Human Brain Atlas Research Articles

Misfolded protein propagation in an integrated computational model of structural network and LRRK2 gene expression.

It has been widely accepted that Parkinson's disease (PD) is triggered and shaped by propagation of misfolded α-synuclein. Converging neurophysiological evidence suggests that leucine-rich repeat kinase 2 (LRRK2) is involved in membrane transport of PD pathogenesis. This study proposed an agent-based computational model by integrating structural connections and gene expression to investigate whether LRRK2 would affect the PD pathology propagation in central nervous system. Gene expression profiles from the Allen Human Brain Atlas (AHBA) and multimodal brain MRI images from Parkinson's Progression Markers Initiative (PPMI) and Human Connectome Project (HCP) were employed for the model construction. The model results exhibit the involvement of LRRK2 gene expression remarkably elevated model fitting (r = 0.73) compared with the traditional susceptible-infected-removed (S-I-R) model (r=0.60). Specifically, our model revealed that LRRK2 is more likely to modulate pathology secretion out of neurons, rather than spreading into neurons. The findings support the theory of LRRK2 gene expression modulating cell-to-cell propagation of misfolded proteins. As a result, the proposed model would bring new insights of understanding PD mechanism in terms of misfolded α-synuclein propagation.

Assessment of Neurobiological Mechanisms of Cortical Thinning During Childhood and Adolescence and Their Implications for Psychiatric Disorders

Many psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. Discovering the neurobiological underpinnings of brain maturation may elucidate molecular pathways of vulnerability and resilience to such disorders. To investigate the underlying neurobiological mechanisms of age-associated cortical thinning during maturation and their implications for psychiatric disorders. This multicohort analysis used data from 3 community-based studies. The Saguenay Youth Study provided data from 1024 adolescents who were recruited at a single site in Quebec, Canada. The IMAGEN cohort provided data from 1823 participants who were recruited in 8 European cities. The Brazil High Risk Cohort Study for the Development of Childhood Psychiatric Disorders provided data from 815 participants who were recruited in 2 Brazilian cities. Cortical thickness was estimated from the results of magnetic resonance imaging (MRI) scans, and age-associated cortical thinning was estimated in 34 cortical regions. Gene expression from the Allen Human Brain Atlas was aligned with the same regions. Similarities in the interregional profiles of gene expression and the profiles of age-associated cortical thinning were measured. The involvement of dendrites, dendritic spines, and myelin was tested using 3 gene panels. Enrichment for genes associated with psychiatric disorders was tested among the genes associated with thinning and their coexpression networks. Data analysis was conducted between March and October 2019. MRI-derived estimates of age-associated cortical thinning and gene expression in 34 cortical regions. A total of 3596 individuals aged 9 to 21 years were included in this study. Of those, 1803 participants (50.1%) were female, and the mean (SD) age was 15.2 (2.6) years. Interregional profiles of age-associated cortical thinning were associated with interregional gradients in the expression of genes associated with dendrites, dendritic spines, and myelin; the variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0.00% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their coexpression networks were enriched for genes associated with several psychiatric disorders. In this study, genetic similarity between interregional variation in cortical thinning during maturation and multiple psychiatric disorders suggests overlapping molecular underpinnings. This finding adds to the understanding of the neurodevelopmental mechanisms of psychiatric disorders.

Common neural and transcriptional correlates of inhibitory control underlie emotion regulation and memory control.

Inhibitory control is crucial for regulating emotions and may also enable memory control. However, evidence for their shared neurobiological correlates is limited. Here, we report meta-analyses of neuroimaging studies on emotion regulation, or memory control and link neural commonalities to transcriptional commonalities using the Allen Human Brain Atlas (AHBA). Based on 95 functional magnetic resonance imaging studies, we reveal a role of the right inferior parietal lobule embedded in a frontal–parietal–insular network during emotion regulation and memory control, which is similarly recruited during response inhibition. These co-activation patterns also overlap with the networks associated with ‘inhibition’, ‘cognitive control’ and ‘working memory’ when consulting the Neurosynth. Using the AHBA, we demonstrate that emotion regulation- and memory control-related brain activity patterns are associated with transcriptional profiles of a specific set of ‘inhibition-related’ genes. Gene ontology enrichment analysis of these ‘inhibition-related’ genes reveal associations with the neuronal transmission and risk for major psychiatric disorders as well as seizures and alcoholic dependence. In summary, this study identified a neural network and a set of genes associated with inhibitory control across emotion regulation and memory control. These findings facilitate our understanding of the neurobiological correlates of inhibitory control and may contribute to the development of brain stimulation and pharmacological interventions.

Advances in Construction of Human Brain Atlases from Magnetic Resonance Images

Advances in Construction of Human Brain Atlases from Magnetic Resonance Images

O5.6. ADVANCED DIFFUSION IMAGING IN PSYCHOSIS RISK: A CROSS-SECTIONAL AND LONGITUDINAL STUDY OF WHITE MATTER DEVELOPMENT

BackgroundStudies in individuals at clinical high risk (CHR) for psychosis provide a powerful means to predict outcomes and inform putative mechanisms underlying conversion to psychosis. In previous work, we applied advanced diffusion imaging methods to reveal that white matter pathology in a CHR population is characterized by cellular-specific changes in white matter, suggesting a preexisting neurodevelopmental anomaly. However, it remains unknown whether these deficits relate to clinical symptoms and/or conversion to frank psychosis. To address this gap, we examined cross-sectional and longitudinal white matter maturation in the largest imaging population of CHR individuals to date, obtained from the North American Prodrome Longitudinal Study (NAPLS-3).MethodsMulti-shell diffusion magnetic resonance imaging (MRI) data were collected across multiple timepoints (1–6 at ~2 month intervals) in 286 subjects (age range=12–32 years). These were 230 unmedicated CHR subjects, including 11% (n=25) who transitioned to psychosis (CHR-converters), as well as 56 age and sex-matched healthy controls. Raw diffusion signals were harmonized to remove scanner/site-induced effects, yielding a unified imaging dataset. Fractional anisotropy of cellular tissue (FAt) and the volume fraction of extracellular free-water (FW) were assessed in 12 major tracts from the IIT Human Brain Atlas (v.5.0). Linear mixed effects (LME) models were fitted to infer developmental trajectories of FAt and FW across age for CHR-converters, CHR-nonconverters and control groups, while accounting for the repeated measurements on each individual.ResultsThe rate at which FAt changed with age significantly differed between the three groups across commissural and association tracts (5 in total; p<0.05). In these tracts, FAt increased with age in controls (0.002% change per year) and in CHR-nonconverters, albeit at a slower rate (0.00074% per year). In contrast, FAt declined with age in CHR-converters at a rate that was significantly faster (-3.944% per year) than the rate of increase in the other two groups. By 25 years of age, FAt was significantly lower in both CHR groups compared to controls (p<0.05). With regard to FW, the rate of change significantly differed between CHR-converters and controls across the forceps major and the left inferior longitudinal and fronto‐occipital fasciculi (IFOF; 3 tracts in total; p<0.05). This was due to increased FW with age in the CHR-converters (0.0024% change per year) relative to controls (-0.0002% per year). Consequently, FW was significantly higher in CHR-converters compared to controls by 20 years of age (p<.05). With regard to symptoms, there was a significant impact of IFOF FW on positive symptom severity across CHR subjects, regardless of conversion status (t=2.37, p<0.05).DiscussionOur results revealed that clinical high-risk for psychosis is associated with cellular-specific alterations in white matter, regardless of conversion status. Only converters showed excess extracellular free-water, which involved tracts connecting occipital, posterior temporal, and orbito‐frontal areas. We also demonstrate a direct impact of free-water on positive symptomatology, collectively, suggesting that excess free-water may signal acute psychosis and its onset. This marker may be useful for patient selection for clinical trials and assessment of individuals with prodromal psychosis.

S157. A MULTICENTER HARMONIZED DIFFUSION TENSOR IMAGING STUDY ON THE ASSOCIATION OF WHITE MATTER STRUCTURE AND CLINICAL FUNCTIONING

BackgroundThe association of white matter (WM) abnormalities with clinical variables in schizophrenia (SCZ) is poorly understood. We investigated the clinical correlates of WM impairments using imaging data of 597 patients with SCZ and 490 healthy controls (HC). We focused on lifelong changes of WM (measured by Fractional Anisotropy [FA]) in SCZ and compared it to that of HC. We investigated how age, duration of illness, and medication influence WM trajectories, and examined how structural impairments are related to symptoms and cognition. Last, we tested for the role of sex in structure-function interactions.MethodsDiffusion-weighted images and clinical measurements were collected as part of 13 independent studies, and data was harmonized across all sites. We registered images to the IIT Human Brain Atlas and averaged FA for forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus (SLF) and uncinate fasciculus.First, we modeled the FA age trajectory of each tract in HC and used it to regress out the effect of age in patients. The residuals in the FA values were utilized for further analyses.We conducted mediator regression analyses with FA as the dependent variable, sex as a covariate, and age and duration of illness as the independent variables. Next, patients were grouped based on Chlorpromazine equivalent dosage (CPZ) and CPZ group was added to the regression model. To examine the association between structure and function, a structural equation model (SEM) was used, with cognition as a mediator. Last, all analyses were repeated for males and females separately.ResultsRegression analyses revealed a significant influence of duration of illness on the forceps major (T=3.24, p<.001), forceps minor (T=3.40, p<.001), and SLF (T=3.83, p<.0001). When adding both age and duration of illness, duration of illness mediated the influence of age on FA.Adding CPZ to the model displayed a significant effect of medication on forceps major (T=3.93, p<.0001).For SEM, FA of all tracts was used to represent structural impairment, and symptom scores were used to reflect functional impairment. All data paths were calculated with an asymptotically distribution-free model. The overall model fit was acceptable (RMSEA =.09) with a medium-strong effect of structural impairment on functional impairment (standardized estimate=.44).When separating sexes, males showed a significant association of duration of illness and FA. Females displayed a stronger influence of structural impairment on functional impairment (standardized estimate: males = .29, females =.52), and cognition had an impact on this relationship for females only.DiscussionThe effect of duration of illness on specific WM tracts suggests a progressive, neurodegenerative pathology, which might contribute to the devastating effects of chronicity. Medication seems to have only a small, localized effect on corpus callosum WM integrity. However, since our analysis used cross-sectional CPZ measures, future studies should include measurements of lifetime dosage. The observed impact of WM abnormalities on function further highlights the importance of WM for SCZ pathology.The association of structure and function seems sex-specific. Men show a stronger effect of chronicity. For females, cognition mediates the effect of structure on function, suggesting the role of cognitive reserve.Our approach provides the first step towards evidence-based medicine, by demonstrating the apparent relationship between structural pathology and functional outcome and suggesting possible mediators of this relationship, including duration of illness, cognition, medication, and sex.

First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain.

This study assessed whether the newly developed PET radioligand [11C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain. Brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas. In the brain, [11C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11C]PS13 binding reflects actual COX-1 density in the human brain. These results from the first-in-human evaluation of the ability of [11C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation. NCT03324646 at https://clinicaltrials.gov/ . Registered October 30, 2017. Retrospectively registered.

Semiologic subgroups of insulo‐opercular seizures based on connectional architecture atlas

Insulo-opercular seizures are characterized by diverse semiology, related to the insula's multiple functional roles and extensive connectivity. We aimed to identify semiologic subgroups and correlate these with insulo-opercular subregions based on connectional architecture. We retrospectively collected a large series of 37 patients with insulo-opercular seizures explored by stereoelectroencephalography (SEEG) from three epilepsy centers. A new human brain atlas (Brainnetome Atlas, BNA) based on both anatomic and functional connections was employed to segment insulo-opercular cortex. Semiology and SEEG changes were carefully reviewed and quantified. Principal component analysis and cluster analysis were used to correlate semiologic characteristics with insulo-opercular subregions. Four main semiologic subgroups were identified, organized along an anteroventral to posterodorsal axis based on BNA. Group 1 was characterized by epigastric sensation and/or integrated gestural motor behaviorswith or withoutfeelings of fear or rage, involving the anteroventral insular regions and mesial temporal lobes. Group 2 was characterized by auditory sensations and symmetric proximal/axial tonic signs involving the posteroventral temporal operculum. The characteristics of group 3 were orofacial and laryngeal signs, involving the intermediate insulo-opercular regions. The features of group 4 were somatosensory signs followed by nonintegrated gestural motor behaviors and/or asymmetric tonic signs involving the posterodorsal insulo-opercular regions with propagation to the mesial frontal lobes. Thus anteroventral seizure organizations predominantly showed limbic system semiology, whereas more posterodorsal regions were associated with semiology involving mainly the sensorimotor system. Subjective symptoms proved to be particularly discriminating factors. Insulo-opercular seizures can be categorized in terms of clinical semiology and correlate with connectional architecture subregions along an anteroventral-posterodorsal axis in line with the cytoarchitectonic gradient rather than the gyral anatomy of the insula cortex. This provides new insights into facilitating differential diagnosis and presurgical localization but also highlights the importance of considering connectional architecture in determining neural correlates of complex semiologic patterns.

Human Brain Atlases in Stroke Management

Stroke is a leading cause of death and a major cause of permanent disability. Its management is demanding because of variety of protocols, imaging modalities, pulse sequences, hemodynamic maps, criteria for treatment, and time constraints to promptly evaluate and treat. To cope with some of these issues, we propose novel, patented solutions in stroke management by employing multiple brain atlases for diagnosis, treatment, and prediction. Numerous and diverse CT and MRI scans are used: ARIC cohort, ischemic and hemorrhagic stroke CT cases, MRI cases with multiple pulse sequences, and 128 stroke CT patients, each with 170 variables and one year follow-up. The method employs brain atlases of anatomy, blood supply territories, and probabilistic stroke atlas. It rapidly maps an atlas to scan and provides atlas-assisted scan processing. Atlas-to-scan mapping is application-dependent and handles three types of regions of interest (ROIs): atlas-defined ROIs, atlas-quantified ROIs, and ROIs creating an atlas. An ROI is defined by atlas-guided anatomy or scan-derived pathology. The atlas defines ROI or quantifies it. A brain atlas potential has been illustrated in four atlas-assisted applications for stroke occurrence prediction and screening, rapid and automatic stroke diagnosis in emergency room, quantitative decision support in thrombolysis in ischemic stroke, and stroke outcome prediction and treatment assessment. The use of brain atlases in stroke has many potential advantages, including rapid processing, automated and robust handling, wide range of applications, and quantitative assessment. Further work is needed to enhance the developed prototypes, clinically validate proposed solutions, and introduce them to clinical practice.

Central neurogenetic signatures of the visuomotor integration system

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.

Transcriptomic signatures of brain regional vulnerability to Parkinson\u2019s disease

The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson’s disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson’s disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of non-neurological subjects, while in two datasets of Parkinson’s disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson’s disease brains.

Early-life trauma endophenotypes and brain circuit-gene expression relationships in functional neurological (conversion) disorder.

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network-trauma relationships in this population. In this neuroimaging–gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. 21 individuals with comparable depression, anxiety and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional-differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar-hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal) and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual-differences in depression/anxiety, PTSD and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of 3 gene-clusters: i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.

Topologically Guided Prioritization of Candidate Gene Transcripts Coexpressed with the 5-HT1A Receptor by Combining In Vivo PET and Allen Human Brain Atlas Data.

The serotonin-1A receptor (5-HT1AR) represents a viable target in the treatment of disorders of the brain. However, development of psychiatric drugs continues to be hindered by the relative inaccessibility of brain tissue. Although the efficacy of drugs selective for the 5-HT1AR has not been proven, research continues to focus on drugs that influence this receptor subtype. To further knowledge on this topic, we investigated the topological coexpression patterns of the 5-HT1AR. We calculated Spearman’s rho for the correlation of positron emission tomography-binding potentials (BPND) of the 5-HT1AR assessed in 30 healthy subjects using the tracer [carbonyl-11C]WAY-100635 and predicted whole-brain mRNA expression of 18 686 genes. After applying a threshold of r > 0.3 in a leave-one-out cross-validation of the prediction of mRNA expression, genes with ρ ≥ 0.7 were considered to be relevant. In cortical regions, 199 genes showed high correlation with the BPND of the 5-HT1AR, in subcortical regions 194 genes. Using our approach, we could consolidate the role of BDNF and implicate new genes (AnxA8, NeuroD2) in serotonergic functioning. Despite its explorative nature, the analysis can be seen as a gene prioritization approach to reduce the number of genes potentially connected to 5-HT1AR functioning and guide future in vitro studies.

Neurogenetic Traits Conferring Vulnerability to Cortical Progression of Parkinson's Disease

Background: The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson’s disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in healthy controls (HC) and PD participants and gene expression patterns across the human cortex – such as the SNCA gene (encoding alpha-synuclein protein, a hallmark of PD pathology). Methods: To characterize the functional scaffolding of connections emanating from PD-related pathology epicenters in the brainstem, we first performed Stepwise Functional Connectivity (SFC) analysis using intrinsic connectivity as revealed by neuroimaging. We then leveraged the Allen Human Brain Atlas (AHBA) to examine the spatial intersection of the observed SFC patterns with genetic transcription profiles. Findings: A rich set of genes were transcriptionally associated to PD-related biologic processes, including dopamine secretion, neuropeptide transmission, and axonal and synaptic assemblies, for which the gene SNCA played a central role. As hypothesized, we further confirmed that brain connectivity originated from PD-related pathology epicenters in the brainstem largely recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. Finally, we discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Interpretation: This study sheds light on exciting new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies. Funding Statement: This research was supported by grants from the National Institutes of Health (NIH; R01AG061811, and R01AG061445 to J.S.), the Ministry of Education, Science, and Technological Development of the Republic of Serbia (grant number 175090), the Italian Ministry of Health (grant number RF-2018-12366746) and Carlos III Institute of Health (PI11/02109) Spain, the Basque Government through the BERC 2018-2021 program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation SEV-2015-0490 and the Spanish Ministry of Economy and Competitiveness (RYC-2017- 21845 and PID2019-105520GB-100 to C.C-G.). Declaration of Interests: S.B. reports no disclosures. F.A. is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Philips, Novartis and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. I.D. reports no disclosures. E.B. reports no disclosures. F.d.O.U. reports no disclosures. M.D-A. report honoraria for lectures, travel, and accommodation to attend scientific meetings from Alter, Bial, Merk, Novartis, Sanofi Genzyme, UCB, and Zambon. C.C-G. reports no disclosures. M.R-O. reports honoraria for lectures, travel and accommodation to attend scientific meetings from Boston Scientific and Bial. T. Stojkovic has received speaker honoraria from Actavis and Alzheimer's Association International Research Grant. V.S. Kostic has received speaker honoraria from Actavis and Solveo. M. Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). J. Sepulcre reports no disclosures. Ethics Approval Statement: Both studies were approved by the local ethics committees at University of Belgrade and Gipuzkoa Clinical Research Ethics Committee respectively and written informed consent to participate in the study was obtained from all participants.

Regional iron distribution and soluble ferroprotein profiles in the healthy human brain

Iron is essential for brain development and health where its redox properties are used for a number of neurological processes. However, iron is also a major driver of oxidative stress if not properly controlled. Brain iron distribution is highly compartmentalised and regulated by a number of proteins and small biomolecules. Here, we examine heterogeneity in regional iron levels in 10 anatomical structures from seven post-mortem human brains with no apparent neuropathology. Putamen contained the highest levels, and most case-to-case variability, of iron compared with the other regions examined. Partitioning of iron between cytosolic and membrane-bound iron was generally consistent in each region, with a slightly higher proportion (55 %) in the ‘insoluble’ phase. We expand on this using the Allen Human Brain Atlas to examine patterns between iron levels and transcriptomic expression of iron regulatory proteins and using quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry to assess regional differences in the molecular masses to which cytosolic iron predominantly binds. Approximately 60 % was associated with ferritin, equating to approximately 25 % of total tissue iron essentially in storage. This study is the first of its kind in human brain tissue, providing a valuable resource and new insight for iron biologists and neuroscientists, alike.

CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults.

Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aβ42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n = 95) and 4 (n = 62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aβ42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A-T- #x2292; A+T- #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.

Brain structural changes in cannabis dependence: association with MAGL

Cannabis use is rising, yet there is poor understanding of biological processes that might link chronic cannabis use to brain structural abnormalities. To lend insight into this topic, we examined white matter microstructural integrity and gray matter cortical thickness/density differences between 89 individuals with cannabis dependence (CD) and 89 matched controls (64 males, 25 females in each group) from the Human Connectome Project. We tested whether cortical patterns for expression of genes relevant for cannabinoid signaling (from Allen Human Brain Atlas postmortem tissue) were associated with spatial patterns of cortical thickness/density differences in CD. CD had lower fractional anisotropy than controls in white matter bundles innervating posterior cingulate and parietal cortex, basal ganglia, and temporal cortex. The CD group also had significantly less gray matter thickness and density in precuneus, relative to controls. Sibling-pair analysis found support for causal and graded liability effects of cannabis on precuneus structure. Spatial patterns of gray matter differences in CD were significantly associated with regional differences in monoacylglycerol lipase (MAGL) expression in postmortem brain tissue, such that regions with higher MAGL expression (but not fatty-acid amide hydrolase or FAAH) were more vulnerable to cortical thinning. In sum, chronic cannabis use is associated with structural differences in white and gray matter, which was most prominent in precuneus and associated white matter tracts. Regions with high MAGL expression, and therefore with potentially physiologically restricted endogenous cannabinoid signaling, may be more vulnerable to the effects of chronic cannabis use on cortical thickness.

Neurofilament-lysosomal genetic intersections in the cortical network of stuttering

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG – a gene involved in the mannose-6-phosphate lysosomal targeting pathways – was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering.

Staging β-Amyloid Pathology With Amyloid Positron Emission Tomography

Different brain regions appear to be involved during β-amyloid (Aβ) accumulation in Alzheimer disease (AD), but a longitudinally valid system to track Aβ stages in vivo using positron emission tomography (PET) is lacking. To construct a longitudinally valid in vivo staging system for AD using amyloid PET. Longitudinal multicenter cohort study using data accessed on August 20, 2018, from the Alzheimer's Disease Neuroimaging Initiative database of scans performed from June 9, 2010, to July 12, 2018, from 741 persons: 304 without cognitive impairment, 384 with mild cognitive impairment, and 53 with AD dementia. Cerebrospinal fluid (CSF) Aβ42 and fluorine 18-labeled florbetapir (18F-florbetapir) data were used to determine early, intermediate, and late regions of Aβ accumulation. β-Amyloid stages ranging from 0 to 3 were constructed using these composites. Each subsequent stage required involvement of more advanced regions. Patients were followed up at 2, 4, and 6 years. Replication and validation were conducted using an independent cohort (Swedish BioFINDER) and gene expression information from the Allen Human Brain Atlas database. Analyses were conducted August 21, 2018, to May 24, 2019. The main outcome was change in stage. Stages were compared for diagnosis, CSF biomarkers of tau, and longitudinal atrophy, cognitive measures, and regional gene expression. Transitions between stages were tested using longitudinal 18F-florbetapir data. Among 641 participants with CSF Aβ42 data and at least two 18F-florbetapir scans, 335 (52.3%) were male. The early region of Aβ accumulation included the precuneus, posterior cingulate, isthmus cingulate, insula, and medial and lateral orbitofrontal cortices. The late region included the lingual, pericalcarine, paracentral, precentral, and postcentral cortices. The intermediate region included remaining brain regions with increased accumulation rates. In 2072 PET scans from 741 participants, 2039 (98.4%) were unambiguously staged. At baseline, participants with stage 0 (n = 402) had a 14.7% (95% CI, 11.2%-18.1%) probability of progression to a higher stage; stage 1 (n = 21), 71.4% (95% CI, 50.0%-90.9%); and stage 2 (n = 79), 53.1% (95% CI, 42.2%-64.0%). Seven of the 741 participants (0.9%) reverted to a lower stage. Higher stages were associated with lower CSF Aβ42 concentrations (from stage 1 at baseline), greater CSF P-tau (from stage 1) and CSF T-tau (from stage 2), and accelerated cognitive decline (from stage 2) and atrophy (from stage 3), even when adjusting for clinical diagnosis. Key findings were replicated in the BioFINDER cohort (N = 474). The regions of different stages differed by gene expression profiles when using the transcriptome from the Allen Human Brain Atlas, especially involving genes associated with voltage-gated ion channel activity especially involving genes associated with voltage-gated ion channel activity, but also blood circulation, axon guidance, and lipid transportation. Results of this study suggest that this robust staging system of Aβ accumulation may be useful for monitoring patients throughout the course of AD. Progression through stages may depend on underlying selective vulnerability in different brain regions.

Corticosteroids and Regional Variations in Thickness of the Human Cerebral Cortex across the Lifespan.

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4–97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.