Healthy Human Brain Research Articles

Reproducibility of 3D chemical exchange saturation transfer (CEST) contrasts in the healthy brain at 3T

Chemical exchange saturation transfer (CEST) imaging may provide novel contrast for the diagnosis, prognosis, and monitoring of the progression or treatment of neurological applications. However, the reproducibility of prominent CEST contrasts like amide CEST and nuclear Overhauser enhancement (NOE) CEST must be characterized in healthy brain gray matter (GM) and white matter (GM) prior to clinical implementation. The objective of this study was to characterize the reproducibility of four different CEST contrasts in the healthy human brain. Using a 3T MRI scanner, two 3D CEST scans were acquired in 12 healthy subjects (7 females, mean age (± SD) 26 ± 4 years) approximately 10 days apart. Scan-rescan reproducibility was measured for four contrasts: amine/amide concentration-independent detection (AACID), Amide*, and inverse magnetization transfer ratio (MTRRex) contrast for amide and NOE. Reproducibility was evaluated between- and within-subjects using coefficients of variation (CV) and the percent difference between measurements. AACID and NOE-MTRRex contrasts demonstrated the lowest within-subject CVs (0.8–1.2% and 1.6-2.0%, respectively), between-subject CVs (1.2–2.1% and 3.4–4.2%, respectively), and percent difference (1.2–1.4% and 2.2–2.8%, respectively) for both GM and WM. AACID and NOE-MTRRex contrasts demonstrated the highest reproducibility and represented stable measurements suitable for characterizing changes in brain tissue caused by pathological processes.

Single-cell somatic copy number variants in brain using different amplification methods and reference genomes

The presence of somatic mutations, including copy number variants (CNVs), in the brain is well recognized. Comprehensive study requires single-cell whole genome amplification, with several methods available, prior to sequencing. Here we compare PicoPLEX with two recent adaptations of multiple displacement amplification (MDA): primary template-directed amplification (PTA) and droplet MDA, across 93 human brain cortical nuclei. We demonstrate different properties for each, with PTA providing the broadest amplification, PicoPLEX the most even, and distinct chimeric profiles. Furthermore, we perform CNV calling on two brains with multiple system atrophy and one control brain using different reference genomes. We find that 20.6% of brain cells have at least one Mb-scale CNV, with some supported by bulk sequencing or single-cells from other brain regions. Our study highlights the importance of selecting whole genome amplification method and reference genome for CNV calling, while supporting the existence of somatic CNVs in healthy and diseased human brain.

Rapid and quantitative CEST-MRI sequence using water presaturation.

Despite the significant potential for in vivo metabolic imaging in preclinical and clinical applications, CEST MRI suffers from long scan time and inaccurate quantification. This study aims to suppress the contaminations among signals under different frequencies, which could shorten the TR and thereby facilitate CEST imaging acceleration and quantification. A novel sequence is proposed by applying a water-presaturation (WPS) module at the beginning of each TR. WPS CEST quickly knocks down the residual signal from previous TRs so that the magnetization of all TRs recovers from zero, which aligns well with the formula of quasi-steady-state theorem and enables accurate quantification within shorter TR. WPS CEST was assessed by simulations, creatine phantom, and healthy human brain scans at 3 T. In simulation and phantom experiment, WPS CEST allows accurate estimation of exchange rate (ksw) using omega plot and using shorter delay time (Td) and saturation time (Ts) (e.g., 1 s/1 s) compared with the conventional CEST. Simulations further showed that WPS CEST could obtain consistent spin-lock relaxation (R1ρ) values over varied Tds and Tss. Six human scans indicated that R1ρ collected from conventional sequences showed significant differences between two groups with Td and Ts of (1 s/1 s) and (2 s/2 s) (amide: 1.721 ± 0.051 s-1 vs. 1.622 ± 0.050 s-1, p = 0.001; nuclear Overhauser enhancement: 1.792 ± 0.046 s-1 vs. 1.687 ± 0.053 s-1, p = 0.004), whereas WPS CEST scans using these 2 Td/Ts values obtained the same mean R1ρ (amide: 1.616 ± 0.053 s-1 vs. 1.616 ± 0.048 s-1, p = 0.862; nuclear Overhauser enhancement: 1.688 ± 0.064 s-1 vs. 1.684 ± 0.054 s-1, p = 0.544). WPS CEST demonstrated accurate quantitation within shorter TR compared with conventional sequences, and thereby may allow rapid quantitative CEST scans in various situations.

Single‐shot multi‐b‐value (SSMb) diffusion‐weighted MRI using spin echo and stimulated echoes with variable flip angles

AbstractConventional diffusion‐weighted imaging (DWI) sequences employing a spin echo or stimulated echo sensitize diffusion with a specific b‐value at a fixed diffusion direction and diffusion time (Δ). To compute apparent diffusion coefficient (ADC) and other diffusion parameters, the sequence needs to be repeated multiple times by varying the b‐value and/or gradient direction. In this study, we developed a single‐shot multi‐b‐value (SSMb) diffusion MRI technique, which combines a spin echo and a train of stimulated echoes produced with variable flip angles. The method involves a pair of 90° radio frequency (RF) pulses that straddle a diffusion gradient lobe (GD), to rephase the magnetization in the transverse plane, producing a diffusion‐weighted spin echo acquired by the first echo‐planar imaging (EPI) readout train. The magnetization stored along the longitudinal axis is successively re‐excited by a series of n variable‐flip‐angle pulses, each followed by a diffusion gradient lobe GD and a subsequent EPI readout train to sample n stimulated‐echo signals. As such, (n + 1) diffusion‐weighted images, each with a distinct b‐value, are acquired in a single shot. The SSMb sequence was demonstrated on a diffusion phantom and healthy human brain to produce diffusion‐weighted images, which were quantitative analyzed using a mono‐exponential model. In the phantom experiment, SSMb provided similar ADC values to those from a commercial spin‐echo EPI (SE‐EPI) sequence (r = 0.999). In the human brain experiment, SSMb enabled a fourfold scan time reduction and yielded slightly lower ADC values (0.83 ± 0.26 μm2/ms) than SE‐EPI (0.88 ± 0.29 μm2/ms) in all voxels excluding cerebrospinal fluid, likely due to the influence of varying diffusion times. The feasibility of using SSMb to acquire multiple images in a single shot for intravoxel incoherent motion (IVIM) analysis was also demonstrated. In conclusion, despite a relatively low signal‐to‐noise ratio, the proposed SSMb technique can substantially increase the data acquisition efficiency in DWI studies.

Rapid imaging of intravenous gadolinium-based contrast agent (GBCA) entering ventricular cerebrospinal fluid (CSF) through the choroid plexus in healthy human subjects

BackgroundPathways for intravenously administered gadolinium-based-contrast-agents (GBCAs) entering cerebrospinal-fluid (CSF) circulation in the human brain are not well-understood. The blood-CSF-barrier (BCSFB) in choroid-plexus (CP) has long been hypothesized to be a main entry-point for intravenous-GBCAs into CSF. Most existing studies on this topic were performed in animals and human patients with various diseases. Results in healthy human subjects are limited. Besides, most studies were performed using MRI methods with limited temporal resolution and significant partial-volume effects from blood and CSF.MethodsThis study employs the recently developed dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI approach to measure GBCA-distribution in the CSF immediately and 4 h after intravenous-GBCA administration in healthy subjects. With a temporal resolution of 10 s, cDSC MRI can track GBCA-induced CSF signal changes during the bolus phase, which has not been investigated previously. It employs a long echo-time (TE = 1347 ms) to suppress tissue and blood signals so that pure CSF signal is detected with minimal partial-volume effects. GBCA concentration in the CSF can be estimated from cDSC MRI. In this study, cDSC and FLAIR MRI were performed immediately and 4 h after intravenous GBCA administration in 25 healthy volunteers (age 48.9 ± 19.5 years; 14 females). Paired t-tests were used to compare pre-GBCA and post-GBCA signal changes, and their correlations with age were evaluated using Pearson-correlation-coefficients.ResultsAt ~ 20 s post-GBCA, GBCA-induced cDSC signal changes were detected in the CSF around CP (ΔS/S = − 2.40 ± 0.30%; P < .001) but not in the rest of lateral ventricle (LV). At 4 h, significant GBCA-induced cDSC signal changes were observed in the entire LV (ΔS/S = − 7.58 ± 3.90%; P = .002). FLAIR MRI showed a similar trend. GBCA-induced CSF signal changes did not correlate with age.ConclusionsThese results provided direct imaging evidence that GBCAs can pass the BCSFB in the CP and enter ventricular CSF immediately after intravenous administration in healthy human brains. Besides, our results in healthy subjects established a basis for clinical studies in brain diseases exploiting GBCA-enhanced MRI to detect BCSFB dysfunction.

The gut microbiome and the brain.

The importance of the gut microbiome for human health and well-being is generally accepted, and elucidating the signaling pathways between the gut microbiome and the host offers novel mechanistic insight into the (patho)physiology and multifaceted aspects of healthy aging and human brain functions. The gut microbiome is tightly linked with the nervous system, and gut microbiota are increasingly emerging as important regulators of emotional and cognitive performance. They send and receive signals for the bidirectional communication between gut and brain via immunological, neuroanatomical, and humoral pathways. The composition of the gut microbiota and the spectrum of metabolites and neurotransmitters that they release changes with increasing age, nutrition, hypoxia, and other pathological conditions. Changes in gut microbiota (dysbiosis) are associated with critical illnesses such as cancer, cardiovascular, and chronic kidney disease but also neurological, mental, and pain disorders, as well as chemotherapies and antibiotics affecting brain development and function. Dysbiosis and a concomitant imbalance of mediators are increasingly emerging both as causes and consequences of diseases affecting the brain. Understanding the microbiota's role in the pathogenesis of these disorders will have major clinical implications and offer new opportunities for therapeutic interventions.

Acid-sensing ion channel 3 is a new potential therapeutic target for the control of glioblastoma cancer stem cells growth

Glioblastoma (GBM) is the most common malignant primary brain cancer that, despite recent advances in the understanding of its pathogenesis, remains incurable. GBM contains a subpopulation of cells with stem cell-like properties called cancer stem cells (CSCs). Several studies have demonstrated that CSCs are resistant to conventional chemotherapy and radiation thus representing important targets for novel anti-cancer therapies. Proton sensing receptors expressed by CSCs could represent important factors involved in the adaptation of tumours to the extracellular environment. Accordingly, the expression of acid-sensing ion channels (ASICs), proton-gated sodium channels mainly expressed in the neurons of peripheral (PNS) and central nervous system (CNS), has been demonstrated in several tumours and linked to an increase in cell migration and proliferation. In this paper we report that the ASIC3 isoform, usually absent in the CNS and present in the PNS, is enriched in human GBM CSCs while poorly expressed in the healthy human brain. We propose here a novel therapeutic strategy based on the pharmacological activation of ASIC3, which induces a significant GBM CSCs damage while being non-toxic for neurons. This approach might offer a promising and appealing new translational pathway for the treatment of glioblastoma.

A human brain atlas of χ-separation for normative iron and myelin distributions.

Iron and myelin are primary susceptibility sources in the human brain. These substances are essential for a healthy brain, and their abnormalities are often related to various neurological disorders. Recently, an advanced susceptibility mapping technique, which is referred to as χ-separation (pronounced as "chi"-separation), has been proposed, successfully disentangling paramagnetic iron from diamagnetic myelin. This method provided a new opportunity for generating high-resolution iron and myelin maps of the brain. Utilizing this technique, this study constructs a normative χ-separation atlas from 106 healthy human brains. The resulting atlas provides detailed anatomical structures associated with the distributions of iron and myelin, clearly delineating subcortical nuclei, thalamic nuclei, and white matter fiber bundles. Additionally, susceptibility values in a number of regions of interest are reported along with age-dependent changes. This atlas may have direct applications such as localization of subcortical structures for deep brain stimulation or high-intensity focused ultrasound and also serve as a valuable resource for future research.

Intrinsic functional and structural network organization in the macaque insula

Abstract In recent decades, in vivo magnetic resonance imaging (MRI) studies have provided previously inaccessible insights into the structure and function of healthy and pathological human brains in the laboratory and the clinic. However, the correlational nature of this work and relatively low resolution mean that ground truth neuroanatomical studies and causal manipulations of neural circuitry must still occur in animal models offering greater tractability and higher resolution, rendering a scale and species gap in translation. Here, we bridge this gap with a detailed, multimodal investigation of the macaque insula in vivo. Using both functional and diffusion MRI—tools available for use in humans—we demonstrate a neural architecture in the macaque insula with clear correspondence to prior in vivo MRI findings in humans and postmortem cytoarchitectural and tract-tracing studies in monkeys. Results converged across analysis methods and imaging modalities, supporting the translational potential of the macaque model.

DOCK-PET: database of CNS kinetic parameters in the healthy human brain for existing PET tracers.

Information about developed positron emission tomography (PET) tracers and obtained clinical PET images is publicly available in a database. However, findings regarding the kinetic parameters of PET tracers are yet to be summarized. Therefore, in this study, we created an open-access database of central nervous system (CNS) kinetic parameters in the healthy human brain for existing PET tracers (DOCK-PET). Our database includes information on the kinetic parameters and compounds of existing CNS-PET tracers. The kinetic parameter dataset comprises the analysis methods, VT, BPND, K parameters, relevant literature, and study details. The list of PET tracers and kinetic parameter information was compiled through keyword-based searches of PubMed and the Molecular Imaging and Contrast Agent Database (MICAD). The kinetic parameters obtained, including VT, BPND, and K parameters, were reorganized based on the defined brain anatomical regions. All data were rigorously double-checked before being summarized in Microsoft Excel and JavaScript Object Notation (JSON) formats. Of the 247 PET tracers identified through searches using the PubMed and MICAD websites, the kinetic parameters of 120 PET tracers were available. Among the 120 PET tracers, compound structures with chemical and physical properties were obtained from the PubChem website or the ChemDraw software. Furthermore, the affinity information of the 104 PET tracers was gathered from PubChem or extensive literature surveys of the 120 PET tracers. We developed a comprehensive open-access database, DOCK-PET, that includes both kinetic parameters of healthy humans and compound information for existing CNS-PET tracers.

Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.

The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.

Single-cell atlas of the human brain vasculature across development, adulthood and disease

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Alpha-synuclein aggregates are phosphatase resistant

Alpha-synuclein (αsyn) is an intrinsically disordered protein that aggregates in the brain in several neurodegenerative diseases collectively called synucleinopathies. Phosphorylation of αsyn at serine 129 (PSER129) was considered rare in the healthy human brain but is enriched in pathological αsyn aggregates and is used as a specific marker for disease inclusions. However, recent observations challenge this assumption by demonstrating that PSER129 results from neuronal activity and can be readily detected in the non-diseased mammalian brain. Here, we investigated experimental conditions under which two distinct PSER129 pools, namely endogenous-PSER129 and aggregated-PSER129, could be detected and differentiated in the mammalian brain. Results showed that in the wild-type (WT) mouse brain, perfusion fixation conditions greatly influenced the detection of endogenous-PSER129, with endogenous-PSER129 being nearly undetectable after delayed perfusion fixation (30-min and 1-h postmortem interval). Exposure to anesthetics (e.g., Ketamine or xylazine) before perfusion did not significantly influence endogenous-PSER129 detection or levels. In situ, non-specific phosphatase calf alkaline phosphatase (CIAP) selectively dephosphorylated endogenous-PSER129 while αsyn preformed fibril (PFF)-seeded aggregates and genuine disease aggregates (Lewy pathology and Papp–Lantos bodies in Parkinson’s disease and multiple systems atrophy brain, respectively) were resistant to CIAP-mediated dephosphorylation. The phosphatase resistance of aggregates was abolished by sample denaturation, and CIAP-resistant PSER129 was closely associated with proteinase K (PK)-resistant αsyn (i.e., a marker of aggregation). CIAP pretreatment allowed for highly specific detection of seeded αsyn aggregates in a mouse model that accumulates non-aggregated-PSER129. We conclude that αsyn aggregates are impervious to phosphatases, and CIAP pretreatment increases detection specificity for aggregated-PSER129, particularly in well-preserved biological samples (e.g., perfusion fixed or flash-frozen mammalian tissues) where there is a high probability of interference from endogenous-PSER129. Our findings have important implications for the mechanism of PSER129-accumulation in the synucleinopathy brain and provide a simple experimental method to differentiate endogenous-from aggregated PSER129.

Seasonal variation in D2/3 dopamine receptor availability in the human brain

PurposeBrain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized.MethodsBased on a historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex.ResultsDaylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26 h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability.ConclusionsSeasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.

47. PET Imaging in Healthy Human Brain Can Quantify Cyclooxygenase-1, a Putative Microglial Biomarker of Inflammation

47. PET Imaging in Healthy Human Brain Can Quantify Cyclooxygenase-1, a Putative Microglial Biomarker of Inflammation

Repeatability of Lac+ measurements in healthy human brain at 3 T.

In vivo quantification of lactate has numerous applications in studying the pathology of both cerebral and musculoskeletal systems. Due to its low concentration (~0.5-1 mM), and overlap with lipid signals, traditional 1H MR spectra acquired in vivo using a small voxel and short echo time often result in an inadequate signal to detect and resolve the lactate peak, especially in healthy human volunteers. In this study, using a semi-LASER acquisition with long echo time (TE= 288 ms) and large voxel size (80 × 70 × 20 mm3), we clearly visualize the combined signal of lactate and threonine. Therefore, we call the signal at 1.33 ppm Lac+ and quantify Lac+ concentration from water suppressed spectra in healthy human brains in vivo. Four participants (22-37 years old; mean age = 28 ± 5.4; three male, one female) were scanned on four separate days, and on each day four measurements were taken. Intra-day values are calculated for each participant by comparing the four measurements on a single day. Inter-day values were calculated using the mean intra-day measurements. The mean intra-participant Lac+ concentration, standard deviation (SD), and coefficient of variation (CV) ranged from 0.49 to 0.61 mM, 0.02 to 0.07 mM, and 4% to 13%, respectively, across four volunteers. The inter-participant Lac+ concentration, SD, and CV was 0.53 mM, ±0.06 mM, and 11%. Repeatability is shown in Lac+ measurement in healthy human brain using a long echo time semi-LASER sequence with a large voxel in about 3.5 min at 3 T.

Additive Effects of Monetary Loss and Positive Emotion in the Human Brain.

In many real-life scenarios, our decisions could lead to multiple outcomes that conflict with value. Hence, an appropriate neural representation of the net experienced value of conflicting outcomes, which play a crucial role in guiding future decisions, is critical for adaptive behavior. As some recent functional neuroimaging work has primarily focused on the concurrent processing of monetary gains and aversive information, very little is known regarding the integration of conflicting value signals involving monetary losses and appetitive information in the human brain. To address this critical gap, we conducted a functional MRI study involving healthy human male participants to examine the nature of integrating positive emotion and monetary losses. We employed a novel experimental design where the valence (positive or neutral) of an emotional stimulus indicated the type of outcome (loss or no loss) in a choice task. Specifically, we probed two plausible integration patterns while processing conflicting value signals involving positive emotion and monetary losses: interactive versus additive. We found overlapping main effects of positive (vs neutral) emotion and loss (vs no loss) in multiple brain regions, including the ventromedial prefrontal cortex, striatum, and amygdala, notably with a lack of evidence for interaction. Thus, our findings revealed the additive integration pattern of monetary loss and positive emotion outcomes, suggesting that the experienced value of the monetary loss was not modulated by the valence of the image signaling those outcomes. These findings contribute to our limited understanding of the nature of integrating conflicting outcomes in the healthy human brain with potential clinical relevance.

Abstract B039: Identification of sex-specific molecular features in glioma transcriptome

Abstract Glioma is a lethal disease with limited treatment options available. Sex differences in glioma are well-documented in clinical settings, with males having twice the risk of developing the disease and increased mortality compared to female counterparts. To investigate the molecular basis of sex differences in glioma, we analyzed transcriptomic sex differences in a collection of three independent glioma datasets and validated them in additional independent studies. The impact of differentially expressed genes were assessed through Gene Set Enrichment Analysis (GSEA) on approximately 5000 gene sets to interpret their biological relevance. Given the well-recognized heterogeneity of glioma, we also integrated three single-cell RNA (scRNA) sequencing datasets to decipher the sex differences in cellular composition and cell-type specific differential gene expression between male and female tumors. The effects of sex on gene expression are modest and primarily driven by the X chromosome (14 out of 16 differentially expressed genes were on the X chromosome). These genes are associated with escape from X-chromosome inactivation (e.g., KDM5C, KDM6A) and are also sex-differentially expressed (DE) in the healthy human brain according to Genotype-Tissue Expression (GTEx) data. GSEA results suggest increased activity in cell proliferation and neuronal signaling in male GBM samples, whereas females show enrichment in glycoprotein/lipid metabolism. By deconvoluting the cell-type composition, we identified a higher percentage of pericytes in the male glioma tumor microenvironment compared to those in females, which is consistent with recent spatial-omic discoveries in glioma. By integrating scRNA sequencing data, we found that both differentially expressed genes and pathways show cell-type-specific enrichment. For example, the female-biased gene GBGT1 is exclusively expressed in the myeloid lineage, while male-biased neuronal pathways are enriched in cancer stem cells. Integrating with the inference of cell trajectories, we observed that male tumors harbor more unconnected, invasive malignant cells than females, which might explain the poor prognosis in male glioma patients. In summary, our results provide a comprehensive multi-level characterization of sex differences in glioma tumors, and these findings will provide novel insights into glioma disease progression and development of new therapy. Citation Format: Yingbo Huang, Yuting Shan, Weijie Zhang, Christina Printzis, Lorenzo Pesce, Barbara Elaine Stranger, R. Stephanie Huang. Identification of sex-specific molecular features in glioma transcriptome [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B039.

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain

BackgroundHeat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer’s disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90β) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet.ResultsIn this study, we developed a novel positron emission tomography (PET) imaging ligand, [11C]BIIB021, by 11C-radiolabeling (a positron emitter with a half-life of 20.4 min) 6-Chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (BIIB021), an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [11C]BIIB021 was synthesized with a high yield, molar activity and radiochemical purity. [11C]BIIB021 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. Radioactivity was well detected in the rat brain (SUV 1.4). It showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Radiometabolite was detected in the brain, however, total distribution volume was well quantified using dual-input graphical model. Inhibition of p-glycoprotein increased brain radioactivity concentrations. However, total distribution volume values with and without p-glycoprotein inhibition were nearly the same.ConclusionsWe have developed a new PET imaging agent, [11C]BIIB021, specifically targeting HSP90α/β. We have been successful in synthesizing [11C]BIIB021 and in vitro and in vivo imaging HSP90α/β. However, the quantification of HSP90α/β is complicated by the presence of radiometabolites in the brain and the potential to be a substrate for p-glycoprotein. Further efforts are needed to develop radioligand suitable for imaging of HSP90α/β.

Genome-wide transcriptome profiling and development of age prediction models in the human brain.

Aging-related transcriptome changes in various regions of the healthy human brain have been explored in previous works, however, a study to develop prediction models for age based on the expression levels of specific panels of transcripts is lacking. Moreover, studies that have assessed sexually dimorphic gene activities in the aging brain have reported discrepant results, suggesting that additional studies would be advantageous. The prefrontal cortex (PFC) region was previously shown to have a particularly large number of significant transcriptome alterations during healthy aging in a study that compared different regions in the human brain. We harmonized neuropathologically normal PFC transcriptome datasets obtained from the Gene Expression Omnibus (GEO) repository, ranging in age from 21 to 105 years, and found a large number of differentially regulated transcripts in the old and elderly, compared to young samples overall, and compared female and male-specific expression alterations. We assessed the genes that were associated with age by employing ontology, pathway, and network analyses. Furthermore, we applied various established (least absolute shrinkage and selection operator (Lasso) and Elastic Net (EN)) and recent (eXtreme Gradient Boosting (XGBoost) and Light Gradient Boosting Machine (LightGBM)) machine learning algorithms to develop accurate prediction models for chronological age and validated them. Studies to further validate these models in other large populations and molecular studies to elucidate the potential mechanisms by which the transcripts identified may be related to aging phenotypes would be advantageous.