Cortical Markers Research Articles

Integrity of central nervous autonomous tracts is associated with cardiac function, cardiovascular risk factors, organ damage and major adverse cardiovascular events

Abstract Background Alterations in the central autonomic nervous system have been linked to the pathogenesis of cardiovascular (CV) risk and disease. Moreover, these conditions are treatable by pharmacological or interventional modification of the activity of the autonomic nervous system. Purpose The UK Biobank enables the investigation of the relationship between changes in the CAN and CV function or disease within a large population. Microstructural integrity of the CAN was assessed for associations with cardiac function, CV risk and damage representations, and major adverse cardiovascular events (MACE). Method Microstructural diffusion metrics for 7 CAN tracts were estimated using a Bayesian approach, which determines the three components of a standard white matter-based tissue model: 1. the free water fraction (CSF); 2. the fraction within neuronal processes, i.e. axons and dendrites (INTRA); and 3. the fraction outside of axons or dendrites (EXTRA), representing the cellular compartment and the extracellular matrix. Volume fractions of the three microstructural components were analysed for associations with cardiac index, blood pressure, CV target organ damage (arterial stiffness, left ventricular mass, and wall thickness), and MACE, using covariate-adjusted regression models that corrected for multiple comparisons. Results Analysis of cardiac function in 26,302 participants revealed significant associations between cardiac index and CAN regions in the cortical and subcortical networks. Arterial stiffness was significantly associated with markers of microstructural integrity in the cortical networks only (n=22,491), while systolic (n=34,114) and diastolic blood pressure (n=34,130), left ventricular mass (n=22,491) and wall thickness (n=22,491) showed extensive associations with the cortical and subcortical CAN. MACE (n=33,444) was associated with cortical markers of microstructural integrity of the CAN in limbic pathways (significant CANs all p<0.002) and the CAN pathways connecting cortical areas (significant CANs left all <0.001, right=0.001). The observed pattern of microstructural metrics suggests that the integrity of neural connections (intra-fraction) positively correlates with adverse outcomes, while an increase in free fluid (CSF) volume was typically associated with a negative impact. Conclusion In this analysis, markers of CAN integrity and degradation showed extensive associations with indicators of CV function, risk factors, damage parameters, and outcomes. This evidence supports the crucial role of autonomic regulation in cardiovascular disease. Future research is needed to determine whether these associations indicate harmful processes, such as neuroinflammation, contributing to cardiovascular (CV) risk and disease development, or if they are consequences of pre-existing elevated risk factors or events.CANs associated with MACEAssociations of CAN with CV organ damage

Superior temporal sulcus folding, functional network connectivity, and autistic-like traits in a non-clinical population.

Autistic-like traits (ALT) are prevalent across the general population and might be linked to some facets of a broader autism spectrum disorder (ASD) phenotype. Recent studies suggest an association of these traits with both genetic and brain structural markers in non-autistic individuals, showing similar spatial location of findings observed in ASD and thus suggesting a potential neurobiological continuum. In this study, we first tested an association of ALTs (assessed with the AQ questionnaire) with cortical complexity, a cortical surface marker of early neurodevelopment, and then the association with disrupted functional connectivity. We analysed structural T1-weighted and resting-state functional MRI scans in 250 psychiatrically healthy individuals without a history of early developmental disorders, in a first step using the CAT12 toolbox for cortical complexity analysis and in a second step we used regional cortical complexity findings to apply the CONN toolbox for seed-based functional connectivity analysis. Our findings show a significant negative correlation of both AQ total and AQ attention switching subscores with left superior temporal sulcus (STS) cortical folding complexity, with the former being significantly correlated with STS to left lateral occipital cortex connectivity, while the latter showed significant positive correlation of STS to left inferior/middle frontal gyrus connectivity (n = 233; all p < 0.05, FWE cluster-level corrected). Additional analyses also revealed a significant correlation of AQ attention to detail subscores with STS to left lateral occipital cortex connectivity. Phenotyping might affect association results (e.g. choice of inventories); in addition, our study was limited to subclinical expressions of autistic-like traits. Our findings provide further evidence for biological correlates of ALT even in the absence of clinical ASD, while establishing a link between structural variation of early developmental origin and functional connectivity.

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer’s disease

Abstract Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer’s disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved. First, past research has not clearly distinguished between two scenarios: hub regions facing a higher risk of connectivity disruption (targeted attack) and all regions having an equal risk (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We refined the hub disruption index to demonstrate a hub disruption pattern in functional connectivity in autosomal dominant AD that aligned with targeted attacks. This hub disruption is detectable even in preclinical stages 12 years before the expected symptom onset and is amplified alongside symptomatic progression. Moreover, hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in amyloid-beta positron emission tomography cortical markers, consistent with the activity-dependent degeneration explanation. Taken together, our findings deepened the understanding of brain network organization in neurodegenerative diseases and could be instrumental in refining diagnostic and targeted therapeutic strategies for AD in the future.

Schizophrenia-Like Deficits and Impaired Glutamate/Gamma-aminobutyric acid Homeostasis in Zfp804a Conditional Knockout Mice.

Zinc finger protein 804A (ZNF804A) was the first genome-wide associated susceptibility gene for schizophrenia (SCZ) and played an essential role in the pathophysiology of SCZ by influencing neurodevelopment regulation, neurite outgrowth, synaptic plasticity, and RNA translational control; however, the exact molecular mechanism remains unclear. A nervous-system-specific Zfp804a (ZNF804A murine gene) conditional knockout (cKO) mouse model was generated using clustered regularly interspaced short palindromic repeat/Cas9 technology and the Cre/loxP method. Multiple and complex SCZ-like behaviors, such as anxiety, depression, and impaired cognition, were observed in Zfp804a cKO mice. Molecular biological methods and targeted metabolomics assay validated that Zfp804a cKO mice displayed altered SATB2 (a cortical superficial neuron marker) expression in the cortex; aberrant NeuN, cleaved caspase 3, and DLG4 (markers of mature neurons, apoptosis, and postsynapse, respectively) expressions in the hippocampus and a loss of glutamate (Glu)/γ-aminobutyric acid (GABA) homeostasis with abnormal GAD67 (Gad1) expression in the hippocampus. Clozapine partly ameliorated some SCZ-like behaviors, reversed the disequilibrium of the Glu/GABA ratio, and recovered the expression of GAD67 in cKO mice. Zfp804a cKO mice reproducing SCZ-like pathological and behavioral phenotypes were successfully developed. A novel mechanism was determined in which Zfp804a caused Glu/GABA imbalance and reduced GAD67 expression, which was partly recovered by clozapine treatment. These findings underscore the role of altered gene expression in understanding the pathogenesis of SCZ and provide a reliable SCZ model for future therapeutic interventions and biomarker discovery.

Electrophysiological auditory measures to identify potential cortical markers of tinnitus

Tinnitus, or the perception of a sound in the absence of an external acoustic stimulus, is a common condition that cannot yet be objectively diagnosed. Current diagnostic tests of tinnitus consist of case history and behavioral measures that rely on subjective responses. This study examined electrophysiological measures, specifically the auditory late response (ALR), mismatch negativity (MMN), and P300 as potential neural biomarkers of tinnitus in both a tinnitus and non-tinnitus control group while utilizing the pitch-matched tinnitus frequencies as the test stimuli. Results of this study found differences in MMN amplitudes and area under the curve, and in P300 topographic maps between tinnitus and control subjects. The differences in MMN responses across groups suggest that dysfunctional processing of acoustic stimuli located near the tinnitus frequency in individuals with tinnitus manifests as soon as 200 ms after initial onset of the stimulus. In addition, results from a global field power analysis and differences in spatial distributions on topographical maps indicate that deficits persist through higher levels of cortical processing. A secondary goal of this study was to determine if electrophysiological measures correlated with reported tinnitus severity on questionnaires. This analysis indicated that P2 latency was a significant predictor of Tinnitus Reaction Questionnaire, Tinnitus Handicap Inventory, and percent of the time participant’s tinnitus was considered bothersome, suggesting that this measure could potentially be used to assess the efficacy of treatment programs for tinnitus.

The 3D in vitro Adrenoid cell model recapitulates the complexity of the adrenal gland

The crosstalk between the chromaffin and adrenocortical cells is essential for the endocrine activity of the adrenal glands. This interaction is also likely important for tumorigenesis and progression of adrenocortical cancer and pheochromocytoma. We developed a unique in vitro 3D model of the whole adrenal gland called Adrenoid consisting in adrenocortical carcinoma H295R and pheochromocytoma MTT cell lines. Adrenoids showed a round compact morphology with a growth rate significantly higher compared to MTT-spheroids. Confocal analysis of differential fluorescence staining of H295R and MTT cells demonstrated that H295R organized into small clusters inside Adrenoids dispersed in a core of MTT cells. Transmission electron microscopy confirmed the strict cell–cell interaction occurring between H295R and MTT cells in Adrenoids, which displayed ultrastructural features of more functional cells compared to the single cell type monolayer cultures. Adrenoid maintenance of the dual endocrine activity was demonstrated by the expression not only of cortical and chromaffin markers (steroidogenic factor 1, and chromogranin) but also by protein detection of the main enzymes involved in steroidogenesis (steroidogenic acute regulatory protein, and CYP11B1) and in catecholamine production (tyrosine hydroxylase and phenylethanolamine N-methyltransferase). Mass spectrometry detection of steroid hormones and liquid chromatography measurement of catecholamines confirmed Adrenoid functional activity. In conclusion, Adrenoids represent an innovative in vitro 3D-model that mimics the spatial and functional complexity of the adrenal gland, thus being a useful tool to investigate the crosstalk between the two endocrine components in the pathophysiology of this endocrine organ.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality

BackgroundHigh levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. MethodsWe modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models. ResultsThe most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. ConclusionsGreater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

Variation in coupling across neural and cardiac systems of regulation is linked to markers of anxiety risk in preschool.

Both cortical and parasympathetic systems are believed to regulate emotional arousal in the service of healthy development. Systemic coordination, or coupling, between putative regulatory functions begins in early childhood. Yet the degree of coupling between cortical and parasympathetic systems in young children remains unclear, particularly in relation to the development of typical or atypical emotion function. We tested whether cortical (ERN) and parasympathetic (respiratory sinus arrhythmia [RSA]) markers of regulation were coupled during cognitive challenge in preschoolers (N = 121). We found no main effect of RSA predicting ERN. We then tested children's typical and atypical emotion behavior (context-appropriate/context-inappropriate fear, anxiety symptoms, neuroendocrine reactivity) as moderators of early coupling in an effort to link patterns of coupling to adaptive emotional development. Negative coupling (i.e., smaller ERN, more RSA suppression or larger ERN, less RSA suppression) at age 3 was associated with greater atypical and less typical emotion behaviors, indicative of greater risk. Negative age 3 coupling was also visible for children who had greater Generalized Anxiety Disorder symptoms and blunted cortisol reactivity at age 5. Results suggest that negative coupling may reflect a maladaptive pattern across regulatory systems that is identifiable during the preschool years.

A simple and reliable method for claustrum localization across age in mice

The anatomical organization of the rodent claustrum remains obscure due to lack of clear borders that distinguish it from neighboring forebrain structures. Defining what constitutes the claustrum is imperative for elucidating its functions. Methods based on gene/protein expression or transgenic mice have been used to spatially outline the claustrum but often report incomplete labeling and/or lack of specificity during certain neurodevelopmental timepoints. To reliably identify claustrum projection cells in mice, we propose a simple immunolabelling method that juxtaposes the expression pattern of claustrum-enriched and cortical-enriched markers. We determined that claustrum cells immunoreactive for the claustrum-enriched markers Nurr1 and Nr2f2 are devoid of the cortical marker Tle4, which allowed us to differentiate the claustrum from adjoining cortical cells. Using retrograde tracing, we verified that nearly all claustrum projection neurons lack Tle4 but expressed Nurr1/Nr2f2 markers to different degrees. At neonatal stages between 7 and 21 days, claustrum projection neurons were identified by their Nurr1-postive/Tle4-negative expression profile, a time-period when other immunolabelling techniques used to localize the claustrum in adult mice are ineffective. Finally, exposure to environmental novelty enhanced the expression of the neuronal activation marker c-Fos in the claustrum region. Notably, c-Fos labeling was mainly restricted to Nurr1-positive cells and nearly absent from Tle4-positive cells, thus corroborating previous work reporting novelty-induced claustrum activation. Taken together, this method will aid in studying the claustrum during postnatal development and may improve histological and functional studies where other approaches are not amenable.

Identifying cortical structure markers of resilience to adversity in young people using surface-based morphometry.

Previous research on the neurobiological bases of resilience in youth has largely used categorical definitions of resilience and voxel-based morphometry methods that assess gray matter volume. However, it is important to consider brain structure more broadly as different cortical properties have distinct developmental trajectories. To address these limitations, we used surface-based morphometry and data-driven, continuous resilience scores to examine associations between resilience and cortical structure. Structural MRI data from 286 youths (Mage = 13.6 years, 51% female) who took part in the European multi-site FemNAT-CD study were pre-processed and analyzed using surface-based morphometry. Continuous resilience scores were derived for each participant based on adversity exposure and levels of psychopathology using the residual regression method. Vertex-wise analyses assessed for correlations between resilience scores and cortical thickness, surface area, gyrification and volume. Resilience scores were positively associated with right lateral occipital surface area and right superior frontal gyrification and negatively correlated with left inferior temporal surface area. Moreover, sex-by-resilience interactions were observed for gyrification in frontal and temporal regions. Our findings extend previous research by revealing that resilience is related to surface area and gyrification in frontal, occipital and temporal regions that are implicated in emotion regulation and face or object recognition.

HOXA3 functions as the on-off switch to regulate the development of hESC-derived third pharyngeal pouch endoderm through EPHB2-mediated Wnt pathway.

Normal commitment of the endoderm of the third pharyngeal pouch (3PP) is essential for the development and differentiation of the thymus. The aim of this study was to investigate the role of transcription factor HOXA3 in the development and differentiation of 3PP endoderm (3PPE) from human embryonic stem cells (hESCs). The 3PPE was differentiated from hESC-derived definitive endoderm (DE) by mimicking developmental queues with Activin A, WNT3A, retinoic acid and BMP4. The function of 3PPE was assessed by further differentiating into functional thymic epithelial cells (TECs). The effect of HOXA3 inhibition on cells of 3PPE was subsequently investigated. A highly efficient approach for differentiating 3PPE cells was developed and these cells expressed 3PPE related genes HOXA3, SIX1, PAX9 as well as EpCAM. 3PPE cells had a strong potential to develop into TECs which expressed both cortical TEC markers K8 and CD205, and medullary TEC markers K5 and AIRE, and also promoted the development and maturation of T cells. More importantly, transcription factor HOXA3 not only regulated the differentiation of 3PPE, but also had a crucial role for the proliferation and migration of 3PPE cells. Our further investigation revealed that HOXA3 controlled the commitment and function of 3PPE through the regulation of Wnt signaling pathway by activating EPHB2. Our results demonstrated that HOXA3 functioned as the on-off switch to regulate the development of hESC-derived 3PPE through EPHB2-mediated Wnt pathway, and our findings will provide new insights into studying the development of 3PP and thymic organ in vitro and in vivo.

Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies

There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/– 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.

Multimodal investigation of the early associations between sleep‐wake regulation, cognition and Alzheimer’s disease neuropathology and risk

AbstractBackgroundAlterations in sleep‐wake regulation are hallmarks of the ageing process and emerge as risk factors for Alzheimer’s disease (AD). While the fine‐tuned coalescence of sleep microstructure elements may influence age‐related cognitive trajectories, its association with AD‐related processes is not fully known. Likewise, whether markers of sleep‐wake regulation assessed during wakefulness are associated with the risk of developing AD is not established.MethodHere, we sought associations between key elements of the electrophysiology of sleep microstructure and of sleep‐wake regulation and hallmarks of AD neuropathology (early Aβ/Tau/neuroinflammation brain burden) or the polygenetic risk in 360 young adults (18‐31y) and 100 late‐midlife healthy individuals (50‐70y). We further investigated relationships with cognitive performance.ResultWe first found that spontaneous arousal during sleep are heterogenous and differently associated with Aβ and cognition. We further found the young‐like co‐occurrence of sleep spindles and slow‐depolarisation slow waves was associated to lower early burden of Aβ and was predictive of memory decline at 2‐year follow‐up. We also find that the dynamics of the daily change in cortical excitability and EEG markers of sleepiness are respectively not associated with early Ab burden and associated with the polygenic risk of developing AD. Cortical excitability dynamics is, however, association with cognitive performance.ConclusionThese findings unravel early links between sleep‐wake regulation, AD‐related processes or genetic risks and their association with cognitive performance. Spontaneous arousals and the altered coupling of sleep microstructure elements that are key to its mnesic functions may contributes to poorer brain and cognitive trajectories in ageing. In addition, associations between markers of sleep‐wake regulation and AD can be detected during quiet wakefulness.Support: ULiège, Wallonia‐Brussels Federation, Fonds de la Recherche Scientifique (FNRS Belgium), Fondation Recherche Alzheimer (SOA‐FRA Belgium), Fondation Léon Fredericq, EU FEDER programme

Speech processing in the brain at risk for dementia

AbstractBackgroundGiven the close relationship between hearing and cognitive function in older age, characterization of speech processing deficits along the auditory pathway is of great importance for the brain at risk of dementia. In the ascending, primary auditory pathway, signals pass through subcortical relay stations in the brainstem and midbrain before being integrated into cortical areas. A recent study suggests that the pathophysiology of MCI extends to speech encoding in the brainstem and that both cortical and subcortical markers of speech processing have predictive potential for putative Mild Cognitive Impairment (MCI). In this project, we are testing these neural speech processing markers to see if they can distinguish healthy older adults with age‐related hearing loss from those at risk for dementia.MethodsElectroencephalography (EEG, 32 channels, sampling rate = 16 384 Hz) will be recorded from N = 40 older participants (age ≥ 60 years, retired) while listening to excerpts from an audiobook. We use a novel EEG paradigm that allows us to simultaneously measure cortical and subcortical responses to natural running speech. Based on their Montreal Cognitive Assessment (MoCA) score, participants are divided into an experimental group with “putative MCI” (MoCA &lt; 26) and a control group (MoCA ≥ 26). In addition, we perform audiometric testing with pure tones (PTA) and speech‐in‐noise (SiN) tests to assess participants' hearing function.ResultsWe are currently in the middle of data collection and will be able to present preliminary results at AAIC. We expect to see altered speech processing in the experimental group, particularly driven by slower and weaker encoding at the subcortical level. In a next step, we aim to use the neural markers of speech processing that emerge from this framework as features for a diagnostic model that predicts MCI using a binary classifier, considering the hearing status of the participants.ConclusionThe main goal of this study is to investigate neural markers of speech processing for their differential diagnostic potential for the brain at risk for dementia. Depending on the results, such neurophysiological markers could prove useful for early diagnosis in the clinic in the longer term.

Post‐mortem MRI white matter hyperintensities are associated with cortical astrocytopathy and water channel expression in the oldest‐old

AbstractBackgroundCerebrovascular small vessel disease, a common cause of cognitive impairment in older individuals, is characterized by the presence of MRI white matter hyperintensities (WMH). Our previous MRI‐targeted histopathological studies have found WMHs and the surrounding NAWM penumbra to be associated with glial markers. This study aims to assess the relationship between cortical markers of glial dysfunction and post‐mortem (PM) MRI WMH.MethodLeft brain hemispheres were obtained from 45 Oregon Alzheimer’s Disease Research Center subjects &gt;/ = 80 years of age without significant AD pathology. Intact and sliced hemispheres were scanned at 7T MRI. MRI scans were used to target histological sampling. Slides were stained for glial fibrillary acid protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), aquaporin‐1 (AQP1), aquaporin‐4 (AQP4), vimentin and amyloid‐beta (ABETA). Slides were co‐registered to MRI. Tissue masks were hand‐drawn to delineate white matter and cortex. Cortical ROIs were quantified for mean pixel value (AQP1, AQP4, GFAP, and Vimentin) or area coverage (IBA1, ABETA). Cassettes with no local WMH were compared with those in the top third of slide WMH coverage (187 cassettes). Global WMH burden was dichotomized at the mean. Linear mixed‐effects models regressed stain quantification on local WMH (in slide) and global WMH burden, with a random effect for staining batch (levels = 4). The final model controlled for age at death and ABETA expression within a slide. Interactions between local and global WMH were included where appropriate.ResultHigh local WMH burden was associated with greater cortical vimentin (p = 0.036), GFAP (p = 0.066), and AQP4 (p = 0.004), while high global WMH burden was associated with greater IBA1 (p = 0.034) and AQP1 (p = 0.071). An interaction was identified between local and global WMH burden for AQP1 (p&lt;0.10), such that in subjects with high global WMH burden, high local WMH burden was associated with higher AQP1. Greater local cortical ABETA was associated with cortical AQP1 (p = 0.004) expression.ConclusionIn oldest‐old individuals without significant AD pathology, high local and global PM‐MRI WMH burden is associated with cortical astrocytopathy, including increased water channel expression and inflammation. Findings implicate WMH as a state marker of widespread cortical pathology that may confer increased vulnerability to cognitive decline with advanced age.

FRI168 LH-hCG Receptor Is Expressed In All Three Zones Of Normal Adrenal Glands But Not In Aldosterone-Producing Micronodules

Abstract Disclosure: S.A. Reda: None. A. Kirschenbaum: None. S. Yao: None. L. Milgram: None. J. Rege: None. A.C. Levine: None. Embryologically, the adrenals and gonads develop from the urogenital ridge with differential migration and differentiation. Post-natally, pituitary adrenocorticotropic hormone (ACTH) stimulates adrenal cortical cell growth and steroidogenesis, whereas pituitary luteinizing hormone (LH) regulates gonadal cell growth and steroidogenesis. However, there are multiple reports of gonadal tumorigenesis driven by high ACTH (in congenital adrenal hyperplasia) and adrenal cortical tumorigenesis driven by high LH/human chorionic gonadotropin (hCG) levels (adrenal tumors in pregnant and postmenopausal females). We studied the immunohistochemical expression of LH/hCG receptor (LH/hCG-R) in normal adrenal glands from 12 kidney donors (four male and eight female, two of which were &amp;lt;50 years of age and six were &amp;gt;50 years of age). Some of these specimens also contained aldosterone producing micronodules (APMs). Staining was performed for Synaptophysin, aldosterone synthase (CYP11B2), LH/hCG-R, WNT/β-Catenin, and DLK-1. In normal adrenal tissue, we first used synaptophysin stain to identify the nerves in the adrenal cortex as well as the adrenal medulla (M). CYP11B2 staining demonstrated immunoreactivity in a linear pattern throughout the Zona Glomerulosa (ZG) in five of the 12 samples. Faint expression of LH/hCG-R was detected in all twelve samples throughout the three layers of the adrenal cortex: the ZG, Zona Fasciculata (ZF) and Zona Reticularis (ZR). However, there were occasional cells in both the ZR and ZF that stained intensely for LH/hCG-R expression. LH/hCG-R immunoreactivity was also noted in the progenitor-rich subcapsular (SC) region. WNT β-Catenin, a transcription factor involved in the proliferation of adrenal cortical cells, stained most heavily in the SC/ZG region, possibly representing adrenal cortical progenitor cells. DLK-1, an adrenal cortical progenitor cell marker, was also expressed in the subcapsular zone. In adrenal tissues containing APMs, CYP11B2 immunostaining revealed areas of CYP11B2 positive cells that dip into the ZF, with no preserved linear staining for CYP11B2 in the ZG. LH/hCG-R stained most densely in the SC and ZG regions, with little to no immunoreactivity in the APMs. WNT β-Catenin likewise stained the SC and ZG regions with no expression in the APMs. Our findings suggests that LH/hCG-R is expressed sporadically in normal adrenal cortical tissue, but densely at times in all three zones of the adrenal cortex and the subcapsular area where the putative adult progenitor cells reside. The LH/hCG-R does not appear to be expressed throughout the entirety of APMs. Presentation: Friday, June 16, 2023

Cortical structural differences following repeated ayahuasca use hold molecular signatures.

Serotonergic psychedelics such as ayahuasca are reported to promote both structural and functional neural plasticity via partial 5-HT2A agonism. However, little is known about how these molecular mechanisms may extend to repeated psychedelic administration in humans, let alone neuroanatomy. While early evidence suggests localised changes to cortical thickness in long-term ayahuasca users, it is unknown how such findings may be reflected by large-scale anatomical brain networks comprising cytoarchitecturally complex regions. Here, we examined the relationship between cortical gene expression markers of psychedelic action and brain morphometric change following repeated ayahuasca usage, using high-field 7 Tesla neuroimaging data derived from 24 members of an ayahuasca-using church (Santo Daime) and case-matched controls. Using a morphometric similarity network (MSN) analysis, repeated ayahuasca use was associated with a spatially distributed cortical patterning of both structural differentiation in sensorimotor areas and de-differentiation in transmodal areas. Cortical MSN remodelling was found to be spatially correlated with dysregulation of 5-HT2A gene expression as well as a broader set of genes encoding target receptors pertinent to ayahuasca's effects. Furthermore, these associations were similarly interrelated with altered gene expression of specific transcriptional factors and immediate early genes previously identified in preclinical assays as relevant to psychedelic-induced neuroplasticity. Taken together, these findings provide preliminary evidence that the molecular mechanisms of psychedelic action may scale up to a macroscale level of brain organisation in vivo. Closer attention to the role of cortical transcriptomics in structural-functional coupling may help account for the behavioural differences observed in experienced psychedelic users.

Assessing the utility of a novel cortical marker of delay discounting (C-DD) in two independent samples of early adolescents: Links with externalizing pathology.

Delay discounting is a well-established risk factor for risky behaviors and the development of externalizing spectrum disorders. Building upon recent work that developed a novel cortical marker of delay discounting (C-DD) in adult samples, the objective of this study was to test whether the C-DD relates to delay discounting and subsequently externalizing pathology in adolescent samples. The current study used two samples: 9992 early adolescents participating in the ABCD study (Mage = 9.93 years old, 48.7% female), and 56 early adolescents recruited from the community (Mage = 12.27 years old, 55.4% female). Cortical thickness was estimated using the FreeSurfer standard pipeline, and the cortical marker of delay discounting (C-DD) was calculated based on procedures outlined by the initial validation study. All data are cross-sectional in nature. As expected, C-DD was positively related to delay discounting in the ABCD sample, even after accounting for age, biological sex, collection site and data quality indicators. Moreover, results showed that C-DD was discriminately associated with externalizing, but not internalizing, symptoms in both samples of young adolescents. Findings replicate those found in adult samples, suggestive that C-DD may be a useful neuroanatomical marker of youth delay discounting. Replication of findings in other samples will be needed to determine whether C-DD has translational relevance to understanding externalizing psychopathology in adolescent samples.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Genetic Overlap Between Global Cortical Brain Structure, C-Reactive Protein, and White Blood Cell Counts

BackgroundFor many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). MethodsLinear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. ResultsCortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (rg_surface_area = −0.13, false discovery rate–corrected p = 4.17 × 10−3; rg_thickness = −0.13, false discovery rate–corrected p = 4.00 × 10−2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. ConclusionsThe findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.