Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology.

ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor (AR) gene, which encodes a ligand-dependent transcription factor. The mutant AR protein, characterized by polyglutamine expansion, is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in SBMA patients. These aggregates alter protein-protein interactions and compromise transcriptional activity. In this study, we reported that in both cultured N2a cells and mouse brain, mutant AR with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-derived neurotrophic factor (MANF). Overexpression of MANF ameliorated the neurotoxicity of mutant AR through the inhibition of mutant AR aggregation. Conversely, knocking down endogenous MANF in the mouse brain exacerbated neuronal damage and mutant AR aggregation. Our findings suggest that inhibition of MANF expression by mutant AR is a potential mechanism underlying neurodegeneration in SBMA.

Multi-pool chemical exchange saturation transfer MRI in glioma grading, molecular subtyping and evaluating tumor proliferation.

PURPOSE: To evaluate the performance of multi-pool Chemical exchange saturation transfer (CEST) MRI in prediction of glioma grade, isocitrate dehydrogenase (IDH) mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and Ki-67 labeling index (LI), based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5). METHODS: 95 patients with adult-type diffuse gliomas were analyzed. The amide, direct water saturation (DS), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer (MT) and amine signals were derived using Lorentzian fitting, and asymmetry-based amide proton transfer-weighted (APTwasym) signal was calculated. The mean value of tumor region was measured and intergroup differences were estimated using student-t test. The receiver operating curve (ROC) and area under the curve (AUC) analysis were used to evaluate the diagnostic performance of signals and their combinations. Spearman correlation analysis was performed to evaluate tumor proliferation. RESULTS: The amide and DS signals were significantly higher in high-grade gliomas compared to low-grade gliomas, as well as in IDH-wildtype gliomas compared to IDH-mutant gliomas (all p < 0.001). The DS, MT and amine signals showed significantly differences between ATRX loss and retention in grade 2/3 IDH-mutant gliomas (all p < 0.05). The combination of signals showed the highest AUC in prediction of grade (0.857), IDH mutation (0.814) and ATRX loss (0.769). Additionally, the amide and DS signals were positively correlated with Ki-67 LI (both p < 0.001). CONCLUSION: Multi-pool CEST MRI demonstrated good potential to predict glioma grade, IDH mutation, ATRX loss and Ki-67 LI.

Quantitative susceptibility mapping of multiple system atrophy and Parkinson's disease correlates with neurotransmitter reference maps.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates. METHODS: A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity. RESULTS: MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits. CONCLUSIONS: Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.

The characterization of metabolic changes in adipose tissues and muscles due to different exercise intensities by Dixon in healthy young men.

PURPOSE: To delineate the alterations in adipose and muscle tissue composition and functionality among healthy young men across varying exercise intensities, which help to elucidate the impact of exercise intensity on weight management and inform fitness planning. METHOD: 3D Dixon MRI scans were performed on the neck and supraclavicular area in 10 high-intensity exercises (HIE) athletes, 20 moderate intensity exercises (MIE) athletes and 19 low-intensity exercises non-athlete male controls (NCM). Twelve imaging parameters, including the total volume of muscle, white adipose tissue (WAT), brown adipose tissue (BAT), and the mean fat-water fraction (FWF) within these tissues. Additionally, ratios of BAT or WAT to total fat (BATr or WATr) and the proportions of muscle, BAT, or WAT to total tissue volume (Musp, BATp, and WATp) were calculated. Parameters were compared across groups and correlated with Body Mass Index (BMI), waistline, and hipline. RESULTS: The HIE group exhibited the highest total muscle (totalMUS) and brown adipose tissue (totalBAT) volumes among the three groups. Conversely, the NCM group had significantly higher fwfFAT and fwfBAT values. The MUSp was higher in the HIE and MIE groups compared to NCM, while the BATp and WATp were lower. Furthermore, the BATr in HIE and MIE groups were higher than NCM group while the WATr were lower. Significant linear relationships were observed between totalBAT, totalWAT, MUSp, BATr, fwfFAT, and BMI, waistline (P < 0.05) across all groups. CONCLUSIONS: MIE is sufficient for the purpose of weight control, While HIE helps to further increase the muscle mass. All three physical indexes were significantly associated with the image parameters, with waistline emerging as the most effective indicator for detecting metabolic changes across all groups.

Cross-ancestry genome-wide association studies of brain imaging phenotypes.

Genome-wide association studies of brain imaging phenotypes are mainly performed in European populations, but other populations are severely under-represented. Here, we conducted Chinese-alone and cross-ancestry genome-wide association studies of 3,414 brain imaging phenotypes in 7,058 Chinese Han and 33,224 white British participants. We identified 38 new associations in Chinese-alone analyses and 486 additional new associations in cross-ancestry meta-analyses at P < 1.46 × 10-11 for discovery and P < 0.05 for replication. We pooled significant autosomal associations identified by single- or cross-ancestry analyses into 6,443 independent associations, which showed uneven distribution in the genome and the phenotype subgroups. We further divided them into 44 associations with different effect sizes and 3,557 associations with similar effect sizes between ancestries. Loci of these associations were shared with 15 brain-related non-imaging traits including cognition and neuropsychiatric disorders. Our results provide a valuable catalog of genetic associations for brain imaging phenotypes in more diverse populations.

TRIM37 is a primate-specific E3 ligase for Huntingtin and accounts for the striatal degeneration in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by preferential neuronal loss in the striatum. The mechanism underlying striatal selective neurodegeneration remains unclear, making it difficult to develop effective treatments for HD. In the brains of nonhuman primates, we examined the expression of Huntingtin (HTT), the gene responsible for HD. We found that HTT protein is highly expressed in striatal neurons due to its slow degradation in the striatum. We also identified tripartite motif-containing 37 (TRIM37) as a primate-specific protein that interacts with HTT and is selectively reduced in the primate striatum. TRIM37 promotes the ubiquitination and degradation of mutant HTT (mHTT) in vitro and modulates mHTT aggregation in mouse and monkey brains. Our findings suggest that nonhuman primates are crucial for understanding the mechanisms of human diseases such as HD and support TRIM37 as a potential therapeutic target for treating HD.

HAP40 modulates mutant Huntingtin aggregation and toxicity in Huntington's disease mice.

Huntington's disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.

Long-term effects of childhood single-parent family structure on brain connectivity and psychological well-being.

The high and increasing proportion of single-parent families is considered a risk factor associated with various childhood trauma experiences. Consequently, concerns have been raised regarding the potential long-term effects of the childhood single-parent family structure. In this study, we employed advanced magnetic resonance imaging technology, including morphometric similarity mapping, functional connectivity density, and network-based analysis, to investigate brain connectivity and behavioral differences among young adults who were raised in single-parent families. Our study also aimed to explore the relationship between these differences and childhood trauma experiences. The results showed that individuals who grew up in single-parent families exhibited higher levels of anxiety, depression, and harm-avoidant personality. The multimodal MRI analysis further showed differences in regional and network-based connectivity properties in the single-parent family group, including increased functional connectivity density in the left inferior parietal lobule, enhanced cortical structural connectivity between the left isthmus cingulate cortex and peri-calcarine cortex, and an increase in temporal functional connectivity. Moreover, elevated levels of anxiety and depression, along with heightened functional connectivity density in the left inferior parietal lobule and increased temporal functional connectivity, were found to be correlated with a greater number of childhood trauma experiences. Through analyzing multiple data patterns, our study provides objective neuropsychobiological evidence for the enduring impact of childhood single-parent family structure on psychiatric vulnerability in adulthood.

The influence of accelerated brain aging on coactivation pattern dynamics in Parkinson's disease.

Aging is widely acknowledged as the primary risk factor for brain degeneration, with Parkinson's disease (PD) tending to follow accelerated aging trajectories. We aim to investigate the impact of structural brain aging on the temporal dynamics of a large-scale functional network in PD. We enrolled 62 PD patients and 32 healthy controls (HCs). The level of brain aging was determined by calculating global and local brain age gap estimates (G-brainAGE and L-brainAGE) from structural images. The neural network activity of the whole brain was captured by identifying coactivation patterns (CAPs) from resting-state functional images. Intergroup differences were assessed using the general linear model. Subsequently, a spatial correlation analysis between the L-brainAGE difference map and CAPs was conducted to uncover the anatomical underpinnings of functional alterations. Compared to HCs (-3.73 years), G-brainAGE was significantly higher in PD patients (+1.93 years), who also exhibited widespread elevation in L-brainAGE. G-brainAGE was correlated with disease severity and duration. PD patients spent less time in CAPs involving activated default mode and the fronto-parietal network (DMN-FPN), as well as the sensorimotor and salience network (SMN-SN), and had a reduced transition frequency from other CAPs to the DMN-FPN and SMN-SN CAPs. Furthermore, the pattern of localized brain age acceleration showed spatial similarities with the SMN-SN CAP. Accelerated structural brain aging in PD adversely affects brain function, manifesting as dysregulated brain network dynamics. These findings provide insights into the neuropathological mechanisms underlying neurodegenerative diseases and imply the possibility of interventions for modifying PD progression by slowing the brain aging process.

The changes of oxygen extraction fraction in different types of lesions in relapsing-remitting multiple sclerosis: A cross-sectional and longitudinal study.

OBJECTIVES: To explore the oxygen metabolism level of different types of lesions in relapsing-remitting multiple sclerosis (RRMS) patients by oxygen extraction fraction (OEF) both cross-sectionally and longitudinally. METHODS: Forty-six RRMS patients and forty-one healthy controls (HC) went MRI examination. The quantitative susceptibility mapping (QSM) and OEF map were reconstructed from a 3D multi-echo gradient echo sequence. MS lesions in white matter were classified as contrast-enhancing lesions (CELs) on post-gadolinium T1-weighted sequence, paramagnetic rim lesions (PRLs), hyperintense lesions and non-hyperintense lesions on QSM, respectively. The susceptibility and OEF of different types of lesions were compared. The susceptibility and OEF values were measured and compared among different types of lesions. Among these RRMS patients, seventeen had follow-up MRI and 232 lesions, and baseline to follow-up longitudinal changes in susceptibility and OEF were measured. RESULTS: PRLs had higher susceptibility and lower OEF than CELs, hyperintense lesions, and non-hyperintense lesions. The hyperintense lesions had higher susceptibility and lower OEF than non-hyperintense lesions. In longitudinal changes, PRLs had susceptibility increased (P < 0.001) and OEF decreased (P < 0.001). The hyperintense lesions showed significant decreases in susceptibility (P = 0.020), and non-hyperintense lesions showed significant increases in OEF during follow-up (P = 0.005). Notably, hyperintense lesions may convert to PRLs or non-hyperintense lesions as time progresses, accompanied by changes of OEF and susceptibility in the lesions. CONCLUSION: This study revealed tissue damage and oxygen metabolism level in different types of MS lesions. The OEF may contribute to further understanding the evolution of MS lesions.

The impact of paramagnetic rim lesions on cortical thickness and gray to white matter contrast in relapsing-remitting multiple sclerosis.

Background: Paramagnetic rim lesions (PRLs) on susceptibility magnetic resonance sequences have been suggested as an imaging marker of disease progression in multiple sclerosis. This retrospective cross-sectional study aimed to investigate the impact of PRLs on cortical thickness and gray matter (GM) to white matter (WM) contrast in relapsing-remitting multiple sclerosis (RRMS). Methods: A total of 82 RRMS patients (40 patients with at least 1 PRL and 42 patients without PRL) and 43 healthy controls (HC) were included in this study. The T1-weighted images (T1WI) were processed with the FreeSurfer pipeline. GM to WM signal intensity ratio (GWR) was obtained from T1WI by dividing the GM signal intensity by the WM signal intensity for each vertex. Group differences in cortical thickness and GWR were tested on reconstructed cortical surface. Results: Compared to HC, patients with PRL had thinner mean cortical thickness (P<0.001), higher mean GWR (P=0.001), and lower brain structure volumes (cortex volume, P=0.001; WM volume, P<0.001; deep GM volume, P<0.001). Vertex-based analysis found significant cortical thinning in several regions and increased GWR in a wider range of regions in patients with PRL. The two types of clusters had both overlapping regions and independent regions. However, in patients without PRL, only a few regions showed significant cortical thickness changes. Correlation analysis found that in patients with PRL, only PRL volume showed a significant negative correlation with mean cortical thickness (P=0.048), and PRL volume and count, non-PRL count, and total lesion volume were significantly and positively correlated with mean GWR (P<0.05). Conclusions: There were significant changes in cortical thickness, GWR, and brain structure volume in RRMS patients with PRL that may contribute to further understanding of the pathological mechanisms underlying neurological tissue damage.

Feasibility of diffusion tensor imaging in cervical spondylotic myelopathy using MUSE sequence.

BACKGROUND CONTEXT: The most frequent type of spinal cord injury is cervical spondylotic myelopathy (CSM). Conventional structural magnetic resonance imaging (MRI) is the gold diagnosis standard for CSM. Diffusion tensor imaging (DTI) could reflect microstructural changes in the spinal cord by tracing water molecular diffusion in early stages of CSM. However, due to the complex local anatomical structure and small field of view of the spinal cord, the imaging effect of traditional DTI imaging on the spinal cord is limited. MUSE (MUltiplexed Sensitivity-Encoding) -DTI is a novel diffusion-weighted imaging (DWI) sequence that achieves higher signal intensity through multiple excitation acquisition. MUSE sequence may improve the quality of spinal cord DTI imaging. STUDY DESIGN: Prospective study. PURPOSE: This study aimed to investigate the clinical diagnosis value of a novel protocol of MUSE-DTI in patients with cervical spondylotic myelopathy (CSM). PATIENT SAMPLE: From August 2021 to March 2022, a total of 60 subjects (22-71 years) were enrolled, including 51 CSM patients (22 males, 29 females) and 9 healthy subjects (4 males and 5 females). Each subject underwent a MUSE-DTI examination and a clinical Japanese Orthopedic Association (JOA) scale. OUTCOME MEASURES: We measured values of FA (Fractional Anisotropy), MD (Mean Diffusivity), AD (Axial Diffusivity), and RD (Radial Diffusivity), and collected the clinical JOA scores of each subject before the MR examination. METHODS: A 3.0T MR scanner (Signa Architect, GE Healthcare) performed the MUSE-DTI sequence on each subject. The cervical canal stenosis of subjects was classified from grade 0 to grade Ⅲ according to the method of an MRI grading system. FA, MD, AD, and RD maps were generated by postprocessing MUSE-DTI data on the GE workstation. Regions of interest (ROIs) were manually drawn at the C2 vertebral body level and C2/3-C6/7 intervertebral disc levels by covering the whole spinal cord. The clinical severity of myelopathy of subjects was assessed by the clinical Japanese Orthopedic Association scale (JOA). RESULTS: MUSE-DTI can acquire a high-resolution diffusion image compared to traditional DTI. The FAMCL values showed a decreasing trend from grade 0 to grade Ⅲ, while the MDMCL, ADMCL, and RDMCL values showed an overall increasing trend. Significant differences in MDMCL, ADMCL, and RDMCL values were found between adjacent groups among grades Ⅰ-Ⅲ (p<.05). The ADC2 values in CSM patients (grade I-Ⅲ) were significantly lower than in healthy individuals (grade 0) (p=.019). The clinical JOA score has a significant correlation with FAMCL (p=.035), MDMCL (p<.001), ADMCL (p<.001), and RDMCL (p<.001) values. CONCLUSIONS: MUSE-DTI displayed a better image quality compared to traditional DTI. MUSE-DTI parameters displayed a grade-dependent trend. All the MUSE-DTI parameters at MCL were correlated with the clinical JOA scores. The ADC2 values can reflect the secondary damage of distal spinal cord. Therefore, MUSE-DTI could be a reliable biomarker for clinical auxiliary diagnosis of spinal cord injury severity in cervical spondylotic myelopathy.

Enlarged choroid plexus in relapsing-remitting multiple sclerosis may lead to brain structural changes through the glymphatic impairment.

OBJECTIVES: To investigate the potential link among choroid plexus (CP) volume, glymphatic clearance and brain structural change in relapsing-remitting multiple sclerosis (RRMS) patients. MATERIALS AND METHODS: Sixty-five RRMS patients and 48 healthy controls (HC) underwent MRI examination. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) was calculated to reflect glymphatic system function. The brain structure volume and DTI-ALPS index were compared between RRMS and HC. The mediating effect of the DTI-ALPS index between CP volume and brain structural changes was further investigated. The longitudinal changes of brain structure and DTI-ALPS index were compared in 20 RRMS patients. RESULTS: Compared to HC, CP volume in RRMS was significantly increased (P < 0.001), and DTI-ALPS index was significantly decreased (P = 0.001). The volumes of white matter, thalamus, putamen and pallidum were significantly decreased in RRMS, and the volumes of lateral ventricle and third ventricle were increased. Mediation analysis showed DTI-ALPS index partially mediated the association between CP enlargement and deep gray matter (DGM) atrophy in RRMS, and between CP enlargement and ventricle enlargement. CP volume and DTI-ALPS index were also significantly correlated with Expanded Disability Status Scale (EDSS) (P = 0.006, P = 0.043). Notably, the variation of DTI_ALPS index during the follow-up period were significantly and negatively correlated with the variation of EDSS (P = 0.045). CONCLUSION: Enlarged CP volume and decreased DTI_ALPS index may be closely related to DGM atrophy and ventricular enlargement in RRMS, and may be potential imaging markers of clinical disability.

A normative modeling approach to quantify white matter changes and predict functional outcomes in stroke patients.

Objectives: The diverse nature of stroke necessitates individualized assessment, presenting challenges to case-control neuroimaging studies. The normative model, measuring deviations from a normal distribution, provides a solution. We aim to evaluate stroke-induced white matter microstructural abnormalities at group and individual levels and identify potential prognostic biomarkers. Methods: Forty-six basal ganglia stroke patients and 46 healthy controls were recruited. Diffusion-weighted imaging and clinical assessment were performed within 7 days after stroke. We used automated fiber quantification to characterize intergroup alterations of segmental diffusion properties along 20 fiber tracts. Then each patient was compared to normative reference (46 healthy participants) by Mahalanobis distance tractometry for 7 significant fiber tracts. Mahalanobis distance-based deviation loads (MaDDLs) and fused MaDDLmulti were extracted to quantify individual deviations. We also conducted correlation and logistic regression analyses to explore relationships between MaDDL metrics and functional outcomes. Results: Disrupted microstructural integrity was observed across the left corticospinal tract, bilateral inferior fronto-occipital fasciculus, left inferior longitudinal fasciculus, bilateral thalamic radiation, and right uncinate fasciculus. The correlation coefficients between MaDDL metrics and initial functional impairment ranged from 0.364 to 0.618 (p < 0.05), with the highest being MaDDLmulti. Furthermore, MaDDLmulti demonstrated a significant enhancement in predictive efficacy compared to MaDDL (integrated discrimination improvement [IDI] = 9.62%, p = 0.005) and FA (IDI = 34.04%, p < 0.001) of the left corticospinal tract. Conclusion: MaDDLmulti allows for assessing behavioral disorders and predicting prognosis, offering significant implications for personalized clinical decision-making and stroke recovery. Importantly, our method demonstrates prospects for widespread application in heterogeneous neurological diseases.

Large-scale functional network connectivity mediates the association between nigral neuromelanin hypopigmentation and motor impairment in Parkinson's disease.

Neuromelanin hypopigmentation within substantia nigra pars compacta (SNc) reflects the loss of pigmented neurons, which in turn contributes to the dysfunction of the nigrostriatal and striato-cortical pathways in Parkinson's disease (PD). Our study aims to investigate the relationships between SN degeneration manifested by neuromelanin reduction, functional connectivity (FC) among large-scale brain networks, and motor impairment in PD. This study included 68 idiopathic PD patients and 32 age-, sex- and education level-matched healthy controls who underwent neuromelanin-sensitive magnetic resonance imaging (MRI), functional MRI, and motor assessments. SN integrity was measured using the subregional contrast-to-noise ratio calculated from neuromelanin-sensitive MRI. Resting-state FC maps were obtained based on the independent component analysis. Subsequently, we performed partial correlation and mediation analyses in SN degeneration, network disruption, and motor impairment for PD patients. We found significantly decreased neuromelanin within SN and widely altered inter-network FCs, mainly involved in the basal ganglia (BG), sensorimotor and frontoparietal networks in PD. In addition, decreased neuromelanin content was negatively correlated with the dorsal sensorimotor network (dSMN)-medial visual network connection (P = 0.012) and dSMN-BG connection (P = 0.004). Importantly, the effect of SN neuromelanin hypopigmentation on motor symptom severity in PD is partially mediated by the increased connectivity strength between BG and dSMN (indirect effect = - 1.358, 95% CI: - 2.997, - 0.147). Our results advanced our understanding of the interactions between neuromelanin hypopigmentation in SN and altered FCs of functional networks in PD and suggested the potential of multimodal metrics for early diagnosis and monitoring the response to therapies.

MRI Radiomics Features of Adenohypophysis Determine the Activation of Hypothalamic-Pituitary-Gonadal Axis in Peri-Puberty Children.

BACKGROUND: The status of the hypothalamic-pituitary-gonadal (HPG) axis is important for assessing the onset of physiological or pathological puberty. The reference standard gonadotropin-releasing hormone (GnRH) stimulation test requires hospital admission and repeated blood samples. A simple noninvasive method would be beneficial. OBJECTIVES: To explore a noninvasive method for evaluating HPG axis activation in children using an MRI radiomics model. STUDY TYPE: Retrospective. POPULATION: Two hundred thirty-nine children (83 male; 3.6-14.6 years) with hypophysial MRI and GnRH stimulation tests, randomly divided a training set (168 children) and a test set (71 children). FIELD STRENGTH/SEQUENCE: 3.0 T, 3D isotropic fast spin echo (CUBE) T1-weighted imaging (T1WI) sequences. ASSESSMENT: Radiomics features were extracted from sagittal 3D CUBE T1WI, and imaging signatures were generated using the least absolute shrinkage and selection operator (LASSO) with 10-fold cross-validation. Diagnostic performance for differential diagnosis of HPG status was compared between a radiomics model and MRI features (adenohypophyseal height [aPH] and volume [aPV]). STATISTICAL TESTS: Receiver operating characteristic (ROC) and decision curve analysis (DCA). A P value <0.05 was considered statistically significant. RESULTS: Eight hundred fifty-one radiomics features were extracted and reduced to 10 by the LASSO method in the training cohort. The radiomics model based on CUBE T1WI showed good performance in assessment of HPG axis activation with an area under the ROC curve (AUC) of 0.81 (95% CI: 0.71, 0.91) in the test set. The AUC of the radiomics model was significantly higher than that of aPH (0.81 vs. 0.65) but there was no significant difference compared to aPV (0.81 vs. 0.78, P = 0.58). In DCA analysis, the radiomics signature showed higher net benefit over the aPV and aPH models. DATA CONCLUSIONS: The MRI radiomics model has potential to assess HPG axis activation status noninvasively, potentially providing valuable information in the diagnosis of patients with pathological puberty onset. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Bilateral brain microstructural alterations in patients with left-sided classic trigeminal neuralgia: a diffusion kurtosis imaging study.

OBJECTIVE: White matter microstructural abnormalities in patients with classic trigeminal neuralgia (TN) have been observed. However, the impact of classic TN in both hemispheres, the difference and extent of alterations in bilateral hemispheres, and the relationship between the impaired area and pain conduction are not fully understood. The purpose of this study was to investigate brain microstructural alterations and compare the bilateral hemispheres in patients with unilateral classic TN, as well as to explore their clinical implications. METHODS: The authors performed a cross-sectional study of 36 patients with left classic TN (TN group; age 40-66 years) and 36 healthy controls (HC group; age 40-66 years). Diffusion kurtosis imaging (DKI; b-values = 0, 1250, and 2500 sec/mm2) was performed in all patients using a 3T MRI scanner. The FMRIB Software Library with tract-based spatial statistics was used to analyze intergroup differences in both hemispheres. Atlas-based region of interest analysis was conducted in fiber tracts and gray matter structures. RESULTS: Decreased fractional anisotropy (FA) and increased mean diffusivity in 2.70% and 5.34% of white matter regions, such as the corona radiata, corpus callosum, internal capsule, superior longitudinal fasciculus, and cingulum, were detected in the TN group compared with the HC group (p < 0.05, family-wise error correction). Reduced mean kurtosis (MK), axial kurtosis, and radial kurtosis were detected in the bilateral thalamus in TN patients. The FA and MK values decreased asymmetrically in both cerebral hemispheres. Atlas-based region of interest analysis revealed more pronounced FA and MK reductions in the left thalamus and posterior corona radiata. There were negative associations of disease duration and pain intensity with the MK values in the thalamus, internal capsule, and superior corona radiata. CONCLUSIONS: The authors concluded that unilateral TN could have asymmetrical microstructural alterations in bilateral hemispheres, which might be due to the compromised fiber tract integrity and abnormal neurons and synapses. The thalamus could be an important relay station in the pain conduction and modulation pathway and could have microstructural abnormalities in both the left and right sides. DKI could provide important information on the CNS pathophysiology of TN and assist in prognostic evaluation.

Diffusion along the perivascular space as a potential biomarker for glioma grading and isocitrate dehydrogenase 1 mutation status prediction.

Background: The diffusion tensor image analysis along the perivascular space (DTI-ALPS) may have the potential to reflect glymphatic dysfunction in patients with glioma. The study aimed to determine the correlation of DTI-ALPS with glioma grade and isocitrate dehydrogenase 1 (IDH1) genotype and to then compare the ALPS index with other diffusion metrics. Methods: In this study, 81 patients with glioma and 31 healthy controls underwent magnetic resonance imaging (MRI) examination. The ALPS-index, fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) were calculated. Comparisons were made between the left and right hemispheres and between patients and controls. IDH1 status was compared after age adjustment. The diagnostic performance of each metric was assessed via receiver operating characteristic (ROC) analysis. Results: In patients with glioma, the ALPS-index of the hemisphere ipsilateral to glioma was significantly lower than that of the hemisphere contralateral to glioma (1.417±0.177 vs. 1.478±0.165; P=0.002), and the bilateral ALPS-index values in patients were significantly decreased compared with those in healthy controls. The ALPS-index was significantly higher in lower-grade gliomas (LrGGs) than that in glioblastomas (GBMs) (1.495±0.151 vs. 1.320±0.159; P<0.001) and was significantly lower in IDH1-wild-type LrGGs than in IDH1-mutant LrGGs (1.400±0.185 vs. 1.530±0.123; P=0.036). FA, MD, and MK also showed significant differences between LrGGs and GBMs and between IDH1-mutant and IDH1-wild-type LrGGs (P<0.05). Furthermore, the combination of the ALPS-index with FA, MD, or MK, exhibited superior discrimination ability compared to each metric used alone. The ALPS-index combined with MD had the highest area under the curve (AUC) of 0.854 as compared to that of 0.614-0.807 for a single metric in glioma grading, while for IDH1 mutation prediction, this combination had the highest AUC of 0.861 as compared to that of 0.707-0.778 for a single metric. Conclusions: The reduced ALPS-index may reflect tumor-induced glymphatic system impairment, and the ALPS-index may be able to complement conventional diffusion metrics in glioma grading and IDH1 genotyping.

Genome-wide association study of hippocampal blood-oxygen-level-dependent-cerebral blood flow correlation in Chinese Han population.

Correlation between blood-oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) has been used as an index of neurovascular coupling. Hippocampal BOLD-CBF correlation is associated with neurocognition, and the reduced correlation is associated with neuropsychiatric disorders. We conducted the first genome-wide association study of the hippocampal BOLD-CBF correlation in 4,832 Chinese Han subjects. The hippocampal BOLD-CBF correlation had an estimated heritability of 16.2-23.9% and showed reliable genome-wide significant association with a locus at 3q28, in which many variants have been linked to neuroimaging and cerebrospinal fluid markers of Alzheimer's disease. Gene-based association analyses showed four significant genes (GMNC, CRTC2, DENND4B, and GATAD2B) and revealed enrichment for mast cell calcium mobilization, microglial cell proliferation, and ubiquitin-related proteolysis pathways that regulate different cellular components of the neurovascular unit. This is the first unbiased identification of the association of hippocampal BOLD-CBF correlation, providing fresh insights into the genetic architecture of hippocampal neurovascular coupling.

Spatiotemporal patterns of brain iron-oxygen metabolism in patients with Parkinson's disease.

OBJECTIVES: Iron deposition and mitochondrial dysfunction are closely associated with the genesis and progression of Parkinson's disease (PD). This study aims to extract susceptibility and oxygen extraction fraction (OEF) values of deep grey matter (DGM) to explore spatiotemporal progression patterns of brain iron-oxygen metabolism in PD. METHODS: Ninety-five PD patients and forty healthy controls (HCs) were included. Quantitative susceptibility mapping (QSM) and OEF maps were computed from MRI multi-echo gradient echo data. Analysis of covariance (ANCOVA) was used to compare mean susceptibility and OEF values in DGM between early-stage PD (ESP), advanced-stage PD (ASP) patients and HCs. Then Granger causality analysis on the pseudo-time-series of MRI data was applied to assess the causal effect of early altered nuclei on iron content and oxygen extraction in other DGM nuclei. RESULTS: The susceptibility values in substantia nigra (SN), red nucleus, and globus pallidus (GP) significantly increased in PD patients compared with HCs, while the iron content in GP did not elevate obviously until the late stage. The mean OEF values for the caudate nucleus, putamen, and dentate nucleus were higher in ESP patients than in ASP patients or/and HCs. We also found that iron accumulation progressively expands from the midbrain to the striatum. These alterations were correlated with clinical features and improved AUC for early PD diagnosis to 0.824. CONCLUSIONS: Abnormal cerebral iron deposition and tissue oxygen utilization in PD measured by QSM and OEF maps could reflect pathological alterations in neurodegenerative processes and provide valuable indicators for disease identification and management. CLINICAL RELEVANCE STATEMENT: Noninvasive assessment of cerebral iron-oxygen metabolism may serve as clinical evidence of pathological changes in PD and improve the validity of diagnosis and disease monitoring. KEY POINTS: • Quantitative susceptibility mapping and oxygen extraction fraction maps indicated the cerebral pathology of abnormal iron accumulation and oxygen metabolism in Parkinson's disease. • Iron deposition is mainly in the midbrain, while altered oxygen metabolism is concentrated in the striatum and cerebellum. • The susceptibility and oxygen extraction fraction values in subcortical nuclei were associated with clinical severity.