brain networks, which can underlie changes in cognitive and emotional processing. Neurofeedback is a promising non-pharmacological approach for the enhancement of brain connectivity. Previously, we showed that a single session of infra-low frequency neurofeedback results in increased connectivity between sensory processing networks in healthy young adults. In the current pilot study, we aimed to evaluate the possibility of enhancing brain connectivity during aging with the use of infra-low frequency neurofeedback. Nine females aged 52 ± 7 years with subclinical signs of emotional dysregulation, including anxiety, mild depression, and somatoform symptoms, underwent 15 sessions of training. A resting-state functional MRI scan was acquired before and after the training. A hypothesis-free intrinsic connectivity analysis showed increased connectivity in regions in the bilateral temporal fusiform cortex, right supplementary motor area, left amygdala, left temporal pole, and cerebellum. Next, a seed-to-voxel analysis for the revealed regions was performed using the post- vs. pre-neurofeedback contrast. Finally, to explore the whole network of neurofeedback-related connectivity changes, the regions revealed by the intrinsic connectivity and seed-to-voxel analyses were entered into a network-based statistical analysis. An extended network was revealed, including the temporal and occipital fusiform cortex, multiple areas from the visual cortex, the right posterior superior temporal sulcus, the amygdala, the temporal poles, the superior parietal lobule, and the supplementary motor cortex. Clinically, decreases in alexithymia, depression, and anxiety levels were observed. Thus, infra-low frequency neurofeedback appears to be a promising method for enhancing brain connectivity during aging, and subsequent sham-controlled studies utilizing larger samples are feasible.

Interoception during aging: Functional neuroimaging data from a heartbeat detection task.

Interoception is critically important for allostatic adaptation and emotional regulation, and aberrant interoceptive processing is increasingly recognized to be involved in the pathogenesis of neurological, psychiatric and cardiovascular diseases. Despite the fact that interoceptive abilities decline with age, the corresponding neural correlates and clinical consequences of these age-related changes have yet to be discovered. We present a dataset that contains task-based functional neuroimaging data from 50 adults aged 40-65 years and 12 adults aged 18-25 years who performed an fMRI-based heartbeat-detection task. Of the 62, 38 participants also took part in a rubber hand illusion experiment outside the scanner. While the dataset was mainly created to study age-related changes in interoception, it can also be used in body perception research in general. The provided group data may serve as a reference for clinical studies on interoception involving older adults.

Sensory integration in interoception: Interplay between top-down and bottom-up processing.

Although the neural systems supporting interoception have been outlined in general, the exact processes underlying the integration of visceral signals still await research. Based on the predictive coding concept, we aimed to reveal the neural networks responsible for the bottom-up (stimulus-dependent) and top-down (model-dependent) processing of interoceptive information. In a study of 30 female participants, we utilized two classical body perception experiments-the rubber hand illusion and a heartbeat detection task (cardioception), with the latter being implemented in fMRI settings. We interpreted a stronger rubber hand illusion, as measured by higher proprioceptive drift, as a tendency to rely on actual sensory experience, i.e., bottom-up processing, while lower proprioceptive drift served as an indicator of the prevalence of top-down, model-based influences. To reveal the bottom-up and top-down processes in cardioception, we performed a seed-based connectivity analysis of the heartbeat detection task, using as seeds the areas with known roles in sensory integration and entering proprioceptive drift as a covariate. The results revealed a left thalamus-dependent network positively associated with proprioceptive drift (bottom-up processing) and a left amygdala-dependent network negatively associated with drift (top-down processing). Bottom-up processing was related to thalamic connectivity with the left frontal operculum and anterior insula, anterior cingulate cortex, hypothalamus, right planum polare and right inferior frontal gyrus. Top-down processing was related to amygdalar connectivity with the rostral prefrontal cortex and an area involving the left frontal opercular and anterior insular cortex, with the latter area being an intersection of the two networks. Thus, we revealed the neural mechanisms underlying the integration of interoceptive information through the interaction between the current sensory experience and internal models.

Anti-NR2 glutamate receptor antibodies as an early biomarker of cerebral small vessel disease.

OBJECTIVES: Cerebral small vessel disease (SVD) associated with age and vascular risk factors is one of the leading causes of cognitive disorders as well as ischemic and hemorrhagic strokes. The pathogenesis of this disease has not been fully understood yet. The previously established association of the antibodies against the NR2 subunit of the NMDA receptor (NR2ab) with the mechanisms of SVD such as ischemia and blood-brain barrier (BBB) disruption, might suggest their importance in the brain damage. DESIGN & METHODS: We studied the NR2ab serum level in 70 patients (45 females, 61.1 ± 6.3 y.o.) with different severity of cognitive impairment and MRI features of SVD and 20 healthy volunteers (12 females, 58.5 ± 6.4 y.o.). RESULTS: The elevated level of NR2ab was associated with subjective cognitive impairment (SCI) (p = 0.028) and mild cognitive impairment (MCI) (p = 0.017), Fazekas grade (F) 2 (p = 0,002) and F3 (p = 0,009) of white matter hyperintensities (WMH) and the numbers of lacunes in the cerebral white matter (less than 5) (p = 0,039). CONCLUSION: The detected increase in serum NR2ab level in patients with SCI, as well as the minimal amount of white matter lacunes, is most likely caused by hypoxia-induced endothelial damage in the early stage of SVD. Normal NR2ab values in patients with F1 WMH, the increased NR2ab level in patients with F2 and F3 WMH and those with the minimal number of lacunes can indicate that NR2bs are involved in diffuse brain damage due to hypoxia-induced loss of BBB integrity.

Mapping of multiple muscles with transcranial magnetic stimulation: absolute and relative test-retest reliability.

The spatial accuracy of transcranial magnetic stimulation (TMS) may be as small as a few millimeters. Despite such great potential, navigated TMS (nTMS) mapping is still underused for the assessment of motor plasticity, particularly in clinical settings. Here, we investigate the within-limb somatotopy gradient as well as absolute and relative reliability of three hand muscle cortical representations (MCRs) using a comprehensive grid-based sulcus-informed nTMS motor mapping. We enrolled 22 young healthy male volunteers. Two nTMS mapping sessions were separated by 5-10 days. Motor evoked potentials were obtained from abductor pollicis brevis (APB), abductor digiti minimi, and extensor digitorum communis. In addition to individual MRI-based analysis, we studied normalized MNI MCRs. For the reliability assessment, we calculated intraclass correlation and the smallest detectable change. Our results revealed a somatotopy gradient reflected by APB MCR having the most lateral location. Reliability analysis showed that the commonly used metrics of MCRs, such as areas, volumes, centers of gravity (COGs), and hotspots had a high relative and low absolute reliability for all three muscles. For within-limb TMS somatotopy, the most common metrics such as the shifts between MCR COGs and hotspots had poor relative reliability. However, overlaps between different muscle MCRs were highly reliable. We, thus, provide novel evidence that inter-muscle MCR interaction can be reliably traced using MCR overlaps while shifts between the COGs and hotspots of different MCRs are not suitable for this purpose. Our results have implications for the interpretation of nTMS motor mapping results in healthy subjects and patients with neurological conditions.

Multimodal Assessment of the Motor System in Patients With Chronic Ischemic Stroke.

BACKGROUND AND PURPOSE: Despite continuing efforts in the multimodal assessment of the motor system after stroke, conclusive findings on the complementarity of functional and structural metrics of the ipsilesional corticospinal tract integrity and the role of the contralesional hemisphere are still lacking. This research aimed to find the best combination of motor system metrics, allowing the classification of patients into 3 predefined groups of upper limb motor recovery. METHODS: We enrolled 35 chronic ischemic stroke patients (mean 47 [26-66] years old, 29 [6-58] months poststroke) with a single supratentorial lesion and unilateral upper extremity weakness. Patients were divided into 3 groups, depending on upper limb motor recovery: good, moderate, and bad. Nonparametric statistical tests and regression analysis were used to investigate the relationships among microstructural (fractional anisotropy (FA) ratio of the corticospinal tracts at the internal capsule (IC) level (classic method) and along the length of the tracts (Fréchet distance), and of the corpus callosum) and functional (motor evoked potentials [MEPs] for 2 hand muscles) motor system metrics. Stratification rules were also tested using a decision tree classifier. RESULTS: IC FA ratio in the IC and MEP absence were both equally discriminative of the bad motor outcome (96% accuracy). For the 3 recovery groups' classification, the best parameter combination was IC FA ratio and the Fréchet distance between the contralesional and ipsilesional corticospinal tract FA profiles (91% accuracy). No other metrics had any additional value for patients' classification. MEP presence differed for 2 investigated muscles. CONCLUSIONS: This study demonstrates that better separation between 3 motor recovery groups may be achieved when considering the similarity between corticospinal tract FA profiles along its length in addition to region of interest-based assessment and lesion load calculation. Additionally, IC FA ratio and MEP absence are equally important markers for poor recovery, while for MEP probing it may be important to investigate more than one hand muscle.

Microstructural Predictors of Cognitive Impairment in Cerebral Small Vessel Disease and the Conditions of Their Formation.

INTRODUCTION: Cerebral small vessel disease (CSVD) is the leading cause of vascular and mixed degenerative cognitive impairment (CI). The variability in the rate of progression of CSVD justifies the search for sensitive predictors of CI. MATERIALS: A total of 74 patients (48 women, average age 60.6 ± 6.9 years) with CSVD and CI of varying severity were examined using 3T MRI. The results of diffusion tensor imaging with a region of interest (ROI) analysis were used to construct a predictive model of CI using binary logistic regression, while phase-contrast magnetic resonance imaging and voxel-based morphometry were used to clarify the conditions for the formation of CI predictors. RESULTS: According to the constructed model, the predictors of CI are axial diffusivity (AD) of the posterior frontal periventricular normal-appearing white matter (pvNAWM), right middle cingulum bundle (CB), and mid-posterior corpus callosum (CC). These predictors showed a significant correlation with the volume of white matter hyperintensity; arterial and venous blood flow, pulsatility index, and aqueduct cerebrospinal fluid (CSF) flow; and surface area of the aqueduct, volume of the lateral ventricles and CSF, and gray matter volume. CONCLUSION: Disturbances in the AD of pvNAWM, CB, and CC, associated with axonal damage, are a predominant factor in the development of CI in CSVD. The relationship between AD predictors and both blood flow and CSF flow indicates a disturbance in their relationship, while their location near the floor of the lateral ventricle and their link with indicators of internal atrophy, CSF volume, and aqueduct CSF flow suggest the importance of transependymal CSF transudation when these regions are damaged.

MRI Types of Cerebral Small Vessel Disease and Circulating Markers of Vascular Wall Damage.

The evaluation of the clustering of magnetic resonance imaging (MRI) signs into MRI types and their relationship with circulating markers of vascular wall damage were performed in 96 patients with cerebral small vessel disease (cSVD) (31 men and 65 women; mean age, 60.91 ± 6.57 years). The serum concentrations of the tumor necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1), vascular endothelial growth factor-A (VEGF-A), and hypoxia-inducible factor 1-α (HIF-1α) were investigated in 70 patients with Fazekas stages 2 and 3 of white matter hyperintensities (WMH) and 21 age- and sex-matched volunteers with normal brain MRI using ELISA. The cluster analysis excluded two patients from the further analysis due to restrictions in their scanning protocol. MRI signs of 94 patients were distributed into two clusters. In the first group there were 18 patients with Fazekas 3 stage WMH. The second group consisted of 76 patients with WMH of different stages. The uneven distribution of patients between clusters limited the subsequent steps of statistical analysis; therefore, a cluster comparison was performed in patients with Fazekas stage 3 WMH, designated as MRI type 1 and type 2 of Fazekas 3 stage. There were no differences in age, sex, degree of hypertension, or other risk factors. MRI type 1 had significantly more widespread WMH, lacunes in many areas, microbleeds, atrophy, severe cognitive and gait impairments, and was associated with downregulation of VEGF-A compared with MRI type 2. MRI type 2 had more severe deep WMH, lacunes in the white matter, no microbleeds or atrophy, and less severe clinical manifestations and was associated with upregulation of TNF-α compared with MRI type 1. The established differences reflect the pathogenetic heterogeneity of cSVD and explain the variations in the clinical manifestations observed in Fazekas stage 3 of this disease.

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease.

Increased salt intake in food probably affects the progression of cerebral small vessel disease (CSVD), which justifies the study of disturbances in sodium homeostasis associated with the development of CSVD. We aimed to clarify the role of salt sensitivity and osmotic fragility in the development of CSVD. Erythrocyte salt sensitivity was measured using the modified salt blood test, and osmotic fragility was measured using the classic osmotic fragility test in 73 patients with CSVD (48 women; 60.1 ± 6.5 years) and 19 healthy volunteers (14 women; 56.9 ± 6.4 years). Salt sensitivity and osmotic fragility exhibited a predictive value in relation to CSVD. These parameters were associated with an increase in white matter hyperintensities (P = 0.019 and 0.004, respectively). Their simultaneous use increased their predictive ability for CSVD (P < 0.000001; AUC (95% CI), 0.824 (0.724-0.923)). The possibility of predicting CSVD using erythrocyte salt sensitivity and osmotic fragility indicates the value of the individual glycocalyx buffer capacity in relation to sodium and the activity of sodium channels in the development of CSVD. Increased salt sensitivity and osmotic fragility seem to be risk factors for CSVD.

The ability to understand emotions is associated with interoception-related insular activation and white matter integrity during aging.

Cerebral small vessel disease (SVD) is a major cause of cognitive impairment in elderly people. While most research focuses on the role of the classical vascular risk factors in SVD, a description of the psychophysiological mechanisms leading to the age-related brain damage may open new possibilities for prophylaxis. In the current study, we evaluated the associations between emotional abilities, interoception, and age-related vascular white matter degeneration. The work was influenced, first, by multiple studies recognizing alexithymia as a cardiovascular risk factor; second, by theories of emotions linking body's allostasis and emotional regulation; and third, by neuroimaging data highlighting the shared role of the insular cortex in interoceptive and emotional processing. In a sample of older female adults (N = 30), we performed the Mayer-Salovey-Caruso Emotional Intelligence Test, functional MRI using the heartbeat detection task, and evaluation of white matter microstructural integrity using diffusion weighted imaging. The ability to understand and analyze emotions-one of the four components of emotional intelligence-was found to be associated with higher interoception-related activation of the right anterior insula and preserved white matter microstructure. We interpret these results in light of the concept of Embodied Predictive Interoception Coding, which proposes that emotional processing, interoception, and allostasis (antecedent top-down regulation of the body's internal milieu) may rely on the shared neural mechanisms of predictive coding. The study demonstrates feasibility of the investigation of cerebrovascular diseases form a psychophysiological perspective and calls for future research.

Tissue Plasminogen Activator and MRI Signs of Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is one of the leading causes of cognitive impairment and stroke. The importance of endothelial dysfunction and high blood-brain barrier (BBB) permeability in pathogenesis, together with ischemia, is under discussion. The aim of this study was to clarify the relationship between tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), and magnetic resonance imaging (MRI) signs of SVD. We examined 71 patients (23 men and 48 women; mean age: 60.5 ± 6.9 years) with clinical and MRI signs of SVD, and 21 healthy volunteers with normal MRIs. All subjects underwent 3T MRI and measurements of t-PA and PAI-1 levels. An increase in t-PA level is correlated with the volume of white matter hyperintensities (WMH) (R = 0.289, p = 0.034), severity on the Fazekas scale (p = 0.000), and with the size of subcortical (p = 0.002) and semiovale (p = 0.008) perivascular spaces. The PAI-1 level is not correlated with the t-PA level or MRI signs of SVD. The correlation between t-PA and the degree of WMH and perivascular spaces' enlargement, without a correlation with PAI-1 and lacunes, is consistent with the importance of t-PA in BBB disruption and its role in causing brain damage in SVD.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.